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Sona Nanotech Inc chief medical officer Dr Carman Giacomantonio takes Proactive's Stephen Gunnion through the company's latest findings related to its targeted hyperthermia therapy (THT), which he described as showing “very enabling immunogenic” effects in recent experiments. The THT platform works by delivering controlled heat to the core of a tumour, triggering a natural cell death response and activating the body's immune system. Giacomantonio explained that this process exposes tumour proteins to immune cells, increasing the chance that they will be recognised and attacked. He noted that “all cancer cells have this kind of evolutionary quality” of resisting cell death, but THT stresses the cells enough to induce it. These latest experiments build on data first shared in December, with increased sample sizes confirming the reproducibility of the results. According to Giacomantonio, tumours treated with saline or checkpoint inhibitors alone continued to grow, while those exposed to THT and the immune modulator PD1 showed complete inhibition or reduction in growth. Looking ahead, he said the company plans to expand testing to demonstrate systemic immune responses, with the goal of treating metastatic cancers by targeting a single tumour site. Visit Proactive's YouTube channel for more company updates. Don't forget to give this video a like, subscribe to the channel, and enable notifications so you never miss future content. #SonaNanotech #CancerTherapy #TargetedHyperthermia #Immunotherapy #BiotechNews #TumourTreatment #CancerResearch #MedicalInnovation #PD1Inhibitor #MetastaticCancer #HealthcareTech #OncologyBreakthrough
In this episode of Chat By The Pitch, we sit down with Gregg Megaw & Meagan Prewitt, the dynamic team behind PD1 Soccer Training, to discuss everything from player development and training structure to the business side of running a premier training academy.Gregg shares how he designs sessions that blend skill work with real-game application, while Meagan explains the importance of branding, structure, and keeping training organized and efficient. They also break down the mental side of the game, helping parents and players understand what it really takes to progress in competitive soccer.From helping young players level up to navigating the world of North Texas soccer, this episode is packed with valuable insights for players, parents, and coaches.Key Talking Points• How Gregg & Meagan built PD1 Soccer Training• The balance between technical skill work and game realism• Why structured training is critical for player growth• The business strategy behind PD1's rapid growth• Challenges of leveling players in training sessions• The role of social media & branding in player development• Why player engagement & positive environments matter• The importance of coaches having the right personality & energy• How PD1 integrates data, technology & tracking progress• The future of PD1 and their plans for expansionTune in to Learn:• How PD1 creates a professional training environment• The science behind structuring effective training sessions• Why mindset and motivation are key to player success• The biggest mistakes in youth player development• How social media has played a huge role in PD1's successQuotes from Gregg Megaw• “A training session should be high-energy, competitive, and fun. If a kid leaves uninspired, we didn't do our job.”• “If your child is just getting beaten in a session, they're not developing—they need a mix of success and challenge.”• “Attention to detail separates great players from good ones—it's not just about talent.”• “I want my sessions to feel like a professional training environment where every rep matters.”• “The best training programs don't just teach skills—they prepare players to execute them in real-game situations.”Quotes from Meagan Prewitt• “We're not just a soccer training program—we're a brand that stands for excellence.”• “Parents need to ask themselves—do you want this for your child, or do they want it for themselves?”• “We set a standard from day one—training at PD1 isn't just about getting better, it's about joining a community.”• “Social media isn't just marketing for us—it's a way to highlight and celebrate our players.”• “A well-run training program is a mix of structure, adaptation, and understanding the needs of each player.”Connect with PD1:
In this episode of Chat By The Pitch, we go behind the scenes of PD1 Soccer Training with Gregg Megaw & Meagan Prewitt, the duo who have built one of Texas' premier skill training programs.Gregg, with his deep coaching experience from Northern Ireland to the U.S., shares his philosophy on technical training, player development, and the importance of structured training environments. Meagan, the mastermind behind PD1's business operations, discusses the strategy behind growing a successful brand, managing logistics, and making training accessible for families.From coaching methodology to business strategy, this conversation is packed with insights for parents, players, and aspiring coaches.Key Talking Points• How Gregg & Meagan built PD1 Soccer Training• The balance between technical skill work and game realism• Why structured training is critical for player growth• The business strategy behind PD1's rapid growth• Challenges of leveling players in training sessions• The role of social media & branding in player development• Why player engagement & positive environments matter• The importance of coaches having the right personality & energy• How PD1 integrates data, technology & tracking progress• The future of PD1 and how they plan to expand their impactTune in to Learn:• How PD1 creates a professional training environment• The science behind structuring effective training sessions• Why personality & energy matter in coaching• The biggest mistakes in youth player development• How social media has played a huge role in PD1's successQuotes from Gregg Megaw• “I don't just want to train players—I want to mentor them and guide their journey.”• “A training session should be high-energy, competitive, and fun. If a kid leaves uninspired, we didn't do our job.”• “If your child is just getting beaten in a session, they're not developing—they need a mix of success and challenge.”• “The best training programs create an environment where players want to push themselves.”• “For me, coaching isn't just about soccer—it's about helping players build confidence and resilience.”Quotes from Meagan Prewitt• “We're not just a soccer training program—we're a brand that stands for excellence.”• “Parents don't realize that in youth sports, our biggest competition isn't another program—it's time.”• “A soccer program is only as strong as its organization, structure, and customer experience.”• “We set a standard from day one—training at PD1 isn't just about getting better, it's about joining a community.”• “Social media isn't just marketing for us—it's a way to highlight and celebrate our players.”Connect with PD1:
In this podcast, we explore the latest advancements in the treatment of PD-1 refractory melanoma. This week, we are joined... The post Therapeutic options for PD1 refractory skin cancer appeared first on VJOncology.
References Endocrinology. 2018 Nov 15;160(1):205–219 J Pharmacol Exp Ther . 2004 Nov;311(2):467-75 J Immunol (2020) 204 (1_Supplement): 229.12. Nature 2024. volume 635, pages 1010–1018. Br J Pharmacol. 2016 May 27;173(14):2165–2181. J Biol Chem . 1969 Sep 10;244(17):4696-703. Giovanni Girolamo Kapsperger 1640 Passacaglia. https://youtu.be/i8Tf1mBzups?si=PD1-d_XDijAFz4Gp Giovanni Battista Gervasio 1762. Mandolin Sonata in D major, Gimo 142 https://youtu.be/e3yBVDzGwHU?si=dhP7J20lA0hc-Xoy Vivaldi, A. 1723. - Winter Violin Concerto https://youtu.be/pCqO-0339k0?si=KgT-HhiiAKIQ_r0C Lennon-McCartney. 1963. "There's a Place" https://youtu.be/vTsbYbN8VVI?si=7W-dzWRdbDlX4JzI Lennon-McCartney. 1963."All My Loving". https://youtu.be/Wz6Q19LU8rU?si=9Xp1LWdmIl4phSj_ Harrison, G. 1965. "I Need You" https://youtu.be/6t24nX_sak8?si=thDtYKeD55SCH2SY --- Support this podcast: https://podcasters.spotify.com/pod/show/dr-daniel-j-guerra/support
Tumor infiltrating lymphocyte (TIL) therapy uses a person's own immune cells to fight advanced melanoma, offering new hope for patients who have limited treatment options. This week, we have a conversation with Brian Gastman, EVP of medical affairs at Iovance Biotherapeutics, about TILs and the company's pipeline.Iovance recently submitted a marketing authorization application to the European Medicines Agency for lifileucel, a TIL cell therapy, for the treatment of adult patients with unresectable or metastatic melanoma previously treated with a PD-1 blocking antibody, and if BRAF V600 mutation positive, a BRAF inhibitor with or without a MEK inhibitor. If approved, lifileucel will be the first and only approved therapy in this treatment setting in all European Union member states.The submission is supported by positive clinical data from the C-144-01 clinical trial in patients with advanced post-anti-PD1 melanoma.Iovance's Amtagvi is the first FDA-approved T cell therapy for a solid tumor indication. 00:47-04:44: About Iovance Biotherapeutics04:44-07:57: What is polyclonal tumor infiltrating lymphocyte treatment?07:57-14:55: What is the production process for TILs?14:55-18:32: Are there any limiting factors for TIL treatment?18:32-20:59: Is early intervention important?20:59-21:22: Does better psychology help?21:22-22:06: Are other companies working on TILs?22:06-27:25: Clinical trials 27:25-29:25: How do you address cost?29:25-34:21: Iovance's pipeline34:21-35:30: Can TILs be improved?35:30-37:21: Where does the TIL space go from here?Interested in being a sponsor of an episode of our podcast? Discover how you can get involved here! Stay updated by subscribing to our newsletter
BUFFALO, NY- May 22, 2024 – A new research paper was published in Oncotarget's Volume 15 on May 17, 2024, entitled, “GZ17-6.02 kills PDX isolates of uveal melanoma.” In this new study, researchers Laurence Booth, Jane L. Roberts, Ivan Spasojevic, Kaitlyn C. Baker, Andrew Poklepovic, Cameron West, John M. Kirkwood, and Paul Dent from Virginia Commonwealth University, Duke University School of Medicine, Genzada Pharmaceuticals, Texas Tech University Health Sciences Center, and University of Pittsburgh Cancer Institute defined the biology of GZ17-6.02 in UM cells and in parallel determined its interaction with irreversible ERBB inhibitors (afatinib, neratinib) and with the cytotoxic agent doxorubicin. “GZ17-6.02 is a novel compound, containing the synthetically manufactured components: curcumin, harmine and isovanillin and has undergone phase I safety evaluation in cancer patients (NCT03775525).” GZ17-6.02 has undergone phase I evaluation in patients with solid tumors (NCT03775525). The RP2D is 375 mg PO BID, with an uveal melanoma patient exhibiting a 15% reduction in tumor mass for 5 months at this dose. Studies in this manuscript have defined the biology of GZ17-6.02 in PDX isolates of uveal melanoma cells. GZ17-6.02 killed uveal melanoma cells through multiple convergent signals including enhanced ATM-AMPK-mTORC1 activity, inactivation of YAP/TAZ and inactivation of eIF2α. GZ17-6.02 significantly enhanced the expression of BAP1, predictive to reduce metastasis, and reduced the levels of ERBB family RTKs, predicted to reduce growth. GZ17-6.02 interacted with doxorubicin or ERBB family inhibitors to significantly enhance tumor cell killing which was associated with greater levels of autophagosome formation and autophagic flux. Knock down of Beclin1, ATG5 or eIF2α were more protective than knock down of ATM, AMPKα, CD95 or FADD, however, over-expression of FLIP-s provided greater protection compared to knock down of CD95 or FADD. Expression of activated forms of mTOR and STAT3 significantly reduced tumor cell killing. GZ17-6.02 reduced the expression of PD-L1 in uveal melanoma cells to a similar extent as observed in cutaneous melanoma cells whereas it was less effective at enhancing the levels of MHCA. The components of GZ17-6.02 were detected in tumors using a syngeneic tumor model. “Our data support future testing GZ17-6.02 in uveal melanoma as a single agent, in combination with ERBB family inhibitors, in combination with cytotoxic drugs, or with an anti-PD1 immunotherapy.” DOI - https://doi.org/10.18632/oncotarget.28586 Correspondence to - Paul Dent - paul.dent@vcuhealth.org Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28586 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, autophagy, ER stress, GZ17-6.02, doxorubicin, afatinib, neratinib About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM
The debacle over widespread errors in the state pension that This is Money and Sir Steve Webb uncovered, continues. As of the end of October last year, DWP had paid out just under half a billion pounds to more than 80,000 people who've been underpaid. But what about those who have died? This week, Tanya Jefferies, Lee Boyce, Angharad Carrick and Georgie Frost reveal the case where a letter was sent to the daughter of an 100 year-old man three years after he passed away, stating he had been unpaid state pension for two decades. Yet, despite the letter – months later, she was left hanging on what the DWP was actually going to do about it. And still on the state pension front, people continue to complain of top-ups chaos as the Government gets ready to launch a new online service next month. Sir Steve is calling on DWP and HMRC to get in more staff. You don't need HMRC to have more staff to answer your call, oh no! You just need to be a VIP. Apparently there is a helpline, also known as Public Department 1 (PD1) which answers calls nine times quicker. We explain more. On the savings front, the FCA is launching a campaign to encourage savers to shop around – and if you rushed to sign up for a one-year fixed-rate cash Isa this time in 2023, Lee explains why you must act. Optional and mandatory service charges at hospitality venues – Georgie, Ang and Lee give their verdict. And finally the price of bitcoin jumped beyond $60,000 this week. What's behind the latest cryptocurrency surge?
ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the voice of the world's oncology professionals. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on this podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so data described here may change as research progresses. The theme of the 2023 ASCO Annual Meeting was “Partnering With Patients: The Cornerstone of Cancer Care and Research.” From June 2 to 6 in Chicago, Illinois, and online, cancer researchers and clinicians from around the world gathered to discuss the latest cancer research and how to ensure that all people receive the cancer care they need. In the Research Round Up series, members of the Cancer.Net Editorial Board discuss the most exciting and practice-changing research in their field presented at the meeting and explain what it means for people with cancer. In today's episode, our guests will discuss new research in melanoma and health equity. First, Dr. Katy Tsai discusses new research in melanoma. Dr. Tsai is a medical oncologist and Assistant Professor of Medicine in the Division of Hematology and Oncology at the University of California, San Francisco. She is also the 2023 Cancer.Net Associate Editor for Melanoma & Skin Cancer. You can view Dr. Tsai's disclosures at Cancer.Net. Dr. Tsai: Hello. Welcome to the ASCO Cancer.Net Research Round Up. I'm Katy Tsai, an associate professor of medicine and the clinical medical director of the Melanoma and Skin Cancer Program at the University of California, San Francisco. I'm happy to be here today to discuss research on melanoma and skin cancers presented at the 2023 ASCO Annual Meeting. I do not have any disclosures relevant to the studies to be discussed. So, it's always exciting to see the latest research presented at ASCO. One theme in particular that I'd like to highlight in this podcast is recent advances in the field of adjuvant therapy. For the listeners who may not be familiar with this terminology, adjuvant therapy refers to drugs given after surgery to try to decrease the risk of cancer recurrence. Specifically, late-breaking abstract 9505 presented updates from KEYNOTE-716, an adjuvant study of pembrolizumab, or pembro, in patients with resected high-risk stage II melanoma. Late-breaking abstract 9503, which I'll also discuss, presented data from KEYNOTE-942, a pivotal study of a personalized cancer vaccine plus pembrolizumab in patients with resected high-risk stage III and stage IV melanoma. So, let's start with KEYNOTE-716. We've known for some time in our field now that adjuvant pembrolizumab or nivolumab can help decrease the risk of recurrence for patients with resected stage III or IV melanoma. What may not be as well-known, however, is that patients with stage IIB or IIC melanomas, in other words, thicker, ulcerated primary melanomas, even without lymph node spread, actually have a comparable risk of melanoma recurrence compared to patients with early stage III melanomas. KEYNOTE-716 was a large, international phase 3 study that randomized patients with stages IIB and C melanoma to receive either pembro or placebo. The positive results showing improvement in relapse-free survival led to approval of adjuvant pembro in December 2021, but what was presented at ASCO was an update on distant metastasis-free survival. This is obviously an important endpoint for us because ultimately, if someone is going to develop widely metastatic disease, unfortunately, it is a development of these distant metastases that we are concerned about. So what we saw here is that with landmark 36-month follow-up, there was a 41% reduction in the risk of developing distant metastasis in patients who were treated with pembro compared to those who received the placebo. In addition, there was a consistent maintained benefit in relapse-free survival, and importantly, no changes in the side effect profile. These are important data because I believe it is practice-changing in the sense that this is a population of patients who historically might not ever have been referred to medical oncology, maybe just monitored serially with their dermatologists. And this is an option that should be discussed. Ultimately, the risk versus benefit about whether to pursue a year of therapy versus maybe consider treatment only at the time of recurrence is a very personalized discussion between a patient and their treating oncologist, but it is an option that should definitely be offered. So let's move on to KEYNOTE-942. The novel drug being tested in this trial is very exciting. We're calling it “individualized neoantigen therapy.” So this is basically a platform that allows us to develop individualized treatment for someone based on characteristics of their own cancer. This involves taking the actual tumor specimen, genomic sequencing, specifically whole-exome sequencing is performed to try to identify any changes in the DNA. And then through a bioinformatic pipeline, the mutations in the DNA that are thought to be most likely to generate proteins that can be bound within presenting molecules are then identified in the computer program, then synthesized within mRNA. So very similar to the way that COVID vaccines have been made. So this actually becomes the actual drug product. So in this study, patients were randomized to receive either pembrolizumab by itself for a year, which is, as we alluded to earlier, standard adjuvant therapy, but then with the addition of this individualized neoantigen therapy starting with dose 3 and then throughout the rest of the year. So the recurrence-free survival data were actually presented earlier this year at another major conference, AACR [American Association for Cancer Research], and were highly positive. At ASCO 2023, I think what was most impressive about the presented data is that distant metastasis-free survival, so again, a similar important endpoint that we discussed with the other trial, is that the distant metastasis-free survival here was quite impressively maintained. There was a hazard ratio of .35, meaning really a 65% reduction in the risk of recurrence for patients who received the personalized neoantigen therapy plus pembrolizumab. So this is a huge advantage for distant metastasis-free survival in this particular population of patients. What was even more intriguing is that usually when we combine therapies, we tend to see additive toxicity, more side effects. And what was really exciting about this particular trial is that the additive toxicity really wasn't as much as you would expect for giving 2 immunotherapies at the same time. I'll also highlight that even though these results are really exciting within melanoma, that part of the reason this data is so exciting is that it represents a really promising platform for therapeutic development and application in other tumors besides melanoma. So this is definitely super exciting. While perhaps not practice-changing in this moment, it's potentially practice-changing. And I look forward to seeing additional data coming in from planned trials using this particular combination in the metastatic setting in addition to the adjuvant setting. So on the whole, I do think that updates in adjuvant therapy for melanoma were super exciting to see at ASCO 2023. As I mentioned earlier, it's a very large conference. A lot of exciting data being presented. So I do think that other themes to pay attention to as we continue to sort through existing data and look forward to incoming data from forthcoming trials is looking at neoadjuvant therapy. For example, drug given before surgery to try to improve long-term outcomes. For example, at ASCO this year, there was interesting neoadjuvant immunotherapy data presented not for melanoma, but for a different type of skin cancer called squamous cell carcinoma. So that would definitely be another theme to pay attention to in the coming months and years. Thinking about novel combinations, for example, what's new in immune checkpoint inhibitors, we've been used to for a long time referring only to anti-PD1 antibodies, anti-CTLA4 antibodies. What was interesting to see this year were updates in novel combinations, for example, PD1 antibodies combined with LAG3 antibodies. Antibodies against TIGIT. So I think this will be another exciting space to pay attention to both in the metastatic skin cancer setting and in the adjuvant and neoadjuvant settings. Thank you for your time and attention. That concludes my research roundup for melanoma and skin cancers. Thank you. ASCO: Thank you, Dr. Tsai. Next, Dr. Manali Patel discusses new research in health equity. Dr. Patel is a medical oncologist and Assistant Professor of Medicine at Stanford University. She is also the 2023 Cancer.Net Associate Editor for Health Equity. You can view Dr. Patel's disclosures at Cancer.Net. Dr. Patel: Hi, my name is Manali Patel. I'm the Associate Editor for Health Equity for Cancer.Net, and I'm so incredibly excited to present some really amazing work that was presented at our ASCO Annual Meeting this past June in Chicago. Before I start, I do have one disclosure. I will be talking about studies that were presented relating to patient navigation and one study in particular that my group presented looking at community health workers. And so that is a little bit of a disclosure that I would like to address upfront. And now, just to get right started. I thought what was really interesting was the amount of work this year that was presented on disparities in health equity. As in past years, we actually saw quite an influx, probably more so this year than previously, on studies that looked at differing outcomes, inequities in cancer care delivery, describing disparities in terms of receipt of treatment, so if people were receiving treatment. There tended to be a lot of studies that focused on looking at and describing a lot of these disparities. But what I was really impressed by came out from the pediatric colleagues, individuals who are taking care of younger patients, children who are less than the age of 18, and how many of those particular studies were focused on moving from description to actually intervening and making a difference in health equity. And so I want to highlight a couple. There was one that was done out of Dana-Farber, and actually, a multi-site group of authors. So lots of authors from all over the place, but Emily Jones was the lead author. And they described and actually evaluated how they could collect, in the context of clinical trials for children, which is called Children's Oncology Group Trial-- how they could collect social determinants of health data, meaning data that evaluates people's income, transportation, where people live, what kind of work they may do, if they have food and housing insecurity. And what they were able to show is that, by embedding a lot of these data points-- they actually made these data points optional for patients when they came into the clinical trial. And they found high feasibility, meaning lots of people that were signing up to do clinical trials for the Children's Oncology Group Trial were able to complete this extra data, which is extremely important and is a remarkable willingness of individuals to participate in providing this data which is important for their treatment. Along those same lines, Amy Newman from the Children's Hospital of Philadelphia really did a very nice study looking at the feasibility of what they called PediCARE. And it was this intervention that was focused on trying to ensure that people-- again, children less than the age of 18 across 2 different clinics. They evaluated whether PediCARE would help people to receive necessary and important resources as it relates to social and economic needs. And so they screened for food insecurity, for housing insecurity, for people that had difficulties paying for utilities, and transportation security. And then they randomized individuals to either PediCARE or to just usual cancer care. And what they found was that 100% of the people that were randomized to PediCARE successfully received grocery and transportation resources. They felt that it was easier to buy food for their family, and they reported it was easier to get to and from the hospital and that they would be very likely to report and to recommend this intervention to other individuals. And so it really shows how these interventions can move from just describing that housing, food insecurity or problems-- number 1, it starts with the collection of the data, right? What's really important is making sure that we collect this data because we don't currently do that in cancer care. And then number 2, when we actually do collect the data, what are we going to do about it? And it shows that these interventions really do help people to move past their housing and social and economic issues that they may experience into actually receiving care that's important and necessary to improve outcomes. We did see a lot of data reflecting the importance of health insurance and big policies, what I call Big P, which are these national policies, like the Affordable Care Act. And now we've seen, just year after year and including this year, plethora of studies showing how beneficial the Affordable Care Act has been on reducing disparities and improving cancer outcomes overall. We also saw other studies, such as one presented by Dr. Gladys Rodriguez from Northwestern, which looked at disparities in the intensity of care at the end of life amongst patients with gastrointestinal cancers. And the team revealed, across almost 20 years of data in California, that patients were receiving higher rates of what would be considered low-quality care. Now, this is lower hospice use, which we know helps to actually improve survival, lower rates of palliative care use, and greater rates of burdensome hospitalizations. And now, why I think this is particularly important is because this study evaluated what we know is a problem, that there is low-quality care amongst patients from particular racial and ethnic populations, such as Black and Hispanic patient populations, that aren't receiving the right care when they're diagnosed. And then what this reveals is that, even at the end of life, they're perhaps still receiving low-quality care. Another study looked at screening, which I thought was really impressive. It was by Nicole Anne Gay from the UM Sylvester Comprehensive Cancer Center in Miami. And what they evaluated was essentially a quality improvement program to reduce disparities in lung cancer screening. As a lung cancer doctor myself, it's still shocking that fewer than 6% of people that should receive lung cancer screening, meaning a screening test to help us identify and to treat patients with lung cancer-- they aren't receiving lung cancer screening. And so we know that this is a problem overall. They put into place what's called a multi-level, meaning that there were improvements in the electronic health record that they embedded. They also provided patients with navigation, and they also helped clinicians in the primary care clinics obtain information about who should be eligible and which patients should be receiving screening. And what they found was that they were able to move screening rates from 25% improvement completed during the project period from their baseline, which is actually quite impressive. We also saw an interesting study, and actually, just an interesting evaluation, of childhood leukemia survival on the U.S.-Mexico border. And it was a description of how to implement changes by strengthening care partnerships. And so they evaluated and they described the implementation of this program to achieve what they called sustainable high-quality care for children with leukemia. It was done by Paula Aristizabal and was really in a unique border health setting. It was in partnership between the North American and Mexican institutions. And they used what was called the strengthening model developed by the World Health Organization to evaluate specific domains and to try to improve a sustainable program for children with acute lymphoblastic leukemia at a public referral hospital right on the border region. And I thought that that study was particularly interesting because it shows how to be able to use an approach to improve the staffing of a leukemia service, to implement a sustainable training program as well for other clinicians to learn how to provide leukemia care, and then also to try to improve clinical outcomes and funding for patients to receive medications through local partnerships. I thought it was a really fantastic description of how to begin to do this work that is extremely necessary in low- and middle-income nations but also even on our own U.S.-Mexico border. There were also a lot of studies that evaluated the importance of social and economic factors. We know that financial toxicity, which is an unfortunate side effect of cancer treatment and cancer care and a cancer diagnosis overall, is associated with worse outcomes. Financial toxicity means the burdens and costs that arise with having a cancer diagnosis. And now we've seen studies that were presented at ASCO this past year by Dr. Khan, who showed that, within 2 years of diagnosis, are at higher risk for dying after adjusting for many social and also clinical factors. And Dr. Hu also presented data looking at the implications of having a lot of medical debt and death. And what both of these studies showed is that medical debt is associated with having perhaps a lower likelihood of surviving. It does make sense for Dr. Hu's study that one would have a lot of medical debt if they also have a lot of other conditions, but it does begin to shed some light on the fact that there are worse clinical outcomes, meaning people aren't doing as well, depending on how much other medical care expenses they may have. And then finally, one important piece, which I think is really crucial for what's happening now in the way that oncologists may perhaps be able to advocate for payment for services that are important, is looking at navigation studies. Now, this is patient navigators, and that is a very broad topic. And so there were lots and lots of studies that came out at ASCO that evaluated the importance of navigation, including our own work that looked at what happens to veterans after receiving a lay health worker or a navigator to assist with advanced care planning, meaning helping veterans to understand their goals and preferences. And what these studies have shown is that there's actually not only clinical benefit but also, in our own study, that perhaps there may be a survival benefit even 10 years later. It was very wonderful to be at ASCO this past year, and I really hope that you all can look at some of these studies or take away the important and amazing work that's going on in the health equity space. And I thank you for listening to our podcast. ASCO: Thank you, Dr. Patel. You can find more research from recent scientific meetings at www.cancer.net. Cancer.Net Podcasts feature trusted, timely, and compassionate information for people with cancer, survivors, and their families and loved ones. Subscribe wherever you listen to podcasts for expert information and tips on coping with cancer, recaps of the latest research advances, and thoughtful discussions on cancer care. And check out other ASCO Podcasts to hear the latest interviews and insights from thought leaders, innovators, experts, and pioneers in oncology. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping people with cancer everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate. [music]
In this JCO Article Insights episode, Davide Soldato interviews Dr. Naqash from University of Oklahoma. Dr. Naqash provides insight into the original article published in the July JCO issue: “Safety and Activity of Immune Checkpoint Inhibitors in People Living With HIV and Cancer: A Real-World Report From the Cancer Therapy Using Checkpoint Inhibitors in People Living With HIV-International (CATCH-IT) Consortium”. The interview offers a deep dive into the manuscript results on efficacy and safety of Immune Checkpoint Inhibitors in this specific population and offers insights on future research direction in this space. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Davide Soldato: Welcome to this JCO Article Insights episode for the July issues of JCO. This is Davide Soldato and today I will have the pleasure of interviewing Dr. Abdul Rafeh Naqash, the author of the manuscript titled "Safety and Activity of Immune Checkpoint Inhibitors in People Living with HIV and Cancer: A Real World Report from the Cancer Therapy Using Checkpoint Inhibitors in People Living with HIV-International Consortium." Dr. Naqash is an Assistant Professor of Hematology-Oncology at the University of Oklahoma and a Medical Oncologist working at the Stephenson Cancer Center. His research interests revolve around early-phase clinical trials in solid tumors, lung cancer, and the study of immunotherapy, biomarkers, and resistance. Welcome, Dr. Naqash, and thank you for accepting our invitation today. Dr. Abdul Rafeh Naqash: Dr. Soldato, thanks so much for having me. I'm really excited to discuss this article with you today. Davide Soldato: So I just wanted to go a little bit over the manuscript with you. So basically, this is a retrospective multicenter study that was conducted across the US, Europe, and Australia by the CATCH-IT Consortium. And so the aim of the study was really to investigate the safety and the activity of immune checkpoint inhibitors among patients diagnosed with cancer and also living with HIV. The article examined two different cohorts, and I just wanted to start with a brief explanation of how the two cohorts were built so that our readers can get a little bit of understanding of what you did then. Dr. Abdul Rafeh Naqash: Sure. Before I take a deep dive into the cohorts, Dr. Soldato, I would definitely like to mention the premise and the background for this paper as to why we did what we did. And one of the primary reasons was that people living with HIV, historically, there have been very limited number of trials that have included these individuals. So it becomes a very important question from a disparity standpoint. And most often we end up, in the real world setting, we end up extrapolating data from clinical trials, but not necessarily know what is the outcome of these individuals in the real world setting. So there have been some very important studies in the last three years or so in people with HIV as far as clinical trials with checkpoint inhibitors go, but most of those trials have been limited by the number of patients, number of people that have been part of those trials. So we wanted to understand it from a broad perspective, whether it is from a broad geographic perspective or from a heterogeneous patient population perspective, which is why we built this consortium called the CATCH-IT Consortium, which basically stands for Cancer Therapy Using Checkpoint Inhibitors in People Living With HIV-International Consortium. And this required a lot of effort from a lot of different centers, including those in the US, Europe, and Australia, as you mentioned. And then we ended up having data worth around 400 plus patients, close to 400 patients or so. And then we wanted to look at obviously outcomes, whether it's related to a certain tumor such as lung cancer, which we did in this case, or a pan tumor assessment of toxicities and safeties. So, to your question, the cohorts that we basically had, we had close to approximately 390 patients that we included in the safety analysis. So first we looked at the safety analysis, which was the entire cohort, and then out of those we excluded around 12 patients or so. Those were patients that were treated in the adjuvant setting. So in the metastatic advanced setting, we had close to 378 individuals that we assessed clinical outcomes for. So, response rates, progression-free survival, and overall survival. And then as far as a separate cohort, we looked at non-small cell lung cancer, which was the most commonly represented tumor type, with approximately 111 patients that had non-small cell lung cancer. We did exclude a certain proportion of those that were earlier stage, stage III. So in the stage IV, basically we ended up matching in this separate cohort, around 60 odd patients or so of non-small cell lung cancer to 110 stage four, non-small cell lung cancers. So basically it was a one-to-two matching and we chose the same site. So if a site had, let's say, two people with HIV and lung cancer treatment checkpoint, we tried to match it to approximately four to five patients from the same site and we used some variables for matching so that we had some level of homogeneity between the HIV patient population and the non-HIV positive lung cancer individuals. So that's basically cohort A was around 370-something patients, tumor agnostic advanced metastatic setting. Cohort B was lung cancer individuals matched to non-HIV positive lung cancer treatment checkpoint inhibitors. Davide Soldato: Thank you very much. That was very clear. Just to go back to what you were saying before because I think that this is very interesting. You mentioned that patients living with HIV were mostly excluded from clinical trials and in the few that included them, there were some restrictive criteria in terms for example of CD4-positive cells in the blood. And so I was wondering if when you included the patients inside of this cohort, you also had this type of exclusion criteria or you chose a broader population to make the results more generalizable and applicable in clinical practice. Dr. Abdul Rafeh Naqash: Right, a very important question. Thank you, Dr. Soldato. So yes, previous clinical trials have had some level of restrictions as far as the inclusion of these individuals, but in our study, this was a real-world study, basically, patients whoever presents to the clinic with a history of HIV, they were all included. So we did not restrict it to certain CD4 counts or viral loads because the important thing was we wanted to understand the ground situation of how these individuals do, irrespective of some of these limitations. As far as what we identified as baseline CD counts or HIV viral load positivity, we took three months before immune checkpoint initiation as a cut off so obviously there's a limitation there. We didn't have results of these CD4, CD at a viral load assessments done like the day of or the week before in some patients. So we took three months and we included individuals that had received at least one or more dose of immune checkpoint therapy between January of 2015 to October of 2021, which was our database lock. And then obviously the regimens included immune checkpoint anti-PD1, PD-L1 monotherapy, or in combination with other anticancer agents including anti-CTLA-4 or chemotherapies targets, which is important to point out here. So the trials that have been mostly done in this space are single-agent checkpoint inhibitors or anti-PD1 with anti-CTLA-4. There's not much data for immune checkpoint inhibition combined with other agents such as targeted therapies, chemotherapies. So we had some of that data in this cohort, which kind of made it interesting. Davide Soldato: Yeah, I think that it's very interesting and it's very wise to choose very broad eligibility criteria for these type of studies because it really answered to the question that we identified and that we spoke about in the beginning. So going back to the results, you said that the cohort A, so the one that included all the patients, irrespectively of the type of tumor that was diagnosed, it was mainly for evaluating what was the safety of immune checkpoint inhibitors in patients living with HIV and with a concurrent cancer diagnosis. So I was wondering if in this cohort you identified some differences compared to historic data in terms of, for example, incidence of grade three or higher toxicities or incidence of immune-related adverse events in general, and if maybe there was some adverse events that was very characteristic or particular in this cohort. Dr. Abdul Rafeh Naqash: So immune-adverse events is a very interesting question not only from this cohort but in general because it overlaps with this question of autoimmunity and cross T cell cross reactivity. And this is a unique patient population where we have the ability, although not fully but to some extent, to look at the role for CD counts and also look for patterns of adverse events. To answer your first part of the question, we didn't see any significant differences for the types of adverse events. We did see the incident was a little lower than what you would expect in the real-world setting for non-HIV individuals. Whether that has something to do with how the immune system is constructed in these individuals, nobody knows. We did look at CD4 and CD8 counts. As far as absolute CD4 counts, about 200 or below 200, we didn't see a difference as far as the cumulative incidence for immune checkpoint inhibitor-related adverse events. When we did a ratio of CD4 to CD8 of greater than 0.4 and compared it to less than 0.4, we did see that at around 24 weeks, there was a difference in terms of the cumulative incidence for adverse events. It was around 10% versus 26% when we use that cut-off of 0.4, suggesting that there might be some role of how the peripheral immune system results in the related adverse events in these individuals, but it's a very important question. I think there are ongoing evaluations that are being done from other prospective studies that had collected blood samples in these individuals. But generally, we saw the same range of adverse events, diarrhea, colitis, pneumonitis, hepatitis. We did have a few patients who had a history of opportunistic infections, but we didn't see any significant reactivation there which was part of the safety assessment in our analysis. Davide Soldato: So basically, because I think that in HIV patients, even if those included in the study were almost all were on antiretroviral therapy, but you didn't observe any opportunistic infection that developed during the course of immunotherapy. Dr. Abdul Rafeh Naqash: You're absolutely right, we did not. In fact, we are trying to look at that in a different setting, in a different cohort because there have been some data on mycobacterial reactivation in individuals in general, not just HIV, but in our cohort of 400 odd patients, we did not see any new opportunistic infections. Davide Soldato: I think that one aspect that pops into my mind right now is also that we have kind of some data regarding also possible HPV reactivation in these types of patients treated with immune checkpoint inhibitors. So maybe that could be also something that you would be interested to look at in the future, I imagine. Dr. Abdul Rafeh Naqash: Yes, we are planning to look at HPV-driven cancers actually for starters, anal and head and neck. We are also looking at hepatitis B-related HCC in a separate ongoing cohort. So there are definitely subsequent steps that we are currently involved in as far as viral-driven cancers and concurrent HIV is concerned. Davide Soldato: Thank you. I think that's very interesting. And I was wondering, you mentioned in the beginning that this patient clearly they have some degree of immune dysregulation or at least some type of dysfunction in terms of immune presentation and immune activation. So I think that one of the concerns or one of the worries of using immune checkpoint inhibitors in this population could also be that the efficacy that we see in patients that do not have HIV could be lower. Could you comment on this if you found any differences both in the cohort including all cancer, but also in the cohort B, that I think you had the strategic idea of pairing these patients living with HIV with patients that were not living with HIV. So I think that this brings very important data to the space. Dr. Abdul Rafeh Naqash: Yes, we tried to look at this one from a tumor-agnostic perspective and a tumor-specific perspective. So the tumor agnostic perspective was looking at a different set of cancers which included skin cancer, melanoma, lung cancer, non-Hodgkin's lymphoma, small cell head and neck, and a couple of other cancers. And one of the things we noticed was that there was a trend, so there was differential efficacy as far as the cancer type is concerned. So for example, skin, Hodgkin's lymphoma, Kaposi sarcoma, melanoma had the highest response rates, somewhere in the range of 60s to 40s. On the other hand, viral-driven cancers such as anal cancer, HCC, head and neck actually had very low response rates, less than 15% or so. So that begs the question of what is going on and we don't necessarily know, which is why we are trying to concentrate on the viral-driven cancers first. Because as you know, melanoma, Kaposi's do have historically shown better responses to checkpoint inhibitors. Now do we know if when we compare these responses or survival to non-HIV individuals in clinical trials, are the outcomes similar? I would say in some of the tumor types the outcomes were somewhat inferior and in some of the tumor types the outcomes were somewhat similar. So for example, lung, we did compare non-small cell lung cancer. As I mentioned, we had two cohorts, we matched it to a non-HIV cohort and there we looked at progression-free survival and overall survival. And again the caveat is that this is a retrospectively matched cohort, this is not a prospectively matched cohort. So these are individuals that are not matched for each and every variable. They're matched for certain top three or four variables as much as we could accommodate. And based on that we didn't see a difference in the progression-free survival and the overall survival when we did an assessment. In fact, we looked at it at a 42 month period where we looked at the restricted median survival time and it was not different, was around 17.8% for people with HIV and 18.4% for people without HIV as far as progression-free survival, and around 42% and 41% overall survival at the two-year mark. So basically there is not much significant difference which reiterates the fact that in the right setting, these individuals could be safely treated with immune checkpoint inhibition and could perhaps have similar outcomes. Maybe not in all tumor types, but in some tumor types. But at the end of the day, and we mentioned this in our manuscript also in subsequent work that we are trying to do, we have emphasized on the fact that it has to be a multidisciplinary discussion between the patient, the physician, the medical oncologist, the treating oncologist, and the infectious disease person. Because these individuals have a lot of complicated aspects because of the underlying HIV and taking that into perspective and then assessing risk-benefit is an important discussion. So the goal of this work was not to establish that immune checkpoint inhibitors are absolutely beneficial or absolutely safe. The goal was more to create awareness that people in the real-world setting actually can benefit, which the next step would be to have more trials and perhaps modify inclusion criteria in clinical trials so that you can have a more inclusive approach, including these individuals. Davide Soldato: Coming back to the multidisciplinary approach because I think that this is very interesting and should be really implemented when we have this type of patient. From the data that you collected, did you add any indication that maybe this patient treated in the real-world setting were not managed in such a multidisciplinary way? Dr. Abdul Rafeh Naqash: The easiest way to point that out is that most of these people or many of these individuals did not have HIV viral loads or CD4 counts done before treatment initiation. And that's an indirect surrogate for telling you that these are things that should have been thought of, but were not thought of if the individual taking care of these people either did not have expertise as far as HIV is concerned or did not have a colleague on the infectious disease side who was actively managing these people. So that's an important indirect way where we kind of got a sense that there has to be more awareness about multidisciplinary care. And especially the immune adverse event situation in these individuals can get complicated because of the way their immune system is constructed and having that multidisciplinary care is very important. We didn't specifically collect data on what teams or what subspecialists were involved in each individual's care, but I think that would be an important assessment for maybe a future quality improvement project to look at why or how some of those things were not done so that it can lead to future improvements. Davide Soldato: So, just expanding on that, you said that you didn't have much data in terms of CD4 cells or in terms of viral load. But for what you had inside of your cohort, did you see any modification of these parameters that we know that are very important in patients living with HIV under immune checkpoint inhibitors therapy? Dr. Abdul Rafeh Naqash: Again, a very important immunological question, I think as far as what we saw- so we had close to around 74, 75 individuals that had CD4 T cell counts available. And we didn't see differences between baseline and post-immune checkpoint therapy changes in CD4 counts. Similarly, we didn't see a difference as far as HIV viral load and we had HIV viral loads present in around 107 individuals and we didn't see a difference. Now, again, 30% of our cohort was CD4 count less than 200, and 70% was CD4 count more than 200, , which is again, important to highlight because many trials don't take individuals with the CD4 count less than 200. But in general, we did not see a difference in this pre and post-assessment both for viral load and both for CD4 count. Now trials in this space have ongoing assessments that they are doing. The AIDS Malignancy Consortium does have a trial looking at changes in CD4/CD8 counts or viral loads. In fact, the CITN trial which is a pembrolizumab trial published a couple of years back did have an assessment done as far as CD4 counts and viral loads are concerned. And I think they did see a slight increase in the CD4 counts and there are some aspects about how the immune system may change with an immune checkpoint inhibitor. But I think the strength of the data is not that much, and I think we probably need more patient samples to assess why or how some of that could change or what implications it would have for patients. Now, there is another concept of HIV viral latency removal that some of the listeners might have heard of, especially in the HIV setting, where you were given an immune checkpoint inhibitor and it can lead to reversal or reduction of the HIV reservoir, which can somehow impact the CD4 counts, and also lead to elimination of the viruses through CD8. But again, that's a more complicated assessment and we didn't have data for it. Davide Soldato: Thank you very much. That was very interesting also for future perspectives in this topic. I just wanted to ask you if the idea for the research came more from ensuring equity in terms of care delivery for patients living with HIV or if it was more also to investigate the immunological components that we discussed just as far or a good mix of the two. Dr. Abdul Rafeh Naqash: I think the idea actually stemmed from this individual who's the first author, Dr. Talal El Zarif and co-first author Dr. Amin Nasser from Dana-Farber, reached out a year and a half back and they wanted to look at outcomes from an HIV standpoint and see what the real world setting is. And the goal was they would have their data and we would have our data and we would eventually collect the data together or combine the data together. But then after some conversations, we started looking at the available data, the available literature, saw that there was a decent gap in what we know. And I know there are some brilliant groups in the HIV space, especially at the NCI. In fact, Dr. Kate Lurain and Dr. Ramaswami are good collaborators of ours and they worked in this space and are currently developing trials in this space. But it just did seem like this would be a more interesting approach of answering a real-world question and then also looking at the disparities of it because as an early-phase drug development trialist, I still see a lot of trials, in fact, majority of the trials, say people with HIV or history of HIV are excluded. Now, the NCI has made important efforts in that space of including those individuals, but I think we still have some ways to go. So basically the idea came from two trainees who were extremely enthusiastic and wanted to pursue this. And I, obviously, seeing their level of enthusiasm and excitement, I was excited too. And then importantly, if you look at the paper, we have a bunch of authors, we have close to 79, 80 authors on that paper. And the primary reason was that each center contributed in certain ways, including patients' data and then expertise. And this ended up being a huge community effort from the oncology community, where everybody's individual effort led to something like this coming to fruition. So it was a multitude of different aspects, but yes, it all started with a question of how these individuals do and the current data where they're missing gaps, and we wanted to sort of supplement those gaps and provide insights using this important real-world data set. Davide Soldato: Thank you very much for the insight on how the idea came to be. Is there anything else you would like to add or to summarize for our listeners? Dr. Abdul Rafeh Naqash: Well, first of all, I appreciate the opportunity to discuss our paper here. I would like to thank you and of course the JCO staff for organizing this, and also the JCO Journal for giving us the opportunity to publish this important work. Some of the things that we would like to highlight as outcomes from this paper, as we sort of discussed, but to summarize those: we saw that we didn't have any significant safety concerns, obviously. We saw that some patients in certain tumor types do benefit, similar to what you might expect in a non-HIV setting in the real world as well. And of course, this was the largest real-world data set of people with HIV and cancer. And we have ongoing efforts in different directions, as I mentioned to you. And we are more than happy to collaborate with anybody who has good ideas because this is a community-level data set. It was created for the community, by the community, and the goal is to utilize this data set. So if there is a listener out there who's interested in collaborating, who has an idea, we're more than happy to share the data set in the right setting. And then hopefully, everybody has the opportunity to lead different efforts in the space. Davide Soldato: Thank you again for being with us today, Dr. Naqash. To hear more from Dr. Naqash, please check out ASCO's JCO Precision Oncology Conversation Podcast. So this is Davide Soldato. In this episode of JCO Article Insights, we discussed the results of the manuscript titled, “Safety and Activity of Immune Checkpoint Inhibitors in People Living with HIV and Cancer: A Real World Report from the Cancer Therapy Using Checkpoint Inhibitors in People Living with HIV-International Consortium.” Thank you for your attention and stay tuned for the next episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Featuring articles on outcomes with donor hearts after circulatory death, treatment of gestational diabetes in early pregnancy, and anti-PD1 therapy plus chemotherapy in endometrial cancer; a review article on posterior reversible encephalopathy syndrome; a case report of a woman with fatigue and eosinophilia; and Perspective articles on moving toward comprehensive care for long Covid, on workplace accommodations for long Covid, and on over-the-counter hearing aids.
Drs Sumanta Pal and Scott Haake discuss the biology of kidney cancer and how to incorporate tissue biomarkers into prospective studies on renal cell carcinoma. Relevant disclosures can be found with the episode show notes on Medscape (https://www.medscape.com/viewarticle/984237). The topics and discussions are planned, produced, and reviewed independently of advertisers. This podcast is intended only for US healthcare professionals. Resources W. Kimryn Rathmell, MD, PhD, MMHC https://www.vumc.org/viiii/person/w-kimryn-rathmell-md-phd-mmhc Novel Emerging Biomarkers to Immunotherapy in Kidney Cancer https://pubmed.ncbi.nlm.nih.gov/34868351/ PD1 and PD-L1 Inhibitors for the Treatment of Kidney Cancer: The Role of PD-L1 Assay https://pubmed.ncbi.nlm.nih.gov/32208115/ Oncogene-Specific Differences in Tumor Mutational Burden, PD-L1 Expression, and Outcomes From Immunotherapy in Non-Small Cell Lung Cancer https://pubmed.ncbi.nlm.nih.gov/34376553/ Multiomics in Primary and Metastatic Breast Tumors From the AURORA US Network Finds Microenvironment and Epigenetic Drivers of Metastasis https://pubmed.ncbi.nlm.nih.gov/36585450/ Avelumab Plus Axitinib Versus Sunitinib in Advanced Renal Cell Carcinoma: Biomarker Analysis of the Phase 3 JAVELIN Renal 101 Trial https://pubmed.ncbi.nlm.nih.gov/32895571/ Clinical Activity and Molecular Correlates of Response to Atezolizumab Alone or in Combination With Bevacizumab Versus Sunitinib in Renal Cell Carcinoma https://pubmed.ncbi.nlm.nih.gov/29867230/ Atezolizumab Plus Bevacizumab Versus Sunitinib in Patients With Previously Untreated Metastatic Renal Cell Carcinoma (IMmotion151): A Multicentre, Open-Label, Phase 3, Randomised Controlled Trial https://pubmed.ncbi.nlm.nih.gov/31079938/ Insights Into the Genetic Basis of the Renal Cell Carcinomas From the Cancer Genome Atlas https://pubmed.ncbi.nlm.nih.gov/27330105/ Genetic Testing to Select Therapy for the Treatment of Advanced or Metastatic Kidney Cancer, OPTIC RCC Study https://clinicaltrials.gov/ct2/show/NCT05361720
In this episode, our team discusses the Checkmate 577 trial, the landmark paper which approved the use of nivolumab for adjuvant treatment of stage II & III esophageal & GE junction cancer. Listen as our team reviews the study population, methods and results of this trial & discusses its clinical application as well as potential areas of future research. Learning Objectives: -Review the staging and treatment of esophageal and GEJ cancer -Discuss the population, methods, and results of the Checkmate 577 trial -Understand the mechanism of action of nivolumab and the PD1 pathway -Discuss the implications of the Checkmate 577 trial in clinical practice and areas of future research Hosts: Kelly Daus MD, Megan Lenihan MD, Peter White MD, and Brian Louie MD Referenced Material https://www.nejm.org/doi/full/10.1056/NEJMoa2032125 Kelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer. N Engl J Med. 2021;384(13):1191-1203. doi:10.1056/NEJMoa2032125 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136921/ Han Y, Liu D, Li L. PD-1/PD-L1 pathway: current researches in cancer. Am J Cancer Res. 2020 Mar 1;10(3):727-742. PMID: 32266087; PMCID: PMC7136921. Ad referenced in episode: A team at the Brooke Army Medical Center is working to better define proficiency-based metrics for competency in commonly performed robotic general surgery procedures. If you are a general surgery resident or practicing surgeon who performs robotic assisted cholecystectomies or inguinal hernia repairs, reach out to the PI, Robert Laverty, MD, at rblaverty@gmail.com for more information on how you could be compensated $500 per video submitted of each (up to $1000 per surgeon). Please visit https://behindtheknife.org to access other high-yield surgical education podcasts, videos and more. If you liked this episode, check out other thoracic surgery episodes here https://behindtheknife.org/podcast-category/cardiothoracic/
Dr. Mohamed Salem, Dr. Myriam Chalabi, and Dr. Andrea Cercek discuss pivotal neoadjuvant immunotherapy clinical trials for patients with MSI-H/dMMR colorectal cancer, focusing on the development of active therapies in the neoadjuvant setting—where patients are treated without surgery, radiation, or chemotherapy—and the importance of patient selection in finding the right target and treatment to improve outcomes. TRANSCRIPT Dr. Mohamed Salem: Hello, and welcome to the ASCO Daily News Podcast. I'm your guest host today, Dr. Mohamed Salem. I'm a GI oncologist at the Levine Cancer Institute at Atrium Health. Today, we will be discussing very promising advancements in the neoadjuvant immunotherapy for patients with MSI-H/dMMR colorectal cancer. And I'm very delighted to welcome two world-renowned oncologists whose research has tremendously helped shape the treatment landscape of colorectal cancer. Dr. Myriam Chalabi is a GI medical oncologist at the Netherlands Cancer Institute, and Dr. Andrea Cercek is a medical oncologist at Memorial Sloan Kettering in the United States. Our full disclosures are available in the transcript of this episode, and disclosures relating to all episodes of the podcast are available on our transcripts at asco.org/DNpod. Dr. Chalabi and Dr. Cercek, welcome to the ASCO Daily News Podcast. Dr. Myriam Chalabi: Thank you for having me. Dr. Andrea Cercek: Thank you very much for having me. Dr. Mohamed Salem: It's a pleasure to have two world-renowned stars like you. Thank you for taking the time. So, before we start going deep into the topic, obviously, now we are seeing emerging data in CRC using immunotherapy as the neoadjuvant approach, which actually can reduce or even eliminate some of the other treatment modalities and potentially save patients from toxicities. Both of you led what I think are landmark studies in this field. I wanted to give you the chance to tell our audience about your studies and why you think they're important. Dr. Cercek? Dr. Andrea Cercek: Sure. Thank you so much. So, our study was a neoadjuvant study in early-stage, locally advanced rectal cancer with tumors that were mismatch repair-deficient or MSI-H. And rectal cancer normally is treated with chemotherapy, chemoradiation, and surgery. And the goal of the trial was to utilize PD-1 blockade alone in this subpopulation and evaluate the response. Patients received six months of dostarlimab, which is a PD-1 blocking agent, and then were evaluated for response. If there was no residual disease, they were able to avoid radiation and surgery. And what we've seen thus far in the presentation at GI ASCO in 2022 was that all patients who received six months of dostarlimab had a clinical complete response, so no residual tumor, and were able to avoid chemotherapy, radiation, and surgery and are on observation. And the study is ongoing and actively accruing patients. Dr. Mohamed Salem: All of us were very excited seeing that presentation at ASCO. And when we came back to the clinic everyone was talking about it, including patients, obviously. Thank you for this, Dr. Cercek. Dr. Chalabi, you also led a similar study that was actually presented in ESMO in 2022. Can you please give us, like, a brief description of that trial? Dr. Myriam Chalabi: Yeah, sure. So, this is the NICHE trial, and actually the NICHE trial has been ongoing for quite some time now. We recently presented a larger NICHE-2 study, but basically– so what we started out by doing in NICHE is giving patients what we considered back then a window of opportunity study. We treated patients with MMR-deficient tumors, which I'll be focusing on for now, with two cycles of nivolumab and one single cycle of low-dose ipilimumab. And patients all undergo surgery within six weeks of registration within the study. And back in 2020, we published the first data of NICHE-1 showing 100% pathologic responses with 60% pathologic complete responses and decided that this should definitely be a treatment that we need to explore in a larger group of patients. And that's where NICHE-2 was born, which we presented at ESMO last year, where we treated over 100 patients with this neoadjuvant approach of two cycles nivolumab, one single cycle ipilimumab, showing 99% pathologic responses, including 95% major pathologic responses and 67% pathologic complete responses. And this was all within five and a half weeks of the first treatment with immunotherapy, so a very short treatment duration with dual checkpoint blockade. Dr. Mohamed Salem: Amazing results, too. And I know you had a standing ovation when you presented the outcome of the study. And again, congratulations to you, your investigator, and also all the patients participated. Dr. Myriam Chalabi: Thank you so much. Dr. Mohamed Salem: I guess the first question that comes to my mind - we have two trials, obviously, now we're moving from one size fits all to precision therapy, like getting actually the right treatment for the right patient. But in the NICHE study, it was a checkpoint inhibitor, and the rectal study was a single agent. I want to start with you, Dr. Chalabi. In your opinion, when should we use single agent or double blockade immunotherapy? Dr. Myriam Chalabi: That is a great question. I'm going to start off by saying that I don't know the exact answer. I don't think we know that answer. And Dr. Cercek is going to share also her thoughts on this because we're seeing, of course, fantastic responses with monotherapy as well in Dr. Cercek's study. And we've also seen that in a study by Dr. Overman with monotherapy. So that may suffice in some patients, although what we're seeing is that you need to treat patients longer, probably to achieve that response, at least clinically. And I think that is the difference with dual checkpoint blockade, that we're giving in NICHE where we're seeing these very deep responses in just under six weeks' time. So, I think it may be more of a question of how long we want to treat patients for to achieve the endpoint that we're aiming for. And, of course, there may be, at some point, patients that need dual checkpoint blockade, but so far, we're seeing great responses in both of our studies. So I think we need more patients, more data to see whether we're going to see non-responders. And hopefully, the studies that are ongoing in the metastatic disease setting will give us at least a little bit of insight into what the differences are in response to mono and dual checkpoint blockade and whether we can tell which patients might benefit more from the combination. But I think there's still a lot of work to be done in that field. Dr. Mohamed Salem: I totally agree. Dr. Cercek, same question to you. What do you think? Dr. Andrea Cercek: Dr. Chalabi answered beautifully and very comprehensively. I agree completely with what she said. It's hard to argue with the responses that we're seeing with PD-1 blockade alone. But then again, dual checkpoint inhibitors in the NICHE study with just one month of therapy had phenomenal responses as well. So I think it's a question of duration of therapy and, really importantly, what we're trying to achieve. If our goal is organ preservation, then perhaps longer duration is better. The question then becomes, can we do, should we do longer duration with dual checkpoint inhibitors versus single agent? So I think, as she concluded, I couldn't agree more that we just need more information, we need more work to do, basically to answer this question for our patients. Dr. Mohamed Salem: More to come and more studies, which is fascinating. So, Dr. Chalabi, you created actually a new term on Twitter called ‘Chalabi Plot'. It was amazing to see such a response. But we're curious, among those patients who achieved complete response so far, did you see any relapse? Dr. Myriam Chalabi: Short answer, no. we're waiting, of course on the disease-free survival data, the three-year DFS data for NICHE-2, and we hope to have that by the end of this year, beginning of next year. But as of now, we showed that data, and so far, we haven't seen any recurrences in, actually, any of the patients treated in NICHE-2. Dr. Mohamed Salem: Fantastic. Dr. Cercek. So I think your slide -- I remember clearly from the ASCO presentation -- was all complete response, every single patient. Same question, did you see any relapse so far? Dr. Andrea Cercek: So far, no, we have not. Dr. Mohamed Salem: Amazing. So, Dr. Cercek, as you know, and obviously, this is metastatic disease, but in KEYNOTE-177, as you know, about 30% of patients with MSI-high tumors did not respond to checkpoint inhibitors. So that makes some of us feel nervous about using checkpoint inhibitors alone in colorectal cancer, even with MSI-high status. I was curious if you can comment on this and if there is a way we can perhaps sort out who actually is likely to respond and who is likely not going to respond. Dr. Andrea Cercek: I think that's a really important question and an excellent point. And we believe that the difference lies in the fact that in KEYNOTE-177, the patients had metastatic disease, whereas in our neoadjuvant studies that we're discussing, they have early-stage disease. And whether that has to do with the tumor differences, young tumors versus older tumors once they become metastatic, or the microenvironment, remains to be determined. But certainly, there is this pattern of incredible responses with checkpoint inhibitors in early-stage dMMR tumors. And in KEYNOTE-177, as you mentioned, about 30% of patients progressed. And I think we don't know why that is. We are seeing this, about a third of progressors repeatedly in the metastatic setting with checkpoint inhibitors. And so perhaps there is a population. But whether this is driven by genomics or something else, we don't know. Dr. Mohamed Salem: Great. So, along the same lines, especially rectal cancer, obviously, because surgical resection is a key component in the treatment paradigm, do you feel patients who achieve pathological complete response should still go under surgical resection or should go under the ‘watch and wait' approach? Dr. Andrea Cercek: In general, I'm a fan of organ preservation. I think in rectal cancer, the reasons are obvious. It's a challenging surgery. It's very toxic to the patients. It changes their lives forever. In survivorship, 30% of them require a permanent colostomy because of the location of the tumor. So there, the field of rectal cancer, in general, is moving towards non-operative management, even in the MSI-proficient patients, by trying to optimize therapy to increase clinical complete responses and therefore omit surgery. So that's the difference with rectal cancer. In colon cancer, it's a different discussion. I think for many patients, surgery is very straightforward. It's a hemicolectomy. It doesn't alter lifestyle in survivorship, so it's not as morbid as it is in rectal cancer. Of course, I think if a patient is older with MSI-deficient tumor perhaps can undergo surgery, then clinical complete responses become critical because then we can monitor them after just checkpoint blockade, and they don't need surgery. The challenge there, and I would love to hear Dr. Chalabi's comments on this, too, is just that imaging is challenging. We have a hard time in colon cancer determining whether someone has a clinical complete response or not. It seems to be very different than in rectal cancer, where with endoscopy and with the rectal MRI, we really can't tell whether the tumor is still present or not. This remains a challenge in colon cancer. Dr. Mohamed Salem: Dr. Chalabi, I would like to hear your thoughts and also how you practice in Europe. I don't know if it's the same like here in US or different. Dr. Myriam Chalabi: I completely agree with Dr. Cercek. Well, if we look at the rectal cancer patients, I think this is fantastic. That even though this is a small population achieving this high clinical complete response rate, not having to operate or even give any chemotherapy or radiation therapy to these patients, it is extremely important both in the short term but also in terms of long-term complications and morbidity. When it comes to the colon cancer responses that we're seeing in NICHE, those are all pathologic responses, of course. And we have been evaluating also preoperatively using scans to see whether we can assess these complete responses based on imaging. That doesn't seem to be the case. We do see responses in all patients, so we see these are all very large bulky tumors that we're treating in NICHE-2. And we do see responses in almost all of these patients, but it's not close to complete responses, definitely not in all of the complete responders that we're seeing. So that makes it difficult. And the question is, what if we would be waiting or treating longer because these bulky tumors need more time to disappear or to be cleared before you're going to see it on the imaging? So that is a question that I don't have an answer to just yet. We may be getting some more data on that with the currently ongoing trials. And as Dr. Cercek pointed out, the endoscopies when you have a right-sided colon tumor are different than doing just a sigmoidoscopy for a rectal tumor. So, we actually do have one patient who hasn't undergone surgery, and that is actually a patient with an MMR-proficient tumor within the NICHE trial who had a complete response. And that patient has a sigmoidal tumor, and he actually had toxicities which prevented him from undergoing timely surgery and now has a complete response after two years, both endoscopically and on imaging. So, he hasn't undergone surgery, and that is a great example of how we may be doing this in the future. It's an interesting case within the trial to follow and see how we can do it in the future. Dr. Mohamed Salem: That's fascinating news. So, was it MMR-proficient? Dr. Myriam Chalabi: Yes, this is an MMR-proficient tumor. Dr. Mohamed Salem Wow. Any particular biomarkers that you think he or she had to predict that? Dr. Myriam Chalabi: We have treated more patients with MMR-proficient tumors. We have 31 patients, and we have seen actually responses in 9 out of 31 patients in the MMR-proficient tumors with the same combination of two doses of nivolumab and one of ipilimumab. We previously published on half of the cohort approximately on what the possible predictive biomarkers of response could be, and that was a costimulation for CD8 and PD-1. So PD-1 positive CD8 T cells. And we're currently doing the same work for the rest of the cohort. So hopefully, we'll be able to show that soon and see whether this still stands for the completed MMR-proficient cohort. But definitely also very exciting data for the MMR-proficient. Dr. Mohamed Salem: So, this is actually a very good segue to my next question because I know all of us are looking for this. Like, obviously, we're seeing a fascinating response in those patients with MSI-high tumors, but majority of colorectal cancer, as you know, they actually have MSS-proficient tumors. Any thoughts about how we can overcome the primary resistance for this tumor to checkpoint inhibitors? So let me start with you, Dr. Cercek. Dr. Andrea Cercek: I'm very much looking forward to Dr. Chalabi's data on this because, honestly, we have not seen such amazing responses to immunotherapy in MSS tumors. The initial studies were complete flatline, no responses at all. And here, she just described a patient that had a complete response to just a month of checkpoint inhibitors. So that's phenomenal, and hopefully, we'll learn from the responders. We believe that there is a subpopulation of MSS colorectal cancer that is more immune sensitive, immune hot, whichever term you like to use. And it's just a matter of appropriately identifying those patients. And personally, I think the answer lies in the neoadjuvant setting in early tumors where they're treatment-naive, not exposed to chemo, not exposed to radiation, younger, have their innate microenvironment. And so, I think it's likely a combination of the above. But obviously, the ultimate goal is to find out who those patients are and then potentially treat them just like this with immunotherapy. And that would be another nice chunk of the pie where we could utilize immunotherapy for our patients. Dr. Mohamed Salem: Very true. Dr. Chalabi, especially with your experience and just showing there is a chance for those people to respond, what are your thoughts about how we can overcome this primary resistance? Dr. Myriam Chalabi: It's great to be here with Dr. Cercek because, obviously, we have very similar interests but it's also good to see that we think the same way because I completely agree with what she just said in terms of neoadjuvant. I think that was one of the most important things that we did here, giving this neoadjuvant treatment in non-metastatic tumors. It's probably a very important driver in the responses that we're seeing. So, we've been seeing data now a bit more in the metastatic disease setting where MSS tumors seem to be responding to new generations of checkpoint blockade. And the question is how those would do in the neoadjuvant setting that would be even different than what we're seeing now. But there's definitely some proof of MSS tumors that can respond to immunotherapy. The question on how to overcome the primary resistance, I think that question is for us: Who are the patients with primary resistant tumors and why are they primarily resistant? And then we can think about how to change that and how to change them into the tumors that are responding. I think these types of data will be key to understand more and know; hopefully, even you said, in the metastatic disease setting, to make these tumors more pliable in response to immunotherapy. Dr. Mohamed Salem: I agree. So, both of you are leading us toward how to choose the right patient with the right target for the right treatment. That's an amazing journey you're taking all of us on. So, Dr. Cercek, I have to admit that with your data, it created some problems for us in the clinic because all patients the following day came in asking for immunotherapy. We had a hard time trying to explain that maybe this is not the right treatment for them or, like, not the right platform. But I wanted to ask you, if we'll have a patient tomorrow in the clinic with localized rectal cancer and happen to have an MSI-high tumor, what would be your recommendation in terms of how to approach that patient? Dr. Andrea Cercek: I think, ideally, you would discuss clinical trials with the patient. We have opened the study now to not just rectal cancer but colon cancer and, in fact, all solid tumors that are mismatch repair-deficient. So I think at this time, the patients really should be treated on a clinical trial. As we learn more, in particular, until we are more comfortable assessing for a clinical complete response and follow-up. I think the surveillance piece will be critically important. In rectal cancer, it's well established, but it's not in the other tumor types. So my recommendation would be to enroll the patient on a trial. Dr. Mohamed Salem: Just to add to that too, obviously, as you know, there is now the cooperative group trial that's looking at that option and we obviously encourage all centers to participate and open that study to have this option for our patients. Dr. Chalabi, so what do you guys do in Europe for these patients? Dr. Myriam Chalabi: In Europe, it's a very different situation. I would have answered this question differently by saying, well, we don't have that option of treating patients outside of clinical trials. So basically, we have to make sure that we have clinical trials for these patients. And that's something that we've had for colon cancer patients. That is still the case. And we're getting rectal cancer trials also for patients with MMR deficient tumors and have those also for MMR proficient tumors. For us and I agree completely that we should be treating patients within clinical trials, we don't have another option. But still, even if we did, I think it's important to create data within clinical trials to be able to ultimately also show why this should be standard of care and how we can make it standard of care. Because if you're not accumulating that data, then it's going to become very difficult if accrual is lacking. Now, we treat patients either with standard-of-care treatments, but usually, we try to find something within clinical trials. Dr. Mohamed Salem: I totally agree. And as we always say, the standard of care should be a clinical trial participation. So, I must say, both of you, Dr. Cercek and Dr. Chalabi, you made 2022 a very exciting year for us in GI cancers. You really changed the way we look at how to treat these patients and give them a huge chance of, I would say, actually cure and obviously organ preservation. So, I'm very curious to know what you are both are working on now and what we should expect in 2023 and 2024. Dr. Andrea Cercek: So, for me, the study is ongoing, as I mentioned, and we've expanded to all mismatch repair-deficient solid tumors with the same approach of six months of dostarlimab and then the option of nonoperative management. And I think that it'll be important for us to learn in terms of responses on the luminal versus some of the other tumor types, like, for example, pancreas cancer, where we don't see these robust responses in the metastatic setting, that will be important to do. We're doing some correlative analysis, as Dr. Chalabi described as well in our patients. And then, I'm interested in optimizing neoadjuvant approaches to minimize therapy in rectal cancer specifically. So, we have a study now for HER-2 amplified RAS wild-type patients with locally advanced rectal cancer with a similar approach of utilizing HER-2 targeted therapy first and then in combination with chemotherapy. In our case, it's a combination of trastuzumab and tucatinib and then chemotherapy with CAPOX and assessing for response and potential omission of radiation and surgery depending on responders. So, I'm very excited that study is open and actively accruing, and hopefully, we can get similar responses that we did in the MSI population with PD-1 blockade. Dr. Mohamed Salem: Is that only available at MSK? Dr. Andrea Cercek: It is at this time. However, we will likely be expanding, so if there's any interest, let me know. Dr. Mohamed Salem: Great. I'm sure many centers will be. Great. What about you, Dr. Chalabi? Any sneak peek in the future? Dr. Myriam Chalabi: So many sneak peeks, where to begin? I think it's very exciting to be working in this space at this time, and we're very lucky to be in it. So, for NICHE, we're actually accruing now in new cohorts for both MMR-deficient and MMR-proficient tumors. For the patients with MMR-deficient tumors, we're actually testing a new combination of nivolumab plus relatlimab, so anti-LAG-3 plus anti-PD1. And we're testing the same co-formulation in patients with pMMR tumors. In addition to another cohort for the pMMR tumors with nivolumab, all within this window of opportunity, as we did previously in NICHE, and to see if we're going to see more responses if these are going to be different tumors than the ones responding to nivolumab and ipilimumab. And for the MMR deficient tumors, we're treating longer with this combination now. So, we're operating after eight weeks instead of six weeks. We're giving two cycles, four weekly cycles, to see whether we can even improve the PCR rates, even though this is, of course, a different combination treatment. So, very exciting times for NICHE, and we'll have the readout for the DFS at the end of this year, so that's also very exciting. And then, well, it's similar to Dr. Cercek. So again, we're on the same page when it comes to these neoadjuvant treatments. We have actually an ongoing trial for neoadjuvant treatment of patients with MMR proficient rectal cancers, and that is using a combination of radiation therapy followed by a combination of atezolizumab or anti-PDL1 with Bevacizumab with the aim of organ sparing approach in these patients. And we actually presented stage 1 of this trial as a poster at ASCO GI, showing that we achieved 56% complete or near complete responses clinically at 12 weeks. And after at least a year of follow-up for all patients, we have 50% organ preservation. So those are very exciting data as well. Also, in the MMR proficient tumors, I'm very excited to hear about the HER-2-positive tumors and Dr. Cercek's study. So there's definitely a lot going on that we hope to share as soon as the data are available. Dr. Mohamed Salem: We'll be looking forward to your next presentation and seeing that. So again, most of your work showed us that we really have to choose the right patient with the right target for the right treatment to achieve the best possible outcome. So we're getting short on time here. But before we conclude, ASCO Daily News Podcast has a huge audience of oncologists, I wanted to give you the chance to share anything you'd like to share with our audience today before we finish. Dr. Cercek? Dr. Andrea Cercek: I believe this is an incredibly exciting time in colorectal cancer. I think it's finally our turn, which feels really nice, and obviously, we have a lot more work that needs to be done. But my personal belief is to keep trying to chip away at the pie and identify responders and keep working to have better-targeted drugs and better treatment options that will improve responses and improve outcomes for our patients. But I certainly believe that we are well on our way there, and it's very exciting. Dr. Mohamed Salem: I totally agree. Dr. Chalabi, any thoughts? Dr. Myriam Chalabi: I think after 2022 and the data that we've been showing, I think it's important to– and I think by now, maybe it's not even necessary anymore to say it– but I think it's important to really look at the tumors and look at these MMR proteins or MSI, and to make sure that you're treating the patient in the right way, and to consider that. Before, it wasn't as important in the neoadjuvant setting or these localized tumors, but now it's becoming essential. And I think if you would have looked five years ago and you would say, yeah, these MSI tumors are important to find, it's a very small proportion of patients, in rectal cancer even lower than in colon cancer. But still, it has such a huge impact on what you're doing in these patients and your chances of cure. So I think that would be my most important giveaway to test for MMR deficiency before deciding on a treatment for your patients. And we're working on trials with neoadjuvant immunotherapy. Also in other tumor types, Dr. Cercek is also doing the same. I think those will be very important also outside of the GI field to see whether this approach works for a much larger patient population, despite the low incidence. Dr. Andrea Cercek: Dr. Chalabi just made a critical point that that is most important is to remember that we do have biomarkers in colorectal cancer that, in the neoadjuvant setting and in the metastatic setting, especially MSI, that we need to test for. And then, just to add from a clinical perspective, in rectal cancer, the large majority of patients that have mismatch-repair deficient or MSI tumors actually have Lynch syndrome. So really, if you identify a patient that's mismatch-repair deficient or MSI-high anywhere, but especially in the rectum, they absolutely should get germline testing. Dr. Mohamed Salem: I echo that and second that. And Dr. Cercek, thank you, and I know you did a lot of work in colorectal cancer in the younger adult population, too, so I think you've had a huge impact on that area too. I would like to thank both of you again for being here today, but more for the great work you and your teams are doing to advance the field. It's really a very exciting time in GI cancers now, and thank you so much for your work and for sharing your insights with us today on the ASCO Daily News Podcast. Dr. Myriam Chalabi: Thank you so much for having me. It's been great. Dr. Andrea Cercek: Thank you for having me. Dr. Mohamed Salem: Of course, and thanks to our listeners for your time today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Thank you very much. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers: Dr. Mohamed Salem @SalemGIOncDoc Dr. Myriam Chalabi @MyriamChalabi Dr. Andrea Cercek @AndreaCercek Learn about other key advances in GI Oncology: SWOG 1815, PARADIGM, and Other Advances at GI23 Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Mohamed Salem: Consulting or Advisory Role: Taiho Pharmaceutical, Exelixis, Bristol-Myers Squibb, Exelixis, QED Therapeutics, Novartis, Pfizer, Daiichi Sankyo/Astra Zeneca Speakers' Bureau: Genentech/Roche, Taiho Pharmaceutical, Daiichi Sankyo/Astra Zeneca, BMS, Merck Dr. Myriam Chalabi: Consulting or Advisory Role: MSD, Bristol-Myers Squibb/Celegne, Numab Research Funding (Institution): Bristol-Myers Squibb, Roche/Genentech, MSD Travel, Accommodations, Expenses: Roche/Genentech, Bristol-Myers Squibb Dr. Andrea Cercek: Consulting or Advisory Role: Bayer, GSK, Incyte, Merck, Janssen, Seattle Genetics, G1 Therapeutics Research Funding (Institution): Seattle Genetics, GSK, Rgenix
COR2ED Medical Education: In this HCC CONNECT podcast HCC Experts Prof. Matthias Pinter and Prof. Jeroen Dekervel, discuss and debate the clinical implications of new HCC Phase 3 clinical trials data presented and discussed at the ILCA and ESMO congresses. They discuss Immuno-oncology agents and their place in the upcoming updated guidance such as the proposed new ILCA Systemic Therapies Guidance algorithm. They also discuss new treatment options in first line for advanced HCC presented at ESMO including the three late breaking abstracts LEAP-002, RATIONALE-301 and tislelizumab monotherapy trials. The latter two studying first-line treatment with an anti-PD1 antibody with or without a kinase inhibitor in patients with advanced hepatocellular carcinoma. The experts evaluate and provide their insights into how to integrate these new treatments for HCC in the clinical practice.
药，事关每一个普通人的生老病死，而新药研发向来高投入、高风险。行业里曾经有一条著名的“双十”定律，即一款创新药的研发往往需要耗费十年时间、花费十亿美元，实际上一款新药从发现源头靶点到病患真正用上成药，整体投入远不止如此，而且每个环节都有相当高的失败概率。2015年中国药审改革以来，国内创新药行业艰难从零起步，在社会责任的驱动下和资本市场的助力下，一大批本土创新药企和创新产品不断涌现，逐渐形成从“中国新”到“全球新”的研发格局。因此本期节目，我们邀请《八点健闻》主编季敏华做客《泰度Voice》，她将作为本期特邀主持与来自正大天晴的生物医药博士陈辉、以及华泰投行的业务同事展开一场对谈，从药企和市场视角，谈谈创新药的研发有多难，有多少关需要闯，以及资本如何给行业助力。陈辉博士曾经有中科院的科研经历，目前他在医药行业从事人力资源工作。与他聊天的两位嘉宾肖家嵩与刘坤酿，在青春职场观察类真人秀节目《闪闪发光的你》投行季节目中，分别担任实习指导与实习生。因此在今天的节目中，你也将听到这三位选择医药行业的契机和决定深耕“创新药”的初心，希望给相关专业毕业生、求职者一些职业道路选择上的启发。 聊天的人 季敏华 《八点健闻》联合创始人、主编 陈辉 正大天晴董事长助理、人力资源副总裁 肖家嵩 华泰联合投行业务线大健康行业部副总监、《闪闪发光的你》投行季实习指导 刘坤酿 《闪闪发光的你》投行季 实习生 时间轴 05:00 创新药从发现靶点到最终上市“九死一生” 12:30 近两年创新药企业上市窗口逐渐提前 17:40 PD1靶向药对于行业发展也是一剂“良药” 22:00 医药行业的融资近期稍稍有些“降温” 24:45 科创板第五套和港股18A的不同 31:25 Biotech和Big Pharma是合作而非竞对关系 35:10 国内市场正在“倒逼”创新药企加速出海 36:20 医保谈判和集采让普通人用得上、用得起好药 42:25 “如果再选一次，我可能会放弃金融选择生物医药” 泰度小课堂 NMPA：即国家食品药品监督管理总局。2018年，国家药品监督管理局组建成立，不再保留国家食品药品监督管理总局，英文简称也从CFDA改为NMPA。 FDA：即Food and Drug Administration，美国食品药品管理局Big Pharma：即Big Pharmaceutical，指大型医药巨头企业。 Biotech：即Biotechnology，常指创新性医药科技公司。 靶点：指能够与特定药物特异结合，并产生良好治疗效果的分子。也就是药物在体内结合的位点，包括基因位点、受体、酶、离子通道和核酸等生物大分子。 港股18A政策：2018年4月，香港联交所修订主板上市规则，新增第18A章《生物科技公司》，允许未有收入、未有利润的生物科技公司提交上市申请。 科创板的第五套标准：2020年，上交所发布《上海证券交易所科创板股票发行上市审核规则》修订版本，提供了五套上市标准。其中，第五套标准规定：预计市值不低于人民币 40 亿元，主要业务或产品需经国家有关部门批准，市场空间大，目前已取得阶段性成果。医药行业企业需至少有一项核心产品获准开展二期临床试验，其他符合科创板定位的企业需具备明显的技术优势并满足相应条件。 IND：即Investigational New Drug，药物在进入临床试验前需要获得的审批资格。 NDA：即New Drug Application，意为新药上市审批。 K药和O药：K药即药厂默沙东（Merck & Co）出品的Keytruda；O药即药厂施贵宝（Squibb）出品的Opdivo；K药和O药是两种非常主流的肿瘤免疫药物，使用PD-1免疫疗法，在治疗癌症方面成效明显。 PD-1/PD-L1：PD-1即Programmed Death-1的缩写，意为“程序化死亡分子1”，而PD-L1即Programmed Cell Death-Ligand 1的缩写，意为“细胞程序化死亡-配体1”。PD-L1蛋白是PD-1蛋白的配体。PD-1与PD-L1一旦结合，会严重影响人体免疫系统对于肿瘤细胞的防御。所以PD-1/PD-L1疗法就是通过阻止PD-1/PD-L1的结合，来保障免疫系统对于肿瘤细胞的抵抗力。 TIGIT/LAG-3：TIGIT是一种抑制性受体，而LAG3是一种免疫检查点受体蛋白，他们都是在PD-1/PD-L1之后发现的新免疫靶点，可以和PD-1/PD-L1治疗手段互为补充。 修美乐：即Humira，是生物药”阿达木单抗”的商品名，主要适应症包括类风湿关节炎、强直性脊柱炎、银屑病等自身免疫疾病。修美乐是有史以来最赚钱的药物之一，有“药王”的绰号。 VBP：即Volume-Based Procurement，意为带量采购，是国家医保局主导的一种药品集中采购方式，针对的是覆盖面广、采购量大、临床成熟的药品。 Organon：即荷兰跨国药企欧加农国际，是最早研发出K药Keytruda的公司，后被几次收购后并入药厂默沙东（Merck & Co）。 院外市场：即处方药的院外市场，是一个覆盖了零售药店、医药电商/互联网医院、基层市场、和商业保险市场的笼统概念。 CXO：即包含CRO、CMO、CDMO等各类型研发机构的简写总称，意为“医药行业的研发外包公司”。 DTP药房：即Direct to Patient，也被称为高值新特药直送平台，直接面向患者提供专业服务的药房。 制作团队 主编：原瑞阳 项目统筹：韦晔 运营支持：刘坤酿、郑家乐（实习） 制作：高海博 声音设计：马若晨、陆佳杰 节目运营：小米粒 本节目录制于2022年7月26日，本播客不保证节目播出时援引数据信息的及时、准确、完整。 法律声明 本播客不是华泰证券股份有限公司研究报告（下称”华泰证券”）的发布平台，旨在为公众提供宏观、产业、市场热点解读，不构成华泰证券开展证券投资咨询业务或提供任何的投资建议、投资分析意见。本播客不构成任何合同或承诺的基础，不因任何单纯订阅本播客的行为而将订阅人视为华泰证券客户。任何读者在订阅本播客前，请自行评估接收相关推送内容的适当性，且若使用本播客所载内容，务必寻求专业投资顾问的指导及解读。 本播客内容可能涉及华泰证券分析师对华泰证券已发布研究报告的解读，或转发、摘编华泰证券已发布研究报告的部分内容及观点，完整的分析应以报告发布当日的完整研究报告内容为准。订阅者仅使用本播客内容，可能会因缺乏对完整报告的了解或缺乏相关的解读而产生理解上的歧义。如需了解完整内容，请具体参见华泰证券所发布的完整报告。 就本播客内容涉及的嘉宾言论，华泰证券已事先提醒嘉宾其言论及信息来源应合法合规，不得泄露内幕信息、上市公司重大未公开信息或其他敏感信息，不得侵犯第三方任何合法权益。本播客内容中的嘉宾言论仅代表嘉宾个人意见，不代表华泰证券立场，也不构成对读者的投资建议。 华泰证券对本播客节目文字、音频、图片、链接等形式所载信息的准确性、可靠性、时效性及完整性不作任何明示或暗示的保证。播客内容所述意见、观点和预测仅作为音频录制日的观点和判断。该等意见、评估及预测无需通知即可随时更改。 在任何情况下，本播客文字、音频、图片、链接等形式所载信息均不构成对任何人的投资建议。订阅者不应单独依靠本播客内容而取代自身独立的判断，应自主做出投资决策并自行承担投资风险。对依据或者使用本播客内容所造成的任何后果，华泰证券及节目嘉宾均不承担任何形式的责任。 本播客所有内容的版权均为华泰证券所有。未经华泰证券书面许可，任何机构和个人不得以任何形式转发、转载或部分转载、发表或引用本播客任何内容。 本节目由华泰证券出品，JustPod制作，小宇宙、喜马拉雅、苹果播客同步上线
An interview with Dr. Lynn Henry from the University of Michigan in Ann Arbor, MI, lead author on "Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline Update." Dr. Henry reviews new biomarkers for the purposes of making treatment decisions for triple-negative breast cancer, and hormone receptor-positive, HER2-negative breast cancer, as well as tumor agnostic tumor biomarkers. Specific biomarkers addressed in this conversation include PIK3CA, ESR1, BRCA 1/2, PALB2, HRD, PD-L1, dMMR/MSI-H, TMB, NTRK, ctDNA, and CTCs. Read the full guideline at www.asco.org/breast-cancer-guidelines. TRANSCRIPT Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs, covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Lynn Henry from the University of Michigan in Ann Arbor, Michigan, lead author on 'Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline Update'. Thank you for being here, Dr. Henry. Dr. Lynn Henry: Thank you very much for inviting me to participate. Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Henry, do you have any relevant disclosures that are related to this guideline topic? Dr. Lynn Henry: No, I do not. Brittany Harvey: Great! Thank you. Then let's talk about the scope of this guideline. So, what prompted this update to the guideline on the use of biomarkers to guide decisions on systemic therapy for patients with metastatic breast cancer, which was last updated in 2015? And what is the scope of this guideline update? Dr. Lynn Henry: Yes, so a lot has happened in the past six or seven years that influence how we treat metastatic breast cancer. And there are many new drugs that have been approved by the FDA during that time. When we reviewed the prior guideline and the new treatment landscape, we realized that while much of what was included in the old guideline was still relevant, there were quite a number of new biomarkers related to new drugs that needed to be included. The newly recommended biomarkers are primarily applicable to making decisions about treatment of estrogen receptor, progesterone receptor, and HER2-negative breast cancer, also called triple-negative breast cancer, as well as for treatment of hormone receptor-positive HER2-negative breast cancer. And finally, there are now some tumor biomarkers that can be tested for that are tumor agnostic, and these were included as well. Brittany Harvey: Great! So, then let's discuss the updated guideline recommendations based off these new biomarkers for our listeners. The guideline reviews testing for several different biomarkers. So, I would like to review each of the biomarkers that the panel assessed. Let's start with what is the role of PIK3CA mutation testing? Dr. Lynn Henry: Yeah! So, PIK3CA activating mutations are commonly found in tumors that are hormone receptor-positive and HER2-negative. Based on the results of the SOLAR-1 trial, patients whose tumors have an activating PIK3CA mutation had improved progression-free survival when treated with the PI3 kinase inhibitor alpelisib plus fulvestrant compared to fulvestrant alone. This improvement was not seen in patients whose cancers didn't have a mutation. So, therefore, this provided the evidence for the clinical utility of evaluating tumors for the somatic PIK3CA mutations. Testing of either a tumor specimen or plasma to look for PIK3CA mutations can be performed. However, it's important that if the plasma is tested, and no PIK3CA mutations are identified in the circulating tumor DNA, then our tumor specimen should really be tested if possible, because of the possibility of a false negative finding in the plasma. Also, since these mutations can be acquired over time, a more recent specimen should be tested if possible, as opposed to testing the primary tumor. Finally, in the SOLAR-1 trial, a patient's tumor had to have one of the 11 pre-specified PIK3CA mutations in exon 7, 9, or 20. And therefore, when mutations are identified using next-generation sequencing, it is important to confirm that the identified mutation is one of those 11 activating mutations and not a different one that may not convey benefit from treatment with a PI3 kinase inhibitor. Brittany Harvey: Great! I appreciate you're reviewing that recommendation, as well as the clinical utility of it and the evidence behind it. So, then following those recommendations, what is the role of testing for ESR1 mutations? Dr. Lynn Henry: At this time, there are insufficient data to support routine testing of metastatic hormone receptor-positive HER2-negative tumors for ESR1 mutations. However, the panel did note that there's a retrospective analysis of two different phases three trials that demonstrated that fulvestrant improved progression-free survival compared to the aromatase inhibitor exemestane in patients who had previously progressed on a non-steroidal AI and whose tumors had an ESR1 mutation. Importantly, there are ongoing clinical trials addressing this issue, including the PADA-1 trial, which is evaluating the effect of the switch of fulvestrant from aromatase inhibitor therapy, versus remaining on that therapy when ESR1 mutations are detected in the blood. However, although preliminary findings were presented at a recent large breast cancer meeting, and were suggestive of a possible progression-free survival benefit from switching therapy, data have not yet been published, and therefore they were not included in this guideline. Brittany Harvey: Great! So, we'll look forward to those updated data to potentially review that recommendation in the future. So, following those recommendations, what is the role of testing for germline BRCA 1 or 2 and PALB2 pathogenic mutations? Dr. Lynn Henry: So, the answer for germline BRCA1 and BRCA2 mutations is relatively straightforward. Patients with metastatic HER2-negative breast cancer can be either hormone receptor-positive or negative, and who are candidates for treatment with a PARP inhibitor should undergo testing for germline BRCA1 and BRCA2 pathogenic or likely pathogenic mutations to determine whether they should receive treatment with a PARP inhibitor. This recommendation is based on the results of two large randomized clinical trials comparing PARP inhibitor therapy to physician's choice chemotherapy, although notably, the chemotherapy options did not include taxanes, anthracyclines, or platinums. In contrast, there remains insufficient evidence to support a recommendation either for or against testing for germline PALB2 pathogenic variant for the purpose of determining eligibility for treatment with a PARP inhibitor. The panel did note, however, that there are small single-arm studies that show that there is high response rate to PARP inhibitors in patients with metastatic breast cancer and coding DNA repair defects, such as either germline PALB2 pathogenic variants or somatic BRCA1 or 2 mutations. It was also noted that it is likely that patients who harbored mutations in these genes will actually be identified through routine testing with panel testing for germline variants. Brittany Harvey: Okay, understood. So, then following those recommendations, what is the role of testing tumors for homologous recombination deficiency? Dr. Lynn Henry: So, although there are emerging data from other solid tumors to support the use of homologous recombination deficiency, or HRD testing to guide therapy, current data do not support the assessment of HRD in the management of metastatic breast cancer. Therefore, we did not recommend routine testing of tumors for HRD at this time. Brittany Harvey: It's important to note where we both have evidence and where we don't have evidence. So, then what is the role of testing for expression of PD-L1 in metastatic breast cancer? Dr. Lynn Henry: So, the panel recommends that patients who are candidates for treatment with immunotherapy, with either a PD1 or PD-L1 inhibitor, should undergo testing for expression of PD-L1 in the tumor and immune cells with an FDA-approved test. At present in the United States, pembrolizumab is the only approved immunotherapy for the treatment of metastatic breast cancer, and it is given in combination with chemotherapy. The FDA-approved test for this drug is the 22C3 assay which evaluates PD-L1 staining in the tumor and surrounding stroma to calculate a combined positive score or CPS, with positive considered to be a score of 10 or greater. Of note, in other countries, there are different anti PD1 and PD-L1 antibodies that are approved for treatment, and each has been approved with its own companion diagnostic. So, it is important to make sure that you're using the right biomarker test, depending on which drug you are planning to use. Brittany Harvey: Great! I appreciate you reviewing the test in addition to the role of the biomarker. So, then, following those recommendations, what is the role of testing for deficient mismatch repair microsatellite instability-high? Dr. Lynn Henry: Similar to PD-L1 testing, it is recommended that patients with metastatic breast cancer who are candidates for a treatment regimen that includes an immune checkpoint inhibitor should undergo testing for deficient mismatch repair or microsatellite instability-high to determine eligibility for treatment with one of the drugs that is currently FDA approved, either dostarlimab or pembrolizumab. In contrast to the PD-L1 data, however, there are no randomized studies that have been conducted specifically in patients with breast cancer addressing this question. The testing recommendation was therefore included in these guidelines because of the tumor agnostic FDA approval of these drugs. In terms of which biomarker methodology to use, it was noted that, while the original studies assessed the deficient mismatch repair and MSI high using immunochemistry, and PCR respectively. The FDA has subsequently approved the next-generation sequencing platform to use in selecting candidates for these treatments. And so, therefore, there are a number of different tests that can be used. Brittany Harvey: Thank you for reviewing those recommendations as well. So, then following, what is the role of testing for tumor mutational burden? Dr. Henry Lynn: So, tumor mutational burden describes the quantity of somatic mutations in the tumor. Similar to the biomarkers we were previously discussing, there are minimal data specifically in metastatic breast cancer to support the assessment of tumor mutational burden for making treatment decisions. However, the testing recommendation was again included in the guidelines because of the tumor agnostic FDA approval of the drug pembrolizumab in the setting of high TMB. And also there is one single arm phase two trial that looked at this specifically. Importantly, the panel noted that there are a variety of factors that influence assessment of TMB. These include sample type, pre-analytical factors so how the sample was handled, the size of the panel and mutations that are tested, depths of the sequencing, type of the mutations that are included on the panel, and cut point variables. So, in particular, assessment of TMB in cell-free DNA assays such as circulating tumor DNA is an area of evolving evidence. There are therefore very important caveats to be aware of when selecting a TMB assay and assessing the results, many of which are outlined in the guideline manuscript itself, and different assays can yield different results for the same tissue specimen. It is therefore very important to use the approved companion assay and the approved cut point when making decisions regarding a specific treatment. Brittany Harvey: Absolutely. I appreciate your reviewing those details. So, then what is the role of testing for neurotrophic tyrosine receptor kinase? Dr. Lynn Henry: So, I'm going to abbreviate that to NTRK. So, NTRK fusions are rare in metastatic breast cancer. One study said 0.39% of all breast cancers have NTRK fusions. So, as with the above biomarkers, the NTRK testing recommendation is based on the results of phase 1 and phase 2 studies that were identified by the panel evaluating the efficacy and safety of these inhibitors for the treatment of advanced solid tumors with NTRK gene fusions, noting that there are only minimal data available that are specific to metastatic breast cancer. Brittany Harvey: Understood. Some of these are very rare in metastatic breast cancer. So, then, following that recommendation, what is the role of using circulating tumor DNA? Dr. Lynn Henry: So, for circulating tumor DNA, although the ctDNA technology holds promise in metastatic disease, for its ability to potentially identify tumor-specific mutations that are shed into the blood and that may be targetable, to date, neither the measurement of changes in ctDNA as a marker of treatment responsiveness nor identification of specific mutations in the blood to direct therapy has actually been prospectively shown to improve patient outcomes compared to standard imaging-based detection of tumor progression. Therefore, at present, the guideline does not recommend routine assessment of ctDNA for monitoring response to therapy among patients with metastatic breast cancer, although many studies are underway evaluating this question. Brittany Harvey: Understood. Then the last biomarker that the panel assessed in this guideline update, what is the role of using circulating tumor cells? Dr. Lynn Henry: Similar to circulating tumor DNA, there are insufficient data to recommend routine use of circulating tumor cells to monitor response to therapy among patients with metastatic breast cancer. To date, studies that have examined the clinical utility of this marker to determine the optimal time for treatment change have not led to improvements in outcomes in metastatic breast cancer. Brittany Harvey: Great! Well, thank you for reviewing all of these recommendations. The panel certainly took on a lot of biomarkers and performed a critical review of all the evidence to make recommendations in this setting. So, in your view, Dr. Henry, what is the importance of this guideline update and what should clinicians know as they implement these updated recommendations? Dr. Lynn Henry: Yeah, that's an excellent question. So, this guideline addresses the key questions that we face, as we're making decisions about how best to treat patients with metastatic breast cancer. Importantly, the guideline highlights the current state of the science, with a focus on the available published data from randomized clinical trials. It also discusses the limitations of our current knowledge, as well as key considerations for different biomarkers. Of course, we recognize that there are new data emerging on a regular basis. And the panel therefore also highlighted where data are anticipated but not yet available, as well as key questions which we hope will be able to be addressed in the more distant future. Brittany Harvey: And then finally, how will these guideline recommendations affect patients with metastatic breast cancer? Dr. Lynn Henry: Yeah, so really, that is the bottom line, isn't it? So, ideally, this guideline will enable the dissemination of best practices in terms of biomarker selection and analysis to guide clinicians as they are making treatment decisions in conjunction with patients. Treatment of metastatic breast cancer has become more complex, with regimen selection affected by both inherited germline genetics and somatic changes in the cancer that can evolve over time. The assessment of relevant biomarkers should allow patients to receive the optimal therapies that are most likely to be effective based on the individual characteristics of their cancers. Brittany Harvey: Well, I want to thank you so much for reviewing this guideline with me today, and all of the recommendations and our gaps in evidence, for our listeners. Thank you for your work on this guideline update and thank you for your time today, Dr. Henry. Dr. Lynn Henry: Thank you so much! Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.
Dr. Diwakar Davar and Dr. Jason Luke, both of the University of Pittsburgh's Hillman Cancer Center, highlight key advances in early phase therapeutics and immunotherapy that were featured at the 2022 ASCO Annual Meeting and also address toxicities, including immune checkpoint inhibitor-associated myocarditis. TRANSCRIPT Dr. Diwakar Davar: Hello, and welcome to the ASCO Daily News Podcast. My name is Dr. Diwakar Davar, and I'm an assistant professor of Medical Oncology, specializing in melanoma and phase 1 therapeutics at the University of Pittsburgh's Hillman Cancer Center. I am the guest host of today's podcast. My guest today is Dr. Jason Luke, a colleague and the director of the Cancer Immunotherapeutics Center at the UPMC Hillman Cancer Center here. Today, we'll be discussing advances in early-phase therapeutics and immunotherapy that were featured at the 2022 ASCO Annual Meeting. You'll find our full disclosures in the show notes, and the disclosures of all guests on the podcast are available on our transcripts at asco.org/podcasts. Jason, thank you for coming on the podcast today. Dr. Jason Luke: Thanks so much for the invitation. It was a great ASCO, and I hope everyone had a good time. Dr. Diwakar Davar: So, onto our abstracts. So, the first one that we'll be discussing, and Jason as you know we've done this before. We'll be rapidly transitioning between phase 1 therapeutics, melanoma, and advanced phase 2 and 3 trials, but you know this is something you do very well. So Abstract 2504, it's a phase 1 trial of TIM-3 inhibitor cobomilab immunotherapy and in combination with PD-1 inhibitors nivolumab and dostarlimab. The AMBER Trial that was presented recently, and in full disclosure, both you and I actually are on this abstract. So, what do you think of this abstract? What do you think of the data that is discussed, and how do we contextualize this in relation to what needs to be done in this space? Dr. Jason Luke: So, I think this is an exciting abstract because it brings forward what may be the next high-priority immune checkpoint to try to target in clinical oncology. To level-set, I think everybody listening will know about PD-1 and CTLA-4 as immune checkpoints. In the last year, we've had LAG-3 come forward as now a standard of care element of armamentarium in melanoma, and we look forward to further studies of LAG-3 and other tumor types as we think it should be a good partner where PD-1 is otherwise approved. So here now, we hear about TIM-3, which is another negative regulatory checkpoint on a number of different immune subsets. And in this abstract, the antibody targeting TIM-3 was cobolimab. So, TIM-3 is a very interesting molecule. It has, what you might call, pleiotropic effects in the immune system. So, while in the context of this abstract, it was being targeted as another immune checkpoint on T cells, it's important to point out that TIM-3 has other regulatory roles in other immune subsets such as myeloid cells and very particularly dendritic cells, and that's important because it might bring in another element of the innate immune system to try to drive anti-tumor responses. So, it's an exciting target because it might be able to expand the groups of patients who could benefit from immune checkpoint blockade. So, in this abstract, we see initially the phase 1 data of combining cobolimab, anti-TIM-3 with anti-PD-1 of a couple of different flavors. And what you could take from this abstract is that in the phase 1 setting, the drug was well-tolerated and combined well, and had pharmacokinetic properties that would be consistent with what we'd expect for this kind of a monoclonal antibody. I think we have to marry this abstract, which is really the phase 1 data about safety in pharmacokinetic (PK) to another abstract presented in the melanoma session, which showed an expansion cohort of patients who got cobolimab plus nivolumab or dostarlimab. And there we did see a 50% response rate, albeit that there was heterogeneity of patients being treatment naïve versus treatment-experienced. So, what I would say to this on a high level is that I think these data are preliminarily exciting, suggesting that further investigation into TIM-3 may be valuable in terms of expanding the population of patients initially in melanoma, but there will data coming soon in lung cancer and in other tumor types with another novel checkpoint. And I think if we think ahead into the future, the question is probably going to end up being, which combinations of checkpoints for which patients. That's pretty exciting to think about. We've seen a lot of data of PD-1 plus other molecules, and I think some future biomarker stratification really will be necessary to know which patient would benefit the most from which of these combos, but for the time being, this is exciting data to see where the field is going to go over the next couple of years. Dr. Diwakar Davar: Great. And I guess, to your point, one important thing to highlight from the abstract is your point about the role of the different compartments. There was actually a very interesting dose-response relationship with the highest dose of the drug not necessarily being the most effective dose, suggesting that yes, as you escalate, you may have different effects in different compartments, and maybe therefore a broad selection of doses might be required to ensure that you have optimal engagement of the optimal target. So, the next abstract is Abstract 3007. This is the tumor-agnostic efficacy and safety of erdafitinib. So, we now know that FGFR pathway aberrations are found from 77% of all malignancies, FGFR targets are now U.S. Food and Drug Administration (FDA) approved in cholangiocarcinoma with pemigatinib, infigratinib, and as well with erdafitinib metastatic urothelial cancer. We know that these agents are not necessarily effective tests in 1 tumor type because these alterations have risen in multiple tumor types. So, the RAGNAR trial, looking at this across multiple tumor types, what do you make of the interim analysis result presented by Dr. Loriot? Dr. Jason Luke: So, I'd say that this is probably the future of targeted therapy. And so, I think that where we have activity in 1 disease, it's very likely we would have activity in others. So, the author has described this as the largest basket trial of a molecularly defined subset that's been pursued to date. There are upwards of more than 200 patients in the study. I think it's really important, as we think about the data, to realize, though, that all FGFR alterations are not exactly the same thing. And so, in this study, they gave erdafitinib to patients with solid tumors of any FGFR altered status. And so that's FGFR1, 2, 3, 4 mutations or gene fusions. And that's a lot of heterogeneity in there actually. And in this study, there were two-thirds fusions and one-third mutations, mostly in FGFR2 and 3. That will become relevant as we start to think about the results. On a high level, I have to say that it is impressive in pan-cancer fashion, just selecting by FGFR alteration, there's about a 30% response rate observed. I think that no matter what, that's going to be valuable considering these were patients with refractory tumors with 3 lines of prior therapy on median. I think what we need to know more is the breakdown of which specific molecular alteration and FGFR in which tumor types drove most of the benefit. So, for example, in bladder cancer where erdafitinib is already approved, that's almost entirely an FGFR3 fusion setting. So we know the drug is effective there. And so I think there will be a further breakdown of the data. As it matures more, you really start to tease out, is it really the case that any FGFR alteration can be treated or there are some that really ought to be the high priorities that we really ought to be going after. I think it would be remiss not to also note, however, that while there's excitement about this sort of pan-cancer approach, the current generation of FGFR inhibitors are not exactly the easiest drugs to take. And so, the in-class, hypophosphatemia and stomatitis really does lead to dose reductions in a lot of the patients. And I think that that's probably really important to emphasize is that despite the pan-tumor activity, there's still a lot of potential in this field to refine further because it's almost certainly the case that if we had less off-target toxicity, so to say, we could improve the efficacy beyond that 30% that we saw here. All the same, I think this is exciting for the concept of a pan-cancer tumor agnostic sort of approach, and we'll really look forward to more data to come from this study over the next, hopefully, few months. Dr. Diwakar Davar: And I guess 1 corollary to that is that we now need to start looking for FGFR alterations in multiple tumor types. So, tests, tests, tests. All right, Abstract 3004, phase 1a/1b dose escalation and expansion study of the MDM2-p53 antagonist BI 907828 in patients with multiple solid tumors including advanced, metastatic, liposarcoma. So, we've recently had data of the previously undruggable KRAS, and now we've got previously undruggable p53, for which we now have targets. So, Jason, what do you make of the p53 targeting approach, in this case, using MDM2 and this particular drug from Boehringer Ingelheim? Dr. Jason Luke: So, I think that this is an exciting abstract exactly for the reason that you mentioned, which is that p53 has been, and unfortunately, to some degree, still remains, one of those holy grails but undruggable targets in oncology. So MDM2, for those who are listening but might not be aware, is a negative regulator of p53. So, the concept here then is if you drug it, you might release p53 to reactivate activity in that pathway, and then p53 being the guardian of the genome, so to say, potentially leading to apoptosis of cancer cells. And so, this drug binds MDM2 and MDM2 can be amplified as a resistance mechanism in p53 and several tumor types. And so here, they showed data for the early part of a clinical trial investigating the small molecule, BI 907828, but then they focus specifically in liposarcoma, which is a disease known to be an MDM2 amplified. And so, the results were pretty interesting. The toxicity of this kind of an approach, just to note, is really in class. It leads to some gastrointestinal (GI) toxicities as well as hematologic problems, and this goes again for most regulators of the cell cycle will have these effects, whether they're CDK inhibitors or MDM2 or p53 modulators. But I think what was very interesting, this is a disease liposarcoma where chemotherapy, functionally speaking, has no role. We, unfortunately, give it to some patients sometimes, but it has almost no activity, and they observe that in poorly differentiated liposarcomas, the response rate was about 12%, but the stable disease was quite durable. And so, I think that really is potentially a big deal because this is an orphan disease. It really lacks any other treatment. But as you zoom out from that, if you start to think about targeting amplified MDM2 in other settings, I think the activity that we see here is intriguing, and potentially suggests that we may be coming to a future where we'll have multiple, sort of, orthogonal approaches after reactivating p53. There were actually other abstracts at ASCO Annual Meeting of other molecules that were less mature also along this line. So, I think, very exciting to take away from this, one, a potential treatment for liposarcoma for all of those patients that anybody listening actually sees, but secondarily this concept of targeting p53, which I think we'll see a lot more of over the next couple of years. Dr. Diwakar Davar: Excellent. Moving on to the Abstract 3002, this is a phase 1, two-part multicenter, first-in-human study of DS-6000a of an antibody-drug conjugate comprising the anti-CDH6 IgG1 monoclonal antibody that is attached to a topoisomerase I inhibitor payload via a cleavable linker. And so basically, a way in which you can give topoisomerase: (1) TOP1 inhibitor, (2) CDH6-expressing cells. This was studied in advanced renal cell carcinoma (RCC) and advanced ovarian cancer in this abstract presented by Dr. Hamilton. Jason, what do you think of the results and what do you think of this approach in general, this antibody-drug conjugate (ADC) approach using novel targets as well as novel payloads? Dr. Jason Luke: I think this is one of those that you can't help but be pretty excited about, and I think in the context of the data shown at the plenary session in breast cancer for antibody-drug conjugates (LBA3), I think this is really where the field is going to start to go. So, you mentioned that this is an antibody-drug conjugate that targets cadherin 6 or CDH6, which people will remember from biochemistry class and medical school, or something is a cell-cell adhesion molecule, really a basement membrane protein. So, the concept of targeting it really is just to go after a latch mechanism to get the molecule into the tumor where you want. And CDH expression is very high in renal cell carcinoma, upwards of 80% of samples, also high in ovarian cancer, which is why they chose those 2 tumors to go after. So, the ADCC, and you described its structure just a little bit, but it's essentially the same backbone as trastuzumab deruxtecan, which we saw this outstanding activity for HER2 and breast cancer on the plenary, with these 8 chemotherapies moieties attached to it, but here now, targeting it instead to HER2, with this molecule now to CDH6. And I think, again, you can't help but be impressed. There were treatment responses on almost every dose level of the dose escalation in this study. There's in fact only 1 patient whose tumor was not, at least, stable disease or a PR, and I think that that just goes to show the power of truly bringing the chemotherapy in a targeted manner into the tumor microenvironment. Responses were heterogeneous. They were not super deep responses per se, but the stable disease was quite durable in the study, and the patients were going out more than 7 months. And again, realizing this is at the lower dose levels as we're increasing the dose and move this in their earlier lives of therapy is likely to be even more effective. They did show a waterfall plot of the reduction in CA 125 for the patients with ovarian cancer that really looked quite impressive. And given that that's our clinical biomarker that we commonly follow, it may actually even more indicative of the benefit we would see as opposed to resist. Now, again, there is some toxicity. It is a chemotherapy moiety that's conjugated to the ADCs. So, the most common toxicities were nausea, vomiting, and low platelet counts, but these are kind of toxicities that we're quite accustomed to with chemotherapy. Just to summarize, I think there's a lot of promise for this kind of antibody-drug conjugate targeting, and I think it can only be impressive that they had this amount of activity in the dose escalation of the study. [I] very much look forward to the expansion cohorts in renal and ovarian, which we'll presumably expect to see later this year, early in the next year. Dr. Diwakar Davar: And as you alluded to, this really was parallel that ASCO, by the standing ovation given to Dr. Modi when she presented the DESTINY04 data of trastuzumab deruxtecan in HER2-low breast cancer, basically now redefining breast cancer from 4 camps, now we have to think of not just HER2 amplified or HER2-high, but also HER2-low. So yes, really have to now rethink how we classify these diseases (LBA3). So Abstract 2509, the efficacy of anti-PD-1/PD-L1 immunotherapy in non–small cell lung cancer dependent based on CD8 and PD-L1 status. So really Dr. Galon taking us into what he has now described as the immunoscore—really a way of characterizing tumors. A way of thinking about tumors that you've also championed, Jason, in terms of this T cell-inflamed and uninflamed hypothesis. So, tell us a little bit about how these jives with your work and how you would think about lung cancer patients responding and not responding to immune checkpoint inhibitors (ICI) therapy in this context? Dr. Jason Luke: Yeah. I think the focus quickly here on the immunoscore, so the people are aware of that, I think is really important for diving into these specific results. You have to realize our fundamental underlying predicate for immune checkpoint blockade inhibitor response is that patients have mounted an adaptive immune response. So, CD8 T-cells have gone into the tumor where they elaborate chemokines and cytokines like interferon gamma, which upregulates the expression of PD-L1 in the tumor but also in the surrounding immune cells. So, you realize that even though antibodies are targeting PD-1, it's really that we're targeting that tumor microenvironment. So, the more robustly we can measure that, and we understand it, the more likely we are to know whether or not the patient is going to benefit. So, this is where the immunoscore comes in. The immunoscore is actually a fairly simple test. It's one slide, immunohistochemistry slide where they can stain jointly for CD8 and PD-L1 on the same slide. And that allows them to do a number of different things beyond just testing the total level of PD-L1. They can test the CD8 density, the PD-L1 expression, but then also the interaction between CD8 T-cells, their distance from each other, from PD-L1 expressing cells, and so on and so forth. And so really [this] can give us a much more robust analysis of what all is going on in the tumor microenvironment again, off of a single slide. So here then, in this abstract, for patients with non–small cell lung cancer receiving anti-PD-1, they then compared the utility of only PD-L1 testing versus doing the immunoscore. And so, it was actually quite a large set. They had about 250 patients in their analytical set and then split about 150 or 180 or something into the training and validation sets, and they compared the immunoscore against 2 different standard PD-L1 antibodies, the 22C3 as well as the SP263. And what they saw was a high concordance for expression between PD-L1 and the immunoscore. That's good, because, again, they're measuring PD-L1 in both of those. And so that was a good, sort of, level set. The immunoscore, however, allows them to look to 7 different parameters, again, beyond just PD-L1, as I mentioned. So, CD8 density, interaction, distance, and this kind of thing. Then in these test and training cohorts, they were able to actually split out patients who are PD-L1 positive into further groups, those that were immunoscore low and that were high. And in so doing, they were actually able to sort of dramatically predict the likely progression-free survival on PD-1 checkpoint blockade in those different non–small cell lung cancer groups. So why is this important? Selection of patients by PD-1 has been very useful in the field of non–small cell lung cancer, but it's hardly a panacea. You're not at all assured your patient is going to do well just because they're PD-L1. And here comes a second assay that can be done in a standard of care setting. So, the immunoscore is a test. You could just order it, and that really does give you much more predictive power about who's likely to do well and who isn't. And I think this test and more broadly multi-spectral imaging is really going to become a core component to how we risk stratify and predict outcomes to checkpoint blockade and lung cancer, but broadly in other tumor types over the next couple of years. Dr. Diwakar Davar: Okay. Now, moving on from a biomarker for PD-L1 and PD-1 to a setting in which PD-1 was just recently U.S. Food and Drug Administration (FDA)-approved, so I'll give a brief background to the trial that you've actually developed and led. And so, this is KEYNOTE-716, the abstract in question is LBA9500 (late-breaking abstract) 9500, but this is the distant metastasis-free survival (DMFS) data readout. The DMFS, distant metastasis-free survival with pembrolizumab versus placebo in the adjuvant setting for patients with stage IIB or IIC, that is high-risk node-negative melanoma and the data from the phase 3 KEYNOTE-716 study. So, this data, at least the recurrence-free survival (RFS) data was actually earlier published, you had presented it earlier last year and also more recently this year, but it was published recently in Lancet. And we know that 716 is a study in which, for the first time ever, we have an immune checkpoint inhibitor PD-1 that was studied against placebo with the high-risk node-negative setting in stage IIB and C melanoma, demonstrated a significant RFS benefit in the setting against placebo. And now we have the DMFS readout. Maybe you could tell us a little bit about both the RFS and the DMFS data, and why this is such an important advance for these patients. Dr. Jason Luke: Thanks. And I agree this really is a sea change in how we thought about stratification of patients with melanoma, but I think this broadly has implications for other tumor types as well. So, in melanoma, we've historically thought of its involvement of the lymph nodes—stage III as being the high-risk disease, but we also, if you look at the outcomes from the AJCC, we see the patients with stage IIB and IIC, so deep primary lesions, actually have similar bad outcomes as those patients with stage IIIA and IIIB. And so anti-PD1 and adjuvant therapy and melanoma were originally proved for stage III, but having understood that about 5 years ago actually, started to think, well, why not also treat the patients with stage II if they're at similar risk. And we pursued KEYNOTE-716 as you mentioned, and it read out last year as a positive trial for recurrence-free survival. And the abstract here then was to look at the impact on distant metastasis-free survival. So, while the regulatory consideration for approval, and it is approved and it's available for patients now, was based on relapse, what we really want to be preventing is the development of metastatic disease because presumably that would correlate with the eventual death of the patient from cancer. So, in the abstract here, we see the first update for DMFS, which also was positive on its first analysis, the hazard ratio at 0.64. And so, again, very similar to the RFS benefit, showing about a 35-36% reduction in distant metastasis-free survival. And this is a theme that we've seen across adjuvant studies in melanoma, all the adjuvant studies in fact, is that the RFS improvement, the relapse-free survival hazard ratio mirrors very closely the distant metastasis-free survival ratio. We saw that again here. I think it just emphasizes that anti-PD-1 immunotherapy is highly effective in melanoma no matter what stage it's in, but rather related to the risk of death for melanoma. And so this really has a practice changing in the field of melanoma oncology. Patients need to be referred to medical oncology early for discussion around risk stratification and consideration of adjuvant therapy—I think even at the same time that they're having resection of their primary lesion, and it even calls into question of whether or not we should even fully be doing procedures like sentinel lymph node biopsies any longer, considering we can make the decision to give adjuvant therapy now based on the primary—albeit that's a controversial area of discussion. And I would just love for this to start to penetrate into other disease settings. We've seen more recently, approval for neoadjuvant therapy in lung cancer and we see in kidney cancer, bladder cancer. We see adjuvant therapy in—I think we're going to see immunotherapy starting to become an important part of the armamentarium in these hard-to-treat cancers, even at the time that perioperatively before or after surgery. So definitely a major change in the way we're thinking about stratifying patients and emphasizes that you need to get those patients with melanoma in to have that discussion around adjuvant therapy probably at the time of the primary lesion resection. Dr. Diwakar Davar: And finally, Abstract 2507, single-cell profiling of human heart and blood in patients with checkpoint inhibitor-associated myocarditis. So, this is data from the NGH Group, Dr. Villani and colleagues are presented by Dr. Blum. We know that myocarditis is an uncommon but very serious immune related adverse event (irAE), and here in this particular dataset, this group which has done a lot of underlying work to really uncover the role of certain key phenotypes, cellular phenotypes, in the development of myocarditis it's presenting the data in the context of ICI-related myocarditis. So, what do you think of this data, what do you think of the use of checkpoint inhibitors are now, as you've said, migrated linear in the lifecycle of the patient, what do we need to be thinking about and how does this improve our understanding of both the use of the drug and what we need to be worried about? Dr. Jason Luke: I think the toxicities of immunotherapy, while, less frequent than, say, chemotherapy, can actually be more disastrous. In the rare patients, we have extreme immune-related adverse events, there is an incidence of actually life-threatening and fatal events. And so, myocarditis, associated with checkpoint blockade, is one of those things that could be seen, and here at ASCO Annual Meeting, we saw a couple of abstracts summarizing the experience from the National Cancer Institute following myocarditis events, and then this abstract in a translational level trying to better understand what is actually going on in terms of the immune response in those myocarditis cases. And so, I thought this was actually a very interesting abstract. There was only a small number of patients. They had 13 samples from patients who had had endomyocardial biopsies in the context of immune-related myocarditis, and you might say, well, only 13 samples, but fortunately, this is quite a rare event, less than 1% of patients who get immune checkpoint inhibitors. And what they saw was relatively unsurprising, which is that in patients who were having myocarditis, they saw an increase in T cells and in K-cells, as well as activated CD8 and CD4 T-cells. I think what was very interesting was when they started to dig into what were the phenotypes of the cells and what were the pathways that were turned on. Again, it was not especially surprising to see that they saw increased levels of interferon signaling and immune-receptor signaling as well as motility and adhesion, but this really, I think emphasizes that there are potentially interventions beyond just the general immune-suppression approaches that we give. They could be more nuanced but perhaps more efficacious because sadly, patients do pass away when they develop this. And in their cohort of 13 patients, 3 of those patients died. And specifically, in looking in those 3 patients, they actually saw that all 3 patients had a shared T cell cluster. And they can't exactly say what it is exactly yet, but I think it's very interesting to see that because it suggests that there's probably something about the T cell response in those patients that disproportionately triggered a fatal event. And if we can understand that better, we then may be able to really tailor our interventions in a way that is more useful. Because, frankly, the way these patients usually present is they show up in the emergency room (ER), and they're seen by an ER doctor who thinks they're having acute coronary. They ship them off to the catheterization (cath) lab. They open him up, and then they get in there, and there's nothing going on. There's no plaque. And so now, all of a sudden, everyone is quite confused. And so, if we had better ways to search for that ahead of time to be aware of it, we might have better interventions because usually what happens right at that moment is everybody gets very confused and starts calling the oncologist, and we start slapping on steroids and other immunomodulatory agents, but sometimes it's late. So, I think this is a great abstract. It's really starting to preliminary give us an idea of what is the actual biology that underpins these terrible events, and we can hope that we can build off that over time hopefully to eventually come up with better predictors and then obviously better interventions to try to avoid these outcomes in a small but real number of patients. Dr. Diwakar Davar: Excellent. One other point is you and I are both involved in drug development, and as we start thinking of side effects. Side effects are really on the flip side of responses in drug development. So really 1 point to make of this is that when people start developing side effects rather than, as you say, putting your hands up in the air and waving them around, 1 of the things that we should be doing in drug development is possibly biopsying these patients because we could get new PD insights into how these drugs work, why they work, and particularly which sub-populations themselves they work on, particularly in the early-drug development setting when you oftentimes don't have that many responses. With that, thank you, Jason, for sharing your insights with us today. Dr. Jason Luke: Thank you. Dr. Diwakar Davar: And thank you to our listeners for your time today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. So, thank you for your attention, and we will sign out. Disclosures: Dr. Diwakar Davar: Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences Consulting or Advisory Role: Instil Bio, Vedanta Biosciences Consulting or Advisory Role (Immediate family member): Shionogi Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences Research Funding (Inst.): Zucero Therapeutics Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy Dr. Jason Luke: Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical , Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof) Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.
Dr. Stephen Ansell, of the Mayo Clinic in Minnesota, tells host Dr. John Sweetenham, of the UT Southwestern Harold C. Simmons Comprehensive Cancer Center, about ECHELON-1's compelling overall survival analysis in newly diagnosed Hodgkin lymphoma and key advances in the SHINE, MOMENTUM, and ASCEMBL trials that were featured at the 2022 ASCO Annual Meeting. TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, the associate director for Clinical Affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center, and host of the ASCO Daily News Podcast. My guest today is Dr. Stephen Ansell, a professor and chair of medicine at the Department of Hematology at the Mayo Clinic in Minnesota. Dr. Ansell shares his insights on key advances in hematologic malignancies that were featured at the 2022 ASCO Annual Meeting. Our full disclosures are available in the show notes and disclosures of all guests on podcasts can be found on our transcripts at asco.org/podcasts. Stephen, it's great to have you on the podcast today. Dr. Stephen Ansell: Thanks so much for having me, John. Dr. John Sweetenham: So, Stephen, I'd like to start with your thoughts on Abstract 7503, which of course is one that you authored, and this is a 6-year follow-up study of the ECHELON-1 trial. This includes a positive overall survival analysis for brentuximab vedotin in newly diagnosed advanced Hodgkin lymphoma. Can you tell us more about this? Dr. Stephen Ansell: Yeah, sure, John. And you know, as you point out, the thing that's really interesting and unique about this trial is we haven't had a lot of studies in Hodgkin lymphoma that show an overall survival advantage as you well know. Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy has actually been quite difficult to beat when it's been an overall survival endpoint that one has been looking at. There have been some other strategies in the past that have been looked at—the escalation of therapies such as escalator BEACOPP, and maybe modification of therapy to minimize toxicity, such as the RATHL trial where bleomycin is dropped out. In all of these studies, there have been advantages for progression-free survival, but not clearly against ABVD as the standard and overall survival advantage. So, our listeners would probably know that ECHELON-1 was a comparison between brentuximab vedotin ABVD chemotherapy, and ABVD chemotherapy as the standard, showing an initially modified progression-free survival advantage and subsequently a progression-free survival advantage. But now with 6 years of follow-up, an overall survival advantage. And I think that's really what makes this quite unique. Dr. John Sweetenham: One of the reasons I think many people, myself included, thought that it was going to be a very high bar to show an overall survival difference in this study was simply the fact that treatments to relapsed and refractory Hodgkin lymphoma, in general, have improved really quite substantially, both before and during the conduct of this trial. Do you have any thoughts on that? Were you surprised? And any thoughts on why we're seeing this in the face of the rapidly evolving treatment landscape in the relapse setting? Dr. Stephen Ansell: Yeah, I think that's an excellent point. And, John, I think there have been 2 schools of thought, as you know, those that have felt that the first shot was always the best one. And you should go hard right off the bat and others have said, you don't need to give everybody intensive treatment, because as you say, subsequent therapies can be very effective. This would actually challenge that second position because when we looked at how patients were managed in both groups when they relapsed, the vast majority of relapsing patients in the group that got ABVD subsequently got brentuximab vedotin, as part of their regimen. Most patients—and it was balanced in both arms—got the standard kind of salvage treatment, autologous stem cell transplant approach, and some patients in both arms, got novel agents, including PD1 blockade, that was a minority, partly because of the timing of when the study was done. But I think all of the things that we would normally do were done, and yet there's still a survival advantage. The one interesting thing I think that's worth taking away from this is when one looked at some of the influences on what might have made that overall survival difference, there were more patients progressing and dying from Hodgkin's in the ABVD arm suggesting that adding brentuximab vedotin does make a difference to the disease itself. But also interestingly, there were fewer patients in the brentuximab arm, who got a second lymphoma. And interestingly, there were quite a substantial number of people in the ABVD arm when they relapsed to or subsequently got a different lymphoma, suggesting that the brentuximab vedotin, may actually target a precursor cell in a heme malignancies space and actually may have a benefit that way. Dr. John Sweetenham: So, what's your overall conclusion from this study now that brentuximab vedotin plus ABVD is the standard of care for patients with newly diagnosed advanced Hodgkin lymphoma? Dr. Stephen Ansell: I would say that if you have advanced-stage disease with classical Hodgkin lymphoma histology, it's very difficult not to say that this would be the standard of care to manage the patients. I think we've learned that this study applied to older patients who are often difficult to treat. And so, hence, that's also a very valid treatment to give. And it's very difficult to argue against giving treatment that has an overall survival advantage for patients. So, in my practice, this has become the standard of care. Dr. John Sweetenham: Okay, great. Thanks, Stephen. Let's move on and talk about LBA7502. This reported on the primary results of a double-blind placebo-controlled study known as SHINE, which looks at the use of ibrutinib in combination with bendamustine and rituximab followed by rituximab maintenance as a first-line treatment for older patients with mantle cell lymphoma. What are your thoughts and key takeaways from this study? Dr. Stephen Ansell: Again, I think this is a very important study in older patients with mantle cell lymphoma. So, as you well know and many of our listening audience would know that we kind of has 2 strategies in mantle cell lymphoma. In younger patients, we may treat them with a more intense approach, sometimes with autologous stem cell transplant, often with a kind of alternating high-intensity therapies. For patients who are older, bendamustine rituximab is really a standard therapy for patients with that demographic. And this now really pushes the field forward by showing that if you take bendamustine rituximab and add ibrutinib an effective therapy in the relapse setting, in the upfront setting, there is a substantial advantage for how patients do. If one looks at the overall outcomes, it shows that progression-free survival is improved; we don't have overall survival benefit yet. But as we track these patients, it'll be interesting to see if that does transpire in time. I will say again that I always like placebo-controlled arms because it helps us really get a handle on toxicities. And in general, in this population of patients, it was well tolerated. So, I think this, again, is a regimen that is going to be very useful in older patients. Dr. John Sweetenham: I think that the lack of an overall survival benefit so far could of course be because there was a crossover in a study for those patients who progressed on the placebo-controlled arm. But my other question about this, just to get your impression, is that there is a subgroup of elderly patients or older patients with a very slowly progressive disease where the management approach has been more of a watch-and-wait and observation-only approach until they become symptomatic. Do you think results like this, which start to show a progression-free survival benefit from upfront therapy, change that philosophy? Should we be thinking harder about whether anyone should be observed now? Dr. Stephen Ansell: I think that's a good question. And to be frank, I will say that in my practice, I still have a spirit of, I'm happy to watch patients who have a very low burden of disease to just get a sense of the pace of the disease. Because as you say, you may be surprised by a subset of patients whom you may not need to treat for a year or even longer. And my view is that a year of no treatment is always better than a prolonged progression-free survival interval on treatment. So, I take the view that if you don't need to treat, that is still the best management. Dr. John Sweetenham: Great, thank you! So, we're going to change gear for a moment and move out of lymphoid malignancy and talk a little about Myeloproliferative Syndrome. I'm interested to hear your thoughts on the MOMENTUM study. So, this was Abstract 7002, another phase 3 randomized study, in this case, looking at the use of momelotinib versus danazol in symptomatic and anemic patients with Myelofibrosis, who previously had a JAK inhibitor. What are your thoughts on this study? Dr. Stephen Ansell: I think again, this is really good and very interesting data because those that treat Myelofibrosis will know these are challenging to treat. And many times, the symptoms they experience, the transfusion challenges they have, and the difficulty they have with very large spleens are all things that impact the quality of life quite profoundly. And therapies, in general, that would benefit those symptoms are always highly valuable. So, I did find, again, I'm not as much of an expert in Myelofibrosis, but certainly, my colleagues who are were very satisfied with these results, basically showing improvement when compared to danazol, which again, I would anticipate as modest control with not particularly good efficacy, again, some of those symptoms I just spoke about, but momelotinib really showed a substantial benefit for the symptoms that this disease causes, and obviously transfusion requirements and improved spleen sizes and spleen symptoms. So, I think in general, for managing patients for whom the quality of life is profoundly impacted, this is going to be a useful agent moving forward. Dr. John Sweetenham: Okay, great. Thanks. And staying on the theme of Myeloid diseases, Abstract 7004 reported on the efficacy and safety, from the so-called ASCEMBL study, another phase 3 study, in this case, looking at the use of asciminib versus bosutinib in patients with Chronic Myeloid Leukemia (CML) who are in chronic phase, and who had already received 2 or more tyrosine kinase inhibitors. And this was an update at week 56 of the study. Why do you think this study should be on our radar? Dr. Stephen Ansell: Well, I think again, we're always looking for agents that make a difference, particularly with subsequent lines of therapy in this disease. I think bosutinib is really regarded as a standard of care in this population of patients and an agent that comes along, ascitinib in this case, that shows a significant benefit, that really brings yet another tool for us to utilize in these patients. I must say, again, as I looked at the results, comparing also looking for the major molecular responses, and the benefit and durability thereof, this was pretty impressive data. And so, I think it's very useful in this disease to have a plethora of tools that we can reach to be able to really impact the outcome of patients. So, I think, again, this is highly relevant data that we would use in the clinic in the not-distant future. Dr. John Sweetenham: Do you think it's likely it'll move into frontline treatment over time? Dr. Stephen Ansell: So, I think that is a good question. I don't know the answer to that, except to say that these results are pretty impressive. And so, I do believe that that's going to need to be tested, but as has been done in CML over the decades and which is really to be applauded, there have been randomized trials, comparing head-to-head agents showing which agent really has the greatest benefit and efficacy. So, I'll watch that space with a lot of interest. Dr. John Sweetenham: Thanks! And finally, I'd like to return to lymphoid malignancy. In the 2020s, it would be almost impossible to review a meeting such as ASCO without saying something about CAR T-cell therapy, and this podcast is going to be no exception. So, I wonder if I could get your thoughts on Abstract 7571. And this was an abstract, which reported real-world outcomes for axicabtagene ciloleucel, otherwise known as the Axi-Cel, for the treatment of large B-cell lymphoma. And it looked at the outcomes according to race and ethnicity. What are your thoughts on this study? Dr. Stephen Ansell: Well, John, I smiled when you were said there's not a possible to really have a conversation without bringing in CAR T-cell somewhere along the way, but what I liked about this abstract, is it really was bringing in the real-world data, because many times and again, I have to stress that real-world data, when it comes to CAR T-cells is probably not the real world in the most real-world nature of things. And that is just you have to have access to certain centers to be able to get this therapy. And I think that's what this abstract actually points to. It does look at almost 1,400 patients treated with Axi-Cel. And now that in large cell lymphoma, this is a standard of care where we either use a post-transplant and now even as a first relapse therapy, this is becoming highly relevant. And the question is just always seeing discrepancies between various population groups when we look at how outcomes transpire from this therapy. And as it turns out, if one looks at Asian populations, those are really not adversely impacted, or Hispanic populations. But the African American population continues to have a less favorable outcome, even with this sophisticated therapy. And that does suggest that possibly, when those patients, in general, can get access to this care, might actually be a little later in the disease, greater disease burden, possibly a little later line of therapy, resulting in not as favorable results. I think this is whereas health care providers, we need to turn our attention in the future. And that is to say, how can we make care be equally good for all patients everywhere within our country, rather than there being nuggets where certain people benefit a lot and other areas where people benefit very little. Dr. John Sweetenham: Yeah, thank you. There was good discussion after this study was presented and I think much of it focused around exactly what you've just said. Most of this difference is almost certainly not biological but it's really related to access to care and so on and that was an important take-home message. So, thanks for emphasizing that. Stephen, thanks so much for sharing your insights with us today regarding the 2022 ASCO Annual Meeting on our podcast. I really appreciate your being willing to talk to us. Dr. Stephen Ansell: John, thank you very much for having me. Dr. John Sweetenham: And thank you to our listeners for joining us today. You'll find links to the abstract discussed today on the transcripts of this episode. Finally, if you value the insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Disclosures: Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness Dr. Stephen Ansell: Honoraria: WebMD, Research to Practice Research Funding (Inst.): Bristol-Myers Squibb, Seattle Genetics, Affimed Therapeutics, Regeneron, Trillium Therapeutics, AI Therapeutics, ADC Therapeutics Disclaimer: The purpose of this podcast is to educate and inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.
A CONVERSATION WITH KEZ Radio Toni Every Day Business shows and the Toni TV channel offer a unique platform for spreading the message of you and your company, to the world. In this video, we chat with GUEST: JULIE RANDALL, the author of Patient 71 In 2012 I thought I was a fit and healthy woman who had just reluctantly turn 50! I was actually training for a state-level touch football tournament. I went off to work few days after my birthday celebrations, came back from lunch, then without any notice, had a massive seizure in the office. 24 hours later I was diagnosed with Stage 4 advanced, metastatic melanoma and given months to live. My teenage daughters were so distraught, I went out on a limb and promised them I would not die. I was brought up to keep my promises so I had to find a way to survive! i searched the world but could not find one survivor. I would have to be the first. There was no treatment here in Australia to save my life, so again I had to search the world for answers. I found a clinical trial in Portland, Oregon that was working with a immunotherapy drug called (at that stage) PD1. Some patients were responding but it was very early days.. I decided I had to be there, I had to give it a shot for my girls.. BUT the trial was only for US citizens and was at full capacity at 70 Patients.. They keep saying no.. but I wouldn't give up.. after 3.5 months of begging and pleading the hospital and the drug company gave in to my pleas .. I would become known to the Scientists as Patient 71.. Today I am alive and healthy and transformed form my experience.. I have become a best-selling author and a speaker and spreading my story of hope and inspiration to the world.. I now have purpose and meaning more than ever before. I have a job to do in the world now and it feels great to be able to help and inspire others. I would have to be the first: Facebook: https://www.facebook.com/julierandall... Toni's Links: LinkedIn: https://www.linkedin.com/in/toni-lont... Facebook Page: https://www.facebook.com/toniradiotoni/ Instagram: https://www.instagram.com/tonimlontis/ Website: https://www.tonilontis.com YouTube: https://www.youtube.com/c/ToniLontis --- Support this podcast: https://anchor.fm/radiotonitv/support
Para contratarme lo tienes aquí: https://cursosdejardineria.com/#consulta Mi boletín aquí: https://claudiodoratto.com/boletin El canal de Telegram: https://t.me/jardineros Seguro que piensas que estoy más malito de la cabeza que la semana pasada cuando te conté de regar con agua de mar. Pero no te preocupes, no es así. Estoy igual, ni con más ni con menos “tocs” de lo habitual. Resulta que el lunes de la semana pasada estaba en una reunión virtual con mi amigo Héctor de Chile hablando de emprendimiento, proyectos a corto y mediano plazo. De jardines regenerativos de suelo, fitorremediación y otras de esas cosas extrañas que me gustan. 😉 Y salió el tema de un amigo que tiene un campo irrigado con agua carbonatada y lo increíble de la producción que ha tenido. Amigo de él, no mío. Fue ahí cuando me di cuenta de que nunca te hablé de ello. De regar con soda. ¡Cómo puede ser! Primero cabe aclarar que no es tan así, pero que en tu casa puedes hacer la prueba con agua gasificada comercial. Vamos con la teoría, ¿te parece? El agua carbonatada tiene CO2 (dióxido de carbono) el mismo que genera el efecto invernadero con otros gases. Es bien conocido que las plantas lo emplean en su fotosíntesis, pero aplicado a nivel de riego tiene otros beneficios. Para la planta y el planeta porque contribuye a la fijación del carbono. Para las plantas es una fertirrigación (riego y fertilización juntas) con los siguientes beneficios: • Acidifica el suelo modificando la solubilidad de los micronutrientes. • Aumenta la calidad y el número de frutos. • Favorece la disolución de los abonos utilizados. Si se riega con sistemas de goteo: • Evita y elimina incrustaciones en la red de riego. Como otra consecuencia, nos ayuda a ahorrar en abonos. Si deseas hacer un ensayo en tu huerta, o con algunas plantas en maceta. Puedes regar con el agua con gas una vez cada tres días, o mezclar en partes iguales soda con el agua común. También es buena para cultivos de hoja como la lechuga e incluso aplicarla con un atomizador o rociador sobre las hojas. Claudio. El Jardinerista. PD: En los cultivos, las dosis de CO2 son precisas. Por ejemplo, en ensayos de tomate se logró aumentar la producción con 0,2 gramos por litro de agua y para aumentar el tamaño de los frutos con 0,35 gr/l. PD1: como con todo, el exceso también es malo.
Para contratarme lo tienes aquí: https://cursosdejardineria.com/#consulta Mi boletín aquí: https://claudiodoratto.com/boletin El canal de Telegram: https://t.me/jardineros No importa si es leche de cabra, vaca u oveja. Ese fuego se apaga con leche. Tal vez te suenen nombres como “Carolina reaper” y “Dragon's breath”, o tal vez no. Comienzo para aclarar que no se tratan de perfumes. Ni para la dama, ni para el caballero. Son ajíes y de los más picantes. Que los conozca de nombre porque me los presentaron alguna vez, no significa que los haya comido. Pero no pierdo la esperanza. Sí he comido varios más como los jalapeños, el jalapeño marrón, unos chiles italianos, otros de Tailandia, unos peruanos de color morado, el piquín, el beso de satanás y más. Los tengo en la huerta, algunos directo en el suelo, otros en macetas grandes y también en tachos de pintura de los de 20 litros. Tengo esa debilidad que me tendría que hacer analizar con el “doctor de la cabeza” porque cuando veo una planta o pienso mucho en esos frutos que encierran fuego en su interior. Yo comienzo a salivar. El asunto es que me gustan y disfruto mientras torturo a mis papilas gustativas. Otra razón para ir a ese doctor del coco, no lo digo yo, me lo dicen parientes y amigos que me dicen “te tenés que hacer ver, no puede ser que te guste y comas las cosas tan picantes”. Yo les respondo que en otra vida tal vez fui mexicano. No quiero imaginar lo que me dirían si se enteran de que me inventé una receta de licor de ají. 🌶 🌶 🌶 Volviendo a los muchachos Capsicum, descubrí que tienen un club de fans muy grande. Así que me quedo por ahora tranquilo. ¿Y a qué viene todo este preámbulo? Hace un par de años, voy a uno de los viveros que más frecuento a comprar unas plantas para un cliente cuando giro mi cabeza a la derecha y ahí estaba. Una maravillosa y colorida planta con ajíes de colores. ¡Quiero una! Le dije a Rodrigo. Me contestó, pero son picantes, me dijeron que se llama “ají picante de 7 colores”. Llego a mi casa, corto y lavo un par de ellos para ver qué tan picantes eran. Fraude total. Un pimiento morrón me hubiera desilusionado menos. En fin, cosas que pasan. El año pasado, un cliente compró unas semillas de los ají que te nombré al principio y otro conocido como “el mostro” que es un híbrido entre los dos. Hice mi almácigo en tres bandejas plásticas con tapa para tener una especie de invernadero en miniatura. Venían bien, ya tenían sus primeras hojas y casi dos centímetros de altura. Estaba ilusionado. Pero un día, nuestro famoso “viento zonda” me tomó por sorpresa fuera de casa. Cuando llegué estaba todo desparramado. Tenía las bandejas sobre una barrica de roble que uso como mesa para trabajar con las plantas más pequeñas. Muy expuestas a las ráfagas. Luego hice otros almácigos y los puse a reparo. Pero ya no tenía de esas semillas, así que mi colección aumentó en número, pero no en variedad. Si te preguntas por cómo logro hacer que las semillas germinen con cierta facilidad. Las hidrato con té de manzanilla por una o dos horas, luego las llevo al almácigo. La manzanilla evitará que durante la germinación sean atacadas por hongos y promueve aparentemente el desarrollo de las raíces. Incluso puedes regar las almacigueras con un té diluido de manzanilla tres veces a la semana hasta que las plantitas estén más fuertes. Claudio. El jardinerista. PD: No me olvidé del fuego que se apaga con leche. Me refería al picante del ají. Si tu boca arde como si tuvieras una brasa al rojo vivo, un buen vaso de leche apaga el incendio. La grasa de la leche disuelve capsaicina y es neutralizada por la caseína que posee. PD1: si tienes semillas de ajíes extraños y picantes. O no tan picantes. Acepto el regalo. (contacto@claudiodoratto.com)
The PD1 that lost, biopharma earns FDA approval, and the Biotech market is cool not dead Find out more athttps://LifeScienceTodayPodcast.comStory ReferencesEli Lilly + Innovent BiologicsAgiosTC BiopharmBlue Water VaccinesMeihua About the ShowLife Science Today is your source for stories, insights, and trends across the life science industry. Expect weekly highlights about new technologies, pharmaceutical mergers and acquisitions, news about the moves of venture capital and private equity, and how the stock market responds to biotech IPOs. Life Science Today also explores trends around clinical research, including the evolving patterns that determine how drugs and therapies are developed and approved. It's news, with a dash of perspective, focused on the life science industry.
En este primer episodio charlaremos con el doctor Delvys Rodríguez Abreu, Jefe del Servicio de Oncología del Hospital Insular de Las Palmas de Gran Canaria. El Dr. Delvys Rodríguez nos contará su participación en numerosos ensayos clínicos con nuevas terapias del cáncer que le han hecho adquirir una gran reputación a nivel internacional, publicando en revistas tan prestigiosas como el “New England Journal of Medicina” o “Lancet”. Hablaremos de sus inicios, de su infancia en Cuba, sus estudios de Medicina y su formación y pasión por la Oncologia. Adentrándonos en el ámbito médico, nos hablará acerca de los avances importantes que han tenido lugar en los últimos años en el tratamiento del cáncer, tales como las terapias dirigidas y la inmunoterapia. Esta Charla nos muestra a un profesional brillante, pero a la vez humilde y enormemente comprometido con la investigación y el estudio de la oncología en beneficio de sus pacientes. El Dr. Delvys Rodríguez nos transmite, de manera muy cercana, algunas de sus experiencias y enseñanzas aprendidas respecto al trato con pacientes con cáncer, lo cual le ha servido para mejorar a nivel profesional y personal. 1:22. Infancia en San Juan de Las Lleras, Cuba, y el despertar de mi interés por la Medicina y la Oncologia 8:50. Estudios médicos en Santa Clara, La Habana, Instituto de Oncología de la Habana 9:55 Ampliación de estudios en Bellinzona, Suiza; Franco Cavalli 15:20 Instituto Catalán de Oncología, Rosell; Servicio de Oncología del Hospital Insular de Gran Canaria, Adolfo Murias. 18:30 Oncología y definición del cáncer 23:10 Avances en los tratamientos del cáncer: secuenciación genética y terapias dirigidas 29:10 La revolución de la inmunoterapia en el cáncer: CTLA-4, PD1, Allison, Honjo, Rosenberg 35:55 Ensayos clínicos. Melanoma y cáncer de pulmón. 41:00 Historia del paciente de La Palma 44:15 Biopsia liquida, screening, diagnostico y chequeo preventivo de cáncer 52:10. CAR-T / anticuerpos conjugados 56:10 Experiencias personales de trabajar con enfermos con cáncer. 1:00:30 Curación espontanea de melanoma metastasico en paciente en Cuba 1:02:50 La muerte cercana e inevitable. “Tenía que haber dedicado mas tiempo a mí y menos al trabajo” 1:06:47 Mi libro preferido, un país para visitar y persona que me gustaría conocer
El 5 de julio de 1996 nació Dolly, una oveja idéntica a su madre de cabo a rabo. En el 98 nacieron Megan y Moran. Otras dos ovejas idénticas. Pero si bien fueron los casos más renombrados, el primer clon fue una rana en 1952 y luego en el 91 unos cerdos en vías de extinción que eran un 90% idénticos a los originales. Para la ciencia fueron logros importantes. Para la sociedad, otra fue la mirada. Muchos a favor. Muchos en contra. ¿Tú qué piensas? Más allá de ello, en la agricultura y jardinería venimos produciendo clones desde hace muchísimos años. De hecho, ayer te contaba que María Rosa multiplicaba crasas. Lo hacía a partir de un tallo o de una hoja. Las plantas obtenidas son idénticas a las “madres” por lo tanto son también clones. Cuando queremos tener un rosal que nos dé flores con la misma belleza que tiene la planta que deseamos multiplicar, no lo haremos desde una semilla, sino de una porción de rama que llamaremos esqueje o estaca. Y tendremos un clon de ese rosal. Si deseas tener un duraznero, manzano, un rosal o incluso otra planta perenne y quieres que te regale la misma belleza que la que te atrapó originalmente. Obtenerla a partir de una porción vegetal como un tallo es el camino. Para ello tengo el curso de “multiplicación vegetal por esqueje de tallo” así aprendes la técnica a aplicar. Claudio. El Jardinerista PD: Si queremos producir “rosas de corte” para su venta, emplearemos ejemplares producidos a partir de una única planta llamada “madre” para que las flores sean idénticas. PD1: en un monte frutal también tendremos clones para unificar la calidad, cantidad y el momento de la producción. El curso lo tienes aquí: https://cursosdejardineria.com/downloads/multiplicacion-vegetal-esquejes-tallo/ Mi boletín aquí: https://claudiodoratto.com/boletin El canal de Telegram: https://t.me/jardineros
Esta historia creo habértela contado hace algún tiempo atrás. Se trata de la bignonia rosada (Podranea ricasoliana) de un cliente que no florecía. Ya corría el mes de febrero (mediados de verano) y en todos los paseos públicos estaban cargadísimas de flores. Pero en la casa de Roberto, no. Por lo que me llamaron para que la vea y le indicara a la persona que le atendía el jardín qué debía hacer. A Roberto y María los conocía desde hacía unos años. Cuando les diseñé su jardín y lo realizamos. Para ser más fiel a la realidad, lo hicimos y rehicimos varias veces gracias a un “socio” que hicimos en su casa. Juanchi Juanchi es un rottweiler en un jardín de 25 metros cuadrados que con su juego destruyó literalmente el jardín dos veces. Pero es una historia que te contaré otro día. Cuando hicimos por tercera vez el jardín María se había enamorado de la bignonia y quiso incorporarla para cubrir la pared del final del patio. Por la forma de crecimiento les sugerí construir una estructura metálica para que la soportara y sea revestida de verde. La planta creció y cubrió casi toda la estructura entre la primavera y los meses de verano que llevaba en el jardín. Pero ni una sola flor. Fue entonces que me llamaron. El problema estaba en la poda. Cada semana se la recortaba para mantenerla parejita y bien formada. Con este trabajo de “peluquería” se cortaban todos los brotes nuevos que son los portadores de las yemas florales. Las que darán origen a los ramilletes de flores. Desde ese momento y con la nueva forma de conducción, todos los años florecen. Si tienes alguna duda sobre cómo podar las plantas y no perder las flores en el camino, tienes el curso de tipos de poda de arbustos que preparó mi amigo Fernando. Claudio. El Jardinerista PD: Cuando incorpores plantas arbustivas o trepadoras por sus flores, debes informarte sobre qué tipo de ramas lo hace. En algunas será sobre brotes del año como la bignonia y los rosales pero en otras lo hará sobre madera más vieja. PD1: si deseas podar tus plantas de la forma correcta, tienes el curso sobre los tipos de poda. PD2: Mañana te cuento sobre la misma planta cuando las coloqué en mi jardín apenas me mudé. El curso aquí: https://cursosdejardineria.com/downloads/tipos-poda-arbustos/ Mi boletín aquí: https://claudiodoratto.com/boletin Planes de iVoox para escuchar mejor: Premium anual: https://www.ivoox.com/premium?affiliate-code=27a8148529dcba4a4dbdf2e9305a45e3 Premium mensual: https://www.ivoox.com/premium?affiliate-code=2498325e5bbbcd2944ab8995da555702 iVoox Plus: https://www.ivoox.com/plus?affiliate-code=b43285875c57af6b39d360e604a7632e
Esta historia se trata de una planta llamada euforbia azul (Euphorbia rigida), muy utilizada en jardines del tipo xerófilo. Pedro se dice a sí mismo que es un jardinero aficionado, y no te puedo ocultar que me genera ciertas dudas esa afirmación. Pero mejor lo dejamos ahí, es medio pariente así que mejor mantener las relaciones. Me cuenta un día que está comenzando a realizar lo que llama “el jardín de sus sueños” que consiste en que se vea lindo y no tener que trabajar en lo absoluto (o lo mínimo indispensable) para mantenerlo. Descartó colocar césped para no tener que regarlo y segarlo. Puso en distintos canteros y macetas plantas que había leído que no necesitaban ser regadas o en el vivero le dijeron que toleran la sequía. Así que se confió. La intención de Pedro era constituir un jardín de fácil mantenimiento, poner unas plantas aquí, otras allí y unas más allá. Cada vez que se inspiraba con su jardín cortaba flores secas y ocasionalmente regaba. Entonces vinieron unos días muy secos y calurosos. Las super resistentes euforbias quedaron desparramadas colgando de las jardineras. Parecían pulpos con los tentáculos cayendo al suelo, inertes. Me envió un par de fotos por “guasap” diciendo que las plantas grises se les habían enfermado, que ¿qué hacía?. Le pedí más fotos para ver algunos detalles más. El diagnóstico era evidente. Deshidratación. A lo que me respondió medio ofendido diciendo que en el vivero le dijeron que no las tenía que regar y bla, bla, bla… Ya sabes, uno en ocasiones se acuerda de la mitad de las recomendaciones. Como medio pariente que es, me armé de paciencia y le expliqué la importancia de “regar” cuando las plantas están en macetas o contenedores. El sustrato se seca más rápido, las raíces no pueden crecer y profundizar en busca de agua, etc. Etc. Eso sin contar con la temperatura que alcanzaban estando a pleno sol como las tenía. Tal vez te preguntes ¿qué decidió hacer para que en el futuro no se repita la situación? Bueno, algunas las trasplantó directo en el jardín y a otras las puso en contenedores más grandes y riega periódicamente. Para evitar posibles problemas al diseñar un jardín y saber concretamente de qué se trata uno pensado para que “casi” no tengas que trabajar en su mantenimiento tienes la colección Nº 2 “La impronta del jardín” PD: la colección está formada por 6 audios hablando de distintos tipos de jardines urbanos. PD1: si buscas las características de un jardín italiano o francés, esta colección no es para ti. Los audios aquí: https://cursosdejardineria.com/downloads/2-la-impronta-del-jardin/ Mi boletín de novedades: https://claudiodoratto.com/boletin Claudio. El jardinerista
欢迎收听雪球和喜马拉雅联合出品的财经有深度，雪球，国内领先的集投资交流交易一体的综合财富管理平台，聪明的投资者都在这里。听众朋友们大家好，我是主播匪石-34，今天分享的内容名字叫做明年估计会是美股生物科技收购大年，来自张小丰。明年估计会是美股生物科技收购大年，原因很简单：买家需求变高，卖家估值变低。现在有好几个大药企有非常强的收购需求，同时美股生物科技股指从最高点174已经跌到115了。跌幅很大，腰斩的小企业比比皆是。通常这时候并购就要来了。我们来分析几个潜在的大买家。1：辉瑞原因很简单，太多钱了。辉瑞通过新冠疫苗和口服药已经赚疯了。预期明年营收可以突破人类历史达到惊人的1000亿美元。手握这么多钱，只有2个选择：并购或者发一次大规模特殊股息。辉瑞本身的业务增长是比较乏力的，所以他们选择并购的概率很大，并且历史上辉瑞一直是并购大买家。所以明年来个大型并购是非常有可能的。2：诺华诺华最近才卖了罗氏的股份拿到200亿美元现金。并且诺华之前的长期预算是每年拿100亿并购。所以诺华可支出的并购预算变成300亿美元。同时从管线的角度来说，这些年几个给予厚望的药物临床失败，导致诺华增长乏力。本身并购的需求就很强。诺华最近甚至在考虑把旗下的仿制药板块直接出售，这样钱就更多了。还有一点就是CEO从之前的履历和并购历史来看是属于非常喜爱黑科技的类型。3：默克默克成也PD1，败也PD1。目前华尔街投资人对默克处于一个非常焦虑的状态：未来PD1专利到期怎么办？那时候Keytruda（派姆单抗）会是一个年收入超过200亿美元的巨无霸。而默克的管线完全没看出有能力填这巨坑。而默克CEO本人也表示：默克有财力做任何规模的并购。随着时间的流逝，默克并购压力只会越来越大。4：百时美施贵宝百时美施贵宝之前并购了新基，也就继承了新基的专利悬崖：超百亿的来那度胺。所以施贵宝一直有并购需求来填坑。现在距离专利悬崖越来越近了，那么并购需求也在增强。5：安进安进也有专利到期的问题。同时内部增长乏力。但安进的自研能力还有保留，更多的可能是做小型并购来扩充管线。6：福泰福泰的CF产品线非常成功，10年之内都没有专利悬崖威胁。但福泰在其他领域这几年是屡战屡败。并且福泰最大的问题在于管线过于单薄，已经配不上自己的体量。而福泰不像再生元那样自研能力极强，自身可以产出非常多的研发项目。所以福泰进入买买买模式来破局的概率也很高。我估计如果出现大型并购，更有可能会在前3家。后3家更多的可能是中小型并购来扩充管线。通常阻碍并购的最大障碍就是高估值，现在估值也下来了
欢迎收听雪球和喜马拉雅联合出品的财经有深度，雪球，国内领先的集投资交流交易一体的综合财富管理平台，聪明的投资者都在这里。听众朋友们大家好，我是主播匪石-34，今天分享的内容名字叫做明年估计会是美股生物科技收购大年，来自张小丰。明年估计会是美股生物科技收购大年，原因很简单：买家需求变高，卖家估值变低。现在有好几个大药企有非常强的收购需求，同时美股生物科技股指从最高点174已经跌到115了。跌幅很大，腰斩的小企业比比皆是。通常这时候并购就要来了。我们来分析几个潜在的大买家。1：辉瑞原因很简单，太多钱了。辉瑞通过新冠疫苗和口服药已经赚疯了。预期明年营收可以突破人类历史达到惊人的1000亿美元。手握这么多钱，只有2个选择：并购或者发一次大规模特殊股息。辉瑞本身的业务增长是比较乏力的，所以他们选择并购的概率很大，并且历史上辉瑞一直是并购大买家。所以明年来个大型并购是非常有可能的。2：诺华诺华最近才卖了罗氏的股份拿到200亿美元现金。并且诺华之前的长期预算是每年拿100亿并购。所以诺华可支出的并购预算变成300亿美元。同时从管线的角度来说，这些年几个给予厚望的药物临床失败，导致诺华增长乏力。本身并购的需求就很强。诺华最近甚至在考虑把旗下的仿制药板块直接出售，这样钱就更多了。还有一点就是CEO从之前的履历和并购历史来看是属于非常喜爱黑科技的类型。3：默克默克成也PD1，败也PD1。目前华尔街投资人对默克处于一个非常焦虑的状态：未来PD1专利到期怎么办？那时候Keytruda（派姆单抗）会是一个年收入超过200亿美元的巨无霸。而默克的管线完全没看出有能力填这巨坑。而默克CEO本人也表示：默克有财力做任何规模的并购。随着时间的流逝，默克并购压力只会越来越大。4：百时美施贵宝百时美施贵宝之前并购了新基，也就继承了新基的专利悬崖：超百亿的来那度胺。所以施贵宝一直有并购需求来填坑。现在距离专利悬崖越来越近了，那么并购需求也在增强。5：安进安进也有专利到期的问题。同时内部增长乏力。但安进的自研能力还有保留，更多的可能是做小型并购来扩充管线。6：福泰福泰的CF产品线非常成功，10年之内都没有专利悬崖威胁。但福泰在其他领域这几年是屡战屡败。并且福泰最大的问题在于管线过于单薄，已经配不上自己的体量。而福泰不像再生元那样自研能力极强，自身可以产出非常多的研发项目。所以福泰进入买买买模式来破局的概率也很高。我估计如果出现大型并购，更有可能会在前3家。后3家更多的可能是中小型并购来扩充管线。通常阻碍并购的最大障碍就是高估值，现在估值也下来了
欢迎收听雪球和喜马拉雅联合出品的财经有深度，雪球，国内领先的集投资交流交易一体的综合财富管理平台，聪明的投资者都在这里。听众朋友们大家好，我是主播匪石-34，今天分享的内容名字叫做投资国产创新药的底层逻辑，来自胡涂的森林。一是新药审批制度改革。源于2015年的一系列药审制度改革，核心就是像FDA看齐，鼓励创新，审批加快。之前一个药物审批上十年，印象深刻的是，那时候吹嘘康缘的银杏内酯B，干了十年，不知道后面做出来没有。改革后缩短到从提交临床到获批最快只要2年时间。中国又加入了ICH组织，相当于加入创新药WTO。创新药拼的就是时间，这点至关重要。二是人才优势。一二十年前讲的“二十一世纪是生物科学的世纪”，忽悠了一大批精英学生读生物专业，我记得那几年很多状元都读北大清华的生物专业。结果这批人毕业时，中国生物医药没发展起来，都只有出国留学了。外国人喜欢刷盘子、解剖小白鼠，中国人聪明又刻苦耐劳，结果后面这些人很多在国外做到了科研机构、大型药企的顶级科学家，掌握了核心技术。现在他们纷纷响应“国家号召”回国发展了。你会看到，这些国内创新药企的高管基本都是这些海归科学家。三是工程师红利。高校扩招后，中国有大量的理工科大学毕业生，虽然整体质量不高，但也能用，最主要是工资低，美国要几万美元的工资，中国也就10-20万，药物研究其实也是个体力活。这几年国内CRO崛起很大程度也是因为工程师红利。四是临床资源优势。中国人多，病人多，缺钱的病人也多。临床招募和费用相对低很多。可以看到美国临床的费用，比如一个病人十万美元成本，中国也就几万十几万，这个也差一个数量级。所以你会看到，国产创新药一个PD1几亿、十亿研发成本，美国欧洲可能是几亿、十亿美元。五是广阔的本土市场。我们人口多，并且有2-3亿人是达到发达国家水平的收入，这部分的销费能力是很强的，国产创新药有中国这一个本土市场，你会看到不少药物国内也能卖到10亿美元级别。不一定像很多小国家的药企一样，它必须、只能去美国、欧洲拼刺刀。说白了，这是国产创新药的安全边际，再不济国内上市也可以卖点。六是医保支持。很多人只看到了集采、医保谈判。没有看到国家对创新药的支持。退过去5年、10年，没有普及医保，医保没有谈判纳入创新药，一个创新药的放量是非常慢的，可能干几年也就干到几亿不得了了，那个时候我就做作医药股，模型从来也就算个上市三年卖到5亿、10亿。现在你可以看到不少纳入医保的创新药，做到第一年10年，第二年20几亿。完全不可同日而语。七是资金支持。人人搞风投的时代，市场不缺钱，只是资金往往锦上添花，并不一定雪中送炭。看创新药企的高管访谈，基本谈创业时融资的艰难。但这几年资金完全时在大水漫灌这个行业。资金涌入，不一定都赚钱，但对行业绝对是极大的推动，总会有项目跑出来。八是国际化。背靠国内利基市场，坐望全球创新。目前国内生物制药行业，有的领域，比如细胞疗法、双抗已经处于全球领先的的位置。每年有很多上十亿美元级别的国际 licence out，已经有创新药在国外上市，未来还会有更多的国产创新药在美国、欧洲上市，赚美元，参与国际市场，一美元就是6.5元人民币，利润会更高。相信就在几个月内，会有一款，全球真正BIC的国产重磅创新药十几亿美元，在美国欧洲上市。九个人能力圈。投资生涯十几年来，我发现我对生物医药行业情有独钟，有可能是我初中的时候很喜欢生物，可惜数学学不好，后面读的文科，有可能是生物医药就像水电站一样，一个个的电站，它的未来投产、收入、利润、实现的概率，是可以大致预估出来的。能够预估未来的收入、利润及实现的概率，这对谨慎的基本面投资者来说是很重要的。这些年我在医药行业成功投资了恒瑞、中生、信达、金斯瑞和康方，获利都在1倍以上，成功概率挺高。所谓，成大事者讲究的天时、地利、人和，是不是都占齐了。国产创新药的未来会是星辰大海
欢迎收听雪球和喜马拉雅联合出品的财经有深度，雪球，国内领先的集投资交流交易一体的综合财富管理平台，聪明的投资者都在这里。听众朋友们大家好，我是主播匪石-34，今天分享的内容名字叫做投资国产创新药的底层逻辑，来自胡涂的森林。一是新药审批制度改革。源于2015年的一系列药审制度改革，核心就是像FDA看齐，鼓励创新，审批加快。之前一个药物审批上十年，印象深刻的是，那时候吹嘘康缘的银杏内酯B，干了十年，不知道后面做出来没有。改革后缩短到从提交临床到获批最快只要2年时间。中国又加入了ICH组织，相当于加入创新药WTO。创新药拼的就是时间，这点至关重要。二是人才优势。一二十年前讲的“二十一世纪是生物科学的世纪”，忽悠了一大批精英学生读生物专业，我记得那几年很多状元都读北大清华的生物专业。结果这批人毕业时，中国生物医药没发展起来，都只有出国留学了。外国人喜欢刷盘子、解剖小白鼠，中国人聪明又刻苦耐劳，结果后面这些人很多在国外做到了科研机构、大型药企的顶级科学家，掌握了核心技术。现在他们纷纷响应“国家号召”回国发展了。你会看到，这些国内创新药企的高管基本都是这些海归科学家。三是工程师红利。高校扩招后，中国有大量的理工科大学毕业生，虽然整体质量不高，但也能用，最主要是工资低，美国要几万美元的工资，中国也就10-20万，药物研究其实也是个体力活。这几年国内CRO崛起很大程度也是因为工程师红利。四是临床资源优势。中国人多，病人多，缺钱的病人也多。临床招募和费用相对低很多。可以看到美国临床的费用，比如一个病人十万美元成本，中国也就几万十几万，这个也差一个数量级。所以你会看到，国产创新药一个PD1几亿、十亿研发成本，美国欧洲可能是几亿、十亿美元。五是广阔的本土市场。我们人口多，并且有2-3亿人是达到发达国家水平的收入，这部分的销费能力是很强的，国产创新药有中国这一个本土市场，你会看到不少药物国内也能卖到10亿美元级别。不一定像很多小国家的药企一样，它必须、只能去美国、欧洲拼刺刀。说白了，这是国产创新药的安全边际，再不济国内上市也可以卖点。六是医保支持。很多人只看到了集采、医保谈判。没有看到国家对创新药的支持。退过去5年、10年，没有普及医保，医保没有谈判纳入创新药，一个创新药的放量是非常慢的，可能干几年也就干到几亿不得了了，那个时候我就做作医药股，模型从来也就算个上市三年卖到5亿、10亿。现在你可以看到不少纳入医保的创新药，做到第一年10年，第二年20几亿。完全不可同日而语。七是资金支持。人人搞风投的时代，市场不缺钱，只是资金往往锦上添花，并不一定雪中送炭。看创新药企的高管访谈，基本谈创业时融资的艰难。但这几年资金完全时在大水漫灌这个行业。资金涌入，不一定都赚钱，但对行业绝对是极大的推动，总会有项目跑出来。八是国际化。背靠国内利基市场，坐望全球创新。目前国内生物制药行业，有的领域，比如细胞疗法、双抗已经处于全球领先的的位置。每年有很多上十亿美元级别的国际 licence out，已经有创新药在国外上市，未来还会有更多的国产创新药在美国、欧洲上市，赚美元，参与国际市场，一美元就是6.5元人民币，利润会更高。相信就在几个月内，会有一款，全球真正BIC的国产重磅创新药十几亿美元，在美国欧洲上市。九个人能力圈。投资生涯十几年来，我发现我对生物医药行业情有独钟，有可能是我初中的时候很喜欢生物，可惜数学学不好，后面读的文科，有可能是生物医药就像水电站一样，一个个的电站，它的未来投产、收入、利润、实现的概率，是可以大致预估出来的。能够预估未来的收入、利润及实现的概率，这对谨慎的基本面投资者来说是很重要的。这些年我在医药行业成功投资了恒瑞、中生、信达、金斯瑞和康方，获利都在1倍以上，成功概率挺高。所谓，成大事者讲究的天时、地利、人和，是不是都占齐了。国产创新药的未来会是星辰大海
欢迎收听雪球和喜马拉雅联合出品的财经有深度，雪球，国内领先的集投资交流交易一体的综合财富管理平台，聪明的投资者都在这里。听众朋友们大家好，我是主播匪石-34，今天分享的内容名字叫做投资国产创新药的底层逻辑，来自胡涂的森林。一是新药审批制度改革。源于2015年的一系列药审制度改革，核心就是像FDA看齐，鼓励创新，审批加快。之前一个药物审批上十年，印象深刻的是，那时候吹嘘康缘的银杏内酯B，干了十年，不知道后面做出来没有。改革后缩短到从提交临床到获批最快只要2年时间。中国又加入了ICH组织，相当于加入创新药WTO。创新药拼的就是时间，这点至关重要。二是人才优势。一二十年前讲的“二十一世纪是生物科学的世纪”，忽悠了一大批精英学生读生物专业，我记得那几年很多状元都读北大清华的生物专业。结果这批人毕业时，中国生物医药没发展起来，都只有出国留学了。外国人喜欢刷盘子、解剖小白鼠，中国人聪明又刻苦耐劳，结果后面这些人很多在国外做到了科研机构、大型药企的顶级科学家，掌握了核心技术。现在他们纷纷响应“国家号召”回国发展了。你会看到，这些国内创新药企的高管基本都是这些海归科学家。三是工程师红利。高校扩招后，中国有大量的理工科大学毕业生，虽然整体质量不高，但也能用，最主要是工资低，美国要几万美元的工资，中国也就10-20万，药物研究其实也是个体力活。这几年国内CRO崛起很大程度也是因为工程师红利。四是临床资源优势。中国人多，病人多，缺钱的病人也多。临床招募和费用相对低很多。可以看到美国临床的费用，比如一个病人十万美元成本，中国也就几万十几万，这个也差一个数量级。所以你会看到，国产创新药一个PD1几亿、十亿研发成本，美国欧洲可能是几亿、十亿美元。五是广阔的本土市场。我们人口多，并且有2-3亿人是达到发达国家水平的收入，这部分的销费能力是很强的，国产创新药有中国这一个本土市场，你会看到不少药物国内也能卖到10亿美元级别。不一定像很多小国家的药企一样，它必须、只能去美国、欧洲拼刺刀。说白了，这是国产创新药的安全边际，再不济国内上市也可以卖点。六是医保支持。很多人只看到了集采、医保谈判。没有看到国家对创新药的支持。退过去5年、10年，没有普及医保，医保没有谈判纳入创新药，一个创新药的放量是非常慢的，可能干几年也就干到几亿不得了了，那个时候我就做作医药股，模型从来也就算个上市三年卖到5亿、10亿。现在你可以看到不少纳入医保的创新药，做到第一年10年，第二年20几亿。完全不可同日而语。七是资金支持。人人搞风投的时代，市场不缺钱，只是资金往往锦上添花，并不一定雪中送炭。看创新药企的高管访谈，基本谈创业时融资的艰难。但这几年资金完全时在大水漫灌这个行业。资金涌入，不一定都赚钱，但对行业绝对是极大的推动，总会有项目跑出来。八是国际化。背靠国内利基市场，坐望全球创新。目前国内生物制药行业，有的领域，比如细胞疗法、双抗已经处于全球领先的的位置。每年有很多上十亿美元级别的国际 licence out，已经有创新药在国外上市，未来还会有更多的国产创新药在美国、欧洲上市，赚美元，参与国际市场，一美元就是6.5元人民币，利润会更高。相信就在几个月内，会有一款，全球真正BIC的国产重磅创新药十几亿美元，在美国欧洲上市。九个人能力圈。投资生涯十几年来，我发现我对生物医药行业情有独钟，有可能是我初中的时候很喜欢生物，可惜数学学不好，后面读的文科，有可能是生物医药就像水电站一样，一个个的电站，它的未来投产、收入、利润、实现的概率，是可以大致预估出来的。能够预估未来的收入、利润及实现的概率，这对谨慎的基本面投资者来说是很重要的。这些年我在医药行业成功投资了恒瑞、中生、信达、金斯瑞和康方，获利都在1倍以上，成功概率挺高。所谓，成大事者讲究的天时、地利、人和，是不是都占齐了。国产创新药的未来会是星辰大海
In this week's episode, we'll review a study providing new insights on megakaryocyte diversity and function, including a unique subpopulation that may act as immune cells. Next, we'll review research that intriguingly reveals a putative role for the PD1 gene in cutaneous T-cell lymphoma. Lastly, we'll conclude with a report demonstrating a lack of cross-reaction between the antibodies that cause vaccine-induced thrombocytopenia and thrombosis, and the COVID-19 spike protein.
Immunotherapy is transforming the treatment landscape for triple-negative breast cancer. Through patient cases, Drs. Ruth O'Regan (medical oncologist, University of Rochester) and Jacob Kettle (Pharmacist, University of Missouri) discuss the application of novel treatment options. Subscribe: Apple Podcasts, Google Podcasts | Additional resources: elearning.asco.org | Contact Us Air Date: 8/18/2021 TRANSCRIPT [MUSIC PLAYING] SPEAKER: The purpose of this podcast is to educate and inform. This is not a substitute for medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. RUTH O'REGAN: Hello and welcome to ASCO's Education Podcast episode, focused on new therapies for triple negative breast cancer. My name is Ruth O'Regan. I'm a medical oncologist and the Chair of Medicine at the University of Rochester. JACOB KETTLE: And I'm Dr. Jacob Kettle. I'm an oncology clinical pharmacy specialist and pharmacy manager at University of Missouri Health Care's Ellis Fischel Cancer Center. We'll start our discussion today with a patient case. So let's say we have a 64-year-old female diagnosed with stage two triple-negative breast cancer three years ago. She received neoadjuvant AC-T and then underwent mastectomy, followed by adjuvant capecitabine. One year after completing therapy, she presented with new neck masts. Imaging demonstrated cervical nodes, probable liver metastases, and lymph node biopsy confirmed suspicion of recurrence, and now metastatic triple-negative breast cancer that is PDL1 positive. So Dr. Regan, what, in this patient, would you be considering for therapy for her. RUTH O'REGAN: Yeah, so I think unfortunately this is a pretty typical history of a patient with triple-negative breast cancer having this recurrence within two to three years of diagnosis. So her cancer is PDL1 positive, so obviously that would mean that we would consider immunotherapy for this patient. And there are two options with regard to this. We can either use atezolizumab or pembrolizumab plus chemotherapy, which could be paclitaxel, nab-paclitaxel, or, indeed, gemcitabine and carboplatin. So just to very briefly review the trials-- so the IMpassion 130 trial randomized patients in the first-line setting with metastatic triple-negative breast cancer to nab-paclitaxel weekly with or without atezolizumab, and it showed a benefit and progression-free survival of about two months in patients whose cancers were PDL1 positive, and also an overall survival advantage that was quite meaningful at about seven months in the patients who received the immunotherapy plus nab-paclitaxel compared to the control arm. So that obviously would be a very reasonable option for this patient. The KEYNOTE-355 trial evaluated chemotherapy, which could be paclitaxel, nab-paclitaxel gemcitabine, carboplatin, with or without pembrolizumab, again in the first-line setting for metastatic triple-negative breast cancer. And so really, very similar results to the IMpassion study with about a two month improvement in progression-free survival in patients whose cancers were PDL1 positive. What we'll talk about later on is how we define PDL1 positivity in this patient population. JACOB KETTLE: Yeah, I think that's an important distinction. RUTH O'REGAN: Yeah, I think we can talk about that, because I think most of us now are actually doing both of the assays. But on the face of it, in somebody who has a cancer that's PDL1 positive, I'm not sure that there's a huge difference. Obviously you can't do cross-trial comparisons. I tend to use atezolizumab plus nab-paclitaxel because that was the first one that was approved. But I also think, in a patient who's had a recent taxane, using pembrolizumab plus gem/carbo would also be very reasonable. The other trial I was just going to mention was the IMpassion 131 trial. JACOB KETTLE: Yeah, absolutely. It's a game changer. RUTH O'REGAN: It really is, because in that study they use paclitaxel with or without atezolizumab and actually didn't see an advantage for the immunotherapy, even in patients with PDL1 positive cancers. We really don't know why that is, but it's definitely an interesting finding. JACOB KETTLE: I mean, I think that really speaks to the importance of sticking with what we know from the trials. RUTH O'REGAN: Absolutely JACOB KETTLE: I think there's a tendency, especially with pembro's FDA approval, says chemo. Just-- that's it, chemo. But the trial, as you mentioned, limits it to paclitaxel, nab-paclitaxel, or the combination of carbo and gemcitabine, but really to extrapolate that to other chemo regimens, other drugs, I think that's a little bit of a stretch. Because, again, we saw an IMpassion 131, maybe it's not, across the board, efficacious. There may be some subtle differences there. I'm glad you brought that up, because I think that's an important distinction. RUTH O'REGAN: It's all about following the data. I think that's a key thing. So Jake, just in your role as a pharmacist, I think will be very interesting for you to talk a little bit about toxicity of these agents, and if there's any difference in the safety profile between these agents. JACOB KETTLE: Yeah, I think what we've seen is pretty consistent as really all our experiences. We've started combining immunotherapy with chemotherapies that really it's not this new emergence of unexpected toxicity or an unacceptable level of toxicity. It's just what we would expect with chemotherapy agents and what we've already known with immune therapy agents. So there's nothing new and emergent or difficult to deal with. And from the IO toxicity profile, it's all the same stuff we're used to. Derm toxicities, GI, pulmonary, endocrinopathies for the most part. We are comparing to PD1 inhibitor in pembrolizumab to PDL1 inhibitor in atezolizumab, so maybe there are some subtle differences. I think some of the things I've read have suggested maybe endocrinopathies are potentially more likely with PD 1 inhibitors. But these are all subtle things, very nuanced-- I don't think anything that would really dictate a difference in choice of therapy. So I think from the side effect profile, fairly interchangeable, at least from the immunotherapy perspective. Obviously, we're talking about the biggest difference is the chemo backbone, and that's going to be a key driver in what regimen you pick. Again atezolizumab-- very limited to the nab-paclitaxel backbone, which is great drug. Like you said, it was the first out. And I think another important caveat is that is the only trial in this space where we have overall survival data. We don't see that yet in KEYNOTE-355. Although, as you pointed out, PFS looks very similar between the two. So we anticipate-- don't extrapolate too much, but anticipate those are, efficacy-wise, pretty interchangeable. But the chemo backbone-- big difference between the two. Again, you have a little bit of flexibility of pembrolizumab to use paclitaxel, nab-paclitaxel. Or I think, again, for those patients that have recently exposed to paclitaxel-- it kind of fits with our case. This patient-- relatively early relapse, pretty early recently exposed to taxanes in the neoadjuvant or adjuvant space, you may want to use a different regimen. Carboplatin and gemcitabine-- a great commonly used triple-negative backbone, especially again, if you have those folks with more disease burden, visceral disease, where you want to get that bigger punch up front. I think that's another potential role there. But one other thing is to talk about logistics. These kind of regimens are very different because of how the immunotherapy is dosed. So when we use atezolizumab with nab-paclitaxel, that aligns very nicely with a 28-day cycle. Atezolizumab on day 1 and 15, nab-paclitaxel on day 1, 8, and 15. An off day at 22 that flows really nicely. Pembrolizumab, when you combine it with carbo and gemcitabine, that aligns really nicely with the 21-day cycle. Again, pembrolizumab on day 1, carbo, gem, day 1 and 8 and off day of 15. The regimen that gets a little funky, for lack of a better word, is when you try to combine pembrolizumab with the taxane, because the taxanes kind of line up on a 28-day cycle, days 1, 8, and 15. And pembrolizumab is a 21-day cycle. So that could become a little bit cumbersome to navigate those waters and get those doses the right days. So you can just, from a logistical perspective, I think there's some differences there. And the challenge really is, how do we kind of get this nice balance of finding the treatment regimen that's compatible with the patient's lifestyle, the monitoring frequency, and just your clinical operations to make sure all those things align? And we do want to have some flexibility. I think that's one of the great gifts in modern oncology, is we have all these good choices, but both are really important. You also want to have some consistency. So anyway, that's a really long-winded answer to side effects. I don't think there's much difference, in terms of side effects. RUTH O'REGAN: I think your point is very important. Because this is all about the patient, of course. Because we've got metastatic triple negative breast cancer. So I think making it as painless as possible for them to come in, as far as their scheduling, I think, obviously, is very important. Now, I think one of the issues with the immunotherapy is that I don't think we got great biomarkers. So we use PD-L1, but really, it's imperfect. And as we kind of alluded to earlier in the IMPASSION study, they used PD-L1 on the immune cells as a marker, and about 40% of the cancers in that study were determined to be positive. And that's where the benefit was seen. In contrast, in the KEYNOTE study, they used what I think a lot of, outside the breast cancer world, is being used a lot, is this CPS, or Combined Positive Score, that basically looks at the PD-L1 positive tumor cells and immune cells and basically looks at them compared to the overall number of tumor cells. So at this point, we're kind of in a situation where we have to kind of check for both. The interesting thing that's been shown is that there's not complete overlap. It's only about 75%. So it is possible that you could have a cancer that was PD-L1 positive by one of the assays, but not by the other. And I guess that might help us decide which agent to use, although I've never seen that myself in my practice. But I don't know what your experience with that is. It would be nice to have a better biomarker, I think. JACOB KETTLE: Yeah, I'm glad you brought that up. Because I would be in the same boat. I haven't seen a case, but obviously it's possible to have some discordance. And we're looking at PD-L1 expression, whether you're looking at the tumor, or you're looking at expression in a combined positive score, regardless of the assay, it's on a scale. It's not a yes or no question. And little, subtle differences can be the make or break between determining whether someone's PD-L1 positive. I've heard-- and I don't want to comment too much-- but there could be discordance whether you're testing archived tissue, whether you're testing metastatic tissue, maybe some differences between what site the metastatic disease was found in. Did you find it in the liver? Did you do the biopsy from the lymph node? Again, that all speaks, it goes back to the imperfection of PD-L1 as a biomarker. It's just kind of this dynamically unstable marker that's not as predictable and not as viable as some of the other biomarkers we use. And we want to take advantage of it as much as we can, and find as many unique treatment options for patients, but also don't want to leave-- we don't want to leave anything on the table. RUTH O'REGAN: And I think the other interesting thing that we'll talk about later is that PD-L1 doesn't appear to be a biomarker at all in the earlier stage setting, which is, I think, very interesting. I think one of the things that's worth mentioning is that, of course, some patients do incredibly well with immunotherapy and have very, very prolonged responses. So trying to work out who those patients are, I think, would be just incredibly valuable. I have a couple of patients that actually came off the immunotherapies because of immune toxicity, but have remained, really, in remission for years after that, even though they actually weren't even receiving the drug. So it's really fascinating. I think the other thing, though, is unfortunately, the majority of patients do not have cancers that are PD-L1 positive. And I guess the question is, what would we do for those patients? And the only really standard is chemotherapy. And I guess I'd be interested in your thoughts on, is there a preference first-line chemotherapy that would be used in your practice, or what are your thoughts on that? JACOB KETTLE: I'd more defer to you on answering that. As far as our practice, you kind of have the whole mix of what you can pick from. You've got taxanes. You've got anthracyclines. You've got gemcitabines. We've got capecitabines of the world. Eribulin is a fantastic drug. Again, a lot of that goes back to what's best for the patient. And I think that is, again, the miracle. It's a challenge, because we all of a sudden have all these options, but it's the great blessing in practicing in oncology today, is there is this wealth of options, and we have the potential to really guide therapy to what's preferential to the patient. RUTH O'REGAN: Yeah, I completely agree with that. And my thought always has been-- and I think this is very much in keeping with the NCCN guidelines-- is that there isn't a huge difference, in terms of efficacy. So I actually quite often use capecitabine in these patients, even though there was some data at one point saying that maybe capecitabine wasn't as effective in ER-negative breast cancer. I think we know that's not true in actual fact. So I think that's a great option. If they haven't had a taxane, either paclitaxel or nab-paclitaxel is a good option. And then I think if somebody's got a large burden of disease, using a doublet like gemcitabine and carboplatin is totally reasonable, as well. Obviously, thinking about clinical trials, and particularly once you get past the first line setting for these patients is very important. And I think one of the complexities about triple-negative breast cancer is the fact that there's at least four different subtypes that probably do require slightly different approaches. But at this point, that's not really standard of care. We kind of just manage them all the same way. But I think that's what's kind of on the horizon, as far as selecting at the best option for patients. I think one very interesting subset is the subset that expresses androgen receptor, and which I think initially, we were super excited about. And I still think it's very interesting, but so far the data looking at antiandrogens in these cancers has not been that impressive, although there are some patients that benefit. JACOB KETTLE: Well, I do think, too, the immunotherapy story, we kind of got talking about biomarkers. Even if you're not PD-L1 positive, even if the tumor doesn't express PD-L1, that's not necessarily the end of the role of immunotherapy in breast cancer. KEYNOTE 119 showed that pembrolizumab monotherapy later on didn't work, but we still need to be assessing for tumor mutation burden, microsatellite instability or mismatch repair. Those are other avenues by which we do have some good data to support that there is a role for immunotherapy in breast cancer, these triple-negative breast cancer patients. Like you said, only about 40% are going to be PD-L1 positive. So that leaves 60%, more than half the pie, that are going to not have a route for immunotherapy. So I do think it's important that we always explore tumor mutation burden and microsatellite instability. Because again-- and you've alluded to this-- the great promise of immunotherapy is this potential for really long, sustained responses. And until we have really good predictive tools to find exactly what patients are going to be that, I think we should be striving to at least offer that glimmer of hope, that potential opportunity to as many patients as we can. But I think it's another important part of breast cancer is that, again, immunotherapy doesn't start with PD-L1. That's just a sliver of the useful biomarkers here. RUTH O'REGAN: I completely agree with that. I think for our patients, it's important to consider sending tumor genomics, for sure, for exactly the reason that you said. I'm obviously also doing genetic testing to see if they've got a BRCA1 or BRCA2 mutation, or indeed a PALB2 mutation. Now there's some data suggesting that PARP inhibitors might actually be effective with those germline mutations as well. So I think definitely, sending that off makes sense. Unfortunately, as we know, in triple negative breast cancer, we don't very often see actionable mutations. We see them, I think, more commonly in ER-positive breast cancers. But certainly we're ascending, I would think. JACOB KETTLE: Excellent. I think that was a great discussion. Let's shift gears and do a second case and talk a little bit about this emergence of immunotherapy in the upfront setting, in the neoadjuvant setting. We'll talk about that a little bit, and then what are some additional later-line options? So we'll do our second case. This will be a 45-year-old female presents with relapsed/refractory triple-negative breast cancer, metastatic disease in the bones and liver. Her initial therapy consisted of neoadjuvant chemotherapy combined with immunotherapy. And that would be what was discussed in the KEYNOTE 522 trial. So before talking about choice of therapy for this patient, let's dive in a little bit about and talk about KEYNOTE 522. What are your thoughts of up-front immunotherapy in triple-negative disease? RUTH O'REGAN: So KEYNOTE 522 took patients with earlier stage triple-negative breast cancer and basically randomized into the standard anthracycline taxane-based chemotherapy with or without pembrolizumab, and actually showed pretty impressive pathologic complete response rate in the immunotherapy arm. It's about 65%, and it was quite a bit higher than the control arm, where it was about 50% or so. And they actually have some data as well looking at event-free survival showing a benefit for the addition of pembrolizumab. It's not FDA approved yet. And obviously, you have to take into account toxicity, which I'd certainly like to get your thoughts on. But I think we know that pathologic complete response is very important, a prognostic factor in triple-negative breast cancer, at least in most subtypes. So getting a pathologic complete response rate that high, I think, is very important. And I have to say, I tend to reserve this approach for patients who have clinically node-positive breast cancers or locally-advanced breast cancers. Because-- I should have said this earlier-- because in KEYNOTE 522, all the patients got carboplatin as well. And that's one of the problems, I think, because it's hard to add carboplatin with paclitaxel. Just to mention that we also, at ASCO, just heard a follow-up of the GeparNuevo study that looked at durvalumab with a slight, somewhat similar anthracycline taxane-based regimen. They saw a higher pathologic complete response rate in the durvalumab arm. But actually, we're showing data, now, on longer-term outcomes, and again showing a benefit for the immunotherapy. So it is interesting. I think you're always weighing up longer-term toxicities with the efficacy seen here. But I think with a pathologic complete response rate that high, I think in a patient who has more higher-stage triple-negative breast cancer, I would consider adding pembrolizumab for that patient in this setting. But I guess I'd like to hear your thoughts on weighing up toxicity. It's a little bit different in this scenario versus the metastatic setting, I think. JACOB KETTLE: I completely agree with you. That PCR rate is supremely promising. Obviously, we need time for the data to mature. But I think there's definitely a subset of patients that I think we're going to find this, hopefully, to be very beneficial. And triple-negative disease is problematic, so any additional tool is useful. But again, it's a very intense chemotherapy backbone. Four cycles of carbo-paclitaxel, and then four cycles of an anthracycline and cyclophosphamide base with pembrolizumab throughout the whole cycle, that's not going to be something that all patients are going to be able to tolerate. So again, as the data matures, my hope is that we can really narrow in on the subset of patients that this is most likely to really deliver a lot of benefit to. And I've probably said this three or four times already, but I really didn't feel like this is the great promise. But again, the great challenge of oncology practice today is, we're going to end up with four or five different great options for up-front therapy in neoadjuvant or adjuvant treatment, and it's really going to be up to us to really tailor therapy and find this ideal balance of risk and benefit ratio to meet patients' needs, and what they value. And so some patients may have, they want to avoid the severe toxicities at all costs. And that's maybe how we pursue, is to get the best benefit with that in mind. And then you'll have patients that will say, I'll go through anything. I want my risk of relapse be absolutely as low as possible, and I'll take all the chemo you're willing to throw. And trying to figure out how to walk that line, I think, is our challenge. So with that in mind, remember back to our case, our second case here, we're going to assume that this patient's relapsed after immunotherapy in the front line. And I think that is another thing we'll explore, as the years go by, is learning, what do we do when we start seeing these therapies early in treatment, whether it's breast cancer or other tumor types? But what would your approach be, if they did relapse after initial immunotherapy? RUTH O'REGAN: Well, I think this is a data-free area. And I should have said when I was talking about the earlier phase studies that PD-L1 is not a biomarker in that scenario. So if we assume this patient has PD-L1 positive cancer, I guess it would really depend on how long it was since she got the neoadjuvant chemotherapy. But I could envision if she was a couple of years out, I might think about rechallenging her, particularly with a different PD-L1 or checkpoint inhibitor. But I think that's not the likely scenario, because most of these patients will have pretty high-stage disease when they present, and they probably relapse pretty quickly. So I guess we're kind of back to the case we talked about earlier, where you're really looking at the different chemotherapy options. So I think there is a potential for rechallenging with immunotherapy. I don't know-- and you may know this-- if there's any data outside of breast cancer, like lung cancer, where this has been done, for example. I'm just not aware of that data. JACOB KETTLE: Yeah. I'm not aware of any really solid evidence. I think you can find anecdotal reports or some retrospective studies that do suggest maybe it's beneficial. And I think, especially like you mentioned, for someone with a nice long response, good, strong tolerability, all those kind of things, may be worth considering. But again, the challenge with immunotherapy, it doesn't work quickly. So you always have that component. And like you said, these are aggressive, rapid relapses. That may not be something you can lean on too heavily. So I think it all speaks back to, we're very confident in pathological complete response as a very strong surrogate marker for long-term benefit. But again, we're using it in a slightly new space. And until that data is very mature, and we have the overall survival data, what we don't know is, how does this all translate to the whole picture for the patient? If we burn out of immunotherapy up front, I don't know. Does that mean it's not useful, and we've lost lines of therapy in the relapse/refractory setting? I don't know. Those are some of the big questions we have. RUTH O'REGAN: And I think it also speaks to what you said earlier, that the whole immuno milieu of the cancer may change, depending on what setting you're looking at. So there could be very good rationale for rechallenging with immunotherapy. But again, I think this is an area where we really would need some data for sure. JACOB KETTLE: Yeah, absolutely. Very tricky. So let's play out the scenario just a little bit more. Let's say we started carboplatin and gemcitabine, for instance, in this patient. She got about nine months of therapy, and then progressed again. What other, maybe, newer options are lingering out there for sort of later-line triple-negative metastatic disease? RUTH O'REGAN: So unfortunately, of course, that's typically what you see. They usually, patients usuallt experience disease progression within six to nine months. And so obviously, alternative chemo options would be on the table, a taxane, if she hasn't had one recently, capecitabine, if she hasn't had that. However, I think for a patient like this, I would strongly consider sacituzumab, which is a relatively new antibody drug conjugate that targets Trop-2. The data from the ASCENT study, which looked at patients with triple-negative breast cancer who'd had at least two prior lines of treatment were randomized to sacituzumab or to physician's choice of chemotherapy, and the data was pretty striking. And the progression-free survival, it was less than two months in the control arm, versus six months in the sacituzumab arm. But the overall survival was doubled from six months to 12 months by using sacituzumab. So that's pretty impressive in this scenario. And it appears that, although most triple-negative breast cancers do express Trop-2, there doesn't appear to be a definitive correlation between Trop-2 expression and benefit from this drug. So there appears to be some kind of a bystander effect from this antibody drug conjugate. I think it's a really interesting drug, and maybe you can talk a little bit about the tolerability of it. JACOB KETTLE: Yeah. So again, like you said, it's a Trop-2 target. That's the antibody component. And Trop-2 is a transmembrane glycoprotein. It's upregulated in a lot of tumor types. So this is not something that you necessarily would do additional testing for. It's not unique to breast cancer. And sacituzumab-govitecan has an approval now in bladder cancer as well. So I think we're going to start seeing more emergence and utilization of Trop-2. And then like you said, it's kind of an enriching biomarker. You might see a slightly higher response rate for those overexpressors. But again, low expressors still respond. But I think when it comes to the side effect profile-wise, it was all driven by the chemo payload. And that's Govitecan, or SN-38. This is the active metabolite of irinotecan. And so a couple of things make this really exciting to utilize in breast cancer. One is, we're all probably fairly familiar with managing the common side effects of irinotecan, predominantly neutropenia and diarrhea. So we don't have to relearn or come up with a new kind of management profile, side effect-wise. But I think part of why we see such a robust response is this is a mechanism of action. Govitecan, it's a topoisomerase inhibitor that almost, I'd say, the vast, vast majority of breast cancer patients have not been exposed to that mechanism at any point in their treatment journey. So you take advantage of that new option. And I think, all things considered, this is why we've seen this kind of recent-- it's not brand new technology-- but we've seen this recent emergence of a lot of antibody-derived conjugates. Because it really does allow you to take advantage of antineoplastic agents that may otherwise be too toxic, but we find a way to deliver it in a very sophisticated, precise manner. And by doing so, again, we're able to take advantage of chemotherapeutic agents that otherwise would be on the shelf. But we can deliver it in a very precise way. And so that's a really exciting piece of the promise for this drug. And again, just to ask you, do you any anecdotal experience or insights with the drug? RUTH O'REGAN: Yeah. I've used it a little bit. I actually started a patient on it today. But overall, I think it's well tolerated. It's unfortunate it causes alopecia, obviously. But I think most patients with the results of the ASCENT trial, they're OK with that, I think. And the tolerability seems to be very reasonable. JACOB KETTLE: I mean, a six-month OS improvement at this stage of the game is pretty clinically meaningful. RUTH O'REGAN: I don't think we've really seen that before, actually, and so it definitely is. I agree with you completely. I think antibody drug conjugates are really the way forward, because they're so much more tailored to the cancer than regular chemotherapy. The other drug, I think, that will be interesting to see in triple-negative breast cancer is trastuzumab-deruxtecan, which obviously is approved for HER2-positive breast cancer, but again, also has a bystander effect. And there's some data from one of the DESTINY studies basically showing activity in cancers that have low expression of HER2. So I think that's going to be very exciting. So I think there's a lot of exciting things happening in triple-negative breast cancer. There's a lot that I think we have to learn. I mean, biomarkers are going to be very important, particularly for immunotherapy. Do you have any other thoughts on other agents you're excited about in this setting? JACOB KETTLE: I'm always fascinated by precision oncology. And like you said, I haven't really found a lot of great targets for triple-negative breast cancer. It's tended to hold out its negativity. It doesn't have-- not as if we're finding a bunch of things. So I hold out hope, just that we come across a good marker, something else targetable for these folks. I share with you the enthusiasm about trastuzumab-deruxtecan, and how it might play a role in HER2 low. Interestingly enough, that's also a topoisomerase inhibitor type, very similar backbone, chemo-wise. But also just watching the IO story continue to play out, I think it was interesting just that breast cancer, really, especially the most common cancers, was really one of the last disease states to really see indications for immunotherapy. So just excited to see that story continue to unfold. And hopeful, always remain hopeful that we continue to push the needle forward, bit by bit, day by day. RUTH O'REGAN: I completely agree, and that was a great discussion. So that's all we have for today. I want to thank you, Dr. Kettle, for a great conversation. And thank you so much to all our listeners tuning into this episode of the ASCO Education Podcast. SPEAKER: Thank you for listening to this week's episode of the ASCO eLearning Weekly Podcast. To make us part of your weekly routine, click Subscribe. Let us know what you think by leaving a review. For more information, visit the comprehensive e-learning center at elearning.asco.org.
This week Harry sits down with Vangelis Vergetis, the co-founder and co-executive director of Intelligencia, a startup that uses big data and machine learning to help pharmaceutical companies make better decisions throughout the drug development process. Vergetis argues that if you put a group of pharma executives in a conference room, then add an extra chair for a machine-learning system, the whole group ends up smarter—and able to make more accurate predictions about which drug candidates will succeed and which will fail.Bringing better analytics into the pharma industry has been an uphill battle, Vergetis says. One survey by McKinsey, his former employer, showed that financial services companies were the most likely to adopt AI and machine learning tools; the least likely were the building and construction trades. But just one rung up from the bottom was healthcare and pharmaceuticals. "The impact that AI could have on health care is "enormous," Vergetis says. "It's in the trillions. But in terms of AI adoption, we are right above construction—and no offense to construction, but it's not the most innovative industry."But with the proper data, machine learning algorithms can help drug makers form far more accurate predictions about the probability that a new drug will perform well in Phase I clinical trials, or whether a drug that's succeeded in Phase I should be advanced to Phase II. "For years we've seen the productivity of R&D declining in our space in pharma and biotech, and I refuse to accept that," Vergetis says. "In the era of a lot of data becoming available, in the era of us being able to use techniques like machine learning to do something with that data, there's gotta be a way to reverse that trend."Please rate and review MoneyBall Medicine on Apple Podcasts! Here's how to do that from an iPhone, iPad, or iPod touch:• Launch the “Podcasts” app on your device. 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You can tap them to leave a rating if you haven't already.• In the Title field, type a summary for your review.• In the Review field, type your review.• When you're finished, click Send.• That's it, you're done. Thanks!Full TranscriptMoneyBall Medicine - Vangelis Vergetis TranscriptHarry Glorikian: I'm Harry Glorikian, and this is MoneyBall Medicine, the interview podcast where we meet researchers, entrepreneurs, and physicians who are using the power of data to improve patient health and make healthcare delivery more efficient. You can think of each episode as a new chapter in the never-ending audio version of my 2017 book, “MoneyBall Medicine: Thriving in the New Data-Driven Healthcare Market.” If you like the show, please do us a favor and leave a rating and review at Apple Podcasts. Harry Glorikian: My guest today is Vangelis Vergetis, the co-founder and co-executive director of Intelligencia. It's big-data analytics startup focused on the pharmaceutical industry. And the argument Vergetis makes to potential clients is that you can take any group of 10 drug development experts in a conference room, and make them a lot smarter by adding an eleventh chair for a machine-learning system.Of course, there's always an art to deciding which drug candidates should advance to clinical trials; which Phase 1 trials should advance to Phase 2; and so on. Decisions that like are risky and expensive, and you can't make them without having a lot of old-fashioned experience and instinct around the table.Even so, sometimes the experts are biased and the experience doesn't apply. And there's only so much data they humans can keep in their heads. And let's be honest: if decision makers at the big drug companies were that smart and talented, they'd have more home runs and fewer strikeouts.Vergetis argues that we've got the historical data and the computing power today to make far more informed predictions about which drug programs to push forward. And if more drug companies used those tools, he thinks, it might reverse the decline in R&D productivity.In the conversation you're about to hear, we talked about how Vergetis and his co-founder Dimitrios Skaltsas started Intelligencia; how they built their own datasets; how they work with clients; and why it is that he and I think a lot alike—to the point of using the same MoneyBall metaphor when we talk about transforming drug discovery and healthcare.So here's my conversation with Vangelis Vergetis.Harry Glorikian: Vangelis, welcome to the show. Vangelis Vergetis: Thank you. Very good to be here. Harry Glorikian: You know, it's interesting. I was looking at the company and looking at what you guys are doing. And I, I've probably talked to, I don't know, close to 70 experts in different areas of healthcare, drug discovery, computer science you know. Out of all those people, I honestly think you and your company Intelligencia might be the most exact reflection of the argument I was making in my 2017 book MoneyBall Medicine. In fact, I actually think you used the MoneyBall metaphor in your own talks. So I want to start out with having you explain the parallels between your company and what Billy Bean did at the Oakland A's.Vangelis Vergetis: it's very funny. You say this Harry, by the way when we started the company, what is it, three, three and a half years ago now, we had a slide actually. You know, baseball did it in the nineties. Is it about time that healthcare does the same? and going through the MoneyBall analogy. So look, the quick or the easiest way to explain it, right, it's the analogy of how do you pick baseball players and build a winning baseball team and how do you pick drug candidates and development programs and build a winning pipeline?So, you know, back in the day, what baseball did is a lot of experts in a big conference room. And these guys have watched—and I say guys, because yeah, they were primarily guys—they watched, you know, thousands of baseball games each, and they had their own perspectives and views and biases and experience in terms of what's you know, who's a good baseball player and who's not, and who they want on the team and how do they complement each other.And that's how they built a baseball team and, you know, the, the kid comes in and, you know, the chubby kid, I think Jonah Hill, right, and tells Brad Pitt, or Billy Bean in real life, I think we can do this differently. And that's a little bit of the analogy here, look, it's not a perfect analogy, like everything. Right? But the analogy here is how do you go from when you design a clinical trial or when you think about the pros and cons and the risks of a development program, how do you take that conversation from a room full of people, the oncology PhD, the statistician, the person who's developed dozens of drugs in the past and so on, and you inject some data science and machine learning capability into that conversation. There is art in drug development. We'll be the first one to acknowledge that, the same way there's art in baseball. So I would not expect that you know, that room gets replaced by a machine in any shape or form and definitely not in the, in the near or even medium, medium future. But the idea is, you know, if you have 10 people in the room, can you pull up an 11th chair, have the machine learning algorithms, sit at a chair. And provide a very unbiased data-driven perspective into that conversation. So that, that, that's what we do. Harry Glorikian: So we're going to, I want to get into some of the details, but I want to step back and fill in some history here for the people and how Intelligencia got started. If I'm not mistaken, your background is computer science, not biology. Right? Okay. And your co-founder Dimitrios [Skaltsas] is trained in law. So you both spent times at McKinsey, is that where you guys met? Vangelis Vergetis: So we, it's a, it's a good, good both of those good points. So you have a former lawyer—which we don't hold against him, we still like him very, very much—and a former computer scientist or electrical engineer who are running a company in drug development. Like, how does that work? A couple of things. As you, as you rightly pointed out, we met at McKinsey. We were both part of the healthcare practice there. Initially I was in the, in the US. Dimitrios was in Europe. We met 10 years before starting a company just running client projects together. We kept in touch over the years. And at some point, I think it was 2014, Dimitrios moved to New York, moved to the US with McKinsey and took some AI responsibilities. McKinsey was doing some internal AI. I think it was called McKinsey Solutions or something like that.So we became closer when he was in New York. We were both in healthcare for the better part of the last a decade, and we were looking for, what is the opportunity? You know, what's the area in, in drug development or frankly in pharma more broadly, where we believe we can have an impact.And it was partly us thinking through different areas. It was frankly customers or clients coming. We were both at McKinsey and we have done this study over and over again. Right. How do you design a better clinical trial? We had, I had done this, I don't know, two dozen times, maybe more. And clients kept asking McKinsey or us, Hey guys, you know, we understand how you do this and you do it very well, but are you using machine learning? Are you using data? And after saying no for about, you know, 50 times we said, okay, we should stop saying no and just go build the damn business. So here we are. Harry Glorikian: Yeah, no, I know that. I mean, from my days having Scientia Advisors, they ask over and over and over again and you keep it. It's great profitability by the way, but because you sort of know the answer. But you couldn't have picked a harder space though this is not a trivial exercise, especially if you go back to 2014 where some of the data was not even truly available or not in a format or not labeled or, or, or, or, or, or—right, to where we are today.Vangelis Vergetis: We started the company basically in 2018. The biggest challenge, I think you, you, you rightly put it, it's getting your hands on the right data. You need to answer the question you want to answer. And we took that view by the way. And some people go differently and I'll have my biases, my own biases, I'll admit. In a lot of places, what we've seen, particularly some big pharma, because they're sitting on a vast amount of their own data, but whether it's CTMS data or whatever clinical trial data they have, and the exercise they mentally do is okay, I have all this data. What questions can I answer? What can I do? And there's a lot of value there. We can answer a lot of good questions. But sometimes the question you ask needs more data than what you have, and you're kind of force-fitting it a little bit and say, yeah. Okay. But maybe I can answer most of it. Well, not really. So we flipped it. We asked the question, the question is, what is the risk of this clinical development program or the flip side of it? How likely is it that this clinical program or this drug will eventually reach a patient, will eventually receive approval by the FDA and be used by a patient. Then we went there. We said, okay, if that's the question, what data do we need to answer that question? Some of it very easily accessible. Some of it doable, but you need to build data pipelines. You need to clean it up. It's a little bit messy, whatever. Some of it doesn't exist. We've got to build it from scratch. So if you do it the other way and say, what do I have, you'll ignore that piece that says, doesn't exist. I have to build this from scratch. You're going to try to solve the problem with the other stuff.And then you realize it's not enough. So we asked the question and then we went very systematically to get all the data we needed to train the machine learning models. To answer that question. Harry Glorikian: Sounds like a consulting approach. What do we need to fill the two by two? So I totally get it. What are the biggest limitations you see right now from pharma's current method of assessing clinical trial risk? Vangelis Vergetis: Yeah, there is, there's a few and some are bigger. Some are smaller. And it's, it's hard to paint the whole industry with a broad brush, but there are some technical limitations that everybody has like as humanity, as a scientific community. Do we really understand drug biology or biology? Really well, human biology. I don't know. We understand it well enough, but from the, total knowledge, biological knowledge, we probably know this much. That's one challenge and it's a technical challenge or a scientific challenge.A technical challenge is and I think you put your finger on it, data availability. But it goes beyond, can I get my hands on the right data? Is it curated in a particular way? Is it well annotated? Is it labeled? Does it have the same quality? Is it consistent? You know, I, I take data from this genomic database. I pick data from that genomic database. Are they structured the same way? Kind of combine them or how much work do I need to do combine them. Now, it's a solvable problem. You know, the understanding of biology. It is solvable over time, but not immediate. The technical aspect of, can I make data consistent, solvable, is incredibly painful, and very few people have the patience for it or are willing to, I mean, we've killed a lot of brain cells pulling that data together, but we've done it.And then there's a third group, I think, of challenges that I would put in the broader, you know, cultural umbrella. You know, there is the, what I call the “every drug is unique” syndrome. A lot of people out there will say, well, you know, there's so many differences between drugs and programs and all that, there's no way you can use machine learning to estimate the success of this drug. Most of it not true, actually there's that syndrome there is the—and it's actually very interesting in the pharma industry, particularly, or in biotech—here is the “I want to see very quick results. I want to try this AI thing, whatever this AI thing is. Let me try it for two, three months. Show something quick. If I can show us a quick win. Great. If not, I'll throw it away. I don't have the patience for it.” And this is an industry that will easily not even think about investing 10 years and a billion dollars to develop, forget clinical, in the preclinical world, to discover a new target or a new molecule that could cure Alzheimer's or pancreatic cancer or something. So we are an industry that we're very much into putting an enormous amount of resources, time, patience, to discover a drug, but when it comes to incorporating an AI system methodology model that may help us tremendously, we are impatient. “Three months. Let's see what I can do. Oh, no results? Throw it away. I'll never see it again.” And there's a little bit about this, I think in all fairness, companies are getting better. So most of the large pharmas, they have now chief digital officers or chief innovation officers with a whole structure underneath them and mandates and all that. So I don't want to be too, too pessimistic here. Right. There's a lot of effort. And I think the industry at the very least has acknowledged they have a cultural barrier that needs to be overcome. But I don't think we're fully there in how we overcome it. But we're making progress, Harry Glorikian: But it's interesting, right. I look at existing big pharma and the lumbering ways they sort of move forward in fits and starts. And, you know, do I want to disrupt my kingdom to implement this thing? I mean, there's, there's a lot of human psychology that's involved here and a lack of understanding right. Of fully understanding this and what it can do for them in different areas.Then I look at the startups that literally from day one are totally data purpose-built right. Everything they're looking at is, “What's the data. How do I label it? Where are we going to use it? How do I manipulate it?” I mean, literally it is from the ground up. And I always think to myself sooner or later on my bet is that the startup is going to out maneuver the big guy.I mean, Google started from as a purpose-built entity and it's, you know, it, it outstrips most of its competitors and reshapes industries. I always think it's harder to take an existing entity and reprogram its DNA rather than have a predesigned piece of DNA from, from day one. Vangelis Vergetis: Harry it's an incredibly interesting thought, and I don't have an answer for it. And only time will tell. I would expect some pharma companies, whether we're talking about big pharma, you know, the big 10 or, you know, the, the massive guys or some of the, you know, in our industry, it's very funny, like a mid-sized biotech, it's still a $20 billion business. So, but I would bet some of them, to use your words, will adapt, will reprogram their DNA to some degree, a little bit painfully, it's going to be a little bit slow or they're going to have some false starts, but somehow they'll, they'll get there. Some others will just buy and we've seen this in the industry, right? So, interesting startup, I'll just buy them. And a few of these have already happened. We've seen, what is it, Flatiron was bought by, I believe it was Roche, right? Yes. There's many other similar examples. That's probably one of them more, the bigger ones, the more prominent ones. So I would expect this reprogramming of DNA will not fully happen organically. Some of it will happen by big pharma realizing, “Yeah. We need to play, you know, if we, if we're not a data company in a few years from now, we're, we'll be nowhere, right? How do we get there? Let's get our stuff stuff organized, and maybe we'll go make a couple of select acquisitions and eventually we'll get there.”So I think all of these flavors will materialize in some shape or form, and some companies will lose. Some companies will do the investments and put the, hire the right people and make the right acquisitions and, and, and they will continue to grow. Harry Glorikian: Yeah. And I look at it as an analogy to like, if I look at say JP Morgan or Goldman Sachs, I mean, they are the amount of money that they're spending trying to transition to this new capability is, we're not spending the same amount of money in pharma for sure. Right? Not even close. Vangelis Vergetis: I don't know the actual amount of money, because I haven't done the analysis. I haven't seen numbers. But my former employer, McKinsey, has done quite a bit of work. I think it was MGI. So MGI is McKinsey's think tank, it's the McKinsey Global Institute. They had done a lot of work on this. And I remember seeing a chart that I thought was, was mind boggling. Areas that are way ahead in AI, or industries that are way ahead in AI, I would say financial services. So the Goldmans and JP Morgans and Morgan Stanleys and some of the world's high-tech of course, and a few others. Who's at the bottom? I think it was like building materials or construction, which I get it. Second from the bottom? Health care. It was literally that bad.Well, it's true. If you look at the data, the, the sad thing for me the part that we need to think about as an industry, the promise or the impact that AI can have in healthcare. And I'm talking about healthcare more broadly now, including hospitals and payers, not just drug development or a pharma. But the impact that AI can have on health care is enormous. It's in the trillions. But in terms of AI adoption, we are right above construction and no offense to the construction, but it's not the most innovative industry.Harry Glorikian: So, this is why I love investing in this area, because it's such an incredible, I mean, some of the other opportunities are still incredible, don't misunderstand me, but this is at its nascent stage in my mind, where the opportunity is dramatic to sort of move the ball forward. Okay. Which brings me to the next question, which is, you know, and you don't have to name any names or anything like that. Walk us through sort of a real world example of how you help a client in practice. Vangelis Vergetis: Ooh. Maybe I'll give you two examples. You asked for one, I'll give you two. Actually I'm gonna give you more, but let, let's start with that. So where do we typically you know, we work with several flavors of customers, right? So we, we serve some of the largest, you know, top five big pharma companies we serve. Some of the smaller, even private biotechs. And we serve a bunch of the mid sized biotechs or midsize pharma companies. One area that that comes or one example is a specific program. So I'll, I'll pick on an actual example. So a specific, it's a phase two asset on a phase two program. It was a combination program, I believe for pancreatic [cancer] that our client was running. It was the phase two. It had been going on for about a year, I want to say. So it was in the middle of phase two, they were starting to see some interim results.They hadn't published anything. They were starting to see some interim results, but they were still waiting for the phase three to complete. And then there were basically three questions with increasing degrees of difficulty, if you will. Question number one, how likely is it that this program, so this combo, so our molecule with, I believe it was chemo for pancreatic cancer, will eventually reach a patient, will eventually receive regulatory approval by the FDA? That was question number one, which is our bread and butter. This is what our algorithms do. I'll make up the number now. It's a, you know, 13%, which by the way, for pancreatic cancer, phase two, that's not bad. The second question was, okay, now let's start thinking forward. So at the end of phase two, we're able to show ABC, how does that probability change? Because given the interim results we've seen, we have pretty decent conviction we'll be able to show something in that range when it comes to OS or ORR or whatever end points we're measuring. What will our probability to change to. It's 13 now, will it go to 20 or we'll go to zero?What if we managed to show something better or something worse. So in that sense, we're trying to calibrate and say, based on what we show at the end of phase two, how do we make a decision? Should we go to phase three or not? Is it too risky still? And it needs to be derisked further? Or are we comfortable with the risk we're taking, and we're willing to write a, you know, $200 million check to run a phase three program. So we did the simulations, if you will, of the analysis to say, based on what your phase two will show, here's what you should expect your risk to be at the beginning of phase three. That was the second layer. The third layer went even a step further and said, okay, let's assume we are now comfortable moving forward. So the risk is within what we're willing to take given the size of the prize, right? Because if you do get this drug approved, we estimate an enormous commercial potential. So we're willing to take significant risks here. How should we do this? So help us think through how different choices for continuing our development program affect our chances for approval.For example, should we run a smaller phase two-B and then two large phase three trials. Should we scrap the phase two-B and go straight to pivotal phase three and do a much larger trial. And there are different trade offs there that have to do with costs, time and risk. We help them think through from the middle of phase two where they are today, how likely is it that they go approved? How will that evolve once they publish results? And if they decide to move forward, what the best path forward is from a risk point of view. So that's one example. Well, I'll spare you. The second one, I spent too long on the first one. Harry Glorikian: So you've written this machine learning model, right? So, and I want to say there's at least a hundred factors, clinical trial, design outcomes, regulatory process, you know, the biology itself that you mentioned, right? The history. You have to train a model like that. Where did you get the data to train this complex model?Vangelis Vergetis: There's no single. So I wish there was. So we we've been to now dozens of data sources. So I think what I said at the very beginning, right? Some of the data was easy to get. So for example, there is a bunch of data that clinical trials.gov has. Of course we have that, and everybody else has that. That's very easy to get right. Valuable, but very easy to get, which is good.There are some data where you need to, it's publicly available, but you need to spend a lot of time cleaning up and curating. So think of genomic databases, whether it's TCGA or GTX, or, you know, dozens of other genomic databases that needs a lot of analysis and lot of processing and a lot of cleanup before you create features out of that data to put in your machine learning algorithms. So that's a, probably a second group.And a third group that goes back to the point initially that, you know, not all the data you want to answer, the question, is available. So you have to build it yourself. We built it ourselves. So an example, there is clinical trial outcome. So there is no to our knowledge and we looked hard. There is no data you can buy that has in an incredibly consistent, systematic way, all the outcomes of clinical trials in a particular therapeutic area for the last 20 years. So let's say, I mean, I mean, oncology, I'll give you an example. There's been a few thousand trials in the last 20 years. Let's say since 2000, we need to know every end point that this trial measured. How many patients were in each patient cohort or in each arm of the trial. What was the value of that endpoint? What ORR did they achieve? What OS did they achieve? Whatever. When was that? Because sometimes we say, OS, Overall Survival, well, was it measured at six months or 12 months. One layer more of specificity of exactly how the end point was captured. And then you need the number. How many patients survived at the six month mark or whatever it is. So there's all that, all that stuff that you need, and then you need it, not just for the trial or the program you're assessing, that's easy to do, right? It's one program. We can get it from the, from the pharma company themselves. We need it for every single trial that has ever succeeded in the past. And for every single trial that has ever failed. That's how you train a machine learning algorithm. That was very painful. We have a whole team in Athens, actually. So if the name didn't give it up, I'm from Greece originally. I've been in New York for like 25 years now, but I'm from Greece originally. So a lot of the team is based in Greece and part of that team, they're a very highly educated team and, you know, PhDs in biology, oncology, immunology, pharmacology, all the ologies. And that team curates in an incredibly systematic way all that data, before our data engineers and before our machine learning team can take over to build models. Right? So to answer your question in a short way, dozens of data sources, some easy to get some much harder with a lot of processing. And some we had to just create from scratch. Harry Glorikian: I mean, that was just thinking about what you were saying. That, that last piece we were just discussing. I mean, I can imagine to hospitals and to doctors that would be—if you could put that into interesting matrix, they could get an interesting view into these drugs instead of memorizing off the top of their head. It's it, you know, I always find all these discussions with companies that have data. I can think of five other things to do easily. Once you've got the data source. Vangelis Vergetis: We've been discussing internally, both as a team, but also with our advisors and even our customers at this point where they're coming to us on the saying, Hey guys, that's amazing what you have. We'll pay you money. Can we now do this. Can we now do that. And some of that we would love to do and we're entertaining it. Some of it, you know, we, we're still a growing company or, you know, there's 40 of us total in the company. You also don't want to get distracted by too many shiny objects. You know, find the right shiny object and focus on a couple of them, but not too many.So for some of them, we'll say, look, we could do it. We can, we don't have the time. We don't have the bandwidth today. Maybe later. For some of them we would say, yeah, that's incredibly interesting. And we were planning to go there anyway. Let's do it faster together. So we're discussing with one of our customers today about building something that goes beyond risk and starts thinking about the commercial implications of what happens when a drug actually gets approved. So it's not just predicting approval, but can you predict anything in the commercial space, whether that's revenue reimbursement market shares and so on. [musical transition]Harry Glorikian: I want to pause the conversation for a minute to make a quick request. If you're a fan of MoneyBall Medicine, you know that we've published dozens of interviews with leading scientists and entrepreneurs exploring the boundaries of data-driven healthcare and research. And you can listen to all of those episodes for free at Apple Podcasts, or at my website glorikian.com, or wherever you get your podcasts.There's one small thing you can do in return, and that's to leave a rating and a review of the show on Apple Podcasts. It's one of the best ways to help other listeners find and follow the show.If you've never posted a review or a rating, it's easy. All you have to do is open the Apple Podcasts app on your smartphone, search for MoneyBall Medicine, and scroll down to the Ratings & Reviews section. Tap the stars to rate the show, and then tap the link that says Write a Review to leave your comments. It'll only take a minute, but it'll help us out immensely. Thank you! And now back to the show.[musical transition]Harry Glorikian: If you have it to say, what is your defensible advantage, your special sauce? Like, what is it that you're doing for pharma that they can't somehow reproduce for themselves? Vangelis Vergetis: That's a great question, Harry. I will say a couple of things. Some are softer, some are harder. On the softer side, and probably more important by the way, is the persistent focus you know, unrelenting pursuit of what we're here to build. In a larger company, it's too easy to lose focus, budgets, get cut, people, get reassigned, promoted, change departments, move.So it's very hard to get a team together to focus on something for an extended period of time and only do that. So that's probably one thing when, when you compare it to a larger pharma company, right. The, the second thing would be. Bringing together people with very different expertise and experiences.So if you go to our office in Athens—and not the last year, given all the mess, we're all living in with coronavirus—but if you go to our office in Athens either before that, or hopefully very soon, it's a room and you have, you know, the data scientist is sitting here. The oncology PhD is right next to her. Right across is the data engineer. The drug developer is sitting over there. The statistician is there. So it's literally having all those people in one room or in, you know, a series of rooms in one floor, let's say, where they work together on the same topic. And it sounds a little bit mundane and it sounds a little trite, but it makes a difference for the biologist to be listening into, as these computer scientists or data scientists are talking about their models. And I'm sitting here entering all the biological clinical data from this New England Journal of Medicine article that I'm reading. I actually understand how they use it and I can offer an idea. I can say, Hey, actually, I can capture it in a way that will help you guys given what you're discussing. So all those things help.So that's the second element, which is a team of you know, we use diversity in many ways. So a diverse team, not just in the, in the racial or, or, you know any other perspective, but also in experiences and backgrounds. And the third one, which is the more technical one. It's the data we actually do have. It does take an enormous amount of time, a lot of people, an enormous amount of effort to actually build and create the data cube that we have. Nobody else has this. It's incredibly painful but we've done it. So that does set us apart. There are companies out there that are trying to solve the same or very similar questions or answer very similar questions based on a much more limited set of data. And they fall short. They're okay. But they will short of, of our predictive power. Not because they're not doing anything wrong, not because they're not good data scientists, all of those things are fine. They just don't have the data we have. Harry Glorikian: And so that brings me to that next question. In all of these models, there there's little issues, fraught throughout the process…Vangelis Vergetis: Oh my God. There's so many. And some of them are longer. Harry Glorikian: Many, right, that you have to think through. Right. That's why whenever somebody says, oh yeah, I've got the perfect answer, I'm like, it's impossible. Perfect? No, right. So what is the accuracy? I mean, if you said your predictive algorithm, how do you, how do you, first of all, what do you compare it against? And then let me just pick and say, if I will, putting it against a traditional way of making decisions. How do you measure your accuracy? And then do you go back and look at real world evidence versus the system?Vangelis Vergetis: Yeah. So we we've done a few things that are very interesting. There is a standard metric for machine learning. So let's not get too technical or I don't know how technical your audience is. But there's the AUC, which is Area Under the Curve, which means the area under the ROC curve…whatever, there's a metric called AUC. It's pretty much a number between 0.5 and 1. I mean, technically it could be low as 0.5, but that's a silly, so it's a number between 0.5 and 1. The higher it is the more predictive your model is. We are in the high eighties, low nineties, which is, which is incredibly predictive for a problem this nuanced and this hard. If you do image recognition and you use deep learning for image recognition, you get close to 0.999.These are very different problems. So with a standard AUC metric, we score very highly and we've compared that with what others have published in literature. And we are higher than at least what we've seen published. But by others then you do obvious things, right? So, so what do you do, you say, okay, let me take an example of hundred trials or a hundred programs for which my algorithm predicts that they are, let's say in the 20 to 30% success.All right. So my algorithm says all of these hundred fall in the 20 to 30% range. Now let me follow them over time and see what happens. What do you want? Ideally you want 25% of them to succeed, you know, somewhere in the middle. And it most often that's what happens. So when we say zero to 10 on average, let's say 7% of them succeed.When we say 10 to 30 on average, 22% succeed. When we say 30 to 50 on average, 39% succeed. So you do that on a large amount of trials, and then you start gaining confidence that dammit, what this algorithm or what this model is telling me eventually reflects reality. Now, of course, these are averages, right? So there will be trials for which you say 5% and they succeed. Now the obvious thing there to say is, and what we like about this actually, it's a true probability measure. So 5%, what does it mean? Right. I don't need to tell you. 5% means one out of 20 should succeed. Otherwise it's not 5%. If every, if every trial for which you say 5% fails, well, it's not 5%. It's zero. So if you say 5%, you should have one out of 20 succeeding. So you want to see that and you do see that, which is good. Similarly, if you go to a drug developer and you say, you know, 80%, they've never heard a higher number in drug development. Those numbers are rarely exist. So 80% to a drug developer means success. Well, no, it means two out of 10 will fail. Right. So you want to see that you run statistical checks, like the bins that I mentioned, Brier scores, AUC. So you run a bunch of statistical tests and you get very high predictive power. Look, I'll summarize it like this in the beginning of phase two, which is pretty early in drug development, right? So you still have, five, six years of, of development left ahead of you. The predictive power of our algorithms are about 90%. So we can tell you with 90% confidence that the probability that we give you is the right probability. When we tell you 20 it's 20, when we tell you it's 60 it's 60, we don't give you a one-zero estimate, we'll give you a number. And we're 90% confident on that number. Harry Glorikian: That's a pretty bold statement. So I'll, you know, let's, let's think about it here though. Right? So two things, right? Mof this stuff at some point has to be explainable, which is typically an issue in machine learning is the explainability of the model. So how have you designed it in a way where you can be like, yeah. Okay. This is why I got to this answer. Vangelis Vergetis: It's a great point. I wish we could do exactly what you said. But we can come close. So a couple of things, culturally, and for the right reasons, if you go, eh in front of the EVP of R&D in a large pharma company or the head of portfolio, whatever, and you tell them the answer is 42, they're going to throw you out of the room. They want to know, “Where does the 42 coming from? Why are you telling me this? Give me some, I need to know what can I do about it? I need to understand it.” Which it's very human and it's also the right thing. So we run, by design, we run machine learning models that are explainable. And there is explainability work being done in the academic community even for, let's say deep learning models, which are still much less explainable than a random forest or a KNN or, or something like that. So we run explainable machine learning algorithms. We spend a lot of time on explainability.And if one goes on our platform or uses our software, if you look at the number and then you literally click on a thing that says, explain to me why, and you see all the features that contribute to that answer and how important each feature is. So the reason I'm telling you that your probability is 42 is because on the positive side—and I'm making it up for a second, right?—a target that's a gene that's highly expressed in the tissue. You're going after let's say the lung or, or, or the breast or the liver or whatever it is. The cancerous tissue versus the healthy tissue. You've designed a very good trial with the right endpoints. It's well sized with the, the amount of patients you're putting in. You have a biomarker, which is a good thing, blah, blah. And maybe we'll also say on the negative side, by the way you know, as a company, you may not have that much experience in this particular disease area. So I'm dinging you a little bit. And the regulator hasn't said anything special about you, you haven't received any breakthrough or accelerated approval or anything like that. The gene you picked is highly expressed, but there has been zero, it's a first in class indication. If it's a first in class molecule that has been no approvals in the past of that target. So that tells me it's a little more risky than the 20th PD1 in the market. So it will give you all that.And people can do two things with that. One, and perhaps less important, but important. It gives them confidence that they understand why the machine is telling something. They can wrap their head around it and they can get more confident, even though I can tell you, yeah, I've run the statistics and the predictive power is 90%, you want to be able to understand it. You want to touch it. You want to feel it. You want to understand why? So it does that. The second thing it does is you might be able to do something about it. So back to the simulation, right? What do we help our customer? I can maybe assess for you what the difference will be if you use the biomarker versus not. If you have a larger trial with another arm or not. If you use this endpoint versus that endpoint. So you may be able to say, okay, I understand that the probability is 42%, but if I change these three things, can I make it 50? And those eight points in PTRS and probability of approval are massive in terms of NPV or whatever, evaluation you use. Harry Glorikian: That was going to be what I would, one of my next questions is, so you're doing all this. And so do they always act on the data or in some cases, do they make a different decision based on what the model said?Vangelis Vergetis: Both. So, and, and the model is not a black or white model, right? It's not going to tell you do this, or don't do this, or move to phase three or don't move to phase two. I'll give you an example, if you are in oncology if I tell you that this asset has a 80% probability of success versus 60% probably of success. It probably doesn't matter. You're going to move ahead. Anyway. It's high enough and the risk is too low. You might as well do it. So sometimes, you know, at the extreme, it may not make a big difference whether if I tell you it's a 5% probability versus a 3% probability, do you actually care? It's pretty damn low. Now in a lot of cases though, they, they fall somewhere in the gray zone and this is where a lot of other factors come in. So what do we think of that commercial potential. What are our competitors doing? How does it fit broadly with the rest of our pipeline and all of the other assets, both approved and the programs we have out there. So there's a lot of other considerations that go into making a decision, whether I move to phase three or whether I de-risk it, or you know, what I do.But for the most part what we've seen is our customers act on the information. They are able to take that information, enhance their decision-making process and make at the end of the day, a better decision either because they stopped something they should have stopped, they progressed something they should have progressed, or they designed the trial a little bit differently, or they you know, put a program in place that maximizes the potential of the asset they have in their pipeline.So all of those things happen. The last thing I'll say, Harry, and this one is where we see a lot of action as well, is in business development. So while most of our, we're not, most actually, a lot of our work is in R&D. So pharma companies developing their own molecules. We see two more areas where this approach is gaining a lot of steam.Actually one is business development. So as I'm looking not for my own pipeline, but as I'm looking to identify or attract programs out there that I may want to go buy or partner with or in-license and do all sorts of things. So we work with a customer early on phase one and they said, you know, what are the innovative, if you will, first-in-class assets in phase one, so risky stuff for a particular indication, RA or IBD or Parkinson's or pancreatic cancer, whatever it is for the indication that I care about, what are the phase one programs out there that one are scientifically innovative. So I don't want the me-too drugs. I don't want the 21st PD1 in the market, but I want something innovative. And two, can I see that list ranked from a risk point of view or from an attractiveness point of view, you know, some have a 2% chance of approval. Some have a 20% chance of approval. Well, I want to talk about the 20.Yes. And we've, we've helped customers identify molecules and programs like that, where they go and they have a conversation with a biotech in south San Francisco or in Zurich, Switzerland, or in Tokyo or wherever, with that biotech about in-licensing or partnerships or acquisitions or whatever it is. So with that we've seen quite a bit of action.Harry Glorikian: Machine learning takes hold in drug development. What's the big picture outcome. What do you think, you know, how do you think…is it the Intelligencias of the world that are going to change the dynamic? Is it going to be the companies themselves? You know, I believe this is going to have a profound impact on how things are done and what goes forward. Vangelis Vergetis: Here's what I'd love to see Harry, I'd love to see… For years we've seen—and there's some change recently—we've seen the productivity of R&D declining in our space in pharma and biotech. I refuse to accept that. In the era of a lot of data becoming available, in the era of us being able to use techniques like machine learning, to do something with that data, there's gotta be a way to reverse that trend, that declining trend in R&D productivity, and see it going up again. Who benefits? Patients, where they see better drugs reaching them faster and curing disease. And of course the broader community of pharma companies, biotechnology companies and so on. So the, the big picture is I'd love to see the productivity of R&D in our space increase.And AI, whether it's Intelligencia—and I'm hoping, and I'm sure we will, but there we'll be honest there and that's great. We all need to think through, you know, how do we reverse the trend? So in, in pharma or, or in drug development, I see that as the big picture you know, how do I pick the winners? How do I invest behind the winners? How do I make sure I don't create any, you know, biases in that way where I miss some of the drugs that would have existed had I made the right choice and make my R&D dollars and R&D hours and effort much more productive at the end of the day for delivering drugs to people that need them.Harry Glorikian: So I saw you were quoted in a report from a law firm called Orrick that I liked. I think you were paraphrasing Derek Lowe from Novartis where you said, “It is not that AI will replace drug developers. It's that the drug developers who use AI will replace those who don't.” And coming back to the beginning, you know, do you think this is happening across the board in all businesses? Whether it's on experimental drugs or winning baseball teams.Vangelis Vergetis: Yeah. So it's a great question. Look, I think it is happening across all industries but each industry is different. So I think the scale of impact and the scale of adoption to date are very different across industries.We talked about, you know, we used construction as an example earlier. If you think about construction, the impact that AI will have a construction, it's not zero. I know one, a friend and a mentor runs a cement business and their AI. I'm not joking. They're using AI in cement production to make it more environmentally friendly, increased productivity, increased—he'll do all those things. So yeah, there will be impact. But it's going to be less in construction and building materials than it is in healthcare. Or it's going to be built different in, in, in financial services, let's say that, than it is in travel and tourism. Again there are opportunities for machine learning in travel and tourism. Probably less than in banking or financial services broadly or healthcare. To attempt to answer your question, because I don't know, I don't know what the answer is, I can tell you what my bias is or my view. Yes, it will be used across industries, but the scale of impact will be materially different, whether you're in healthcare or in travel.And two, the adoption to date is very different. All this excitement about AI and all this energy and all this impact that it can have, it's fantastic, and it will have it, but let's also be thoughtful here. I think we all are. But you need experts. There's a lot of art and a lot of things that happen. There's art in drug development. There is art in baseball, there's art, in a lot of things. There is instincts, gut feels that humans have. Some of it is bad because it's biased, but some of…he didn't miss it. There's decisions that doctors make every day as they treat patients. Forget drug development, that yes, that can be made better by AI. Maybe they can be guided by AI, but I'm not sure an AI will take over a physician's job and anytime soon.Harry Glorikian: No, I mean, I think the two together always, at least right now, will equate to step wise function up, right? The AI may not miss a piece of data that the physician didn't see. I've been with physicians where they call it and they were missing a piece of data. Had they had that data, that decision would have been different. The machine isn't going to miss that last piece, right, necessarily. And so I think the two together can be much more powerful than any one alone per se.Vangelis Vergetis: Yeah. And it varies a lot by the use case, meaning can a machine read a lung image or can it tell me if this picture is a dog or a cat? Yeah. Probably can do it better than a human or, or equally good, equally well. But in use cases that are much more intricate than, you know, reading looking at an image, whether it's building a baseball team or designing a phase three trial or anything approaching that level of complexity, the two need to come together and will for a long time to come. So I think Derek is right in that sense. Yeah. If, you know, the ones that use drug development will replace the ones that don't, but AI by itself is not going to replace everybody. Not anytime soon. Harry Glorikian: Yep. I agree. Well, listen, it was great to speak to you. I look forward to continuing our conversation, because I can see that there's many areas of overlap. And it's been great. Vangelis Vergetis: Thank you, Harry. I appreciate it. Harry Glorikian: Thank you. Vangelis Vergetis: Bye.Harry Glorikian: That's it for this week's show. You can find past episodes of MoneyBall Medicine at my website, glorikian.com, under the tab “Podcast.” And you can follow me on Twitter at hglorikian. Thanks for listening, and we'll be back soon with our next interview.
El Dr. Jerónimo Rodríguez Cid, oncólogo médico adscrito al Instituto Nacional de Enfermedades Respiratorias en la Ciudad de México, México, junto al Dr. Luis Ubillos, oncólogo médico subdirector del Insituto Nacional del Cáncer INCA-ASSE en Montevideo, Uruguay, nos comentan sobre lo más destacado en melanoma presentado en ASCO 2021, resaltando los siguientes estudios: Melanoma (adyuvancia): KEYNOTE 054: Estudio fase III, aleatorizado, doble ciego el cual evaluó a 1019 pacientes con melanoma. Su objetivo primario fue comparar el tratamiento de inmunoterapia adyuvante con un anticuerpo monoclonal anti-PD-1 (pembrolizumab) vs. placebo después de la resección completa de un melanoma en estadio III de alto riesgo. SWOG 1404: Estudio fase III, doble ciego el cual evaluó a 1378 pacientes con melanoma resecado de alto riesgo y que comparó el tratamiento con interferón de dosis altas o ipilimumab vs. pembrolizumab. Melanoma (metastásico): RELATIVITY 047: Estudio fase II/III, doble ciego, aleatorizado el cuál evaluó a 700 pacientes con melanoma metastásico o irresecable no tratado previamente. Este comparó el tratamiento de relatlimab combinado con nivolumab vs. nivolumab solo. CHECKMATE 064: Estudio fase II, aleatorizado, de etiqueta abierta con 138 pacientes inscritos con melanoma avanzado o metastásico, el cual evaluó el tratamiento de nivolumab administrado secuencialmente con ipilimumab. ABC: Estudio fase II, aleatorizado, de etiqueta abierta el cual evaluó a 76 pacientes con melanoma con metástasis cerebrales y que comparó el tratamiento de nivolumab vs. nivolumab + ipilimumab. COLUMBUS: Estudio fase III multicéntrico, abierto, aleatorizado, el cual comparó dos partes de LGX818 + MEK162 vs. la monoterapia con vemurafenib + LGX818 en 907 pacientes con melanoma BRAF V600 mutado irresecable o metastásico. Pembrolizumab + lenvatinib: Estudio que evaluó la combinación de pembrolizumab + lenvatinib en pacientes con melanoma que hayan progresado a un tratamiento anti-PD-1 o anti-PD-L1 previo. Abstract “Eficacia de la inhibición de los puntos de control en el melanoma acral avanzado”: La población de este estudio consistió en pacientes del Registro Holandés de Tratamiento del Melanoma prospectivo a nivel nacional entre 2014 - 2020, y la tasa de respuesta objetiva fue calculada en todos los pacientes con melanoma acral no resecable en estadio III y IV y con melanoma cutáneo, los cuales fueron tratados con anti-PD1 y con la combinación anti-PD1 + anti-CTLA4.
欢迎收听雪球和喜马拉雅联合出品的财经有深度，雪球，3500万投资者在线交流，一起探索投资的智慧，听众朋友们大家好，我是主播匪石-34，今天分享的稿件名字叫做我看好的一些医药细分赛道，来自于马曼然。 医药产业在2008年时总营收是八千亿，2020年是三万亿，说明医药行业的蛋糕在不断扩大。医药行业分很多方向，比如它的需求端，一是医保，二是商业保险，三是消费者自费，我们对未来的判断是：商业保险增速会高于医保，医保也会有一个增速，自费的比例会大幅提高。医保占GDP的比重在未来二十年会不断放大，但医药行业过去的挣钱逻辑主要靠医保一方买单，未来将形成三方买单，基础医保加商业保险再加自费，从这三个角度去买单。未来几年在医药产业中，创新药、特殊药像疫苗、血制品、麻精类用药、慢病中的糖尿病、品牌中药，这是未来我们较看好的方向，互联网医疗，我觉得互联网医疗是渠道端，我们暂时对渠道类公司保持一个谨慎观望的态度。因为我们注意到渠道类细分这么多年时刻都会受科技冲击，所以我们更看好制造业，像药品创新、研发、制造包括一些依赖独家资源、成长靠提价的品牌中药。我们在选择行业时要根据行业的性质，我们要在医药产业中选择一个好的细分赛道，同时要有优秀的管理团队。优秀的管理团队在任何行业都很重要，只有极少数的企业对管理团队的依赖不强，我认为在医药产业中管理团队尤为重要。除个别公司外，没有优秀的团队，公司就做不好，无论是消费、医药还是科技。医药是靠研发，团队不好，研发以及销售能力都跟不上，像同仁堂这种有资源、有品牌、有产品，但由于管理跟不上造成股票长期回报很差，但同仁堂，我们长期始终对这个公司不放弃，未来随着体制的改制，会迎来周期性的转折，所以一个好的团队对一家医药公司至关重要，云南白药的团队是优秀级别的甚至说天才级别的也不为过，片仔癀的团队我认为也不错。西药类公司对团队的要求更为严格，我们在选择西药类公司也非常关注管理团队的考核，所以我们的选择面很窄，最典型的像我们比较看好恒瑞医药孙飘扬的团队。他们这种团队形成了企业的创新文化，类似于比亚迪的工程师文化。尤其是做创新药，公司团队的研发能力、企业文化更为重要。华东医药是以销售为主体的企业文化，恒瑞医药是以创新为主的企业文化，虽各有特色，但从长期一个全球的视野或竞争力上来说，研发型团队跑的更远、做的更大，销售型的团队也会做大，但必须转型，不然在研发上会是一个长期瓶颈。创新药和品牌中药的区别，品牌中药偏消费类，它也需要创新，但药品本身的创新极其有限，过去我们也希望中国的中药能出现大量的创新，但这确实很难，以岭药业做中药现代化出身，做出了像连花清瘟等很多优秀的创新类中药，但从长期来说，我认为很难做到大规模的持续创新从而形成行业颠覆性的创新，因为中药我们判断本质上是吃老本，所以中药可投资的标的极其有限。很多人问我广州白云山，它和北京同仁堂长期发展都不太好，很难再创新。像白云山做凉茶做不好，后来的金戈以及化药做的都很一般，所以品牌中药里能创新好的很稀缺。我觉得东阿阿胶、同仁堂以后也有希望，但整个行业的希望空间不大，行业中会跑出个别牛股，所以目前来看我们只能聚焦这种龙头，包括消费也一样。2020年我们比较看好青岛啤酒这种一线品牌，我们从来不说燕京啤酒、珠江啤酒等其他啤酒，因为青岛啤酒是行业一家独大。看好啤酒不是看好啤酒行业而是看好啤酒行业中的某家公司。创新药的牛股还会不断的更迭，中国的创新药占中国医药产业消费量的5%，欧美大概达到70%-80%，天风证券研究结果是如果十年以后中国的创新药提高到30%或50%的比例，那么整个行业会有十到十五倍的涨幅甚至更高，这是按行业4%的增速保守估算。如果十年后整个行业都有十到二十倍的涨幅，我们认为行业龙头公司极有可能实现十年几十倍的涨幅。而且这个行业刚起步，从2017年我国的创新药才开始，所以我们比较看好创新药，尤其是顶级创新药、高端创新药。这其中我们认为会出现很多牛股，我们认为一线的品种更为稳妥，比如恒瑞医药、信达生物等相对更稳妥，但期间也会有不断的变化，所以需要动态的跟踪。生物药我觉得可能会多出几个新的龙头，这几年像免疫治疗单抗、双抗、都在崛起，因此我觉得可能会出现一些机会。中国的创新药是最有可能先进行国际化的行业之一，我们在投资时看赛道，赛道就类似于滚雪球，越长越好。我们还要聚焦于国外市场，如果企业未来在国际上立足，那市值的天花板与在国内立足完全是两个不同级别。因为像欧美这些国家的药品支付能力比我国大很多，他们对药价的限制比我国小很多。如果我国创新药能做到同类第一或同类最优，比如我们某个PD1的疗效能在全球做到同类最优，那国外的医保局就没理由不接受这个产品，这也为他们国家的医保降低负担。这里不存在文化差异，像食品饮料存在文化差异，外国人接受白酒是一个很漫长的过程，但药品的规格、疗效以及性质一样，评估标准也相同且临床试验结果在全球都通用，所以医药行业很容易被国外所接受。我认为中国的医药产业具有全球竞争力。一方面是我国在研发上能做到全球同类最优，甚至可以开发出全球名列前茅的药，比如原研药是第一，我国从第二开始做同类最优。另外一方面是我国的成本极低，与国外中间差了几十倍，国外研发一款新药需要十亿美金，我国可能只需两亿人民币。由于中国员工成本低，同岗位工资会相差几十倍且我们的临床代价低，同样是三千名患者的临床，在中国和在美国的成本差距甚远。像PD1在国际上一个疗程一年几十万甚至上百万的费用，中国可以做到一年的费用不超过十万，而且企业能达到80%-90%的毛利率。虽然国外以后也会有一些壁垒，像美国怕中国对美国医药产业产生产业上的冲击也会设置一些人为的壁垒，但只要能达到同类最优，长期来说没理由不用我国的产品，就像我国的纺织服装能超过美国的纺织服装行业一样。中国的医药产业在非常严格的医保控费体系下，如果达到一个独特的创新模式（以极低成本达到极高质量的状态），我们的医药产业是最有可能进入国际化的产业。互联网产业国际化存在很大难度，主要原因是国外会认为涉及到个人隐私问题以及社会问题，抖音、阿里在国外都受限。中国创新药这几年刚起步，大家对创新药国际化这方面缺少了解，根据我们的研究发现，如果我预测正确，我觉得十到十五年左右的时间，中国顶级的创新药市值应该能达到世界前三名。从长期的角度来说，甚至可以像现在的新能源汽车或互联网一样占到世界的半壁江山。这两年大多数投资人关注点都是短期的医保集采控费这些问题，但凡事有利有弊，医保集采会影响短期像仿制药的利润，但同时也会打造中国医药产业的创新力，任何事情都有双面性。像当时限制白酒的三公消费，当时大家觉得老百姓不消费，但现在茅台依旧供不应求。我看好创新药，一方面是抗肿瘤药、慢病创新药、孤儿药，美国的阿斯利康收购了一家创新药公司，一家专门做孤儿病（小病种，病人很少）的公司。目前全球有五千多种孤儿病，其中只有5%的病种有相应的治疗办法，所以空间很大。阿斯利康几千亿收购，但这家公司目前才几亿的收入，估值非常高。以后医药行业会越来越高级，比如免疫治疗这种最顶级的技术，包括孤儿药、慢病创新药，慢病创新药主要体现在像糖尿病的长效口服制剂或长效注射制剂。糖尿病的慢病创新药在国际上目前做的也非常好，不要只看胰岛素这些，我们要看新产品，像国际上日本武田做的口服降糖药一周一次效果非常好，国内以后用药慢慢会往这方面转型。小分子化药也行，但我认为竞争会较为激烈。另一方面是疫苗、血制品、麻精类，麻精类总体我们看的标的与创新药的龙头加在一起。我非常看好疫苗行业，因为疫苗和创新药在中国同样是刚起步，目前整个行业处在春秋战国时代，未形成龙头各有特色，如果存在疫苗指数我认为会非常省事。这个行业的调研难度较高，容易出现质量问题，所以这个行业不适合重仓且要分散投资。疫苗行业这么多年都是问题消息不断，但这个行业长期是大牛股，包括现在很多跌下去的公司以后还会上来，只要不出现大问题。所以疫苗行业目前处于非常早期的阶段，疫苗主要是二类疫苗，二类疫苗以自费为主。未来疫苗会越来越多样化，像宫颈疫苗包括肺炎疫苗，现在国际上的疫苗销量都非常好，包括流感疫苗，以前没人接种流感疫苗现在供不应求。核酸疫苗我认为是新一代疫苗技术，因此一定要重视，现在在国际上非常厉害。核酸疫苗不光是疫苗还是核酸肿瘤，它是针对DNA片段来开发新药，过去抗肿瘤都是针对蛋白质靶点，现在直接打到DNA，药物现在开始往更微观领域的方向发展。这就会形成一个活体，类似于对DNA进行改造从而形成疫苗的反馈，包括抗肿瘤也会通过DNA。血制品终端的需求量每年大概有10%-15%的增长，但供给端不增长。因为供给端大概从九几年以后就不再有新批次的牌照，供给受政策管控。这个行业里的国企老大是天坛生物，民营企业老大就是华兰生物，但这个行业我认为更多是起到锚定的作用，只要公司正常经营就能带来稳定的现金流。我们不单独投资血制品，我们只是把血制品当成一个稳定的基础，所以不是所有的医药行业都投资。品牌中药我们看好，品牌中药需注意两点：能否长期进行提价、需求能否长期增长，片仔癀就看着价和量的提升；品牌中药的外延增长，就像云南白药开发牙膏、洗发水等产品。这些企业也都涉及药妆，这块也值得期待，中国的化妆品行业我认为长期在国际竞争的话，我认为药妆是中国的一大特色，运用中国的一些植物中草药的技术做药妆，符合消费者未来对健康的需求同时也是中国的特色和优势。目前国内也出现很多新兴的彩妆品牌，但我认为这些品牌还需要进一步构筑长期竞争力。
欢迎收听雪球和喜马拉雅联合出品的财经有深度，雪球，3500万投资者在线交流，一起探索投资的智慧，听众朋友们大家好，我是主播匪石-34，今天分享的稿件名字叫做我看好的一些医药细分赛道，来自于马曼然。 医药产业在2008年时总营收是八千亿，2020年是三万亿，说明医药行业的蛋糕在不断扩大。医药行业分很多方向，比如它的需求端，一是医保，二是商业保险，三是消费者自费，我们对未来的判断是：商业保险增速会高于医保，医保也会有一个增速，自费的比例会大幅提高。医保占GDP的比重在未来二十年会不断放大，但医药行业过去的挣钱逻辑主要靠医保一方买单，未来将形成三方买单，基础医保加商业保险再加自费，从这三个角度去买单。未来几年在医药产业中，创新药、特殊药像疫苗、血制品、麻精类用药、慢病中的糖尿病、品牌中药，这是未来我们较看好的方向，互联网医疗，我觉得互联网医疗是渠道端，我们暂时对渠道类公司保持一个谨慎观望的态度。因为我们注意到渠道类细分这么多年时刻都会受科技冲击，所以我们更看好制造业，像药品创新、研发、制造包括一些依赖独家资源、成长靠提价的品牌中药。我们在选择行业时要根据行业的性质，我们要在医药产业中选择一个好的细分赛道，同时要有优秀的管理团队。优秀的管理团队在任何行业都很重要，只有极少数的企业对管理团队的依赖不强，我认为在医药产业中管理团队尤为重要。除个别公司外，没有优秀的团队，公司就做不好，无论是消费、医药还是科技。医药是靠研发，团队不好，研发以及销售能力都跟不上，像同仁堂这种有资源、有品牌、有产品，但由于管理跟不上造成股票长期回报很差，但同仁堂，我们长期始终对这个公司不放弃，未来随着体制的改制，会迎来周期性的转折，所以一个好的团队对一家医药公司至关重要，云南白药的团队是优秀级别的甚至说天才级别的也不为过，片仔癀的团队我认为也不错。西药类公司对团队的要求更为严格，我们在选择西药类公司也非常关注管理团队的考核，所以我们的选择面很窄，最典型的像我们比较看好恒瑞医药孙飘扬的团队。他们这种团队形成了企业的创新文化，类似于比亚迪的工程师文化。尤其是做创新药，公司团队的研发能力、企业文化更为重要。华东医药是以销售为主体的企业文化，恒瑞医药是以创新为主的企业文化，虽各有特色，但从长期一个全球的视野或竞争力上来说，研发型团队跑的更远、做的更大，销售型的团队也会做大，但必须转型，不然在研发上会是一个长期瓶颈。创新药和品牌中药的区别，品牌中药偏消费类，它也需要创新，但药品本身的创新极其有限，过去我们也希望中国的中药能出现大量的创新，但这确实很难，以岭药业做中药现代化出身，做出了像连花清瘟等很多优秀的创新类中药，但从长期来说，我认为很难做到大规模的持续创新从而形成行业颠覆性的创新，因为中药我们判断本质上是吃老本，所以中药可投资的标的极其有限。很多人问我广州白云山，它和北京同仁堂长期发展都不太好，很难再创新。像白云山做凉茶做不好，后来的金戈以及化药做的都很一般，所以品牌中药里能创新好的很稀缺。我觉得东阿阿胶、同仁堂以后也有希望，但整个行业的希望空间不大，行业中会跑出个别牛股，所以目前来看我们只能聚焦这种龙头，包括消费也一样。2020年我们比较看好青岛啤酒这种一线品牌，我们从来不说燕京啤酒、珠江啤酒等其他啤酒，因为青岛啤酒是行业一家独大。看好啤酒不是看好啤酒行业而是看好啤酒行业中的某家公司。创新药的牛股还会不断的更迭，中国的创新药占中国医药产业消费量的5%，欧美大概达到70%-80%，天风证券研究结果是如果十年以后中国的创新药提高到30%或50%的比例，那么整个行业会有十到十五倍的涨幅甚至更高，这是按行业4%的增速保守估算。如果十年后整个行业都有十到二十倍的涨幅，我们认为行业龙头公司极有可能实现十年几十倍的涨幅。而且这个行业刚起步，从2017年我国的创新药才开始，所以我们比较看好创新药，尤其是顶级创新药、高端创新药。这其中我们认为会出现很多牛股，我们认为一线的品种更为稳妥，比如恒瑞医药、信达生物等相对更稳妥，但期间也会有不断的变化，所以需要动态的跟踪。生物药我觉得可能会多出几个新的龙头，这几年像免疫治疗单抗、双抗、都在崛起，因此我觉得可能会出现一些机会。中国的创新药是最有可能先进行国际化的行业之一，我们在投资时看赛道，赛道就类似于滚雪球，越长越好。我们还要聚焦于国外市场，如果企业未来在国际上立足，那市值的天花板与在国内立足完全是两个不同级别。因为像欧美这些国家的药品支付能力比我国大很多，他们对药价的限制比我国小很多。如果我国创新药能做到同类第一或同类最优，比如我们某个PD1的疗效能在全球做到同类最优，那国外的医保局就没理由不接受这个产品，这也为他们国家的医保降低负担。这里不存在文化差异，像食品饮料存在文化差异，外国人接受白酒是一个很漫长的过程，但药品的规格、疗效以及性质一样，评估标准也相同且临床试验结果在全球都通用，所以医药行业很容易被国外所接受。我认为中国的医药产业具有全球竞争力。一方面是我国在研发上能做到全球同类最优，甚至可以开发出全球名列前茅的药，比如原研药是第一，我国从第二开始做同类最优。另外一方面是我国的成本极低，与国外中间差了几十倍，国外研发一款新药需要十亿美金，我国可能只需两亿人民币。由于中国员工成本低，同岗位工资会相差几十倍且我们的临床代价低，同样是三千名患者的临床，在中国和在美国的成本差距甚远。像PD1在国际上一个疗程一年几十万甚至上百万的费用，中国可以做到一年的费用不超过十万，而且企业能达到80%-90%的毛利率。虽然国外以后也会有一些壁垒，像美国怕中国对美国医药产业产生产业上的冲击也会设置一些人为的壁垒，但只要能达到同类最优，长期来说没理由不用我国的产品，就像我国的纺织服装能超过美国的纺织服装行业一样。中国的医药产业在非常严格的医保控费体系下，如果达到一个独特的创新模式（以极低成本达到极高质量的状态），我们的医药产业是最有可能进入国际化的产业。互联网产业国际化存在很大难度，主要原因是国外会认为涉及到个人隐私问题以及社会问题，抖音、阿里在国外都受限。中国创新药这几年刚起步，大家对创新药国际化这方面缺少了解，根据我们的研究发现，如果我预测正确，我觉得十到十五年左右的时间，中国顶级的创新药市值应该能达到世界前三名。从长期的角度来说，甚至可以像现在的新能源汽车或互联网一样占到世界的半壁江山。这两年大多数投资人关注点都是短期的医保集采控费这些问题，但凡事有利有弊，医保集采会影响短期像仿制药的利润，但同时也会打造中国医药产业的创新力，任何事情都有双面性。像当时限制白酒的三公消费，当时大家觉得老百姓不消费，但现在茅台依旧供不应求。我看好创新药，一方面是抗肿瘤药、慢病创新药、孤儿药，美国的阿斯利康收购了一家创新药公司，一家专门做孤儿病（小病种，病人很少）的公司。目前全球有五千多种孤儿病，其中只有5%的病种有相应的治疗办法，所以空间很大。阿斯利康几千亿收购，但这家公司目前才几亿的收入，估值非常高。以后医药行业会越来越高级，比如免疫治疗这种最顶级的技术，包括孤儿药、慢病创新药，慢病创新药主要体现在像糖尿病的长效口服制剂或长效注射制剂。糖尿病的慢病创新药在国际上目前做的也非常好，不要只看胰岛素这些，我们要看新产品，像国际上日本武田做的口服降糖药一周一次效果非常好，国内以后用药慢慢会往这方面转型。小分子化药也行，但我认为竞争会较为激烈。另一方面是疫苗、血制品、麻精类，麻精类总体我们看的标的与创新药的龙头加在一起。我非常看好疫苗行业，因为疫苗和创新药在中国同样是刚起步，目前整个行业处在春秋战国时代，未形成龙头各有特色，如果存在疫苗指数我认为会非常省事。这个行业的调研难度较高，容易出现质量问题，所以这个行业不适合重仓且要分散投资。疫苗行业这么多年都是问题消息不断，但这个行业长期是大牛股，包括现在很多跌下去的公司以后还会上来，只要不出现大问题。所以疫苗行业目前处于非常早期的阶段，疫苗主要是二类疫苗，二类疫苗以自费为主。未来疫苗会越来越多样化，像宫颈疫苗包括肺炎疫苗，现在国际上的疫苗销量都非常好，包括流感疫苗，以前没人接种流感疫苗现在供不应求。核酸疫苗我认为是新一代疫苗技术，因此一定要重视，现在在国际上非常厉害。核酸疫苗不光是疫苗还是核酸肿瘤，它是针对DNA片段来开发新药，过去抗肿瘤都是针对蛋白质靶点，现在直接打到DNA，药物现在开始往更微观领域的方向发展。这就会形成一个活体，类似于对DNA进行改造从而形成疫苗的反馈，包括抗肿瘤也会通过DNA。血制品终端的需求量每年大概有10%-15%的增长，但供给端不增长。因为供给端大概从九几年以后就不再有新批次的牌照，供给受政策管控。这个行业里的国企老大是天坛生物，民营企业老大就是华兰生物，但这个行业我认为更多是起到锚定的作用，只要公司正常经营就能带来稳定的现金流。我们不单独投资血制品，我们只是把血制品当成一个稳定的基础，所以不是所有的医药行业都投资。品牌中药我们看好，品牌中药需注意两点：能否长期进行提价、需求能否长期增长，片仔癀就看着价和量的提升；品牌中药的外延增长，就像云南白药开发牙膏、洗发水等产品。这些企业也都涉及药妆，这块也值得期待，中国的化妆品行业我认为长期在国际竞争的话，我认为药妆是中国的一大特色，运用中国的一些植物中草药的技术做药妆，符合消费者未来对健康的需求同时也是中国的特色和优势。目前国内也出现很多新兴的彩妆品牌，但我认为这些品牌还需要进一步构筑长期竞争力。
欢迎收听雪球和喜马拉雅联合出品的财经有深度，雪球，3500万投资者在线交流，一起探索投资的智慧，听众朋友们大家好，我是主播匪石-34，今天分享的稿件名字叫做我看好的一些医药细分赛道，来自于马曼然。 医药产业在2008年时总营收是八千亿，2020年是三万亿，说明医药行业的蛋糕在不断扩大。医药行业分很多方向，比如它的需求端，一是医保，二是商业保险，三是消费者自费，我们对未来的判断是：商业保险增速会高于医保，医保也会有一个增速，自费的比例会大幅提高。医保占GDP的比重在未来二十年会不断放大，但医药行业过去的挣钱逻辑主要靠医保一方买单，未来将形成三方买单，基础医保加商业保险再加自费，从这三个角度去买单。未来几年在医药产业中，创新药、特殊药像疫苗、血制品、麻精类用药、慢病中的糖尿病、品牌中药，这是未来我们较看好的方向，互联网医疗，我觉得互联网医疗是渠道端，我们暂时对渠道类公司保持一个谨慎观望的态度。因为我们注意到渠道类细分这么多年时刻都会受科技冲击，所以我们更看好制造业，像药品创新、研发、制造包括一些依赖独家资源、成长靠提价的品牌中药。我们在选择行业时要根据行业的性质，我们要在医药产业中选择一个好的细分赛道，同时要有优秀的管理团队。优秀的管理团队在任何行业都很重要，只有极少数的企业对管理团队的依赖不强，我认为在医药产业中管理团队尤为重要。除个别公司外，没有优秀的团队，公司就做不好，无论是消费、医药还是科技。医药是靠研发，团队不好，研发以及销售能力都跟不上，像同仁堂这种有资源、有品牌、有产品，但由于管理跟不上造成股票长期回报很差，但同仁堂，我们长期始终对这个公司不放弃，未来随着体制的改制，会迎来周期性的转折，所以一个好的团队对一家医药公司至关重要，云南白药的团队是优秀级别的甚至说天才级别的也不为过，片仔癀的团队我认为也不错。西药类公司对团队的要求更为严格，我们在选择西药类公司也非常关注管理团队的考核，所以我们的选择面很窄，最典型的像我们比较看好恒瑞医药孙飘扬的团队。他们这种团队形成了企业的创新文化，类似于比亚迪的工程师文化。尤其是做创新药，公司团队的研发能力、企业文化更为重要。华东医药是以销售为主体的企业文化，恒瑞医药是以创新为主的企业文化，虽各有特色，但从长期一个全球的视野或竞争力上来说，研发型团队跑的更远、做的更大，销售型的团队也会做大，但必须转型，不然在研发上会是一个长期瓶颈。创新药和品牌中药的区别，品牌中药偏消费类，它也需要创新，但药品本身的创新极其有限，过去我们也希望中国的中药能出现大量的创新，但这确实很难，以岭药业做中药现代化出身，做出了像连花清瘟等很多优秀的创新类中药，但从长期来说，我认为很难做到大规模的持续创新从而形成行业颠覆性的创新，因为中药我们判断本质上是吃老本，所以中药可投资的标的极其有限。很多人问我广州白云山，它和北京同仁堂长期发展都不太好，很难再创新。像白云山做凉茶做不好，后来的金戈以及化药做的都很一般，所以品牌中药里能创新好的很稀缺。我觉得东阿阿胶、同仁堂以后也有希望，但整个行业的希望空间不大，行业中会跑出个别牛股，所以目前来看我们只能聚焦这种龙头，包括消费也一样。2020年我们比较看好青岛啤酒这种一线品牌，我们从来不说燕京啤酒、珠江啤酒等其他啤酒，因为青岛啤酒是行业一家独大。看好啤酒不是看好啤酒行业而是看好啤酒行业中的某家公司。创新药的牛股还会不断的更迭，中国的创新药占中国医药产业消费量的5%，欧美大概达到70%-80%，天风证券研究结果是如果十年以后中国的创新药提高到30%或50%的比例，那么整个行业会有十到十五倍的涨幅甚至更高，这是按行业4%的增速保守估算。如果十年后整个行业都有十到二十倍的涨幅，我们认为行业龙头公司极有可能实现十年几十倍的涨幅。而且这个行业刚起步，从2017年我国的创新药才开始，所以我们比较看好创新药，尤其是顶级创新药、高端创新药。这其中我们认为会出现很多牛股，我们认为一线的品种更为稳妥，比如恒瑞医药、信达生物等相对更稳妥，但期间也会有不断的变化，所以需要动态的跟踪。生物药我觉得可能会多出几个新的龙头，这几年像免疫治疗单抗、双抗、都在崛起，因此我觉得可能会出现一些机会。中国的创新药是最有可能先进行国际化的行业之一，我们在投资时看赛道，赛道就类似于滚雪球，越长越好。我们还要聚焦于国外市场，如果企业未来在国际上立足，那市值的天花板与在国内立足完全是两个不同级别。因为像欧美这些国家的药品支付能力比我国大很多，他们对药价的限制比我国小很多。如果我国创新药能做到同类第一或同类最优，比如我们某个PD1的疗效能在全球做到同类最优，那国外的医保局就没理由不接受这个产品，这也为他们国家的医保降低负担。这里不存在文化差异，像食品饮料存在文化差异，外国人接受白酒是一个很漫长的过程，但药品的规格、疗效以及性质一样，评估标准也相同且临床试验结果在全球都通用，所以医药行业很容易被国外所接受。我认为中国的医药产业具有全球竞争力。一方面是我国在研发上能做到全球同类最优，甚至可以开发出全球名列前茅的药，比如原研药是第一，我国从第二开始做同类最优。另外一方面是我国的成本极低，与国外中间差了几十倍，国外研发一款新药需要十亿美金，我国可能只需两亿人民币。由于中国员工成本低，同岗位工资会相差几十倍且我们的临床代价低，同样是三千名患者的临床，在中国和在美国的成本差距甚远。像PD1在国际上一个疗程一年几十万甚至上百万的费用，中国可以做到一年的费用不超过十万，而且企业能达到80%-90%的毛利率。虽然国外以后也会有一些壁垒，像美国怕中国对美国医药产业产生产业上的冲击也会设置一些人为的壁垒，但只要能达到同类最优，长期来说没理由不用我国的产品，就像我国的纺织服装能超过美国的纺织服装行业一样。中国的医药产业在非常严格的医保控费体系下，如果达到一个独特的创新模式（以极低成本达到极高质量的状态），我们的医药产业是最有可能进入国际化的产业。互联网产业国际化存在很大难度，主要原因是国外会认为涉及到个人隐私问题以及社会问题，抖音、阿里在国外都受限。中国创新药这几年刚起步，大家对创新药国际化这方面缺少了解，根据我们的研究发现，如果我预测正确，我觉得十到十五年左右的时间，中国顶级的创新药市值应该能达到世界前三名。从长期的角度来说，甚至可以像现在的新能源汽车或互联网一样占到世界的半壁江山。这两年大多数投资人关注点都是短期的医保集采控费这些问题，但凡事有利有弊，医保集采会影响短期像仿制药的利润，但同时也会打造中国医药产业的创新力，任何事情都有双面性。像当时限制白酒的三公消费，当时大家觉得老百姓不消费，但现在茅台依旧供不应求。我看好创新药，一方面是抗肿瘤药、慢病创新药、孤儿药，美国的阿斯利康收购了一家创新药公司，一家专门做孤儿病（小病种，病人很少）的公司。目前全球有五千多种孤儿病，其中只有5%的病种有相应的治疗办法，所以空间很大。阿斯利康几千亿收购，但这家公司目前才几亿的收入，估值非常高。以后医药行业会越来越高级，比如免疫治疗这种最顶级的技术，包括孤儿药、慢病创新药，慢病创新药主要体现在像糖尿病的长效口服制剂或长效注射制剂。糖尿病的慢病创新药在国际上目前做的也非常好，不要只看胰岛素这些，我们要看新产品，像国际上日本武田做的口服降糖药一周一次效果非常好，国内以后用药慢慢会往这方面转型。小分子化药也行，但我认为竞争会较为激烈。另一方面是疫苗、血制品、麻精类，麻精类总体我们看的标的与创新药的龙头加在一起。我非常看好疫苗行业，因为疫苗和创新药在中国同样是刚起步，目前整个行业处在春秋战国时代，未形成龙头各有特色，如果存在疫苗指数我认为会非常省事。这个行业的调研难度较高，容易出现质量问题，所以这个行业不适合重仓且要分散投资。疫苗行业这么多年都是问题消息不断，但这个行业长期是大牛股，包括现在很多跌下去的公司以后还会上来，只要不出现大问题。所以疫苗行业目前处于非常早期的阶段，疫苗主要是二类疫苗，二类疫苗以自费为主。未来疫苗会越来越多样化，像宫颈疫苗包括肺炎疫苗，现在国际上的疫苗销量都非常好，包括流感疫苗，以前没人接种流感疫苗现在供不应求。核酸疫苗我认为是新一代疫苗技术，因此一定要重视，现在在国际上非常厉害。核酸疫苗不光是疫苗还是核酸肿瘤，它是针对DNA片段来开发新药，过去抗肿瘤都是针对蛋白质靶点，现在直接打到DNA，药物现在开始往更微观领域的方向发展。这就会形成一个活体，类似于对DNA进行改造从而形成疫苗的反馈，包括抗肿瘤也会通过DNA。血制品终端的需求量每年大概有10%-15%的增长，但供给端不增长。因为供给端大概从九几年以后就不再有新批次的牌照，供给受政策管控。这个行业里的国企老大是天坛生物，民营企业老大就是华兰生物，但这个行业我认为更多是起到锚定的作用，只要公司正常经营就能带来稳定的现金流。我们不单独投资血制品，我们只是把血制品当成一个稳定的基础，所以不是所有的医药行业都投资。品牌中药我们看好，品牌中药需注意两点：能否长期进行提价、需求能否长期增长，片仔癀就看着价和量的提升；品牌中药的外延增长，就像云南白药开发牙膏、洗发水等产品。这些企业也都涉及药妆，这块也值得期待，中国的化妆品行业我认为长期在国际竞争的话，我认为药妆是中国的一大特色，运用中国的一些植物中草药的技术做药妆，符合消费者未来对健康的需求同时也是中国的特色和优势。目前国内也出现很多新兴的彩妆品牌，但我认为这些品牌还需要进一步构筑长期竞争力。
Viktor Grünwald discusses treatment for progression of disease after front lines PD1 based therapy.
欢迎收听雪球和喜马拉雅联合出品的财经有深度，雪球，3500万投资者在线交流，一起探索投资的智慧，听众朋友们大家好，我是主播匪石-34，今天分享的稿件名字叫做为什么要全职投资？来自于simon0123456。 从年前提辞职到办完离职手续，时间比我预想的快了许多，内心盼望很久的全职投资的想法终于落地，感觉还是有点不太真实。 有两个“高光时刻”深深的刻在我的脑海中，这辈子应该都不会忘记。 1. 16年前，我收到了一个电话，那是我梦寐以求的公司的OFFER，还清晰的记得自己对着镜子握拳傻笑的样子，那时候觉得生活充满阳光、充满希望；2.去年12月份重仓的恒瑞因为PD1谈判落地几乎涨停，提前实现了我个人投资的一个小目标，我当时激动难耐趴在座位上，眼里噙满泪水，使我确信我找对了努力的方向，使我坚信我有能力通过投资过上自己想要的生活。 全职投资是一个争议性很大的话题，现在也不是一个讨论这种话题的好时机。今年以来很多抱团股动不动就调整了百分之20、30，甚至腰斩的也不少，令人感叹在股市活着的不易。本来犹豫着是否应该写这篇文章，但是全职投资是我考虑了很多年、一直很想去努力尝试的一件事情，记录一下我自己的想法、记录一下我自己的经历，我觉得是一个有意义的事情。等多年以后回头来看看可能会有点意思，如果还能得到一些同道中人的共鸣那就更加开心了。 为什么会有要全职投资的想法?我在一家外企的IT公司工作了16年多了，因为众所周知的原因，来自国内对手的竞争越来越激烈，外企在国内的日子越来越难过了。公司在近十年来几乎每年都在裁员，我很早就看清楚了一个残酷的事实，无论我如何努力工作我都很难保住我的工作、特别是当我年纪大需要养老的时候，以后我如何养活自己和家人，这令我一度很焦虑。以前外企还带有一定的光环，公司福利待遇、公司文化、人性化管理等都有吸引力，现在因为竞争激烈不能不跟着市场有变化；但IT行业普遍工作强度大，最重要的是新技术层出不穷，资本的力量会将人的脑汁都要砸干，以后即使公司不裁员年纪大了肯定跟不上。出路通常有两条，第一是创业，第二是找好工作。因为在外企绝大部分人都只是一个螺丝钉，只能接触到行业工作很窄的一部分，加上我所在的行业比较特殊，基本上没有看见过有个人创业成功的例子，创业对资源、能力的要求太高了，创业我觉得对我是高不可攀。找好工作难度也非常大，我所在的公司、我所做的工作已经是行业比较好的了，但依然给不了我安全感、给不了我未来，跳槽到国内同行也不能同时满足我工作生活兼顾的需求。所幸我们公司同事炒股的风气比较浓厚，老员工基本上都是股民，我自己也算是有点经验的股民。有几个水平不错的同事，他们获利不菲似乎给我打开了一扇观察世界的窗口。 为什么选择全职投资？全职投资只是我个人的最优选择，我觉得选择全职投资不外乎两个原因：1.热爱投资、喜欢全职投资的生活；我觉得判断是否适合全职投资的首要条件是是否热爱投资，这个才是最根本的。只有热爱，你才能不知疲倦、甘之如饴的去学习，才有希望成为投资高手。喜欢全职投资简单、有规律的生活，对生活方式有绝对的自主权。 2.觉得在投资上可以比做其它事情更好，做任何事情都应该去找到自己的比较优势。如果觉得创业有更高的成功率、有更大的激情，那当然是选择去创业。 为什么不工作和投资兼顾？愿望是美好的，现实是残酷的。 1.本职工作已经觉得很难受，高密度的新知识新技术学习已经让我疲于奔命，需要心无旁鹭、聚焦才能成为专家能手。我不可能只分50%的时间精力给投资，而50%的时间精力给本职工作我也不能很好的胜任。在股市投资上越看到希望，我对本职工作的不满意就越来越大，不满意工作强度、不满意绞尽脑汁的那种感觉、不满意出差、不满意夜班、不满意24小时和节假日随时待命、不满意参加项目比997还严重的加班。 2.百分百投入做一样工作我都不能保证能做得很好，要同时打好两份工我觉得成功的概率更低。必须有所侧重、有舍才有得。 全职投资最怕的事情是什么？1.不能盈利；盈利是一切问题的基础，不能盈利表明你所做的事情是海市蜃楼。全职投资的前提是你必须已经有一个比较成熟的投资体系，已经有一个比较长时间的成功投资经历，我不相信任何冠冕堂皇的口号，只看事实。盈利模式越稳定，盈利的时间长度越久，水平才越高。开始全职投资的本金越多，安全边际越高。 2.与社会脱节、没有社交。 喜欢全职投资的人多数是比较甘于寂寞、独立独行的人，通常都喜欢安静平和的生活，独处的时候大多-是享受的。但是每个人都是社会人、都有社交需求。因为疫情原因我可以在家办公，提前体验了一段全职投资的生活。时间久了没人交流、没有朋友聚会，心情是会受到影响的。现实中我是一个比较喜欢安静的人，朋友也不多，有网络、有书、有电影我就可以过得很轻松。但我还是希望全职投资后要保持或扩大一个交流沟通的圈子，既满足马斯洛需求的社交需求，也希望能过上更有质量的生活。 有以下计划：A.多进行体育锻炼；我非常喜欢运动，特别是打篮球，打了几十年了，周末有空我都会去篮球场出一身汗，心情也变得愉悦很多。最近肚子开始有增大的迹象，计划除了打篮球还要增加一些慢跑了。B.多参加一下户外活动；以前因为时间精力问题，比较少参加户外活动，其实内心挺喜欢大自然、喜欢户外的活动，既能锻炼身体、又是一个非常健康的娱乐方式，计划以后多参加一下户外俱乐部的活动；C.很想找到一些全职投资的同类人，既是人际交往的需要、也想找到更多的投资高手共同学习；D.多主动和老同学、老同事、老朋友联系；E.以后考虑做个微信公众号，多一个聊天、沟通的地方。 说实话我觉得跟社会脱节没有社交这个难题不算多大，跟不能盈利的难度不是一个数量级的。 全职投资的策略我个人这几年把自己投资的行业划定在医药、消费和科技这三个行业，因为从美股历史来看这三个大行业非常容易出大牛股，而且三个行业我觉得对于个人投资者来说足够了，我需要的是聚焦在这三个行业、在里面深耕、构筑自己的比较优势。我之前做了个5年计划，已经执行了三年多，主要持有恒瑞茅台和可转债等，坚持投资优秀公司、长期持有。所以未来两年我计划还要继续执行，让自己固定在恒瑞、茅台、腾讯、泰格、片仔癀、通策、可转债等少数个股上面，尽量不盲目扩大自己的能力圈，同时也是为了保持自己策略的一致性，希望能顺利度过转型全职投资的头两年时间。 短期目标:时间自由，工作地点自由，在股市活下来，赚到生活费用。 长期目标：财务自由，可以有能力帮助更多的人，过上自己想要的生活。 梦想还是要有的，万一实现了呢？ 作者：simon0123456链接：https://xueqiu.com/6073843435/175679412来源：雪球著作权归作者所有。商业转载请联系作者获得授权，非商业转载请注明出处。风险提示：本文所提到的观点仅代表个人的意见，所涉及标的不作推荐，据此买卖，风险自负。
欢迎收听雪球和喜马拉雅联合出品的财经有深度，雪球，3500万投资者在线交流，一起探索投资的智慧，听众朋友们大家好，我是主播匪石-34，今天分享的稿件名字叫做为什么要全职投资？来自于simon0123456。 从年前提辞职到办完离职手续，时间比我预想的快了许多，内心盼望很久的全职投资的想法终于落地，感觉还是有点不太真实。 有两个“高光时刻”深深的刻在我的脑海中，这辈子应该都不会忘记。 1. 16年前，我收到了一个电话，那是我梦寐以求的公司的OFFER，还清晰的记得自己对着镜子握拳傻笑的样子，那时候觉得生活充满阳光、充满希望；2.去年12月份重仓的恒瑞因为PD1谈判落地几乎涨停，提前实现了我个人投资的一个小目标，我当时激动难耐趴在座位上，眼里噙满泪水，使我确信我找对了努力的方向，使我坚信我有能力通过投资过上自己想要的生活。 全职投资是一个争议性很大的话题，现在也不是一个讨论这种话题的好时机。今年以来很多抱团股动不动就调整了百分之20、30，甚至腰斩的也不少，令人感叹在股市活着的不易。本来犹豫着是否应该写这篇文章，但是全职投资是我考虑了很多年、一直很想去努力尝试的一件事情，记录一下我自己的想法、记录一下我自己的经历，我觉得是一个有意义的事情。等多年以后回头来看看可能会有点意思，如果还能得到一些同道中人的共鸣那就更加开心了。 为什么会有要全职投资的想法?我在一家外企的IT公司工作了16年多了，因为众所周知的原因，来自国内对手的竞争越来越激烈，外企在国内的日子越来越难过了。公司在近十年来几乎每年都在裁员，我很早就看清楚了一个残酷的事实，无论我如何努力工作我都很难保住我的工作、特别是当我年纪大需要养老的时候，以后我如何养活自己和家人，这令我一度很焦虑。以前外企还带有一定的光环，公司福利待遇、公司文化、人性化管理等都有吸引力，现在因为竞争激烈不能不跟着市场有变化；但IT行业普遍工作强度大，最重要的是新技术层出不穷，资本的力量会将人的脑汁都要砸干，以后即使公司不裁员年纪大了肯定跟不上。出路通常有两条，第一是创业，第二是找好工作。因为在外企绝大部分人都只是一个螺丝钉，只能接触到行业工作很窄的一部分，加上我所在的行业比较特殊，基本上没有看见过有个人创业成功的例子，创业对资源、能力的要求太高了，创业我觉得对我是高不可攀。找好工作难度也非常大，我所在的公司、我所做的工作已经是行业比较好的了，但依然给不了我安全感、给不了我未来，跳槽到国内同行也不能同时满足我工作生活兼顾的需求。所幸我们公司同事炒股的风气比较浓厚，老员工基本上都是股民，我自己也算是有点经验的股民。有几个水平不错的同事，他们获利不菲似乎给我打开了一扇观察世界的窗口。 为什么选择全职投资？全职投资只是我个人的最优选择，我觉得选择全职投资不外乎两个原因：1.热爱投资、喜欢全职投资的生活；我觉得判断是否适合全职投资的首要条件是是否热爱投资，这个才是最根本的。只有热爱，你才能不知疲倦、甘之如饴的去学习，才有希望成为投资高手。喜欢全职投资简单、有规律的生活，对生活方式有绝对的自主权。 2.觉得在投资上可以比做其它事情更好，做任何事情都应该去找到自己的比较优势。如果觉得创业有更高的成功率、有更大的激情，那当然是选择去创业。 为什么不工作和投资兼顾？愿望是美好的，现实是残酷的。 1.本职工作已经觉得很难受，高密度的新知识新技术学习已经让我疲于奔命，需要心无旁鹭、聚焦才能成为专家能手。我不可能只分50%的时间精力给投资，而50%的时间精力给本职工作我也不能很好的胜任。在股市投资上越看到希望，我对本职工作的不满意就越来越大，不满意工作强度、不满意绞尽脑汁的那种感觉、不满意出差、不满意夜班、不满意24小时和节假日随时待命、不满意参加项目比997还严重的加班。 2.百分百投入做一样工作我都不能保证能做得很好，要同时打好两份工我觉得成功的概率更低。必须有所侧重、有舍才有得。 全职投资最怕的事情是什么？1.不能盈利；盈利是一切问题的基础，不能盈利表明你所做的事情是海市蜃楼。全职投资的前提是你必须已经有一个比较成熟的投资体系，已经有一个比较长时间的成功投资经历，我不相信任何冠冕堂皇的口号，只看事实。盈利模式越稳定，盈利的时间长度越久，水平才越高。开始全职投资的本金越多，安全边际越高。 2.与社会脱节、没有社交。 喜欢全职投资的人多数是比较甘于寂寞、独立独行的人，通常都喜欢安静平和的生活，独处的时候大多-是享受的。但是每个人都是社会人、都有社交需求。因为疫情原因我可以在家办公，提前体验了一段全职投资的生活。时间久了没人交流、没有朋友聚会，心情是会受到影响的。现实中我是一个比较喜欢安静的人，朋友也不多，有网络、有书、有电影我就可以过得很轻松。但我还是希望全职投资后要保持或扩大一个交流沟通的圈子，既满足马斯洛需求的社交需求，也希望能过上更有质量的生活。 有以下计划：A.多进行体育锻炼；我非常喜欢运动，特别是打篮球，打了几十年了，周末有空我都会去篮球场出一身汗，心情也变得愉悦很多。最近肚子开始有增大的迹象，计划除了打篮球还要增加一些慢跑了。B.多参加一下户外活动；以前因为时间精力问题，比较少参加户外活动，其实内心挺喜欢大自然、喜欢户外的活动，既能锻炼身体、又是一个非常健康的娱乐方式，计划以后多参加一下户外俱乐部的活动；C.很想找到一些全职投资的同类人，既是人际交往的需要、也想找到更多的投资高手共同学习；D.多主动和老同学、老同事、老朋友联系；E.以后考虑做个微信公众号，多一个聊天、沟通的地方。 说实话我觉得跟社会脱节没有社交这个难题不算多大，跟不能盈利的难度不是一个数量级的。 全职投资的策略我个人这几年把自己投资的行业划定在医药、消费和科技这三个行业，因为从美股历史来看这三个大行业非常容易出大牛股，而且三个行业我觉得对于个人投资者来说足够了，我需要的是聚焦在这三个行业、在里面深耕、构筑自己的比较优势。我之前做了个5年计划，已经执行了三年多，主要持有恒瑞茅台和可转债等，坚持投资优秀公司、长期持有。所以未来两年我计划还要继续执行，让自己固定在恒瑞、茅台、腾讯、泰格、片仔癀、通策、可转债等少数个股上面，尽量不盲目扩大自己的能力圈，同时也是为了保持自己策略的一致性，希望能顺利度过转型全职投资的头两年时间。 短期目标:时间自由，工作地点自由，在股市活下来，赚到生活费用。 长期目标：财务自由，可以有能力帮助更多的人，过上自己想要的生活。 梦想还是要有的，万一实现了呢？ 作者：simon0123456链接：https://xueqiu.com/6073843435/175679412来源：雪球著作权归作者所有。商业转载请联系作者获得授权，非商业转载请注明出处。风险提示：本文所提到的观点仅代表个人的意见，所涉及标的不作推荐，据此买卖，风险自负。
欢迎收听雪球和喜马拉雅联合出品的财经有深度，雪球，3500万投资者在线交流，一起探索投资的智慧，听众朋友们大家好，我是主播匪石-34，今天分享的稿件名字叫做为什么要全职投资？来自于simon0123456。 从年前提辞职到办完离职手续，时间比我预想的快了许多，内心盼望很久的全职投资的想法终于落地，感觉还是有点不太真实。 有两个“高光时刻”深深的刻在我的脑海中，这辈子应该都不会忘记。 1. 16年前，我收到了一个电话，那是我梦寐以求的公司的OFFER，还清晰的记得自己对着镜子握拳傻笑的样子，那时候觉得生活充满阳光、充满希望；2.去年12月份重仓的恒瑞因为PD1谈判落地几乎涨停，提前实现了我个人投资的一个小目标，我当时激动难耐趴在座位上，眼里噙满泪水，使我确信我找对了努力的方向，使我坚信我有能力通过投资过上自己想要的生活。 全职投资是一个争议性很大的话题，现在也不是一个讨论这种话题的好时机。今年以来很多抱团股动不动就调整了百分之20、30，甚至腰斩的也不少，令人感叹在股市活着的不易。本来犹豫着是否应该写这篇文章，但是全职投资是我考虑了很多年、一直很想去努力尝试的一件事情，记录一下我自己的想法、记录一下我自己的经历，我觉得是一个有意义的事情。等多年以后回头来看看可能会有点意思，如果还能得到一些同道中人的共鸣那就更加开心了。 为什么会有要全职投资的想法?我在一家外企的IT公司工作了16年多了，因为众所周知的原因，来自国内对手的竞争越来越激烈，外企在国内的日子越来越难过了。公司在近十年来几乎每年都在裁员，我很早就看清楚了一个残酷的事实，无论我如何努力工作我都很难保住我的工作、特别是当我年纪大需要养老的时候，以后我如何养活自己和家人，这令我一度很焦虑。以前外企还带有一定的光环，公司福利待遇、公司文化、人性化管理等都有吸引力，现在因为竞争激烈不能不跟着市场有变化；但IT行业普遍工作强度大，最重要的是新技术层出不穷，资本的力量会将人的脑汁都要砸干，以后即使公司不裁员年纪大了肯定跟不上。出路通常有两条，第一是创业，第二是找好工作。因为在外企绝大部分人都只是一个螺丝钉，只能接触到行业工作很窄的一部分，加上我所在的行业比较特殊，基本上没有看见过有个人创业成功的例子，创业对资源、能力的要求太高了，创业我觉得对我是高不可攀。找好工作难度也非常大，我所在的公司、我所做的工作已经是行业比较好的了，但依然给不了我安全感、给不了我未来，跳槽到国内同行也不能同时满足我工作生活兼顾的需求。所幸我们公司同事炒股的风气比较浓厚，老员工基本上都是股民，我自己也算是有点经验的股民。有几个水平不错的同事，他们获利不菲似乎给我打开了一扇观察世界的窗口。 为什么选择全职投资？全职投资只是我个人的最优选择，我觉得选择全职投资不外乎两个原因：1.热爱投资、喜欢全职投资的生活；我觉得判断是否适合全职投资的首要条件是是否热爱投资，这个才是最根本的。只有热爱，你才能不知疲倦、甘之如饴的去学习，才有希望成为投资高手。喜欢全职投资简单、有规律的生活，对生活方式有绝对的自主权。 2.觉得在投资上可以比做其它事情更好，做任何事情都应该去找到自己的比较优势。如果觉得创业有更高的成功率、有更大的激情，那当然是选择去创业。 为什么不工作和投资兼顾？愿望是美好的，现实是残酷的。 1.本职工作已经觉得很难受，高密度的新知识新技术学习已经让我疲于奔命，需要心无旁鹭、聚焦才能成为专家能手。我不可能只分50%的时间精力给投资，而50%的时间精力给本职工作我也不能很好的胜任。在股市投资上越看到希望，我对本职工作的不满意就越来越大，不满意工作强度、不满意绞尽脑汁的那种感觉、不满意出差、不满意夜班、不满意24小时和节假日随时待命、不满意参加项目比997还严重的加班。 2.百分百投入做一样工作我都不能保证能做得很好，要同时打好两份工我觉得成功的概率更低。必须有所侧重、有舍才有得。 全职投资最怕的事情是什么？1.不能盈利；盈利是一切问题的基础，不能盈利表明你所做的事情是海市蜃楼。全职投资的前提是你必须已经有一个比较成熟的投资体系，已经有一个比较长时间的成功投资经历，我不相信任何冠冕堂皇的口号，只看事实。盈利模式越稳定，盈利的时间长度越久，水平才越高。开始全职投资的本金越多，安全边际越高。 2.与社会脱节、没有社交。 喜欢全职投资的人多数是比较甘于寂寞、独立独行的人，通常都喜欢安静平和的生活，独处的时候大多-是享受的。但是每个人都是社会人、都有社交需求。因为疫情原因我可以在家办公，提前体验了一段全职投资的生活。时间久了没人交流、没有朋友聚会，心情是会受到影响的。现实中我是一个比较喜欢安静的人，朋友也不多，有网络、有书、有电影我就可以过得很轻松。但我还是希望全职投资后要保持或扩大一个交流沟通的圈子，既满足马斯洛需求的社交需求，也希望能过上更有质量的生活。 有以下计划：A.多进行体育锻炼；我非常喜欢运动，特别是打篮球，打了几十年了，周末有空我都会去篮球场出一身汗，心情也变得愉悦很多。最近肚子开始有增大的迹象，计划除了打篮球还要增加一些慢跑了。B.多参加一下户外活动；以前因为时间精力问题，比较少参加户外活动，其实内心挺喜欢大自然、喜欢户外的活动，既能锻炼身体、又是一个非常健康的娱乐方式，计划以后多参加一下户外俱乐部的活动；C.很想找到一些全职投资的同类人，既是人际交往的需要、也想找到更多的投资高手共同学习；D.多主动和老同学、老同事、老朋友联系；E.以后考虑做个微信公众号，多一个聊天、沟通的地方。 说实话我觉得跟社会脱节没有社交这个难题不算多大，跟不能盈利的难度不是一个数量级的。 全职投资的策略我个人这几年把自己投资的行业划定在医药、消费和科技这三个行业，因为从美股历史来看这三个大行业非常容易出大牛股，而且三个行业我觉得对于个人投资者来说足够了，我需要的是聚焦在这三个行业、在里面深耕、构筑自己的比较优势。我之前做了个5年计划，已经执行了三年多，主要持有恒瑞茅台和可转债等，坚持投资优秀公司、长期持有。所以未来两年我计划还要继续执行，让自己固定在恒瑞、茅台、腾讯、泰格、片仔癀、通策、可转债等少数个股上面，尽量不盲目扩大自己的能力圈，同时也是为了保持自己策略的一致性，希望能顺利度过转型全职投资的头两年时间。 短期目标:时间自由，工作地点自由，在股市活下来，赚到生活费用。 长期目标：财务自由，可以有能力帮助更多的人，过上自己想要的生活。 梦想还是要有的，万一实现了呢？ 作者：simon0123456链接：https://xueqiu.com/6073843435/175679412来源：雪球著作权归作者所有。商业转载请联系作者获得授权，非商业转载请注明出处。风险提示：本文所提到的观点仅代表个人的意见，所涉及标的不作推荐，据此买卖，风险自负。
Pengaturan skor, narkoba, judi, kriminal, dan perselingkuhan cukup melekat dengan sepak bola. Bahkan sejak PD1 sudah ada kasus yang mewarnai olahraga yang kita semua cintai ini. Inilah side pitch, selamat mendengarkan.
On this edition of The Friday Packet with Stocky and Stout, we condense roughly 18 hours of Billings Montana City Council into an hour of listening pleasure. We talk, CIP, SBURA, PD1, RE:Code, and the current councils struggles with Robert's Rules of parliamentary procedures. *Email us at thefridaypacket@gmail.com with comments, questions, concerns. *Go to https://www.patreon.com/thefridaypacket to “buy that for a dollar” and become a sustaining member of the podcast!!
FDA 批准MitraClip治疗心力衰竭继发的二尖瓣返流 NEJM 达格列净在射血分数下降的心功能不全的患者中的作用Circulation 恩格列净治疗心力衰竭过程中心脏和肾脏的获益Lancet 支持联合使用ARNI、β受体阻滞剂、盐皮质激素拮抗剂和SGLT2抑制剂作为心衰的新标准治疗Nature PCSK9抑制剂可增强肿瘤的免疫治疗的疗效MitraClip 2019年3月，FDA为MitraClip经导管二尖瓣修复装置增加了新的适应症，用于治疗症状性心力衰竭症状合并继发性或功能性二尖瓣返流（SMR或FMR）。《COAPT研究：经导管二尖瓣修复术治疗心力衰竭患者》New England Journal of Medicine，2018年12月 (1) 左心室功能不全伴有二尖瓣返流的心力衰竭患者预后较差。研究的目的是评价经导管二尖瓣修复术是否能改善预后。研究纳入了心衰、合并中重度二尖瓣返流患者614人，这些患者在使用指南指导下的、最大剂量药物治疗后仍有症状，随机分为经导管二尖瓣修复术加药物治疗（器械组）和单纯药物治疗组（对照组）。器械组24个月内因心力衰竭住院的比例为35.8/100人年，对照组为67.9/100人年（风险比 0.53，P < 0.001）；器械组24个月全因死亡率为29.1%，对照组为46.1%（风险比 0.62，P10mm2或返流量>30ml）的患者，EF介于15%-40%，随机分入器械组（经皮二尖瓣修复加药物治疗）和对照组（单纯药物治疗）。这篇文章汇报了24个月的随访结果24个月时，器械组全因死亡和心衰住院的患者占63.8%，对照组为67.1%（风险比 1.01，无统计学意义）。器械组的全因死亡率为34.9%，对照组为34.2%（风险比 1.02，无统计学意义）。器械组心衰住院比例为55.9%，对照组61.8%（风险比 0.97，无统计学意义）。结论：在心力衰竭合并严重二尖瓣返流的患者中，经皮二尖瓣修复加药物治疗与单纯药物治疗相比，在2年内心衰死亡或住院的风险没有显著降低。小羽点评：MitraClip治疗心力衰竭合并继发性或功能性二尖瓣返流患者的两项大型临床研究COAPT研究和MITRA-Fr研究的结果并不一致，但是FDA根据COAPT研究的结果还是批准了MitraClip治疗心衰的适应症。现在也有文献讨论这种治疗心衰策略的机制，但似乎仍不足以解释我心中的疑惑——这种治疗策略究竟有没有大规模推广的理论基础和确凿的证据。慢性心功能不全治疗 —— SGLT2抑制剂钠-葡萄糖协同转运蛋白2（SGLT2）表达于肾近端小管，介导约90%的滤过葡萄糖的重吸收。SGLT2抑制剂促进肾脏对葡萄糖的排泄，因此可降低血糖、降低血压和体重，通常不会导致低血糖。2020年5月，FDA批准达格列净用于治疗射血分数降低的心衰患者，用以降低心血管死亡和因心力衰竭再住院的风险。这是SGLT2抑制剂中首个获批，用于治疗射血分数降低、纽约心功能分级II-IV级的患者。《DAPA-HF研究：达格列净在射血分数下降的心功能不全的患者中的作用》New England Journal of Medicine，2019年11月 (3)在这个III期、安慰剂对照研究中，纳入了选取了4744名患者纽约心功能分级II-IV级的、射血分数低于40%的患者接受达格列净10mg qd或安慰剂治疗。随访18.2个月，达格列净治疗组主要心血管事件的风险比0.74；心衰恶化的风险比为0.70；心血管死亡风险比0.82；全因死亡危险比为0.83。糖尿病与非糖尿病患者相似；与容量不足、肾功能不全和低血糖相关的不良事件发生频率在治疗组之间没有差异。结论：达格列净可减少心衰恶化或心血管死亡的风险。《DAPA-HF研究亚组分析：达格列净对有或没有糖尿病的射血分数下降的心功能不全的患者的治疗作用》JAMA，2020年3月 (4)DAPA-HF研究中有54%的参与者并未患糖尿病。其中糖尿病患病情况分三种：（1）患糖尿病（有糖尿病史或糖化血红蛋白≥6.5%，n=2,139），（2）前驱糖尿病（糖化血红蛋白5.7%～6.5%；n=1,748），（3）没有糖尿病（糖化血红蛋白＜5.7%；n=839）。患糖尿病的参与者中有更多黑人，心功能更差，更可能有缺血性改变。试验结束时（中位随访时间为，16.6～18.0个月），糖尿病、前驱糖尿病和无糖尿病亚组的风险均出现了相似且与达格列净相关的显著降低（风险比分别为0.75、0.74和0.67；无交互作用）。最常见的不良反应是容量不足和肾损伤，其发生率与治疗或糖尿病状况不相关。结论：射血分数降低的心衰患者中，即使没有糖尿病，使用达格列净仍可以显著降低了心衰恶化或心血管死亡的风险。《DAPA-HF研究亚组分析：达格列净和利尿剂联用治疗射血分数下降的心功能不全的研究》Circulation，2020年7月 (5)DAPA-HF研究中，根据患者是否在服用利尿剂，将患者分为无利尿剂组、利尿剂40mg/d组。这四组患者中，达格列净降低了这些亚组的主要终点时间的风险，风险比分别为0.57、0.83、0.77和0.78。达格列净疗效和治疗的耐受性在各个亚组是一致的。在随访期间，大多数患者的利尿剂剂量没有变化。结论：达格列净在各个利尿剂亚组中的安全性和有效性是一致的。《DAPA-HF研究亚组分析：达格列净和沙库巴曲缬沙坦联用治疗射血分数下降的心功能不全的研究》JACC Heart Failure，2020年7月 (6)DAPA-HF研究中，根据患者是否在随机服用沙库巴曲缬沙坦进行分析。其中10.7%的参与者在基线时接受了沙库巴曲缬沙坦治疗， 这些患者通常来自北美和欧洲，心功能通常更差、血压更低。心血管死亡或心衰恶化的风险比，在服用沙库巴曲缬沙坦人群中为0.75；在未服用沙库巴曲缬沙坦人群中为0.74。次要终点和安全终点，包括与低血容量有关的事件，两组都是相似的。结论：两种药物联合使用可进一步降低射血分数下降的心功能不全患者的发病率和死亡率。《DAPA-HF研究亚组分析：达格列净对门诊射血分数降低心衰的恶化的影响》Circulation，2020年10月 (7)DAPA-HF研究中，根据心衰住院、心衰恶化或心血管死亡为终点事件进行亚组分析，达格列净组22.2%的患者出现终点事件、安慰剂组为28.8%，风险比0.73，P
Hartmut Ehrlich and Philippe Pouletty discuss Abivax Pipeline of Clinical Programs involving Covid-19, Ulcerative Colitis, Crohn's Disease and more. https://www.abivax.com/pipeline/ - #COVID-19 https://www.abivax.com/pipeline/abx464-for-covid-19/ Ongoing Phase 2b/3 trial with ABX464 in Covid-19 (miR-AGE trial), the unique properties of the lead candidate (antiviral, anti-inflammatory, tissue repair) to treat elderly and high-risk Covid-19 patients, the rial is ongoing in Europe and Brazil (Mexico, Peru and Chile to follow shortly) -#Cancer https://www.abivax.com/pipeline/abx196/ ABX196 has been developed as a synthetic agonist of iNKT cells from a proprietary platform technology that identifies agonists of these types of cells that demonstrate immune enhancing effects in cancer models. Preclinical data showed that ABX196 enhanced anti-tumoral activity when used alone and in combination with anti-PD1 antibodies or doxorubicin. - Ulcerative Colitis https://www.abivax.com/pipeline/abx464-ibd-uc/ ABX464 in Inflammatory Bowel Diseases (Abivax development priority), excellent two-year efficacy and safety data for ABX464 ulcerative colitis Phase 2a maintenance study and ongoing ulcerative colitis Phase 2b trial in 15 countries, the US and Canada - Crohn's disease https://www.abivax.com/pipeline/abx464-for-crohns-disease/ Planned pivotal Phase 2b/3 trial with ABX464 in Crohn's disease (FPI Q1 2021) and ngoing clinical trial with ABX464 in rheumatoid arthritis in 5 European countries - HC Ongoing clinical trial with second molecule, ABX196, in patients with hepatocellular carcinoma in the US
The Oncology Journal Club - Delivering Oncology News DifferentlyThe Oncology Podcast, brought to you by Oncology News Australia, is proud to present Episode 11 in our series The Oncology Journal Club.Today's episode includes an in-depth review of two key papers – Eva talks us through the I-SPY 2 trial and Hans is focused on the National Lung Matrix trial. Eva also has her 'mind boggling' paper of the week on the #MedBikini controversy. This week we are very lucky to have a special interview with the incredible Professor Dorothy Keefe, Medical Oncologist and CEO of Cancer Australia. In this episode, Dorothy and Craig discuss recently published papers on Optimal Care Pathways but watch out for the extended interview later in the week where Dorothy passionately discusses her priorities for Cancer Australia, disparity and what she hopes will be her lasting legacy leading the Australian national government agency for cancer.We also have Quick Bites on pregnancy after breast cancer, a diagnostic biopsy-adapted immunoscore and PD1 blockade resistance. With the usual top quality banter, papers you won't hear of anywhere else and expert analysis from our Hosts, you are in for another great episode of The Oncology Journal Club!Full bios and the list of all papers discussed are available on our website.For the latest oncology news visit www.oncologynews.com.au and for regular oncology updates for healthcare professionals, please subscribe to The Oncology Newsletter.The Oncology Podcast - An Australian Oncology Perspective
出品：中国科普博览 SELF格致论道讲坛导语：为什么吃了这么多药我的病还不好，我们还处于“万人一药”的传统用药阶段。如何“因地制宜”地对病灶进行精准打击？这需要高性能计算对海量生命数据进行计算与分析得到能精准治疗的策略。---嘉宾介绍---牛北方中国科学院计算机网络信息中心高性能计算技术与应用发展部副主任演讲实录：大家知道人体带有3.7乘以10的13次方这么多个细胞，除了这些细胞还有细菌就是说我们人体的微环境。大家知道人体各种各样器官的细胞包括从各种组织的比如说肌肉的细胞，骨髓的细胞，肺，每一个组织它的细胞的种类和细胞的profile（外形）都是不同的。除了这些细胞还有我们人体的微环境。大家知道有些人他吃很多但是他始终不胖，但是有些人他喝点水也要胖，这就是我们人体微环境的一些东西。其实大家可别小瞧这个细菌，因为人体微环境的细菌可能它的种类和它细胞的数目比我们人体的细胞种类还要多，你会看到这个HMP的项目，美国除了开展人体的肿瘤基因组研究之外，它还开展了人体环境的研究，也就是研究人体各个组织的各个部位的微环境的组学研究。 介绍一下人类基因组，大家知道可能大家在各种各样的场合都听说过这样的事情，就是说人类基因组大概有3个G的这样的数据量，也就是说由ACGT四个字符组成的这一个长长的字符串，这个字符串的容量大概是3个G。大家可别小瞧这3个G，因为这3个G的数据是全世界的人努力花了十年的时间，花了多少钱呢？花了3个G的美元，也就是每一个碱基每一个字符就花了一个美元，全世界的科学家一起努力到两千零几年的时候完成了人类基因组的破译。这么多的数据量大家可能没有一个概念，下面我们举一个例子来说明一下，这些数据量在我们生命当中到底是有多少。 随着我国开展精准医学计划、开展万人基因组数据的万人基因组的研究我们大概有这样的一个比喻，大家可以看到在屏幕上边也就是说一万人的基因组，大概是1个PB的数据，如果我们把这些数据，就是ACGT这样的字符串把它打印成新华字典的话大家一般都用这个来比喻大概有6.67亿本这样的新华字典能够全部打满这样的ACGT的字符，6.67亿本的新华字典如果我们铺满一个楼的话大概我们一般都用这个数据产生单位也就是咱们中科院的基因组研究所那个大楼来比喻的话，如果把这些新华字典全部排满整个楼的话大概需要5.68个这样的楼才盛得下这么大的数据。 大家可能有问题问了这么大的数据对我们的医疗有什么意义呢？我们到底是怎么从这些数据里面来解析，怎么来找到我们的致病基因呢，这就是我们高性能计算所需要干的事情，在介绍这个高性计算来解决这样的问题之前呢。我首先介绍一下我们医疗的状况，可能每个人都去过医院，我们去医院看病可能现在的状态就是千人一刀，万人一药的情况，比如你去看病感冒我们可能就只有一种药，或者说几种药来治大家都用这样的药。是不是准的呢？特别是复杂性疾病，比如说简单的病可能我们抗生素，比如说这个感冒药都可以解决问题，但是对于复杂性疾病呢，我们用药的情况到底是一个什么样的情况呢？大家会看到这样的一篇文章，题目叫做不精准的医学，这个是Nature发表的一篇文章，介绍我们现在的医疗的，传统的医疗用药的现状，你会看到这里面有十种药，那么这里面，蓝色的表明是吃了有效果的，红色的表明是吃了这种药没有效果的，大家会看到这十种药里边，第一种药你会看到有五个人，四个人吃了是没有效的，只有一个人吃了是有效果的，这一种药还是可以接受的，你会看到第二种药大概是有25个人吃这样的一种药，但是只有一个人是有效果的，说明我们的现在的传统用药物的状况是非常不精准的，也就是说我们要怎么才通过我们的数据分析才达到这个数据精准的状况呢，这个状况我觉得已经存在了很多年，已经非常的严重。在2015年1月大家知道奥巴马总统提出了这个精准医学的计划，你会看到他旁边有一个双螺旋的模型，他呼吁国会去投入2.15亿美元 来开展精准医学的计划，也就是说我们要做到精准用药。我们要做到精准的治疗大家会看到有一个小女孩，奥巴马总统大家可能都比较熟悉但是大家是否知道这个小女孩，他为什么要把这个小女孩拉到这个讲台上去呼吁国会来投入这2.15亿美元来开展精准医学计划呢，这个小女孩呢她叫Elana Simon她在高中的时候得了纤维板层的肝细胞癌这样的一种复杂性疾病，也就是我们现在说的癌症肿瘤这样的病，这个小女孩她得了这个病以后没有什么很好的方法来治疗，所以说这个小女孩就立志要研究她本身得的这样一种肿瘤，她考上了哈佛大学医学院，在哈佛大学医学院的时候就开始对她这种肿瘤进行研究，她找到一个非常有用的这样的一个靶点就是gene fusion，什么是gene fusion呢？就是两个基因它融合在一块儿了，是她得纤维板层的肝细胞癌一个非常重要的因素，所以说奥巴马总统会把这个Elana Simon拉到这个讲台上呼吁国会来投入这些钱进行精准医学的研究。 精准用药的现状到底是什么样子的呢？举一个简单点的例子你会看到这里边有一种药就是镇痛药，非常常用的镇痛药你会看到有一种基因变异的话，它会对对这个药有效，但是如果没有这种基因变异的话对这种药是没有效果的，也有一种情况可以这么来说就是说这种药它适合A不适合B，适合欧洲人但是不适合亚洲人，我们知道我们很多药由于我们技术水平的限制和研究水平的限制，很多药都是从美国或者是欧洲这些大的制药公司来出产的，所以说这是精准用药的不准确的现状另外一种就是我们精准治疗。 大家知道肿瘤，可能一听肿瘤大家都比较恐惧现在治疗肿瘤的手段也是很有限的。大家知道化疗，常规的化疗如果你去就诊，如果某一个人他得了肿瘤，如果不做精准的话很可能就是说进行常规的化疗，这个时候就会很容易出现耐药，但是如果我们经过数据分析来得到这样的肿瘤的情况到底是什么样子的，然后采取一种精准的化疗手段你会看到下面它就对化疗是敏感的。举两个例子就简单来介绍一下通过我们精准医学通过数据分析，通过计算我们能得到一个精准治疗的一个策略，这就说到我们精准医疗需要高性能计算来支持你会看到这么大的数据量，一万人的数据大概是一百个PB的数据量，大概是需要十万台的PC，就是我们平常用的PC机的存储能力然后包括各种各样的数据，有组学数据，有影像学的数据，有暴露组各种各样的数据，但是除了数据存储需要我们高性能计算来支持以外我们同样知道我们得到这些数据存在那里没有用的，我们要解析，要找到我们的致病基因，也就是今天我要演讲的题目，我们怎么做？大家会看到这样一个比较简单的例子就是我们进行基因组测序的第一步，现在我们还没有能力把整个人体的基因组一下给读出来，一长串 3个G的字符，那么我们怎么做呢，我们只能读出很短的一段，比如说一百到两百这样的字符，那么面临着这样的一个首要的计算问题就是我们怎么把这些数据给它拼装起来，把它连成一条长串三个GB的字符串，所以这样的问题如果用人工，大家经常用这样一个非常搞笑的图片来表示就是说一堆人对着一堆的数据，那么怎么办所以说这个问题如果用人工的话是解决不了的，如果采用个人电脑的话大概需要几百年的时间，用高性能计算机解决这样的问题我们可能只需要几分钟的时间，这就是说明这个精准医学的研究，特别是基因的研究就是如何来找到我们的致病基因呢，是需要高性能计算来参与的，离开高性能计算我们是解决不了这样的问题的，特别是现在的数据爆炸的时代。举两个简单的图片来说明高性能计算很简单也就是说高性能，我们平常用的PC机可能一个CPU来解决这样的问题，但是高性能并行机，它是有多台CPU，即上万个CPU来解决这样的问题，所以时间非常快，这样的话这个任务就面临了一个最基本的问题，就是如何把这个任务来分解的问题，就是说我们用高性能并行机，这么多CPU怎么来一块儿来做这个事儿。我们怎么把这个任务来分解，这个里面你会看到有四块，我们把这个任务分成了四块但是另外一个片子呢我们要把这个任务分成多片比如几百万核的话，这样的话才会做到刚才我讲的能够几分钟把这个基因的数据给解析出来，找到我们的致病基因，我会给大家介绍两个例子也就是说大家可能比较疑惑，就是精准医学从数据分析的手段到底是如何做的，怎么来找到这个肿瘤的致病基因，比如说靶点它的过程是什么样子的？ 大家会看到这个片子里面，一个人的肺上面这个蓝色的组织是正常的肺组织，那个红色的就是在肺表面找到一个肺肿瘤的组织，那么我们如何做的呢，这个里边的女老师就是我在美国的时候我的研究所的领导，她是世界上第一个发明这种方法去找到肿瘤致病基因的这样的一个人，也是全世界很有名的一个计算基因组学的专家。她发明的这种方法就是把肿瘤组织提取出来，然后把正常的组织提取出来进行基因组测序，你会看到那个蓝色的和那个红色的经过这两套数据测出来以后，这就是我们高性能计算领域计算科学家所要解决的问题，就是说我们要比对这两套数据，这两套数据经过比对以后你会发现在正常的肺组织里边，我们没有发现这些变异位点，但是在肿瘤组织里边我们发现了变异位点，然后这个位点经过我们的生物学知识，我们找到这些位点以后根据这些位点来进行一个处方，比如我们找到RB1这样的一个基因，然后我们根据这个基因得到一个处方也就Rx，这是整套利用数据分析计算手段来解决这样的一个肿瘤治疗的问题。 下面我讲一下我亲身经历的一个例子，大家会看到这个上面有我的一张照片，旁边的是Dr.Lucas博士也是我的同事，这个人他在未成年的时候得了白血病也就是我们平常说的血癌，在我国的儿童里边发病率也是非常高的，他未成年的时候他幸好还有一个弟弟因为美国是不限制生多少个孩子的，他有个弟弟在他未成年的时候给他做了骨髓移植从医学上来讲就是说他缓解了，什么叫缓解就是说他好了，暂时没有病，但是他在工作的时候也在和我当同事的时候在华盛顿大学基因组研究所当同事的时候，他的白血病复发，大家知道成人的白血病复发的话基本上就是要死掉的也就是说成活率非常低，这个时候正赶上我们进行基因组就是精准医学用计算技术来解决这个问题，进行研究非常火的时候，我们的研究所里一个顶级的一个血癌的基因组学顶级专家你会看到中间那个老先生就是我们基因组所的另外一个领导，他是美国进行白血病血癌研究的基因组研究的顶尖人物，当时Lucas已经非常严重了他说我们为何不试一试就是用我们的计算技术用我们的研究所整体的人力去试一下是不是可以找到可以救他的命的（方法），我们就进行（研究）对Dr.Lucas博士进行三套数据的测序，第一套测序就是全基因组的测序进行全基因组测序以后，我们没有找到什么任何有意义的靶点然后又对Dr.Lucas进行转录组的测序，这两个测序到底是什么意思？进行这两套测序数据分析以后我们也没有找到任何有意思的靶点，就是说对他个人有特异的这个靶点，我们大家都很沮丧，之后就对Dr.Lucas进行表达组的测序的时候，我们找到了一个利用我们的计算技术数据分析技术所有的机器都在运转，大概花了一个多星期的时间我们找到了一个FLT3的基因，这个基因的表达和其他基因的表达差距非常大，你会看到在这个上面其他基因的表达都是非常平缓的FLT3基因的表达是非常高的，我们把这个信号输入我们自己的开发的一套计算系统也是DGIdb的选药，筛药和治疗方案的一个自动化的系统，我们找到了一种药，大家会看到底下的那个药叫索坦(Sutent)在国内已经上市，但是当时在FDA在进行临床实验还没有上市，我记得我们全基因组研究所的人捐款向FDA申请走绿色通道把这种药买回来，给Dr.Lucas吃完以后就奇迹发生了，真的他的发烧什么都没有了然后他就好了，这个例子也登到了华盛顿邮报已经五年了，他现在还是好好的他现在带着实验室学生做研究，同时他也在满世界跑，去讲他这样的一个例子。 另外一个例子就是免疫疗法，就是现在非常火的肿瘤免疫治疗。什么是免疫治疗呢？就是说我们要把癌细胞给吃掉我们把自身的免疫系统给加强，把这个癌细胞吃掉，我就介绍另外一个例子也就是美国总统卡特他得了黑色素瘤，晚期的黑色素瘤比较危险的是这个晚期的黑色素瘤的转移已经到他的脑部 ，因为美国的免疫治疗是走在咱们全世界的前列的，他就对卡特进行免疫疗法进行各种各样的治疗，现在它转移到脑部的这个肿瘤已经完全没有了，其实免疫疗法也是需要高性能计算来支持的，现在有两种方法：一种方法就是说我们把肿瘤病人的免疫细胞，把它拿出来进行体外培养，很简单地说就是我要选一种特种部队选一个身体素质非常好的的细胞把它集中在一起进行体外培养，培养完再把这种免疫细胞输入到病人体内，然后对癌细胞进行攻击，另外一个我们要研究这个药，也就是世界各大药厂比如辉瑞、葛兰素史克这些都有自己的PD1这种抑制剂去切断免疫细胞和肿瘤细胞之间的连接，而阻止它的功能也就是说去攻击癌细胞，上面是讲了一些我们从基因的角度、从靶向治疗的角度这个高性能计算是如何应用的下面我介绍一下我们高性能计算在其他领域的应用。 比如说高性能计算，在天气预报领域也得到很好的应用，比如说画天气网格，网格画的越小就是说参与计算的CPU的个数越高，我们计算的速度越快，我们想得到下面一小时甚至几分钟的这样的天气的情况，然后另外一个应用就是核武器的数值模拟，大家知道这个核武器我们现在是不能实际上去爆炸的，就需要我们用高性能计算，用很多个大的计算能量去模拟核武器的爆炸然后提升我国的国防实力，另外一个就是我们的航天领域大家知道我们这个大飞机我们国内的飞机的水平特别是发动机的水平还是比较落后，所以说我们就现在利用高性能计算去辅助飞机进行外形、材料、噪声、控制方面的设计；另外一个就是我们现在我想大家可能很多人都坐过高铁，它运行的过程当中，它的湍流是什么样的形状呢，大家知道它跑三百公里，它每增加十公里的时候，它的造成的湍流对周围湍流的影响对运行安全的本身的影响，它不是线性的，就是它每增加一公里可能它的危险系数就会非常非常的高，所以说我们也利用高性能计算来进行数字模拟它的湍流的情况，另外一个就是高性能并行机本身的研究，你会看到这三个机器都是美国的机器，你会看到漂亮的布线，漂亮的刀片还会看到布满全身的水管，大家可能对高性能并行机为什么要插满水管（很疑惑），我们平时用的个人电脑和笔记本你会看到它的风扇在呜呜的运转在散热 那么我们的高性能并行机，不仅需要这样的风扇我们还需要一些水冷，也就是说我们把凉水遍布到全身进行水冷。那么最后给大家讲一下我们这个极富我们民族自豪感的事情也就是神威太湖之光，就是全球最快的超级计算机是咱们国家的也就是说现在全世界（最快的），我们国家是自主产权，原来我们的高性能并行机核心CPU肯定是用的是国外的，但是现在我们从内部的核心CPU到系统架构到整个网络的设计都是我们国家自主创新生产的，并且我们的计算速度在全世界都是排名第一的好，我今天的报告就到这里吧，希望我们的高性能计算能让我们走得更远，从各个行业，不仅从医疗行业，从咱们的各个国民经济的各个行业主战场发挥我们更大的作用。谢谢大家！“SELF格致论道”是中国科学院全力推出、中国科普博览承办的科学讲坛，致力于精英思想的跨界传播，由中国科学院计算机网络信息中心和中国科学院科学传播局联合主办。登陆“SELF格致论道”官方网站、关注微信公众号“SELF格致论道讲坛”、微博“SELF格致论道”获取更多信息。更多合作与SELF工作组self@cnic.cn联系。
This week on HealthTree Podcast for Multiple Myeloma we welcome Dr. Don Benson of The James Comprehensive Cancer Center at Ohio State University back to discuss his research in nk cells, immunotherapy, and an upcoming PD-1 trial.
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