Podcasts about t790m

Dr. Jyoti Patel is back on the podcast to discuss the updates to the living guideline on therapy for stage IV NSCLC with driver alterations. She shares updated recommendations in the first- and second-line settings for patients with stage IV NSCLC and classical EGFR mutations, and the impact of these updates for clinicians and patients. We also look to the future to discuss ongoing developments in the field. Read the full living guideline update “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.3” at www.asco.org/living-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/living-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-24-02785     Brittany Harvey: Welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows including this one at asco.org/podcasts.   My name is Brittany Harvey and today I'm interviewing Dr. Jyoti Patel from Northwestern University, co-chair on “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.3.” It's great to have you back on the show today, Dr. Patel. Dr. Jyoti Patel: Thanks so much. Happy to be here. Brittany Harvey: And then before we discuss this guideline, 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 disclosures of potential conflicts of interest for the guideline panel, including Dr. Patel, who has joined us here today, are available online with the publication of the guideline and in the Journal of Clinical Oncology, which is linked in the show notes. So then, to dive into the content of this update, Dr. Patel, this clinical practice guideline for systemic therapy for patients with stage IV non small cell lung cancer with driver alterations is living, meaning that it's continuously reviewed and updated. So what data prompted this latest change to the recommendations? Dr. Jyoti Patel: Thanks so much. So it's really been an exciting time in the treatment of EGFR lung cancer, particularly this past year has required us to rethink approaches to front- and second-line therapy. In this particular update, we examined what patients in the front-line setting may be offered by their clinicians. And so we're talking about the population of classical EGFR mutations, so exon 19 and exon 21 L858R substitution. And so certainly for this population, osimertinib has a high level of evidence and should be offered to all patients at the time of diagnosis when they present with advanced disease. Our last update included a recommendation that patients could also get platinum doublet chemotherapy with osimertinib or osimertinib alone. This current recommendation also introduces another alternative therapy and that's the combination of amivantamab plus lazertinib. And so now, clinicians are faced with three really good options for their patients with EGFR exon19 deletion or L858R. Brittany Harvey: It's great to hear that there's this advance in the space, particularly for patients with these classical EGFR mutations that you mentioned. So what should clinicians know as they implement these new first-line recommendations? Dr. Jyoti Patel:  I think it's become more complex than ever. Certainly, we know again that patients should get osimertinib in the frontline setting. But we've been kind of stuck at progression-free survival that's between a year and a half and two years. And so we've really been looking at opportunities to intensify therapy. So one could certainly be with chemotherapy or switching over to amivantamab, the bispecific antibody that targets EGFR and MET plus lazertinib, an oral TKI that's very similar in structure to osimertinib. And when you're talking to a patient, it's really a conversation about balancing efficacy with toxicity. Unfortunately, as we know, there aren't that many free lunches. And so if we think about what a patient is hoping for in their therapy and how we can further personalize treatment options, really is important to look at some of the analyses for this study. So in the study of amivantamab plus lazertinib, we know that there were increased toxicities with a combination of both therapies. In fact, up to 75% of patients had over grade 3 toxicities, versus about 43% of patients with osimertinib monotherapy. And we know if we look back at FLAURA2, almost two thirds of patients with osimertinib and chemotherapy had grade 3 toxicities, compared to 27% of patients with osimertinib alone. So we certainly see an increase in toxicities. Then we have to ask ourselves, are those paper toxicities or ones that really impact patients? And we know that amivantamab, for example, causes significant cutaneous toxicities. With both of these therapies, whether it's chemotherapy or adding amivantamab, there's the burden of infusional visits and increased time in the doctor's office. Certainly with chemotherapy, there can be an increased incidence of myelosuppression. And so when we're thinking about advising our patients, certainly we need to talk about the toxicities. But one thing that we've been able to do is to look at the patients that were included in this trial. And what we really find is that in higher risk cohorts, particularly those that we know historically have done less well with standard osimertinib, so patients, for example, with CNS metastasis, for those patients with co-mutations, it may be that that additive benefit is significant. And so one example I think would be from the MARIPOSA study, again, the study of amivantamab and lazertinib versus chemotherapy. What we can say is that patients who had co-mutations, so patients with EGFR mutations as well as TP53, lazertinib and amivantamab led to a hazard ratio of 0.65 compared to osimertinib alone. So that was 18.2 months versus 12.9 months. And so this may be really important to patients. And we also see conversely that patients with wild type TP53, so those patients who didn't have the mutation, probably had equivalent survival regardless of therapy. So certainly, we need to prospectively study some of these high-risk cohorts. We've only seen progression-free survival in these studies. And so at this juncture, we can advise our patients about toxicity, the improvements in certain categories of progression-free survival, but we really still don't know how this pans out in overall survival. In many of these studies, all patients do not necessarily cross over to the study arm and so they may have lost the benefit of subsequent therapy. Brittany Harvey: Absolutely. It's very important to talk about that balance of benefits and risks and particularly those toxicities that you discussed. So I appreciate reviewing that recommendation and the considerations for clinicians for first-line therapy. This update also included a second-line treatment update. What is that update for patients with EGFR alterations? Dr. Jyoti Patel: So this is where it gets super tricky because we have a frontline option with amivantamab and now we've had an update in the second line option. So what we said is that for patients who have progressed on an EGFR TKI, and in the United States, certainly that's predominantly osimertinib, or those in other parts of the world that may have gotten an earlier generation TKI, but do not have evidence of T790M or other targetable mutations, we can offer patients chemotherapy with or without amivantamab. And so certainly we have seen that this again leads to improved survival. There have also been a number of studies looking at incorporation of PD-L1 and anti-VEGF therapies. And what we can say, I think pretty clearly is that multiple phase 3 trials have really shown no benefit of the addition of PD-1 to platinum chemotherapy. But there are some emerging bispecific antibodies that may target PD-1 as well as VEGF, or combinations of antibodies that target both of those pathways that may improve outcome. At this juncture, I think we feel that the evidence surrounding chemotherapy plus amivantamab is strongest, but there is certainly work in this space that will be of interest. Now, what happens if your patient received amivantamab and lazertinib in the frontline setting and then has progression? And so we're trying to understand resistance mechanisms and opportunities for treatment. What the panel decided to recommend, based on the available evidence, was that certainly those patients should get platinum-based chemotherapy, but there may also be a role for antivascular endothelial growth factor targeting therapy such as bevacizumab in patients in whom it would be safe. Brittany Harvey: Great. I appreciate you detailing those recommendations when it gets complicated in the second-line setting. So what should clinicians know as they implement these second-line recommendations too? Dr. Jyoti Patel: So certainly the frontline setting matters significantly. So if a patient gets osimertinib in the frontline setting, we generally suggest that patients undergo repeat testing to see if they have another targetable mutation. If they don't, then I think preferred therapy would be chemotherapy with or without amivantamab. And amivantamab leads to a significant improvement in progression-free survival and response rate at the cost of increased risk of toxicity. For patients who get FLAURA2 in the frontline setting, chemotherapy plus osimertinib, it's a little bit of an unclear space. Those patients most likely would get docetaxel with or without ramucirumab. But there are other agents that we hope to have available to our patients in the near future. For patients who receive amivantamab and osimertinib, we recommend that those patients get chemotherapy probably with anti-VEGF as demonstrated by multiple trials that have shown the improved progression-free survival with introduction of an anti-VEGF agent. And we've seen evidence of amivantamab in the third line setting, so it is likely that this question about sequencing really takes center stage in our next set of trials. When you're talking to a patient, I think again, it's absolutely important to discuss: What are their goals? How symptomatic or how fast is their progression? Are there ways in which patients may benefit from spot treatment oligoprogression such as radiation? When is the right time for introduction of amivantamab and when do we think patients need chemotherapy? Is it up front or predominantly in the second-line setting? Brittany Harvey: Definitely. And then you've just touched on the goals of treatment for individual patients. So in your view, what does this update mean for patients with stage IV non-small cell lung cancer and an EGFR alteration? Dr. Jyoti Patel: For patients, this is a time in which shared decision making really needs to take center stage. So our best patients are those patients that are best informed not only about their disease but also have a good understanding about what is important to them and their families in terms of care. And so bringing that shared understanding to the table again helps us think about this particular cancer as more of a journey rather than just a one off treatment. Therapy will hopefully be prolonged, and so it's absolutely important that we address toxicities, make therapies more tolerable, again, with the shared goal of living long and living well. Brittany Harvey: Absolutely. Those are key points to making sure that patients are living both longer and have a good quality of life during that time as well. So then, before you mentioned the possibility of future sequencing trials and other ongoing developments. What additional studies or future directions is the panel examining for future updates to this living guideline? Dr. Jyoti Patel: So certainly we're thinking about trials that look at, for example, cfDNA clearance. So are there patients that do well and can we detect that early on without having to intensify therapy on day 1 so it may be that we add chemotherapy a little bit later. I think really exciting are some of the new bispecific. The HARMONi-A trial was a trial in China of a novel bispecific, ivonescimab. And this drug targets both PD-1 and VEGF and it was combined with chemotherapy. And this trial found almost a doubling of progression-free survival with this drug in combination chemotherapy in an EGFR patient population. That study is being planned and being run in the United States to see if we have similar outcomes with a more diverse population. So certainly that's exciting. There are a number of antibody drug conjugates that are being studied in the post-chemotherapy setting as well. And I think we'll likely soon see a better understanding of what co-mutations and burden of disease really mean when we're thinking about assigning treatment. So which patients, again, need intensification of therapy and which patients may do really well on just an oral agent that they're taking at home with more tolerable toxicity than dual treatment. Brittany Harvey: Yes, we'll look forward to continued developments in these fields and seeing some of those studies come to fruition. So with that, I want to thank you for your work to rapidly and continuously update this guideline, and thank you for your time today, Dr. Patel. Dr. Jyoti Patel: Thanks so much, Brittany. It's really an exciting time for lung cancer and we hope that these updates really help physicians decide the best treatments for their patients. Again, it's a rapidly evolving landscape which is fantastic, but it does become more cumbersome to stay ahead of the literature. Brittany Harvey: Definitely. And so we appreciate your time and the panel's time spent reviewing this literature and providing this much needed information to clinicians everywhere. So finally, thank you to all of our listeners for tuning into the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the  Apple App Store 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.  

In the relentless battle against non-small cell lung cancer (NSCLC) driven by epidermal growth factor receptor (EGFR) mutations, the development of resistance has long been a formidable obstacle. Historically, first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) like gefitinib, erlotinib, afatinib, and dacomitinib have faced a significant hurdle: the emergence of the T790M point mutation in approximately 50% of patients, rendering the tumor resistant to these therapies. This resistance stems from a sobering reality – before treatment, a small subset of cancer cells already harbor the T790M mutation, conferring no selective advantage initially. However, once treatment commences, these rare mutated cells proliferate selectively, eventually dominating the tumor population and diminishing the effectiveness of first- and second-generation TKIs. Full blog - https://www.oncotarget.org/2024/06/06/dr-blagosklonnys-strategy-from-osimertinib-to-preemptive-combinations/ Paper DOI - https://doi.org/10.18632/oncotarget.28569 Correspondence to - Mikhail V. Blagosklonny - Blagosklonny@oncotarget.com, Blagosklonny@rapalogs.com Video short - https://www.youtube.com/watch?v=UO5BGLIggTE Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28569 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, lung cancer, NSCLC, EGFR, resistance, afatinib, gefitinib, capmatinib 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 Contact MEDIA@IMPACTJOURNALS.COM 18009220957

In this JCO Article Insights episode, Rohit Singh provides summary on two articles published in the April 10th issue of the Journal of Clinical Oncology. The first article, "Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Mutated Non–Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04)" describes a randomized, open-label, multicenter, phase III study evaluating the efficacy of atezolizumab plus bevacizumab, paclitaxel, and carboplatin (ABCP ) in EGFR- or ALK-mutated NSCLC that progressed before TKI therapy. The second is the accompanying Oncology Grand Rounds. TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Dr. Rohit Singh: Hello and welcome to JCO Article Insights. I'm your host, Dr. Rohit Singh. Today I will provide a summary of a Phase III, Randomized Study of Atezolizumab Plus Bevacizumab and Chemotherapy in Patients With EGFR- or ALK-Mutated Non–Small-Cell Lung Cancer (ATTLAS, KCSG-LU19-04), by Dr. Park and colleagues from Seoul, Korea. The purpose of this study was to evaluate the efficacy and safety of the ABCP regimen based on IMpower150 in patients with EGFR or ALK mutated non-small cell lung cancer who had progressed on prior targeted treatment.   I will also discuss an Oncology Grand Round case titled "Management of Treatment Resistance in Patients with Advanced EGFR Lung Cancer: Personalization, Parsimony, and Partnership", by Dr. Vallillo and colleagues from Lahey Hospital Medical Center and Tufts University School of Medicine, Boston, Massachusetts. Oncology Grand Round cases help us to give a clinical context to the clinical trial.   While TKIs are the established standard of care for non-small cell lung cancer harboring driver mutations, most patients will develop resistance to these treatments. Immune checkpoint inhibitors, with or without chemo, have shown clinical benefits of immune checkpoint monotherapy in patients with EGFR-mutated non-small cell lung cancer. Consequently, platinum-based chemo is the standard of care for patients with EGFR TKI failure. This was a phase III, multicenter, open-label, randomized trial conducted at 16 hospitals across the Republic of Korea. Patients diagnosed with stage four non-small cell lung cancer with sensitizing EGFR mutation or ALK translocation were included in the study. Patients were randomly assigned to the ABCP arm or chemo-only arm in a 2:1 ratio. Eligible patients were stratified on the mutation type (EGFR mutation vs. ALK translocation) and the presence of brain metastasis. No crossover to atezolizumab was permitted.  The recruitment with T790M mutation was capped at 30%. Patients who responded continued to receive maintenance with atezolizumab until disease progression or unacceptable toxicities occurred. If a patient was identified to have an acquired T790M mutation after the failure of a first or second-generation EGFR TKI, the patient had to be treated with a third-generation EGFR TKI before enrollment. The primary endpoint was investigator-assessed objective response rate according to research criteria. The secondary endpoints included overall survival and progression-free survival at one and two years, and the duration of response, along with a safety analysis. Investigators also did an exploratory biomarker analysis based on PD-L1 expression and its correlation with the response. They also analyzed the distribution of tumor-infiltrating lymphocytes, and a cut-off of 20% inflamed score was used to compare the two arms. Overall, 228 patients were enrolled, 154 in the ABCP arm and 74 in the chemo-only arm. Most patients were female at 56.1% and never smokers at 62.7%. Brain metastasis was present in 42.7% of patients. Most patients had previously received EGFR TKI therapy, however, only 8% and 30% received third-generation TKI as first-line therapy in the ABCP arm and  chemo-only arm, respectively. The majority of the patients were EGFR at  90%.  The median duration of follow-up for the study population was 26 months. The objective response rate in the ABCP arm was significantly higher at 69.5% compared to 42% in the chemotherapy alone arm. The median PFS was significantly longer in the ABCP arm at 8.48 months versus 5.6 months, and the duration of response was similar at around seven months in both arms. The median overall survival was also similar at around 20 months in both arms, with a hazard ratio of 1.01. In the subgroup of patients with brain metastasis at the time of study enrollment, PFS was significantly longer in the ABCP arm at 8.4 months compared to 4.4 months in the chemotherapy-only arm. In contrast, no difference in PFS was observed in the subgroup without brain metastasis. Regarding EGFR mutation status, there was no difference in PFS or OS between the two arms in the EGFR deletion 19 subgroup. However, a favorable PFS was observed in the EGFR L858R subgroup. For those with acquired EGFR T790M mutation, there was no difference in PFS between groups, whereas a favorable PFS was observed in the subgroup without EGFR T790M mutation.  In the exploratory biomarker analysis, interestingly, the impact on PFS was correlated with PD-L1 expression. The study found that the higher the PD-L1 expression, the better the PFS. In patients with PD-L1 expression of more than 50%, the hazard ratio was 0.24 for PFS. This is an interesting observation. As in previous studies, we have seen that PD-L1 expression does not have a strong association with response to checkpoint inhibitors in patients with driver mutations. Based on the distribution density of tails in the tumor bed, the inflamed score was calculated using artificial intelligence. For patients with 20% of the imflamed score, the ABCP arm has significantly prolonged PFS at 12.9 months compared to 4.8 months. The median number of ABCP treatment cycles was 4, with 12 for atezolizumab and 8 for bevacizumab as maintenance therapy, pemetrexed maintenance was administered for a median of 10 cycles. The incidence of grade 3 or higher side effects was 35.1% in the ABCP arm compared to 15% in the chemotherapy-only arm. Peripheral neuropathy, alopecia, and myalgias were the most prevalent side effects. Interesting notably, 54% of patients in the ABCP arm required treatment interruption or dose modification, and there were three reported deaths in the ABCP arm, two due to pneumonia and one due to cerebral embolic infarction. Around 10 patients or 13.5% of patients in the chemotherapy-only arm required dose interruption or modification.   In conclusion, patients with EGFR-mutated or translocated non-small cell lung cancer who had failed prior TKI ABCP regimen showed a statistically significant prolongation of PFS and response rate compared to chemo alone. Patients in the subgroup with EGFR L858R, without acquired T790M mutation, and presence of brain met showed more benefit. There was no difference in overall survival, though we need more mature data. Adverse events were higher in the ABCP arm. Interestingly, in the exploratory analysis, a high PD-L1 and an inflamed score of more than 20% showed PFS benefits. Though we need to take into consideration that this trial was done and all the patients were grouped from a single country considering Asian ethnicity. And most importantly, the majority of patients were treated with first- and second-generation TKIs, whereas third-generation TKIs are the standard of care in the United States.  Coming to the Oncology Grand Round, in this case, we will discuss the management of treatment resistance in patients with advanced EGFR-mutated lung cancer. A patient with a 20-pack-a-year history of tobacco use presents with weight loss and hip pain, found to have a lung mass, skeletal mets, and brain mets, and was diagnosed with lung adenocarcinoma. The patient goes with palliative radiotherapy for the brain mets. Comprehensive tumor Merkel profiling demonstrated an EGFR mutation exon 19 and alteration P53. The patient was started on third-generation EGFR TKI osimertinib. However, after 17 months, the patient has symptomatic disease progression. Usual approach, if feasible, re-biopsy at the time of progression to evaluate for possible new mutations which can guide treatment options. As mentioned earlier, in the trial, acquired resistance to the TKI is inevitable and heterogeneous. There were various mechanisms which have been proposed regarding resistance, including a second-site EGFR alteration, upregulation of bypass pathway, histological transformation to small cell histology, or suboptimal drug penetration.  There are various approaches after disease progression on EGFR TKI. Combining EGFR-directed therapies to address resistance is an option. Prime results from the MARIPOSA-2 study showed amivantamab plus chemotherapy with or without lazertinib in EGFR-mutated non-small cell lung cancer after disease progression showed a better objective response rate at 64% compared to 36% in the chemo-alone arm. It also showed improved PFS with a median of 6.3 compared to 4.2 in the chemo-alone arm. Combining immune checkpoint inhibitors, EGFR-mutated non-small cell lung, I say has been disappointing in advance of EGFR-mutated non-small cell lung, and combination therapy studies are needed to improve outcomes. Studies, as I discussed ATTLAS, have shown that combining a VEGF inhibitor with ICIs and chemotherapy can lead to a better objective response rate and PFS. However, further clinical trials are needed to figure out the better subgroup of patients who can benefit from this combination.   Should the TKI be continued beyond progression in EGFR-mutated advanced non-small cell lung cancer? Continuing the primary EGFR TKI treatment beyond progression may be considered for patients with indolent or asymptomatic progression or localized progression. We can consider radiation, surgery, or ablation. This approach will potentially delay the need to change systemic therapy in patients. However, for patients with multifocal disease progression requiring chain systemic therapy it may be more beneficial to switch to next-line systemic therapy options like platinum doublet with or without immunotherapy and VEGF inhibitors. In the case presented, the decision was made to continue osimertinib along with platinum doublet, deferring the addition of immunotherapy and VEGF inhibitor. This choice was based on factors like the patient's history of brain metastases and intracranial control. There is also a high risk of toxicity, especially pneumonitis, with immune checkpoint inhibitors after using targeted therapy, the patient showed clinical and radiographic improvement while on this treatment regimen.  The decision to continue or change therapy at cancer progression is based on factors like drug tolerability, patient preferences, and specific subgroups with different outcomes, such as those with brain metastasis or specific EGFR mutation subtypes. Choosing between combination therapy strategies that concept progression involves personalized decision-making to optimize treatment outcomes. Ultimately, the approach to management should be tailored to individual patient needs, preferences, and eligibility for different treatment modalities.  This is Rohit Singh. Thank you for listening to JCO Article Insights. Don't forget to give us a rating or review and be sure to subscribe so you never miss an episode. You will find all the ASCO shows at asco.org/podcasts. Thank you. 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 ofASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.        

Dr. Shannon Westin and her guests, Dr. Judy Garber and Dr. Geoffrey Oxnard, discuss the paper "Germline EGFR Mutations and Familial Lung Cancer" recently published in the JCO. TRANCRIPT The guest on this podcast episode has no disclosures to declare.   Shannon Westin: Hello, and welcome to JCO After Hours, the podcast where we get in-depth on articles that are published in the Journal of Clinical Oncology. I am your host, Shannon Westin, Social Media Editor for the JCO and Gynecologic Oncologist by trade. And it is my great pleasure to speak today with you about an amazing manuscript entitled, “Germline EGFR Mutations and Familial Lung Cancer.” It was published in the JCO on August 14, 2023.  The authors have no conflicts of interest, and they are Dr. Geoffrey Oxnard, he's a Thoracic Oncologist and Associate Professor, Hematology and Medical Oncology at Boston Medical Center.  Welcome, Geoff. Dr. Geoffrey Oxnard: Hi, Shannon. Thanks. Shannon Westin: And Dr. Judy Garber, the chief of the Division of Cancer Genetics and prevention at the Dana-Farber Cancer institute in Boston. Welcome, Judy. Dr. Judy Garber: Thank you. Hi, Shannon. Hi, Geoff.  Shannon Westin: So excited you both could be here. Let's get started. So first I just want to levelset for our audience. Can you speak just a little briefly about the incidence and mortality of lung cancer and how that's been changing over time? Dr. Geoffrey Oxnard: Sure. Lung cancer is common and it's deadly, more than 200,000 cases a year in the United States, more than 100,000 deaths a year in the United States. But I think importantly, it's evolving. Its biology is evolving as smoking incidence goes down. We've identified these genomic subtypes of lung cancer that are sort of increasingly apparent and important as we think about its treatment. Outcomes are changing with emerging therapies, presentation is changing with lung cancer screening and with a growing ability to now find cancers early and prevent them. And so it's in that setting of a very dynamic disease that we chose to study a really unique little slice of it, which is germline risk. Shannon Westin: So let's take that one step further because I think that's really interesting. You mentioned the genomic aberrations and kind of how you're using that to target. Can you expand upon that a little bit more for me? Dr. Geoffrey Oxnard: Lung cancer that I've long studied is different than breast cancer when Judy has long studied because we think about its somatic alterations, we've always thought about KRAS mutations, EGFR mutations, and smaller and smaller splice limit. ALK, RAS, RET HER2, etc. And so tumor testing in lung cancer has one of the first to be standard across on solid tumor oncology. And the germline genetics was kind of an afterthought and is the flip, I think, of how genetic testing evolved in the breast cancer space for example. Dr. Judy Garber: I might argue a little bit if breast cancer was earlier and it was subtyped some molecularly it doesn't have as many molecular subtypes yet perhaps as lung cancer. But we've all been studying the somatic space to look for targets for therapy. And the germline space, certainly in breast cancer, came much earlier. And everybody knows about BRCA1 and 2. Now, we hope everybody knows about Lynch Syndrome, but certainly not everybody's thinking about inherited lung cancer risk. Dr. Geoffrey Oxnard: Yeah, these have converged. I think 10 years ago when this kicked off, I felt like a super outlier for thinking about, wait a second, what about the genetics behind all this that is leading to this strange variable presentation of lung cancer? For example, we know that in Asian populations, one type of lung cancer, EGFR mutant lung cancer, is more common. There must be some geneticness that leads to that. What explains the sort of pattern of presentation of these genetic subtypes in the populations we see in the US, that's pretty unclear?  Dr. Judy Garber: So, I think, Shannon one of the clues about all this came from the fact that the EGFR mutations were being identified in the tumors. And then I really should let Geoff tell this story, but as the amateur thoracic person in the room here, to me, it was so interesting that there were the EGFR mutations, then there was treatment exploiting EGFR mutations, and the most common resistance mutation was this T790M variant. But when labs started testing EGFR, there was a small group of people who had that resistance variant without ever having been treated at all. So that was the obvious question, what was it doing there? And that's where Geoffrey came in.  Dr. Geoffrey Oxnard: Yeah, this is a patient I met more than a decade ago at my fellowship in MSKCC. She'd been living with a T790M mutation in her tumor for years and years and years. I was like, “Well, I don't understand. Why is this sitting there?” And she had this sort of slightly mysterious history of lung cancer in her family. And we realized, wait a second, this T790M was behind her cancer from the beginning, and in fact, might have been the basis of why she developed lung cancer. And so that actually motivated a career development award I submitted to the Conquer Cancer Foundation of ASCO, a grant I received, and that then led to a program that I led at Dana-Farber under Judy's mentorship, where over the past decade, we sort of focused in and studied this strange, rare syndrome, really to dig into inheritedness as a kind of different flavor of lung cancer genetics.  Dr. Judy Garber: Well, and now it's really a good time to think about this because we're recognizing there are younger cancers, colon cancer, like an epidemic, and lung cancers, and we're not sure how many of them are genetic or come from other exposures. Geoff talked about the differences in Asia, some of which are certainly genetic, some which may be environmental, especially in the lung, where that's such an issue. But trying to sort these things out, you have to be willing to think a little bit differently. And that was fun when Geoff came from the lung program, interested in the germline, we said, “Oh, we have to do this.”   Shannon Westin: Well, let's talk about what you did. I would love to hear and I know the audience would as well about the design of this study, so called INHERIT study. Very good name. I love a good name. This is a good one.   Dr. Geoffrey Oxnard: Yeah. So that stands for Investigating Hereditary Risk of T790M, INHERIT. I forget where we coined that. Let me give you a case example. A patient presents in his 40s. I remember this man. He has an EGFR mutation in his tumor. He has a T790M in his tumor as well. He had routine tumor testing that lung cancer patients were getting. And he says, “Oh, also, my brother had lung cancer in his 40s just a couple of years ago. He was a smoker, though. He never had genetic testing.” And so this patient we test on the study, we hypothesized that when patients present with T790M at diagnosis, that it would be a representation of an underlying germline EGFR mutation. Our hypothesis was that about 50% of the time T790M at diagnosis would be explained by a germline behind the doll. And that that could then empower families like this one to understand the kinds of lung cancer they're getting in their family, the kinds of treatment they should be getting, and the kinds of testing they should be getting to look for lung cancer at risk early on.   It really saddens me that in a family that doesn't know about this condition, the brother would never get testing and would never think that I might be getting or might never get testing, might not be disposed to getting testing, and might not realize there's a therapy available to target that EGFR mutation if he died young without even much treatment. But this individual, we tested his lung cancer, we found him a therapy, we put him on a pill therapy that could last a very long time. And so we set up a program with a consortium alchemy, the Addario Lung Cancer Medical Institute, where we enrolled at three sites, both at Dana-Farber in Boston, Vanderbilt, and Ohio State, with some motivated investigators there that we appreciate their collaboration.  But also, again, this is now more than 10 years ago, set up shop where people could enroll remotely, that if you found a T790M in your tumor, for whatever reason, you could reach out to the team at Dana-Farber centrally and get consented online and even get counseling. And this is one of the early ways of getting this remote participation. And you can imagine, over the course of the study, we quickly ran out of individuals at any given site, but that remote enrollment accelerated and really allowed us to get to the large population of remote study. Dr. Judy Garber: We were lucky that things were happening. The things you don't expect. So EGFR testing was not routine at that time. And the EGFR testing that had developed in Dana-Farber and NGH became standard of care at Dana-Farber so we were finding those patients, and then grew outside as well, at institutions and testing labs. And these people would somehow emerge so we were very lucky that we were able to set up remote testing. We could send and get a saliva sample and be able to test. Or these were people who got tested through their own doctors, found out they had this mutation and then went online and said, “Who knows anything about this?”  I would say that we and our amazing genetic counselors who spoke to all these patients, took their detailed family histories, got their other information, and were able then to really build out these cohorts so we can understand them. And to look at, for example, Geoff's question, it was really his question, “Why did we have such clusters in certain parts of the country? Could it be that there were the so-called founder mutations that somebody had this mutation and they spread their genes around so that they're around the country and that turned out to be true. Shannon Westin: It's so fascinating, and I love how you kind of almost crowdsourced getting these patients to you because I was mystified because it's such a rare aberration and you had so many patients. Let's talk a little bit maybe about your patient population and who volunteered, and is it reflective of kind of you do think, the general population? Dr. Geoffrey Oxnard: I want to give a shout out to the GO2 Lung Cancer Foundation. That really was a lot of the ‘rah rah', getting people to know about this, having some word of mouth and spreading the word. And so certainly there are physicians around the country that have been like found patients that I've got to know because they sent us patients to study over the years. We ended up getting germline testing on 141 individuals who presented eligible for testing because of either a relative or a mutation that was suspicious for inherited. Most of those were enrolled remotely, in the end, as you might expect. We found what you might expect, that this was Mendelian in its inheritance, that if you had a first degree relatives, they had 50% chance of having this. And so we sort of slowly built these pedigrees of individuals who once they were positive, would refer in their relatives and say, “Please go get testing. Let's describe our family and help understand our risk.”   It ended up boiling down to six individuals with a germline EGFR mutation from 39 different families. I remember one family where two different cousins presented separately to the program, not knowing each other was participating. And so, of course, there's not that many of these families around the United states, but we're really very lucky to have touched so many different individuals. What did we find? That if you had a germline EGFR mutation, your tumor almost always had an EGFR mutation. That really is the dominant biology of lung cancer that presents in these affected individuals, that it presents young, that the likelihood of developing lung cancer is around 55% by age 40 to 50. So it really is– I'm trying to make sure I'm quoting that right, actually, Shannon, I'm looking at the numbers here, but it was a really broad range of diagnosis.  We had a 28-year-old who was affected and an 83-year-old who was affected. I saw a family where the grandson had lung cancer, but his father and grandfather who had germline EGFR mutations, did not. So variable penetrance. Judy, of course, told me, “Geoff, this is the way families present. Come on, Geoff.” But other families, incredible penetrance– not everyone having lung cancer, many of them smoking, some of them not smoking. But for these families, what a sense of empowerment to say, “Oh, this helps explain what's going on in our family, why this is happening at a younger age.” And helps explain the therapies that we had some concern about giving these potent EGFR inhibitors originally, understanding every cell in their body has this EGFR mutation. Are we going to somehow cause toxicity? No. These potent therapies can be effective, can be tolerated, and can work for many years. So we really feel hopeful that we've described a syndrome that's out there that people see and that has a distinct presentation, a distinct treatment pattern, and a clear association with lung cancer risk. Dr. Judy Garber: And I think that now the opportunity is to say, can you find these people before they get their lung cancers? Some of them have abnormalities on scans. Think of it's like the APC, the polyposis coli of lung cancer. You can see these adenomas forming, but we can't really predict exactly who's going to develop tumor when. And that, I think, is a challenge that families have to help us with because we need to continue to identify some of these people who have not had cancer. They have children. They want to know what to tell them besides not smoking adamantly and maybe with some hopes that we're going to do some screening.  I am afraid there probably is not good data that EGFR inhibitors could be used for prevention, but it's tempting to think that way. So there's plenty of work to do still to sort out the questions. This is the nature of genetics. We often find inherited susceptibility and people want to know, “Well, why would I want to know? What am I going to do about it?” And here I would say, “We're going to figure out what's your risk more specifically, and how can we help reduce that risk, in addition to telling you not to smoke.” Dr. Geoffrey Oxnard: I do want to allude to Judy's comment about founder effect. I didn't tell you exactly about the presentation, but these families, first off, we only found germline EGFR mutations in Caucasian individuals and in black individuals, and it was mostly in the United States and in fact, enriched in the southeast United States. And don't get me wrong, we had enthusiastic participation from Vanderbilt. But still it seemed like there was more southeast United States prevalence. And even families I met in the Boston area would say, ‘Oh yeah, I have relatives going back to Arkansas.”   And so we ended up with a bit of a suspicion for this geographic enrichment, studying the genomes of these affected individuals, and in fact did find a very large region of chromosome 7 that was shared in more than 90% of the folks we tested, suggesting a founder effect in the southeast United States, probably white and black. And that goes back hundreds of years, maybe 200, 300, 400 years, as far as we can estimate, making me think that this is a fairly unique syndrome that we're seeing in North America, but actually may not be prevalent in other parts of the globe. Though we did identify a single individual in Australia, it might be a unique phenomenon in North America. Dr. Judy Garber: At least more common. But these days, people travel, so hard to know. Shannon Westin: I don't know if you've gotten a chance to do this - any other cancer type seeming to be associated with this mutation? Dr. Judy Garber: No, fortunately not. Shannon Westin: Okay, very interesting. And what about outcome? What was the association, or was there any association of these mutations with cancer related outcomes? Dr. Geoffrey Oxnard: I would say the survival of these cancers isn't that different than EGFR mutant lung cancers. If they get to effective therapy, they can live for years on therapy. If they don't, they can do quite poorly. One interesting finding is that they can present in a multinodular fashion that might be multiple primaries. And so you can kind of use an approach of eliminating individual clones. Sometimes it's been described these different tumors have different mutations, and so you might treat them like a stage IV lung cancer, but actually they lived for a long time because actually they had multiple stage I lung cancers, so it can present a little bit differently. And then we tried to collect CT scans on affected carriers who did not yet have lung cancer to see if they might develop lung cancer. It was not required on study, and it's sort of an area of future investigation. But as you can imagine, lots of lung nodules and certainly anecdotes of individuals where we found early precancers through the screening effort, motivating the investigation that Judy was alluding to. Dr. Judy Garber: I think this is what you expect in inherited predisposition that you have an earlier chance. So some of them are younger, not the 84-year-old, but that they could be younger, that they could have multifocal disease, that their biology could be different, but could be the same, maybe accelerated, maybe not. Some of these are slower. And I think that's why we're excited to be able to continue this work with the group at Dana-Farber.  Now, Jaclyn LoPiccolo is going to lead the INHERIT study, but much of the team is the same. And now the focus will be even more on trying to really quantify the risk and help think about prevention strategies and screening for these patients. It's a little tricky to want to do too much chest CT screening. On the other hand, there are lower dose CTs now, and we hope the guidelines will clarify the role of inherited risk. At ASCO this year there were a lot of talks about inherited lung cancer risk, but nothing is quite as well characterized as, I think, the T790M population. Shannon Westin: Well, thank you all so much. This was fascinating. I learned a ton and I know our listeners did as well. And thank you to our listeners. This was “Germline EGFR Mutations and Familial Lung Cancer.” Again, published in the JCO August 14, 2023. So go check it out and check out our other podcasts on the website or wherever you get your podcasts. Have an awesome day.  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. Vamsi Velcheti and Dr. Benjamin Neel, of the NYU Langone Perlmutter Cancer Center, and Dr. John Heymach, of MD Anderson Cancer Center, discuss new therapeutic approaches for KRAS-mutant lung cancers and therapy options for RAS-altered tumors.   TRANSCRIPT Dr. Vamsidhar Velcheti: Hello, I'm Dr. Vamsidhar Velcheti, your guest host for the ASCO Daily News podcast today. I'm the medical director of the Thoracic Oncology Program at Perlmutter Cancer Center at NYU Langone Health. I'm delighted to welcome two internationally renowned physician-scientists, Dr. John Heymach, the chair of Thoracic-Head & Neck Medical Oncology at the MD Anderson Cancer Center, and my colleague, Dr. Benjamin Neel, the director of the Perlmutter Cancer Center at NYU Langone Health, and professor of Medicine at NYU Grossman School of Medicine. So, we'll be discussing new therapeutic approaches today for KRAS-mutant lung cancers, and we will talk about emerging new targeted therapy options for RAS-altered tumors. Our full disclosures are available in the show notes, and the disclosures of all the guests of the podcast can be found on our transcript at: asco.org/podcast. Dr. Heymach and Dr. Neel, it's such a great pleasure to have you here for the podcast today. Dr. John Heymach: My pleasure to be here. Dr. Benjamin Neel: Same here. Dr. Vamsidhar Velcheti: Dr. Neel, let's start off with you. As you know, RAS oncogenes were first discovered nearly four decades ago. Why is RAS such a challenging therapeutic target? Why has it taken so long to develop therapeutic options for these patients? Dr. Benjamin Neel: Well, I think a good analogy is the difference between kinase inhibitors and RAS inhibitors. So, kinase inhibitors basically took advantage of an ATP-binding pocket that's present in all kinases, but is different from kinase to kinase, and can be accessed by small molecule inhibitors. So, the standard approach that one would've thought of taking, would be to go after the GTP-binding pocket. The only problem is that the affinity for binding GTP by KRAS is three to four orders of magnitude higher. So, actually getting inhibitors that are GTP-binding inhibitors is pretty much very difficult. And then, until recently, it was felt that RAS was a very flat molecule and there weren't any surfaces that you could stick a small molecule inhibitor in. So, from a variety of biochemical and medicinal-pharmacological reasons, RAS was thought to be impervious to small molecule development. But as is often the case, a singular and seminal insight from a scientist, Kevan Shokat, really broke the field open, and now there's a whole host of new approaches to trying to drug RAS. Dr. Vamsidhar Velcheti: So, Dr. Neel, can you describe those recent advances in drug design that have enabled these noble new treatments for KRAS-targeted therapies? Dr. Benjamin Neel: So, it starts actually with the recognition that for many years, people were going after the wrong RAS. And by the wrong RAS, the overwhelming majority of the earlier studies on the structure, and for that matter, the function of RAS centered on HRAS or Harvey RAS. We just mutated in some cancers, most prominently, bladder cancer, and head & neck cancer, but not on KRAS, which is the really major player in terms of oncogenes in human cancer. So, first of all, we were studying the wrong RAS. The second thing is that we were sort of thinking that all RAS mutants were the same. And even from the earliest days, back in the late eighties, it was pretty clear that there were different biochemical properties in all different RAS mutants. But this sort of got lost in the cause and in the intervening time, and as a result, people thought all RASes were the same and they were just studying mainly G12V and G12D, which are more difficult to drug. And then, the third and most fundamental insight was the idea of trying to take advantage of a particular mutation in KRAS, which is present in a large fraction of lung cancer patients, which is, KRAS G12C. So, that's a mutation of glycine 12 to cysteine and Kevan's really seminal study was to use a library of covalently adducting drugs, and try to find ways to tether a small molecule in close enough so that it could hit the cysteine. And what was really surprising was when they actually found the earliest hits with this strategy, which was actually based on some early work by Jim Wells at Sunesis in the early part of this century, they found that it was actually occupying the G12C state or the inactive state of RAS. And this actually hearkens back to what I said earlier about all RASes being the same. And in fact, what's been recently re-appreciated is that some RAS mutants, most notably, G12C, although they're impervious to the gap which converts the active form into the inactive form, they still have a certain amount of intrinsic ability to convert from the inactive form. And so, they always cycle into the inactive form at some slow rate, and that allows them to be accessed by these small molecules in the so-called Switch-II Pocket, and that enables them to position a warhead close enough to the cysteine residue to make a covalent adduct and inactivate the protein irreversibly. Scientists at a large number of pharmaceutical companies and also academic labs began to understand how to access various other pockets in RAS, and also even new strategies, taking advantage of presenting molecules to RAS on a chaperone protein. So, there's now a whole host of strategies; you have a sort of an embarrassment of riches from an impoverished environment that we started with prior to 2012. Dr. Vamsidhar Velcheti: Thank you, Dr. Neel. So, Dr. Heymach, lung cancer has been a poster child for personalized therapy, and we've had like a lot of FDA-approved agents for several molecularly-defined subsets of lung cancer. How clinically impactful is a recent approval of Sotoracib for patients with metastatic lung cancer? Dr. John Heymach: Yeah. Well, I don't think it's an exaggeration to say this is the biggest advance for targeted therapies for lung cancer since the initial discovery of EGFR inhibitors. And let me talk about that in a little more detail. You know, the way that lung cancer therapy, like a lot of other cancer therapies, has advanced is by targeting specific driver oncogenes. And as Dr. Neel mentioned before, tyrosine kinases are a large percentage of those oncogenes and we've gotten very good at targeting tyrosine kinases developing inhibitors. They all sort of fit into the same ATP pocket, or at least the vast majority of them now. There are some variations on that idea now like allosteric inhibitors. And so, the field has just got better and better. And so, for lung cancer, the field evolved from EGFR to ALK, to ROS1 RET fusions, MEK, and so forth. What they all have in common is, they're all tyrosine kinases. But the biggest oncogene, and it's about twice as big as EGFR mutation, are KRAS mutations. And as you mentioned, this isn't a tyrosine kinase. We never had an inhibitor. And the first one to show that it's targetable, to have the first drug that does this, is really such an important breakthrough. Because once the big breakthrough and the concept is there, the pharmaceutical companies in the field can be really good at improving and modulating that. And that's exactly what we see. So, from that original insight that led to the design of the first G12C inhibitors, now there's dozens, literally dozens of G12C inhibitors and all these other inhibitors based on similar concepts. So, the first one now to go into the clinic and be FDA-approved is Sotoracib. So, this again, as you've heard, is inhibitor G12C, and it's what we call an irreversible inhibitor. So, it fits into this pocket, and it covalently links with G12C. So, when it's linked, it's linked, it's not coming off. Now, the study that led to its FDA approval was called the CodeBreak 100 study. And this was led in part, by my colleague Ferdinandos Skoulidis, and was published in The New England Journal in the past year. And, you know, there they studied 126 patients, and I'll keep just a brief summary, these were all refractory lung cancer patients. They either had first-line therapy, most had both chemo and immunotherapy. The primary endpoint was objective response rate. And for the study, the objective response rate was 37%, the progression-free survival was 6.8 months, the overall survival was 12.5 months. Now you might say, well, 37%, that's not as good as an EGFR inhibitor or the others. Well, this is a much harder thing to inhibit. And you have to remember in this setting, the standard of care was docetaxel chemotherapy. And docetaxel usually has a response rate of about 10 to 13%, progression-free survival of about 3 months. So, to more than double that with a targeted drug and have a longer PFS really is a major advance. But it's clear, we've got to improve on this and I think combinations are going to be incredibly important now. There's a huge number of combination regimens now in testing. Dr. Vamsidhar Velcheti: Thank you, Dr. Heymach. So, Dr. Neel, just following up on that, unlike other targeted therapies in lung cancer, like EGFR, ALK, ROS, and RET, the G12C inhibitors appear to have somewhat modest, I mean, though, certainly better than docetaxel that Dr. Heymach was just talking about; why is it so hard to have more effective inhibitor of KRAS here? Is it due to the complex nature of RAS-mutant tumors? Or is it our approach for targeting RAS? Is it a drug-related problem, or is it the disease? Dr. Benjamin Neel: Well, the short answer is I think that's a theoretical discussion at this point and there isn't really good data to tell you, but I suspect it's a combination of those things. We'll see with the new RAS(ON) inhibitors, which seem to have deeper responses, even in animal models, if those actually work better in the clinic, then we'll know at least part of it was that we weren't hitting RAS hard enough, at least with the single agents. But I also think that it's highly likely that since KRAS-mutant tumors are enriched in smokers, and smokers have lots of mutations, that they are much more complex tumours, and therefore there's many more ways for them to escape. Dr. Vamsidhar Velcheti: Dr. Heymach, you want to weigh in on that? Dr. John Heymach: Yeah, I think that's right. I guess a couple of different ways to view it is the problem that the current inhibitors are not inhibiting the target well enough, you know, in which case we say we get better and better inhibitors will inhibit it more effectively, or maybe we're inhibiting it, but we're not shutting down all the downstream pathways or the feedback pathways that get turned on in response, in which case the path forward is going to be better combinations. Right now, I think the jury is still out, but I think the data supports that we can do better with better inhibitors, there's room to grow. But it is also going to be really important hitting these compensatory pathways that get turned on. I think it's going to be both, and it seems like KRAS may turn on more compensatory pathways earlier than things like EGFR or ALK2, you know, and I think it's going to be a great scientific question to figure out why that is. Dr. Vamsidhar Velcheti: Right. And just following up on that, Dr. Heymach, so, what do we know so far about primary and acquired resistance to KRAS G12C inhibitors? Dr. John Heymach: Yeah. Well, it's a great question, and we're still very early in understanding this. And here, if we decide to call it primary resistance - meaning you never respond in the first place, and acquired - meaning you respond and then become resistant, we're not sure why some tumors do respond and don't respond initially. Now, it's been known for a long time, tumors differ in what we call their KRAS-dependence. And in cell lines and in mouse models, when you study this in the lab, there are some models where if you block KRAS, those cells will die immediately. They are fully dependent. And there's other ones that become sort of independent and they don't really seem to care if you turn down KRAS, they've sort of moved on to other things they're dependent on. One way this can happen is with undergoing EMT where the cell sort of changes its dependencies. And EMT is probably a reason some of these tumors are resistant, to start with. It may also matter what else is mutated along with KRAS, what we call the co-mutations, the additional mutations that occur along with it. For example, it seems like if this gene KEAP1 is mutated, tumors don't respond as well, to begin with. Now, acquired resistance is something we are gaining some experience with. I can say in the beginning, we all knew there'd be resistance, we were all waiting to see it, and what we were really hoping for was the case like with first-generation inhibitors with EGFR, where there was one dominant mechanism. In the first-generation EGFR, we had one mutation; T790M, that was more than half the resistance. And then we could develop drugs for that. But unfortunately, that's not the case. It looks like the resistance mechanisms are very diverse, and lots of different pathways can get turned on. So, for acquired resistance, you can have additional KRAS mutations, like you can have a KRAS G12D or V, or some other allele, or G13, I didn't even realize were commonly mutated, like H95 or Y96 can get mutated as well. So, we might be able to inhibit with better inhibitors. But the more pressing problem is what we call bypass; when these other pathways get turned on. And for bypass, we know that the tumor can turn on MET with MET amplification, NRAS, BRAF, MAP kinase, and we just see a wide variety. So, it's clear to us there isn't going to be a single easy to target solution like there was for EGFR. This is going to be a long-term problem, and we're going to have to work on a lot of different solutions and get smarter about what we're doing. Dr. Vamsidhar Velcheti: Yeah. Thank you very much, Dr. Heymach. And Dr. Neel, just following up on that, so, what do you think our strategies should be or should look like while targeting KRAS-mutant tumors? Like, do we focus on better ways to inhibit RAS, or do we focus on personalized combination approaches based on various alterations or other biomarkers? Dr. Benjamin Neel: Yeah. Well, I'd like to step back a second and be provocative, and say that we've been doing targeted therapies, so to speak, for a long time, and it's absolutely clear that targeted therapies never cure. And so, I think we should ask the bigger question, "Why is it that targeted therapies never cure?" And I would start to conceive of an answer to that question by asking which therapies do cure. And the therapies that we know do cure are immune therapies, or it's therapies that generate durable immune response against the tumor. And the other therapies that we know that are therapies in some cases against some tumors, and radiation therapy in some cases against some tumors. Probably the only way that those actually converge on the first mechanism I said that cures tumors, which is generating a durable immune response. And so, the only way, in my view, it is to durably cure an evolving disease, like a cancer, is to have an army that can fight an evolving disease. And the only army I know of is the immune system. So, I think ultimately, what we need to do is understand in detail, how all of these different mutations that lead to cancer affect immune response and create targetable lesions in the immune response, and then how the drugs we'd give affect that. So, in the big picture, the 50,000-foot picture, that what we really need to spend more attention on, is understanding how the drugs we give and the mutations that are there in the first place affect immune response against the tumor, and ultimately try to develop strategies that somehow pick up an immune response against the tumor. Now in the short run, I think there's also lots of combination strategies that we can think of, John, you know, alluded to some of them earlier. I mean one way for the G12C inhibitors, getting better occupancy of the drug, and also blocking this so-called phenomenon of adaptive resistance, where you derepress the expression of receptor tyrosine kinases, and their ligands, and therefore bypass through normal RAS or upregulate G12C into the GTP state more, that can be attacked by combining, for example, with the SHIP2 inhibitor or a SOS inhibitor. Again, the issue there will be therapeutic index. Can we achieve that with a reasonable therapeutic index? Also in some cases, like not so much in lung cancer, but in colon cancer, it appears as if a single dominant receptor tyrosine kinase pathway, the EGF receptor pathway, is often the mechanism of adaptive resistance to RAS inhibitors, and so, combining a RAS inhibitor with an EGF receptor inhibitor is a reasonable strategy. And then of course, some of the strategies they're already getting at, what I just mentioned before, which is to try to combine RAS inhibitors with checkpoint inhibitors. I think that's an expected and understandable approach, but I think we need to get a lot more sophisticated about the tumor microenvironment, and how that's affecting the immune response. And it's not just going to be, you know, in most cases combining with a checkpoint inhibitor. I think we ought to stop using the term immunotherapy to refer to checkpoint inhibitors. Checkpoint inhibitors are one type of immunotherapy. We don't refer to antibiotics when we mean penicillin. Dr. Vamsidhar Velcheti: Dr. Heymach, as you know, like, there's a lot of discussion about the role of KRAS G12C inhibitors in the frontline setting. Do you envision these drugs are going to be positioning themselves in the frontline setting as a combination, or like as a single agent? Are there like a subset of patients perhaps where you would consider like a single agent up front? Dr. John Heymach: So, I think there's no question G12C inhibitors are moving to the first-line question. And the question is just how you get there. Now, the simplest and most straightforward approach is to say, “Well, we'll take our standard and one standard might be immunotherapy alone, a PD-1 inhibitor alone, or chemo with the PD-1 inhibitor, and just take the G12C inhibitor and put it right on top.” And that's a classic strategy that's followed. That may not be that simple. It's not obvious that these drugs will always work well together or will be tolerated together. So, I think that's still being worked out. Now, an alternative strategy is you could say, “Well, let's get a foot in a door in the first-line setting by finding where chemotherapy and immunotherapy don't work well, and pick that little subgroup.” There are some studies there using STK11-mutant tumors, and they don't respond well to immunotherapy and chemotherapy and say, “Well, let's pick that first.” And that's another strategy, but that's not to get it for everybody in the first-line setting. That's just to pick a little subgroup. Or we may develop KRAS G12C inhibitor combinations by themselves that are so effective they can beat the standard. So, what I think is going to happen is a couple things; I think they'll first be some little niches where it gets in there first. I think eventually, we'll figure out how to combine them with chemotherapy and immunotherapy so it goes on top. And then I think over time, we'll eventually develop just more effective, targeted combos where we can phase out the chemo, where the chemo goes to the back of the line, and this goes to the front of the line. Dr. Vamsidhar Velcheti: And Dr. Heymach, any thoughts on the perioperative setting and the adjuvant/neoadjuvant setting, do you think there's any role for these inhibitors in the future? Dr. John Heymach: Yeah, this is a really exciting space right now. And so that makes this a really challenging question because of how quickly things are moving. I'll just briefly recap for everybody. Until recently, adjuvant therapy was just chemotherapy after you resected a lung cancer. That was it. And it provided about a 5% benefit in terms of five-year disease-free survival. Well, then we had adjuvant immunotherapy, like atezolizumab, approved, then we had neoadjuvant chemo plus immunotherapy approved; that's a CheckMate 816. And just recently, the AEGEAN study, which I'm involved with, was announced to be a positive study. That's neoadjuvant plus adjuvant chemo plus immunotherapy. So now, if you say, well, how are you going to bring a G12C inhibitor in there? Well, you can envision a few different ways; if you can combine with chemo and immunotherapy, you could bring it up front and bring it afterwards, or you could just tack it in on the back, either with immunotherapy or by itself, if you gave neoadjuvant chemo plus immunotherapy first, what we call the CheckMate 816 regimen. So, it could fit in a variety of ways. I'll just say neoadjuvant is more appealing because you can measure the response and see how well it's working, and we in fact have a neoadjuvant study going. But the long-term benefit may really come from keeping the drug going afterwards to suppress microscopic metastatic disease. And that's what I believe is going to happen. I think you're going to need to stay on these drugs for a long while to keep that microscopic disease down. Dr. Vamsidhar Velcheti: Dr. Neel, any thoughts on novel agents in development beyond KRAS G12C inhibitors? Are there any agents or combinations that you'd be excited about? Dr. Benjamin Neel: Well, I think that the YAP/TAZ pathway inhibitors, the TEAD inhibitors in particular, are potentially promising. I mean, it seems as if the MAP kinase pathway and the GAPT pathway act in parallel. There's been multiple phases which suggest that YAP/TAZ reactivation can be a mechanism of sort of state-switching resistance. And so, I think those inhibitors are different than the standard PI3 kinase pathway inhibitor, PI3 kinase mTOR inhibitor, rapamycin. I also think as we've alluded to a couple of times, the jury's still out in the clinic, of course, but it'll be very exciting to see how this new set of RAS inhibitors works. The sort of Pan-RAS inhibitors, especially the ones that hit the GTP ON state. So, the G12C inhibitors and the initial preclinical G12D inhibitors that have been recorded, they all work by targeting the inactive state of RAS, the RAS-GDP state. And so, they can only work on mutants that cycle, at least somewhat, and they also don't seem to be as potent as targeting the GTP or active state of RAS. And so, at least the Rev meds compounds, which basically use cyclophilin, they basically adapt the mechanism that cyclosporine uses to inhibit calcineurin. They basically use the same kind of a strategy and build new drugs then that bind cyclophilin and present the drug in a way that can inhibit multiple forms of RAS. So, it'll be interesting to see if they are much more efficacious in a clinic as they appear to be in the lab, whether they can be tolerated. So, I think those are things to look out for. Dr. Vamsidhar Velcheti: Dr. Heymach? Dr. John Heymach: Yeah, I agree with that. I'm excited to see that set of compounds coming along. One of the interesting observations is that when you inhibit one KRAS allele like G12C, you get these other KRAS alleles commonly popping up. And it's a little -- I just want to pause for a second to comment on this, because this is a little different than EGFR. If you inhibit a classic mutation, you don't get multiple other separate EGFR alleles popping up. You may get a secondary mutation in cyst on the same protein, but you don't get other alleles. So, this is a little different biology, but I think the frequency that we're seeing all these other KRAS alleles pop up tells us, I think we're going to need some pan-KRAS type strategy as a partner for targeting the primary driver. So for example, a G12C inhibitor plus a pan-KRAS strategy to head off these other alleles that can be popping up. So, I think that's going to be probably a minimum building block that you start putting other things around. And by partnering an allele-specific inhibitor where you might be able to inhibit it a little more potently and irreversibly with a pan-KRAS, you may solve some of these problems at the therapeutic window. You can imagine KRAS is so important for so many different cells in your body that if you potently inhibit all KRAS in your body, bad things are likely to happen somewhere. But if you can potently inhibit the mutant allele and then dampen the other KRAS signaling that's popping up, it's more hopeful. Dr. Benjamin Neel: There is a mouse model study from Mariano Barbacid's lab, which suggests that postnatal, KRAS at least, complete inhibition is doable. So, you could take out KRAS postnatally and the mice are okay. Whether that translates to human of course, is not at all clear. And you still have the other RAS alleles, the HRAS, the NRAS that you'd still have to contend with. Dr. John Heymach: Yeah, it's an interesting lesson. We've shied away from a lot of targets we thought weren't feasible. I did a lot of my training with Judah Folkman who pioneered targeting angiogenesis. And I remember hearing this idea of blocking new blood vessels. I said, "Well, everyone is just going to have a heart attack and die." And it turns out you can do it. You have to do it carefully, and in the right way but you can separate malignant or oncogenic signaling from normal signaling in an adult, pretty reasonably in a lot of cases where you don't think you could. Dr. Vamsidhar Velcheti: All right. So, Dr. Neel, and Dr. Heymach, any final closing comments on the field of RAS-targeted therapies, you know, what can we hope for? What can patients hope for, let's say five years from now, what are we looking at? Dr. John Heymach: Well, I'll give my thoughts I guess first, from a clinical perspective, I think we're already seeing the outlines of an absolute explosion in targeting KRAS over the next five years. And I think there's a really good likelihood that this is going to be the major place where we see progress, at least in lung cancer, over these next five years. It's an example of a problem that just seemed insolvable for so long, and here I really want to acknowledge the sustained support for clinical research and laboratory research focused around RAS. You know, the NCI had specific RAS initiatives and we've had big team grants for KRAS, and it shows you it's worth these large-scale efforts because you never know when that breakthrough is going to happen. But sometimes it just takes, you know, opening that door a little bit and everybody can start rushing through. Well, I think for KRAS, the door has been opened and everybody is rushing through at a frantic rate right now. So, it's really exciting, and stay tuned. I think the landscape of RAS-targeting is going to look completely different five years from now. Dr. Benjamin Neel: So, I agree that the landscape will definitely look different five years from now, because it's reflective of stuff that's been in process for the last five years. And it takes about that long to come through. I want to make two comments; one of which is to slightly disagree with my friend, John, about these big initiatives. And I would point out that this RAS breakthrough did not come from a big initiative, it came from one scientist thinking about a problem uniquely in a different way. We need a basic science breakthrough, it almost always comes from a single lab person, thinking about a problem, often in isolation, in his own group. What big initiatives can help with is engineering problems. Once you've opened the door, and you want to know what the best way is to get around the house, then maybe big initiatives help. But I do think that there's been too much focus on the big team initiative and not enough on the individual scientists who often promote the breakthrough. And then in terms of where I see the field going, what I'd really like to see, and I think in some pharmaceutical companies and biotechs, you're seeing this now, and also in academia, but maybe not enough, is that sort of breaking down of the silos between immunotherapy and targeting therapy. Because I agree with what John said, is that targeted therapy, is just sophisticated debulking. If we want to really make progress-- and on the other hand, immunotherapy people don't seem to, you know, often recognize that these oncogenic mutations in the tumor actually affect the immune system. So, I think what we need is a unification of these two semi-disparate areas of therapeutics in a more fulsome haul and that will advance things much quicker. Dr. Vamsidhar Velcheti: Thank you both, Dr. Neel and Dr. Heymach, for sharing all your valuable insights with us today on the ASCO Daily News podcast. We really appreciate it. Thank you so much. Dr. John Heymach: Thanks for asking us. Dr. Benjamin Neel: It's been great having us. Dr. Vamsidhar Velcheti: And thank you all to our listeners, and thanks for joining us today. If you value our insights that you hear on the ASCO Daily News podcast, please take a moment to rate, review and subscribe. 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. Follow today's speakers: Dr. Vamsi Velcheti @VamsiVelcheti Dr. Benjamin Neel @DrBenNeel Dr. John Heymach Want more related content? Listen to our podcast on novel therapies in lung cancer.    Advances in Lung Cancer at ASCO 2022 Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn Disclosures: Dr. Vamsi Velcheti: Honoraria: Honoraria Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline Dr. Benjamin Neel: None disclosed Dr. John Heymach: None disclosed    

Lung cancer is one of the most commonly diagnosed type of cancer and so it is fitting that we start the first of our disease-specific oncology series with this diagnosis. This week, we continue our discussion on metastatic non-small cell lung cancer, focusing on NSCLC with driver mutations. * The approach to treatment of a patient with widespread metastatic NSCLC (mNSCLC) is very different than a patient without distant disease, which highlights why we do what we do:- Important to complete staging (discussed in prior episodes) to determine the extent of disease- Important to check molecular testing (looking for mutations in the cancer cells) and IHC for tumor proportion score (TPS) helps determine treatment options - If your molecular testing is identified in a driver mutation gene, there are targeted options for this! *Driver mutations are predictive of response to an oral therapy and a LACK of response to immune therapy (particularly in EGFR and ALK mutated patients) * EGFR Mutation:- Pay attention to the types of mutation in EGFR (not all are the same):-- Exon 19 deletion -- Exon 19 L858R-- Exon 21 T790M-- Exon 20 Insertion (Osimertinib [see below] cannot be used for this mutation)- Osimertinib is first-line standard of care for patients with EGFR-- Used to be a second-line agent. Many patients with EGFR mutations receiving earlier generation TKIs would develop resistance and when these tumors were sequenced, they would have Exon 21 T790M mutations. Osimertinib was effective even with this mutation and had superior overall survival data compared to chemotherapy (AURA3 Trial)--Now it is used in first-line setting for patients with EGFR mutation based on the FLAURA trial --- In this study, patients received osimertinib as first line vs. older generation EGFR-targeting TKIs (erlotinib or gefitib) and Osimertinib had better outcomes: ---- Showed that the median OS was 38.6 months with Osi vs. 31.8 months; also improved brain penetration! ---- Also effective in patients with metastatic disease to the brain: ----- Only 6% of patients had CNS progression with Osi vs. 15% with others- What if a patient is on Osi and later develops new brain mets?-- If there is progression within just the brain (and good control in other sites of the body) you can refer patient to Radiation Oncology for SRS-- Remember, based on discussion with Dr. Osmundson in our RadOnc lectures (Episode 028), it is important to HOLD Osimertinib if patient is going to get radiation to minimize the side effects- What is patient had progression of disease in several sites throughout the body?-- Management is less straightforward. -- In many of these cases, you can consider:--- Consolidative radiation - If small amounts of disease--- Changing therapy - If there has been widespread progression; likely would change to chemotherapy (without IO, since lower predictive response to IO with EGFR mutation)---- No clear guidelines if you should continue the TKI---- Remember that IO + TKIs can cause increased risk of side effects, such as pneumonitis and hepatitis. DO NOT DO THIS!* ALK Mutation:- There are many options for ALK mutations-- The first generation drug is crizotinib--- Lots of side effects —> “It is crazy to start with crizotinib”--- Studies for later generation TKIs were compared to crizotinib -- Many people today will use third generation ALK-inhibitor alectinib (Important trials: ALEX Trial and J-ALEX Trial)--- With alectinib, PFS 34.8 months, RR 83%, less CNS progression (12% vs 45%)--- 5 year OS rate 62.5%- What to do with disease progression while on ALK inhibitor?-- In ALK, you can actually switch to another ALK inhibitor and many will respond well--- Of course, with each change, you may expect not as great of a response * Lots of other mutations!- TFOC recommends just looking these up!-- Link to NCCN Guidelines on NSCLC; Page 41 has full list!- Another way to think about this, when do we NOT do TKIs as first line: -- KRAS G12C-- EGFR Exon 20 Insertion-- HER2- How do you counsel a patient when considering/starting a TKI? -- Patients with highest chance of having a targeted mutation are younger non-smokers with adenocarcinoma-- Set expectations: great outcomes overall, but still not a cure. -- Remembering the drugs: All TKIs usually end in “-nib” -- In general, the way we recommend remembering this: “Fatigue, GI, Derm (skin/nail changes)”; rarely pneumonitis References:* AURA3 Trial - https://www.nejm.org/doi/full/10.1056/NEJMoa1612674Established osimertinib was better than chemo for patients with EGFR mutation and acquired Exon 21 T790M resistance mutation* FLAURA Trial - https://www.nejm.org/doi/full/10.1056/nejmoa1713137 Established osimertinib as first-line agent for patients with EGFR mutation * ALEX Trial - https://www.nejm.org/doi/full/10.1056/nejmoa1704795Helped establish alectinib as superior for ALK mutations compared to crizotinib * J-ALEX Trial - https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)30565-2/fulltextHelped establish alectinib as superior for ALK mutations compared to crizotinib * NCCN Guidelines on NSCLC - https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450 Please visit our website (TheFellowOnCall.com) for more information Twitter: @TheFellowOnCallInstagram: @TheFellowOnCallListen in on: Apple Podcast, Spotify, and Google PodcastLove what you hear? Tell a friend and leave a review on our podcast streaming platforms!

In this episode, Ryan D. Gentzler, MD, MS, and Jonathan Riess, MD, MS, answer audience questions on managing EGFR-mutated non-small-cell lung cancer (NSCLC) from a live meeting series. The episode includes expert insights on:• Identifying patients who may benefit the most from adjuvant osimertinib  • Testing for EGFR mutations in early-stage NSCLC• Critical importance of getting molecular test results before starting immunotherapy• Monitoring cardiac toxicity in patients receiving osimertinib• Key ongoing trials in EGFR-mutated NSCLC for patients with newly diagnosed disease and following progression on osimertinibPresenters:Ryan D. Gentzler, MD, MSAssociate ProfessorDivision of Hematology/OncologyDepartment of MedicineUniversity of VirginiaThoracic Medical OncologistUniversity of Virginia Comprehensive Cancer CenterCharlottesville, VirginiaJonathan Riess, MD, MSAssociate ProfessorDepartment of Internal Medicine/Hematology-OncologyUniversity of California, DavisMedical Director, Thoracic OncologyUniversity of California, Davis Comprehensive Cancer CenterSacramento, CaliforniaLink to full program: https://bit.ly/3DZGzSO  

El Dr. Juan Carlos Samamé, oncólogo médico adscrito al Hospital Nacional Arzobispo Loayza, a la Clínica San Felipe y al Centro Oncológico ALIADA, en Lima, Perú, tiene como invitado especial al Dr. Andrés Felipe Cardona, oncólogo clínico adscrito al Centro de Tratamiento e Investigación sobre Cáncer “Luis Carlos Sarmiento Angulo” (CTIC) en Bogotá, Colombia, para desarrollar un caso clínico sobre cáncer de pulmón presentado por la Dra. Erika Pavón, residente de Oncología Médica en el Hospital Eugenio Espejo, en Quito, Ecuador, en este episodio de Comité de tumores. Dentro de su conversación, los expertos resuelven las siguientes preguntas sobre un caso clínico de un masculino de 74 años con un diagnóstico inicial de un cáncer de pulmón estadio IV y metástasis óseas (T12): ¿Cuál es la conducta frente a la progresión a los TKI's de 1L? Con relación a la disponibilidad de osimertinib frente a la mutación T790M, si es que se hubiera administrado este medicamento tras la progresión, ¿Qué otros medicamentos podríamos dar y que SLE podríamos alcanzar con estos medicamentos? Si encontramos una expresión alta de PD-L1 además de la mutación de EGFR, ¿Se prefiere la inmunoterapia o los TKI's? ¿Cuáles podrían ser los mecanismos de resistencia que influyeron en este caso para la resistencia a los TKI's? Participe en el programa mandándonos su caso clínico a ser discutido con un líder de opinión al correo: contacto@sciencelink.com Videograbado: 05 de abril de 2022 Todos los comentarios emitidos por los participantes son a título personal y no reflejan la opinión de ScienceLink u otros. Se deberá revisar las indicaciones aprobadas en el país para cada uno de los tratamientos y medicamentos comentados. Las opiniones vertidas en este programa son responsabilidad de los participantes o entrevistados, ScienceLink las ha incluido con fines educativos. Este material está dirigido a profesionales de la salud exclusivamente.

An interview with Dr. Natasha Leighl, Dr. Andrew Robinson, and Dr. Gregory Riely on “Therapy for Stage IV Non-Small Cell Lung Cancer with Driver Alterations: ASCO and OH (CCO) Guideline Update.” This guideline provides recommendations on systemic therapy for patients with stage IV NSCLC whose cancer has driver alterations, focusing on seven targets - EGFR, ALK, ROS-1, BRAF V600e, RET, MET exon 14 skipping mutations, and NTRK. Read the full guideline at asco.org.   TRANSCRIPT PRESENTER: 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. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. 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 podcasts.asco.org. My name is Brittany Harvey, and today, I'm interviewing Dr. Natasha Leighl from Princess Margaret Cancer Center in Toronto, Ontario, Dr. Andrew Robinson from Queen's University in Kingston, Ontario, and Dr. Gregory Riely from Memorial Sloan Kettering Cancer Center in New York, New York, authors on Therapy for Stage IV Non-Small-Cell Lung Cancer with Driver Alterations: American Society of Clinical Oncology and Ontario Health (Cancer Care Ontario) Guideline Update. Thank you for joining me today, Drs. Leighl, Robinson, Riely. DR. ANDREW ROBINSON: Thank you for having us. DR. NATASHA LEIGHL: Thanks for having us, Brittany. 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. Leighl, do you have any relevant disclosures that are related to this guideline topic? DR. NATASHA LEIGHL: I don't have relevant disclosures, but I do have institutional research funding from a number of companies, including Amgen, ARRAY, AstraZeneca, EMD Serono, Guardant Health, Eli Lilly, Merck, Pfizer, Roche, and Takeda, and personal fees from Bristol-Myers and MSD, which are unrelated. Thanks. BRITTANY HARVEY: Thank you. And Dr. Robinson, do you have any relevant disclosures that are related to this guideline? DR. ANDREW ROBINSON: I do not have any relevant disclosures related to this guideline. My institutional list of research funding is not as extensive as Dr. Leighl's, but is still fairly extensive and includes many of those companies. BRITTANY HARVEY: And Dr. Riely, do you have any relevant disclosures? DR. GREGORY RIELY: I receive institutional research funding from Novartis, Roche, Genentech, GlaxoSmithKline, Pfizer, Moradi, Merck, and Takeda. But those are my only disclosures. BRITTANY HARVEY: Thank you all. Then let's get into some of the content of this guideline update. So this guideline is an update of an earlier ASCO guideline on the systemic treatment of patients with stage IV non-small cell lung cancer, which was then divided into two companion guidelines, one on systemic therapy treatment options for patients without driver alterations, which was published in 2020, and then this one for patients whose cancer has driver alterations. So Dr. Robinson, can you give us a general overview of what this particular guideline covers? DR. ANDREW ROBINSON: Thank you, Brittany. It was a great experience to be part of this important guideline and an honor. As you mentioned, this guideline is on treatment of stage IV non-small cell lung cancer patients with driver mutations. And it's a companion guideline to the earlier guideline published on treatment of stage IV non-small-cell lung cancer without driver mutations. The guideline followed a robust evidence gathering and evaluation process as a standard for ASCO-Ontario Health guidelines. In this case, we ended up reviewing several phase III trials, as well as many earlier phase studies and specific driver mutation groups. If we look back to 2017, there were four driver mutation group recommendations included in the guideline. We now have recommendations for seven different oncogenes, as well as some recommendations that are specific not only for the oncogene involved, but also the specific mutation within that gene. The non-driver mutation guideline is referenced as well frequently in this guideline, as many of the treatment options that are recommended in that guideline are also appropriate for patients with driver mutations, with the exception of a couple of key mutation groups such as EGFR. Recommendations in the guideline are qualified as weak, moderate, or strong, and the level of evidence for each recommendation is given. For many of these novel agents, the evidence is relatively low in comparison to what we are used to with recommendations based on phase II trials without comparator arms, and with surrogate endpoints for patient benefits such as response rates and duration of response, as opposed to quality of life and overall survival. Nonetheless, it was felt appropriate to include many of these agents in the recommendations, with the caveat that the level of evidence is weak or non-evidence-based. One of the recommendations in the introduction to these guidelines is to continue with studies such as phase III clinical trials in many of these settings, in order to move from an informal consensus-based recommendation, to a recommendation based on moderate to high quality evidence. We hope oncologists and their patients will find these guidelines useful. BRITTANY HARVEY: Great. Then, as you just mentioned, this guideline focuses on seven targets, EGFR, ALK, ROS1, BRAF, RET, MET, and NTRK. I'd like to review those key recommendations for each of those targets. So first, Dr. Robinson, what is recommended for patients with stage IV non-small-cell lung cancer and an epidermal growth factor receptor mutation? DR. ANDREW ROBINSON: Thank you. In terms of stage IV EGFR mutation positive lung cancer, the recommendations in the 2017 guidelines were to use tyrosine kinase inhibitors upfront, such as gefitinib, afatinib, or erlotinib, and to follow that with osimertinib if a mutation was found in T790M, or chemotherapy depending on what was available. In the current treatment guideline, we have recommendations not only for first and second line treatment, but also some acknowledgment and recommendations for treatment of patients with EGFR mutations other than the classical exon 19 deletion mutation or LA58R. For patients with a classical EGFR mutation, several strategies have been shown to be superior to first generation tyrosine kinase inhibitors in the first line setting. And the panel strongly recommended osimertinib to be used as first line therapy with a high level of evidence, based on the FLAURA clinical trial. This demonstrated not only an overall survival benefit, but a quality-of-life benefit. Other strategies that have been shown to benefit include dacomitinib as first line therapy, gefitinib plus chemotherapy as first line therapy. Erlotinib/bevacizumab and erlotinib/ramucirumab are also options with a lower level of evidence, as they have not been shown yet to be associated with improved overall survival. But they are associated with improved progression-free survival. Most of the recommendations, other than osimertinib, are really recommendations for what to pursue if osimertinib is not available. If we move to patients with sensitizing but non-classical EGFR mutations, the evidence is certainly much more sparse, as are these patients. And the recommendation was for afatinib first line or osimertinib was also considered an option based on phase II data. For patients with EGFR exon 20 insertion mutations, recommendation at this time was not to use a targeted agent first line, but to default to the non-driver mutation guidelines. For second line therapy, after tyrosine kinase inhibition stops benefiting, the recommendation was to use doublet platinum chemotherapy with or without bevacizumab. The atezolizumab/bevacizumab/carboplatin/paclitaxel combination was acknowledged as an option based on an exploratory analysis of the phase III EMPOWER trial, but this was considered exploratory and this regimen was not strongly recommended until further evidence accrues. BRITTANY HARVEY: OK, thank you. Then Dr. Leighl, what is recommended for patients with stage IV non-small-cell lung cancer and ALK rearrangement? DR. NATASHA LEIGHL: So for patients with ALK rearranged stage IV lung cancer, in the first line setting, next generation ALK inhibitors alectinib or brigatinib should be offered to patients. This is based on randomized trials comparing these to first generation inhibitors, crizotinib specifically, demonstrating better outcomes including progression-free survival and better intracranial activity. If you live in a region where alectinib and brigatinib are not available, earlier inhibitors like crizotinib or ceritinib should be offered again based on high quality evidence randomized trials demonstrating that these are better than chemotherapy. In the second line setting, if your patient has received alectinib or brigatinib first line, lorlatinib may be offered. If your patient received an earlier generation inhibitor crizotinib, they should be offered alectinib, brigatinib, or ceritinib, again based on randomized trials. And later, lorlatinib third line may be offered. It's also important to remember that in this group of patients, chemotherapy, especially pemetrexed-based chemotherapy, is very active. And we would refer you to the ASCO-Ontario Health non-driver mutation guidelines for chemotherapy recommendations when targeted therapy is no longer an option. I should also note that when we drafted these guidelines, we did not yet have results of the first line lorlatinib study, the CROWN study, where we found that lorlatinib was also superior to crizotinib, the first generation inhibitor. This is currently under review by the US FDA. So while it's not recommended in our guideline, we may see this added to future guidelines in our next guideline update. BRITTANY HARVEY: Great. Thank you. And then, what is recommended for patients with ROS1 rearrangement? DR. NATASHA LEIGHL: So for patients with ROS1 rearranged stage IV lung cancer, in the first line setting, specific ROS1 inhibitors, crizotinib or entrectinib may be offered. Because this is based on very impressive response rates and prolonged duration of response and patient benefit, in single arm studies, we have to recognize that alternatives may also include standard treatment based on the ASCO non-driver mutation guidelines, as well as other target agents, such as ceritinib or lorlatinib, that may be offered. If, though, your patient has progressive disease and previously received non-targeted therapy, targeted therapy with crizotinib, ceritinib, or entrectinib, can certainly be offered. Also, if your patient has received ROS1 targeted therapy in the first line setting, standard treatment based on the ASCO non-driver mutation guidelines should be offered also with consideration of clinical trials. BRITTANY HARVEY: And then additionally, what is recommended for patients with stage IV non-small-cell lung cancer and an NTRK fusion? DR. NATASHA LEIGHL: Thanks, Brittany. For patients with stage IV disease and an activating NTRK fusion, entrectinib or larotrectinib may be offered in the first line setting based on single arm studies, including patients with lung cancer and very dramatic response rates and prolonged duration of response. However, standard treatment based on the non-driver mutation guideline chemotherapy-based may also be offered in the second line setting. If NTRK targeted therapy was given first line, standard treatment with chemotherapy-based options may be offered second line based on the non-driver mutation guideline. If NTRK targeted therapy, though, was not given in the first line setting, entrectinib or larotrectinib may be offered to your patient. And I think at this point, we really don't know what the optimal sequence is for these patients. But I think it's very clear from the data that we do have, that we want to try and identify this target and get patients on targeted therapy as soon as possible in the course of their disease. BRITTANY HARVEY: Great. Then Dr. Riely, can you review what the guideline recommends for patients with stage IV non-small cell lung cancer and a BRAF mutation? DR. GREGORY RIELY: Thank you, Brittany. I'll highlight that the BRAF mutation guideline pertains specifically to those patients with BRAF V600E mutations. The other BRAF mutations that we observed, we don't have sufficient data to make recommendations. But for those patients with BRAF V600E alterations, again, based on the quality of the data and the type of data available, the guidelines recommend consideration of first line use of dabrafenib with trametinib. This is a consideration rather than a should recommendation, given the absence of randomized clinical trial evidence. But nonetheless, we recommend that they be considered in the first line setting. If, in fact, you choose to use a non-targeted approach in the first line setting, then the guidelines do recommend consideration of dabrafenib with trametinib in the second line setting. So it's, again, the first line setting, dabrafenib/trametinib combination. Or, if not used in the first line setting, then recommendation dabrafenib/trametinib in the second line setting. BRITTANY HARVEY: OK, then, what is recommended for patients with stage IV non-small-cell lung cancer and a MET mutation? DR. GREGORY RIELY: Again, specific for MET, we're talking about MET exon 14 alterations rather than MET amplification with other mutations, which we might call emerging targets. So for patients with metastatic exon 14 altered non-small cell lung cancer, the recommendation is for the use of capmatinib or tepotinib. These are newer MET inhibitors that have recently been approved. And again, the guidelines recommend that they should be considered in the first line setting. If, however, you choose to use non-targeted therapies in the first line setting, then MET directed therapy such as capmatinib or tepotinib should be considered in the second line setting. BRITTANY HARVEY: And then the final target addressed in this guideline, what is recommended for patients with stage IV non-small cell lung cancer and RET rearrangement? DR. GREGORY RIELY: RET rearrangements are relatively uncommon, but important in a subset of patients with non-small cell lung cancer. And we have MET targeted agents that are available. The current guidelines recommend that in the first line setting, we consider the use of selpercatinib. And in the second line setting, if patients have not previously received a RET inhibitor, one should consider selpercatinib in that context. Patients who have received a targeted therapy in the first line then conventional chemotherapy with or without immunotherapy or bevacizumab should be considered. I will note that the guidelines were finalized prior to the approval of pralsetinib, and pralsetinib is another RET inhibitor with similar data in this context. BRITTANY HARVEY: Great. Thank you all for reviewing those recommendations. So Dr. Robinson alluded to this earlier, but Dr. Riely, could you describe what emerging targets the panel reviewed but were unable to make recommendations for at this time? DR. GREGORY RIELY: The development of treatments in patients with non-small cell lung cancer has really proceeded at a breakneck pace over the past 10 years. We've seen newer alterations identified, new drugs tested in those populations, and new drugs approved in relatively rapid succession. We have a number of targets that are currently being studied with new drugs, but we don't quite have enough data yet and the drugs aren't yet approved, so they can't be included in the guidelines. Some of these targets include KRAS G12C, recently seen a number of direct KRAS inhibitors that have been developed and seem to have activity in that group of patients. And that's a hot area to look forward to. We've also seen that patients with EGFR exon 20 insertions don't seem to benefit from currently available EGFR TKIs at the standard recommended dose. And so we don't have recommendations for their utilization here, but there are new drugs that are being developed to target this group of patients. Similarly, patients with HER2 mutations seem to not benefit from available therapies, but there are drugs that are being developed, and we look forward to seeing more data in that context. Finally, patients with NRG1 fusions are another emerging target, but we don't have good recommendations yet or good drugs yet. BRITTANY HARVEY: Great. Understood. So then, Dr. Robinson, in your view, why is this guideline important, and how will it impact clinical practice? DR. ANDREW ROBINSON: Well, this guideline is important because it's taking a problem that we see in the real world, which is patients with lung cancer with an ever-expanding number of driver mutations, and trying to give recommendations for the integration of new therapies with standard clinical practice. It's important that I've highlighted that for most of these mutations, without phase III evidence, the recommendations were to consider the targeted agent as first line therapy. But also, if it's not given first line, to use it in subsequent lines. And I think we need to recognize that these targeted agents, it's most important that patients get these drugs at some point in their care, even if we don't know exactly what the optimal point in their care is. The guideline was sort of the first one in lung cancer, where we've taken a number of these rare mutations and examined the phase II data, and will likely be the template for what is going forward with an ever-expanding number of medications. So hopefully, we get a bit of standardization out of it. Hopefully, we've highlighted some of the areas that are still unclear and can be a template for the next round of targeted therapy guidelines. BRITTANY HARVEY: Definitely, it's an ever-changing landscape. So finally, Dr. Leighl, what do these updated guideline recommendations mean for patients with stage IV non-small-cell lung cancer? DR. NATASHA LEIGHL: So this is really great news. And as Dr. Riely and Dr. Robinson have highlighted, in just a very short number of years since 2017, we've made tremendous progress. We have at least three new targets, many new treatments for almost every class of targeted therapy indication in lung cancer. And most of these new targets are their oral therapies or pills. And many of them should now be offered to patients as first or second line treatment instead of chemotherapy. So for patients, this really means many more will be able to enjoy a chemotherapy-free world, or at least a chemotherapy-free period for a time. I think it's really important for patients and the oncology team to remember that genomic testing is essential. And it's an essential part of the stage IV non-squamous, non-small-cell lung cancer diagnostic process, and in some places, you know, any non-small-cell lung cancer. And this may be a very important part of the process. And it really doesn't depend on clinical factors like smoking. It's really about your pathologic diagnosis or in your tumor sample. So it's really key that we make sure that patients get their samples tested as soon as possible in their lung cancer journey, preferably with comprehensive profiling so we can identify any of these targets, if our patients have them, and then get them onto the right treatment as fast as possible. If there isn't enough tissue for testing, liquid biopsy has emerged as a potential alternative. And I think it's so important for patients and oncology professionals to remember that PD-L1 expression, which is an important marker for immune therapy, is not enough. At least a quarter of our patients with PD-L1 expression that suggests immunotherapy should be an option, in fact, have these actionable genomic targets. And we do know that in these patients, targeted therapy should come first. So again, tremendous progress, many exciting opportunities for our patients to be chemo-free for much longer. And again, important to get the right test as soon as possible so we can get you onto the right treatment as soon as possible. BRITTANY HARVEY: Great. Well, thank you all for reviewing the extensive literature associated with this guideline and developing these recommendations, and for taking the time to speak with me today, Dr. Leighl, Dr. Riely, and Dr. Robinson. DR. GREGORY RIELY: Thank you. DR. ANDREW ROBINSON: You're welcome, and thanks a lot to the ASCO staff for doing all of the work in sort of herding the cats that are oncologists, as well as getting all the references and the deep literature searches for us. DR. NATASHA LEIGHL: Agreed. Thanks 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/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in 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.

Go online to PeerView.com/MWN860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in thoracic oncology discuss the latest options for treatment of EGFR-mutated advanced NSCLC, including the rationale for and evidence supporting dual targeting of VEGF and EGFR pathways as well as the role of the first FDA approved combination of VEGF and EGFR inhibitors for newly diagnosed patients. Additionally, the experts explore the nuances and practicalities of individualized treatment selection and sequencing throughout the continuum of advanced disease to maximally extend the benefits patients with EGFR-mutated NSCLC can derive from targeted therapies. Upon completion of this activity, participants will be able to: Discuss the current understanding of the underlying biology of EGFR mutations in NSCLC, including exon 19 and 21 mutations, and mechanisms of acquired resistance, such as T790M, and their implications for treatment selection in first-line and later lines of therapy in advanced EGFR mutation–positive NSCLC, Assess the mechanistic rationale for targeting the VEGFR and EGFR pathways through combination therapy, Cite updated evidence on validated treatment options and emerging evidence on the use of novel regimens in the management of EGFR-mutated NSCLC, including newer antiangiogenic and TKI combinations or agents, Implement evidence-based, individualized, precision treatment plans for patients with advanced EGFR-mutant NSCLC, including for those patients who acquire resistance on prior lines of treatment.

Go online to PeerView.com/MWN860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in thoracic oncology discuss the latest options for treatment of EGFR-mutated advanced NSCLC, including the rationale for and evidence supporting dual targeting of VEGF and EGFR pathways as well as the role of the first FDA approved combination of VEGF and EGFR inhibitors for newly diagnosed patients. Additionally, the experts explore the nuances and practicalities of individualized treatment selection and sequencing throughout the continuum of advanced disease to maximally extend the benefits patients with EGFR-mutated NSCLC can derive from targeted therapies. Upon completion of this activity, participants will be able to: Discuss the current understanding of the underlying biology of EGFR mutations in NSCLC, including exon 19 and 21 mutations, and mechanisms of acquired resistance, such as T790M, and their implications for treatment selection in first-line and later lines of therapy in advanced EGFR mutation–positive NSCLC, Assess the mechanistic rationale for targeting the VEGFR and EGFR pathways through combination therapy, Cite updated evidence on validated treatment options and emerging evidence on the use of novel regimens in the management of EGFR-mutated NSCLC, including newer antiangiogenic and TKI combinations or agents, Implement evidence-based, individualized, precision treatment plans for patients with advanced EGFR-mutant NSCLC, including for those patients who acquire resistance on prior lines of treatment.

Go online to PeerView.com/MWN860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in thoracic oncology discuss the latest options for treatment of EGFR-mutated advanced NSCLC, including the rationale for and evidence supporting dual targeting of VEGF and EGFR pathways as well as the role of the first FDA approved combination of VEGF and EGFR inhibitors for newly diagnosed patients. Additionally, the experts explore the nuances and practicalities of individualized treatment selection and sequencing throughout the continuum of advanced disease to maximally extend the benefits patients with EGFR-mutated NSCLC can derive from targeted therapies. Upon completion of this activity, participants will be able to: Discuss the current understanding of the underlying biology of EGFR mutations in NSCLC, including exon 19 and 21 mutations, and mechanisms of acquired resistance, such as T790M, and their implications for treatment selection in first-line and later lines of therapy in advanced EGFR mutation–positive NSCLC, Assess the mechanistic rationale for targeting the VEGFR and EGFR pathways through combination therapy, Cite updated evidence on validated treatment options and emerging evidence on the use of novel regimens in the management of EGFR-mutated NSCLC, including newer antiangiogenic and TKI combinations or agents, Implement evidence-based, individualized, precision treatment plans for patients with advanced EGFR-mutant NSCLC, including for those patients who acquire resistance on prior lines of treatment.

Go online to PeerView.com/MWN860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in thoracic oncology discuss the latest options for treatment of EGFR-mutated advanced NSCLC, including the rationale for and evidence supporting dual targeting of VEGF and EGFR pathways as well as the role of the first FDA approved combination of VEGF and EGFR inhibitors for newly diagnosed patients. Additionally, the experts explore the nuances and practicalities of individualized treatment selection and sequencing throughout the continuum of advanced disease to maximally extend the benefits patients with EGFR-mutated NSCLC can derive from targeted therapies. Upon completion of this activity, participants will be able to: Discuss the current understanding of the underlying biology of EGFR mutations in NSCLC, including exon 19 and 21 mutations, and mechanisms of acquired resistance, such as T790M, and their implications for treatment selection in first-line and later lines of therapy in advanced EGFR mutation–positive NSCLC, Assess the mechanistic rationale for targeting the VEGFR and EGFR pathways through combination therapy, Cite updated evidence on validated treatment options and emerging evidence on the use of novel regimens in the management of EGFR-mutated NSCLC, including newer antiangiogenic and TKI combinations or agents, Implement evidence-based, individualized, precision treatment plans for patients with advanced EGFR-mutant NSCLC, including for those patients who acquire resistance on prior lines of treatment.

Go online to PeerView.com/MWN860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in thoracic oncology discuss the latest options for treatment of EGFR-mutated advanced NSCLC, including the rationale for and evidence supporting dual targeting of VEGF and EGFR pathways as well as the role of the first FDA approved combination of VEGF and EGFR inhibitors for newly diagnosed patients. Additionally, the experts explore the nuances and practicalities of individualized treatment selection and sequencing throughout the continuum of advanced disease to maximally extend the benefits patients with EGFR-mutated NSCLC can derive from targeted therapies. Upon completion of this activity, participants will be able to: Discuss the current understanding of the underlying biology of EGFR mutations in NSCLC, including exon 19 and 21 mutations, and mechanisms of acquired resistance, such as T790M, and their implications for treatment selection in first-line and later lines of therapy in advanced EGFR mutation–positive NSCLC, Assess the mechanistic rationale for targeting the VEGFR and EGFR pathways through combination therapy, Cite updated evidence on validated treatment options and emerging evidence on the use of novel regimens in the management of EGFR-mutated NSCLC, including newer antiangiogenic and TKI combinations or agents, Implement evidence-based, individualized, precision treatment plans for patients with advanced EGFR-mutant NSCLC, including for those patients who acquire resistance on prior lines of treatment.

Go online to PeerView.com/MWN860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in thoracic oncology discuss the latest options for treatment of EGFR-mutated advanced NSCLC, including the rationale for and evidence supporting dual targeting of VEGF and EGFR pathways as well as the role of the first FDA approved combination of VEGF and EGFR inhibitors for newly diagnosed patients. Additionally, the experts explore the nuances and practicalities of individualized treatment selection and sequencing throughout the continuum of advanced disease to maximally extend the benefits patients with EGFR-mutated NSCLC can derive from targeted therapies. Upon completion of this activity, participants will be able to: Discuss the current understanding of the underlying biology of EGFR mutations in NSCLC, including exon 19 and 21 mutations, and mechanisms of acquired resistance, such as T790M, and their implications for treatment selection in first-line and later lines of therapy in advanced EGFR mutation–positive NSCLC, Assess the mechanistic rationale for targeting the VEGFR and EGFR pathways through combination therapy, Cite updated evidence on validated treatment options and emerging evidence on the use of novel regimens in the management of EGFR-mutated NSCLC, including newer antiangiogenic and TKI combinations or agents, Implement evidence-based, individualized, precision treatment plans for patients with advanced EGFR-mutant NSCLC, including for those patients who acquire resistance on prior lines of treatment.

Go online to PeerView.com/MWN860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in thoracic oncology discuss the latest options for treatment of EGFR-mutated advanced NSCLC, including the rationale for and evidence supporting dual targeting of VEGF and EGFR pathways as well as the role of the first FDA approved combination of VEGF and EGFR inhibitors for newly diagnosed patients. Additionally, the experts explore the nuances and practicalities of individualized treatment selection and sequencing throughout the continuum of advanced disease to maximally extend the benefits patients with EGFR-mutated NSCLC can derive from targeted therapies. Upon completion of this activity, participants will be able to: Discuss the current understanding of the underlying biology of EGFR mutations in NSCLC, including exon 19 and 21 mutations, and mechanisms of acquired resistance, such as T790M, and their implications for treatment selection in first-line and later lines of therapy in advanced EGFR mutation–positive NSCLC, Assess the mechanistic rationale for targeting the VEGFR and EGFR pathways through combination therapy, Cite updated evidence on validated treatment options and emerging evidence on the use of novel regimens in the management of EGFR-mutated NSCLC, including newer antiangiogenic and TKI combinations or agents, Implement evidence-based, individualized, precision treatment plans for patients with advanced EGFR-mutant NSCLC, including for those patients who acquire resistance on prior lines of treatment.

Go online to PeerView.com/MWN860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. In this activity, experts in thoracic oncology discuss the latest options for treatment of EGFR-mutated advanced NSCLC, including the rationale for and evidence supporting dual targeting of VEGF and EGFR pathways as well as the role of the first FDA approved combination of VEGF and EGFR inhibitors for newly diagnosed patients. Additionally, the experts explore the nuances and practicalities of individualized treatment selection and sequencing throughout the continuum of advanced disease to maximally extend the benefits patients with EGFR-mutated NSCLC can derive from targeted therapies. Upon completion of this activity, participants will be able to: Discuss the current understanding of the underlying biology of EGFR mutations in NSCLC, including exon 19 and 21 mutations, and mechanisms of acquired resistance, such as T790M, and their implications for treatment selection in first-line and later lines of therapy in advanced EGFR mutation–positive NSCLC, Assess the mechanistic rationale for targeting the VEGFR and EGFR pathways through combination therapy, Cite updated evidence on validated treatment options and emerging evidence on the use of novel regimens in the management of EGFR-mutated NSCLC, including newer antiangiogenic and TKI combinations or agents, Implement evidence-based, individualized, precision treatment plans for patients with advanced EGFR-mutant NSCLC, including for those patients who acquire resistance on prior lines of treatment.

Featuring a discussion on recent advances in the treatment of EGFR mutation-positive non-small cell lung cancer with Dr Pasi Jänne, including the following topics: Recent advances in non-small cell lung cancer with EGFR mutation — Pasi A Jänne, MD, PhD (00:00) Case: A woman in her mid-50s with metastatic NSCLC with an EGFR exon 19 deletion who receives osimertinib (15:18) Case: A man in his mid-40s and a never smoker with metastatic NSCLC with an EGFR exon 20 insertion mutation (24:59) Case: A woman in her late 40s with Stage IV NSCLC and EGFR L858R and T790M mutations who experiences disease progression during second-line therapy with osimertinib (32:44) CME information and select publications

Striving for Consensus on the Optimal Management of Metastatic Non-Small Cell Lung Cancer — Part 2: A roundtable discussion featuring Borghaei, Brahmer, Garon and Govindan. Genomic profiling for patients with metastatic NSCLC; role of liquid biopsy (00:00) Therapeutic approach for patients with NSCLC with no targetable mutations (10:02) Case (Dr Deutsch): A woman in her late 60s with metastatic squamous cell carcinoma of the lung and a high PD-L1 tumor proportion score (TPS) of 60% initially treated with pembrolizumab monotherapy receives carboplatin/paclitaxel and maintenance pembrolizumab upon disease progression (21:32) Case (Dr Picton): A man in his mid-80s and previous smoker receives carboplatin/paclitaxel/pembrolizumab as first-line therapy for metastatic squamous cell carcinoma of the lung (27:35) Selection of second-line therapy for patients with metastatic nonsquamous NSCLC; benefits and risks with the addition of ramucirumab to docetaxel (32:17) Perspective on the use of bevacizumab or ramucirumab in combination with an immune checkpoint inhibitor and chemotherapy for metastatic NSCLC (37:03) Case (Dr Martins): A man in his early 70s and previous smoker with metastatic nonsquamous NSCLC develops diarrhea with bleeding after receiving first-line pembrolizumab (45:42) Screening and clinical care of patients with lung cancer during the COVID-19 pandemic (48:59) Case (Dr Picton): A woman in her early 50s with metastatic squamous NSCLC with a BRAF tumor mutation receives carboplatin/pemetrexed/pembrolizumab followed by maintenance pemetrexed/pembrolizumab and develops immune-related colitis (55:18) Management of metastatic NSCLC with targetable EGFR mutations (1:01:56) Case (Dr Deutsch): A woman in her late 40s and never smoker with metastatic adenocarcinoma of the lung with an EGFR tumor mutation develops a T790M mutation 2 years after treatment with erlotinib and bevacizumab on a clinical trial (1:11:18) CME information and select publications

CME credits: 0.25 Valid until: 29-04-2021 Claim your CME credit at https://reachmd.com/programs/cme/acquired-resistance-to-targeted-therapy-of-nsclc-a-global-perspective/11313/ EGFR tyrosine kinase inhibitors, or EGFR-TKIs, have resulted in dramatic improvements for patients with EGFR-mutant advanced non-small cell lung cancer. However, acquired resistance continues to limit their long-term benefit. While often due to an acquired T790M mutation, dysregulation of the MET pathway in non-small cell lung cancer is emerging as an important participant in acquired EGFR-TKI resistance. Join us as we discuss the dysregulation of the MET pathway in non-small cell lung cancer, as well as the therapeutic potential of MET pathway inhibitors.

CME credits: 0.25 Valid until: 29-04-2021 Claim your CME credit at https://reachmd.com/programs/cme/acquired-resistance-to-targeted-therapy-of-nsclc-a-global-perspective/11313/ EGFR tyrosine kinase inhibitors, or EGFR-TKIs, have resulted in dramatic improvements for patients with EGFR-mutant advanced non-small cell lung cancer. However, acquired resistance continues to limit their long-term benefit. While often due to an acquired T790M mutation, dysregulation of the MET pathway in non-small cell lung cancer is emerging as an important participant in acquired EGFR-TKI resistance. Join us as we discuss the dysregulation of the MET pathway in non-small cell lung cancer, as well as the therapeutic potential of MET pathway inhibitors.

This podcast describes the results of the BLOOM study, evaluating the efficacy of osimertinib in EGFR-mutated lung cancer with leptomeningeal disease after failure of prior EGFR TKI therapy. TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article “Osimertinib In Patients With Epidermal Growth Factor Receptor Mutation-Positive Non-Small-Cell Lung Cancer and Leptomeningeal Metastases: The BLOOM Study” by Yang et al. My name is Jürgen Wolf and I am the medical director of the Center for Integrated Oncology at the University Hospital of Cologne in Germany. I am a medical oncologist with expertise in personalized lung cancer care.   About 10% of patients with advanced EGFR-mutated lung cancer suffer from leptomeningeal disease. While this disease manifestation in non-small-cell lung cancer is generally associated with a particularly poor prognosis, with survival times of only a few months, the question arises whether treatment with specific tyrosine kinase inhibitors might enable a better disease control. Most studies evaluating the efficacy of 1st and 2nd generation EGFR-TKIs in leptomeningeal disease were retrospective and difficult to interpret, given the heterogeneity of the disease as well as of the preceding treatment procedures. Small prospective studies with patient numbers below 20 tested standard dose erlotinib or afatinib as well as high-dose pulsatile EGFR TKI treatment and reported disappointing results with survival times of around 4 months only.   The 3rd generation EGFR TKI osimertinib initially was approved for T790M positive failure of 1st and 2nd generation EGFR TKIs and is now commonly regarded as 1st line standard treatment for EGFR-mutated lung cancer based on a superior progression-free survival, overall survival and toxicity profile. In studies with primates and healthy volunteers, osimertinib has been shown to exert a higher blood-brain barrier permeability and a higher brain exposure compared with other TKIs. In the AURA clinical development program for osimertinib, 22 patients with T790M-positive relapse after EGFR TKI treatment and leptomeningeal disease were retrospectively identified, and an impressive median overall survival of 18.8 months was reported. A small prospective Japanese trial evaluated osimertinib in 13 patients with T790M-positive leptomeningeal disease which, however, could be confirmed only in 5 patients. Responses were seen in some patients, and the median progression free survival for all patients was reported with 7.2 months.   The BLOOM study part B, which is discussed in this podcast, is a multicenter phase I study evaluating osimertinib in EGFR-mutated lung cancer patients with leptomeningeal metastases and failure of previous EGFR TKI treatment. Study objectives were the assessment of clinical parameters like response, overall survival neurological status, and safety but also pharmacokinetics in blood and cerebrospinal fluid. Main inclusion criteria included confirmed diagnosis of EGFR Exon 19 deletion or L858R mutation and confirmation of leptomeningeal disease by positive cytology of cerebrospinal fluid and at least one leptomeningeal site assessable by MRI. There were two sequential cohorts, one unselected for the T790M mutation and with stable non-CNS disease at enrollment, and one for T790M positive patients without the requirement for stable non-CNS disease. Osimertinib dose was 160 mg once daily, which is twice the approved dose. Besides investigator-based response assessment, according to RECIST, leptomeningeal disease was also assessed by a neuroradiological blinded central review according to the RANO-LM working group criteria, which integrates clinical examination, cerebrospinal fluid cytology and neuraxis MRI.   41 patients from South Korea and Taiwan were included, 20 in the unselected and 21 in the T790M-positive cohort. About 70% of the patients had co-existing brain mets and about 50% prior radiotherapy. For 4 patients, no response data from the independent review were available.   The confirmed overall response rate for leptomeningeal disease was impressive at 62% as assessed by blinded independent review and nearly identical between both cohorts.  By comparison, the overall response rate was only 27% by investigator assessment, which, in turn, revealed a higher stable disease rate. Prior brain radiotherapy had no influence on efficacy. Median duration of response was comparable between blinded independent review and investigator, with 15.2 and 18.9 months, respectively. In about one third of the evaluable patients confirmed CSF clearance could be observed. PK analysis indicated that plasma concentration of osimertinib and its active metabolites reached steady state by day 15; the ratio for osimertinib exposure in cerebrospinal fluid vs. plasma was around 16%.   Surprisingly, only half of the patients had an abnormal neurological baseline assessment, most of them with mild symptoms. Symptom stabilization occurred in 54% during treatment; only 5% showed regression of neurological functions.   Overall, median progression-free survival, as assessed by the investigators, was 8.6 months and median overall survival 11 months. Progression-free survival and overall survival differed markedly between both cohorts. For instance, overall survival was 16.6 months in the unselected and 8.1 months in the selected group. Possibly, the requirement for stable non-CNS disease in the unselected group was partly responsible for the better survival outcome in this subset . However, this has to be interpreted cautiously in view of small patient numbers and large confidence intervals.   Osimertinib 160mg was well tolerated in the majority of patients with the known osimertinib side-effect profile. However, 24% of the patients suffered from adverse events grade 3 or more—possibly related to osimertinib, according to the investigators’ assessment. Dose reduction had to be performed in 12% and discontinuation of treatment in 22% of the patients due to adverse events. 17% of the patients had fatal events that did not appear to be causally related to osimertinib.   What can we learn from this study? This is the largest prospective study so far in this setting and osimertinib clearly shows clinical efficacy. The study methodology was sound, with response assessment by blinded independent review and based on RECIST criteria as well as on the RANO criteria established in particular for leptomeningeal disease. The overall response rate of leptomeningeal disease of around 60% and the duration of response of around 15 months is clinically relevant in particular, as it is correlated with improvement or at least neurological stabilization in most patients. Although the toxicity of the treatment is substantially higher than reported in osimertinib trials so far, it is manageable, and the risk/benefit ratio appears to be favorable.   What are the limitations of the study? Patient numbers are small, and the patients are heterogeneous with respect to several important factors such as pretreatment whole-brain radiotherapy, occurrence of simultaneous CNS metastases and neurological symptoms. Thus, absolute values for efficacy have to be interpreted cautiously, and comparison with already published trials remains difficult. Also, unfortunately in view of the toxicity, the question remains open whether the 160mg dose, which is not approved, is actually necessary. Finally, since osimertinib increasingly becomes the first-line treatment standard in EGFR-mutated lung cancer, the number of patients with failure of 1st- or 2nd-generation EGFR TKI treatment will decrease.   Despite these limitations, the trial provides the most convincing data so far in this special patient population and, in my opinion, defines  an important new option to consider for patients with EGFR-mutated lung cancer and leptomeningeal disease after failure of previous EGFR TKI treatment.   This concludes this JCO Podcast. Thank you for listening.

Subscribe through iTunes and Google Play.   Welcome to this ASCO in Action podcast. This is ASCO's podcast series where we explore policy and practice issues that can impact oncologists, the entire cancer care delivery team, and those individuals we care for, people with cancer. My name is Clifford Hudis, and I'm the CEO of the American Society of Clinical Oncology. I serve as the host of the ASCO in Action podcast series. And today, I am really pleased to have as my guest Dr. Richard Schilsky. He is ASCO's senior vice president. And chief medical officer, and Rich is here to talk about our new clinical cancer advances report, which was just released. In clinical cancer advances, ASCO identifies the most important clinical research advances of the past year across the full range of cancers, and from prevention to screening to treatment and survivorship. The report also announces what ASCO has identified as our advance of the year. And for the first time in this year's report, we will debut what we believe are the research priorities with greatest potential to advance progress against cancer. Rich, welcome and thank you for joining me today. Thanks, Cliff. Great to be back. now let's start with what we always do. Every year, we announced the advance of the year, the one area of clinical cancer research that has demonstrated the most significant progress in a year's time. And we've seen tremendous progress in the treatment of rare cancers, earning it the 2019 advance of the year recognition. Rich, can you talk about why this area was chosen? Why is this particular line of research so important for individuals with cancer? Well, first, let me start with a definition of what we mean by rare cancers. And generally, what we're talking about are cancers that are diagnosed with a frequency of less than six cases per 100,000 cancer diagnoses each year. Collectively, though, because there are many kinds of rare cancers, overall rare cancers comprise about 20% of all new cancer diagnoses every year. But those numbers may not even tell the full story, because as we learn more and more about the molecular subtyping of cancer, what we're learning, of course, is that there are many very, very rare mutations and fusions and other genomic alterations that occur in a very small proportion of even common cancer diagnoses. So the patient with lung cancer, who has a RET fusion that occurs in about 1% of all lung cancer cases, that begins to become a very rare subset, even though it's overall a common disease. So we're going to be dealing more and more with this general area of rare cancers. But the reason that it's so important to single this area out, of course, is because historically, we haven't been able to learn very much about these rare cancers, simply because they are rare. There aren't very many of them that occur each year. Therefore, they're difficult to study. It's difficult to complete clinical trials. It's difficult to find patient samples to be able to understand the underlying biology of these diseases. And yet, many of them are refractory to standard treatments. Many of them have a very aggressive clinical course. And for patients who are affected by one of these rare cancers, they desperately need new treatments. And this year, we're seeing, for the first time, some real progress being made in a number of these rare cancers. I'll give you some specific examples that we called out in the report. So for example, although thyroid cancer is a very common form of cancer, anaplastic thyroid cancer represents only about 2% of all thyroid cancers. And of those anaplastic thyroid cancers, about 16%-- so now we're talking 16% of 2% have a BRAF mutation. But it's clear now that treatment with BRAF directed therapy produces a very high response rate in this rare group of individuals who have BRAF mutant anaplastic thyroid cancer. Another example, take the drug we're all familiar with, trastuzumab. We know now, of course, that trastuzumab is effective not only in breast cancer, but also in gastroesophageal adenocarcinoma that's HER2 amplified. And there's emerging data that HER2 directed therapy may be active in other tumor types, where the HER2 gene is amplified. And one of those is uterine serous carcinoma. So uterine serous carcinoma is a rare subtype of endometrial cancer. And about 20% or 30% of those patients have a HER2 amplified gene driving their tumor. And trastuzumab has been shown to be an effective therapy in those patients as well. Last example I'll give you right now. A tumor that most oncologists probably will never confront in their practice, tenosynovial giant cell tumor. This is a very rare soft tissue tumor that occurs in the joints, typically of young adults, typically is refractory to all standard known cancer treatments. And yet, this year, we saw very promising results reported for a new class of anticancer drug, a CSF 1 inhibitor, called pexidartinib, that produced a 40% objective response rate in patients with these advanced tumors, compared to a placebo treated control group. So we're starting to make real progress in treating these rare cancers, particularly when we can begin to understand their underlying biology, and develop a therapy that's directed at the key drivers. It sounds to me-- I mean, in listening to that wonderful list of successes, that we've rolled up a process and an approach to drug development and science into a category that is appropriately called rare cancers. Because when you think about the way you presented it, which I think is lovely, first, rare cancers, as a group, aren't rare is what you said. Two, rare cancers cross from the rare histologies to include some of the common histologies. But the underlying theme, if I think about the way we present this, is a deeper understanding of the driver mutations, allowing us to move a little bit off of histology towards genomics to define these diseases. And that's not to say that genomics is the only way we're going to make progress. But the unifying theme in these cancers is probably that shared trait of an alteration and a driver mutation and an available drug. And that's the advance that's helping us with rare cancers. Is that a fair roll up of that? I think that is very fair. And you can think about it in terms of a common histology, like lung adenocarcinoma, having a large number of rare genomic subtypes, each of which comprises a rare cancer, if you will. Alternatively, you could think about it as in the trastuzumab example, of saying, well, if you look at the universe of HER2 driven tumors, those HER2 driven tumors comprise a whole bunch of different histologies. But they all are responsive to HER2 directed therapy. And so you know, as we understand the underlying biology of cancer much more clearly, it's moving us away from the long held view that the way you diagnose cancer is looking under the microscope. And if you see something that you see only very rarely, you say it's a rare cancer, to we're not going to interrogate the cancer if we see a rare genomic alteration that occurs infrequently in the population of cancer patients. That's what we're going to call a rare cancer. Yeah, I just say think it's almost like an introduction or a preview of an interesting future where more and more of the cancers we treat may be selected on this basis, rather than their conventional light microscopy appearance, right? To be sure. I mean, we know still that context is important. Not all of these molecular drivers behave in the same way in every tumor type. We already have examples where not all the targeted therapies work equally well against the same alteration, again, in every tumor type. But slowly, but surely, I think the science is moving us toward a day where we will be identifying cancers, primarily, if not exclusively, by their genomic profile. It may not be a single driver. It may be a signature. But that is ultimately is what we use to direct therapy. So to some degree, this is a fulfillment of a multi-year view that we've had about where to invest in cancer research, and the fruits, I think, are obvious. But this wasn't the only advance that we reported on last year. It's the one we named as the advance of the year. But what were some of the other advances that we called out for recognition? So as in the last several years, where we named some aspect of immunotherapy as the advance of the year, this year we continue to see progress in immunotherapy of cancer, particularly with extending the range of indications for many of the immune checkpoint inhibitor drugs, as well as new indications for CAR T cell therapies. So that continues to be a rapidly emerging area where there's a lot of progress continuing to be made. We continue to make progress how with the introduction of second and third generation targeted therapies. We've come to understand, of course, that many targeted therapies although they work well for a period of time, cancers ultimately develop resistance, patients need additional treatment options after the first line of targeted therapy. And of course, the science has responded by giving us the insight as to the mechanisms of resistance, which has led to the development of second and third generation inhibitors that can effectively overcome the treatment resistance. We're seeing this particularly in lung cancer, particularly with drugs recently introduced like osimertinib, which is effective against the T790M mutation, the common resistance mutation in EGFR mutated non small cell lung cancer. And interestingly, some of these drugs are also now showing much greater effectiveness in treating or even preventing the onset of brain metastases in lung cancers that commonly spread to the brain. So this has opened up actually a whole new area of research on effectively treating and preventing brain metastases in those tumor types, where there's a high propensity for such metastases to occur. The last thing I'll mention as another area of continuing progress is the continuing development of new biomarker strategies to help us refine the way in which we select patients to receive treatment. And certainly, this last year, the big news were the results of the so-called TLRX trial in breast cancer, a test, a gene expression profiling test, that clearly indicates that there is a substantial proportion of women with hormone receptor positive early stage breast cancer who can safely forego treatment with adjuvant chemotherapy with no detrimental effect. And this type of test I think is now going to really move us even further down the road of precision medicine, because it's allowing us to identify those patients who are most likely to benefit from adjuvant chemotherapy. They should get treated, and they will certainly benefit. But it also is allowing us to identify those patients for whom adjuvant chemotherapy is unnecessary, and who can be spared both the physical toxicity and the financial toxicity of adjuvant treatment. The more of those tests that we can develop, going forward, the better we'll be able to refine prognosis, the better we'll be able to apply adjuvant therapy in the future. I think one of the subtleties here is this highlights something we almost touched on before, which is precision medicine doesn't have to be only about gene rearrangements. There are multiple paths towards some degree of precision in treatment selection for individual patients. And this is, I think, a good example of that. It also is a good example of the fact that precision medicine is not actually just about treatment selection. It's about risk assessment, risk stratification, assessment of prognosis, identifying early recurrence, as well as directing patients to the right therapy at the right time, based on the biological characteristics of their cancer. So one of the things that we've done this year, and it's a first for us, is to announce a set of research priorities. These represent areas that our leading volunteers and others have identified as needing urgent attention. They are areas where the progress is promising, but not fulfilled completely. Can you talk a little bit about the motivation for creating this kind of a research agenda, as well as a criteria for actually selecting the specific research priorities? So obviously, you know, our field is advancing very rapidly. But there are still very many unmet medical needs. There are many clinical conundrums that oncologists face every day in practice. And we felt that given all the potential directions that research could take, ASCO is in a strong position to be able to at least begin to describe those areas, where we thought the potential benefits in patient care would be greatest, and could be realized soonest. ASCO, because we are the physicians who treat patients with cancer, we have a pretty good sense as to what the unmet medical needs of our patients are, what the lack of evidence is that our doctors struggle with every day in making clinical decisions with patients, where the field needs to continue to grow and to develop new information, to help fill those evidence gaps. So we felt that we could take a stab at setting a research agenda, and putting out there where we thought the unmet needs, where we thought the opportunities were ripe for investment in research, and trying to articulate how, if we were successful in fulfilling those research needs and priorities, the field would ultimately be transformed. So that's what we've done with the nine research priorities that we are offering this year. So the nine priorities that's important for readers in a moment, if they go look at this or pick up our publication to recognize, they're not rank ordered. They just happen to be nine. Maybe next year, there'll be fewer or more. And the second thing is in no particular order, as I understand it, we've divided them into a couple or maybe three big buckets. One is essentially the issue of who really benefits from IO, the advance that you already talked about, as a multi-year call out from us. The second is really a little bit about health care disparities and precision medicine all rolled up in the concept of special populations. And related to that is access to research itself. And then the third is something which we always worry about, but have, I think struggled with as a field for decades, and that is reducing cancer risk, along with screening, which is surprisingly still controversial in many settings. We'll talk a little bit more about some of the specifics, but I would just remind everybody listening that you can find a list of these nine research priorities if you go to our website asco.org/cca. So Rich, as you think about the nine areas that are rolled up in those three broad areas, can you talk a little bit about how specific research would potentially transform patient care? And you've set a relatively short timeline for results in introducing this. And what kind of resources might these projects need? If you take the first area, for example, of essentially getting the right treatment to the right patient at the right time, you know, we've touched on some of these themes already. Look at the results so far with immune therapy for cancer. It's remarkable that a significant, although still small fraction of patients across multiple tumor types, who receive an immune checkpoint inhibitor, will have prolonged disease control, 20% or so of patients apparently surviving, without disease progression, or even disease free for many, many years in melanoma and diseases that previously were death sentences for patients. The question is why is it only 20%, and who are they? Because these drugs are toxic. They're expensive. And what we'd like to be able to understand is, what are the characteristics of the tumor or of the host or of the treatment that makes the treatment so effective in a proportion of patients, so that we can then learn how to increase its effectiveness in those groups of individuals, where it has so far been less effective. The same is true, as we touched on a moment ago, regarding adjuvant post-operative therapy. If you think about solid tumors, broadly speaking, roughly 50% of patients with a newly diagnosed solid tumor are cured by surgery alone. They don't need and can't benefit from adjuvant therapy. Of the remaining group, who are at higher risk of recurrence. Many of them will not benefit from whatever adjuvant therapy they might receive. So what we observe in most clinical trials of adjuvant therapies are relatively small absolute improvements in say disease free and overall survival for the entire population of patients treated. But of course, what that likely represents is a substantial benefit for a small proportion of that population. So what we are suggesting in this research priority is additional research, similar to what we saw presented this year with the TAILORx study, that allows us to understand the biology, the biomarkers, the testing that can be done to identify the patients most likely in need of and those who will most likely benefit from adjuvant therapy. And then the third area within this general theme goes back to immunotherapy and the enormous promise of CAR T cells, which so far, has been realized almost exclusively in patients with hematological malignancies. So that's wonderful. And we want to extend that benefit as far as it will go. But the question is, can those treatments be effective in solid tumors, which generally have a much more complex biology than many human hematological malignancies, and how do we develop CAR T cell therapies that can be effective in the solid tumor setting, that can be delivered to a solid tumor patient population, and ideally, and this may still be a bit of a pipe dream, can we develop CAR T cell therapies then that can be developed and administered off the shelf, so that they don't have to be custom made for each individual patient, which drives up the complexity and the cost of treatment. So those are the key elements of this initial theme. And in a similar way, we would have similar, or we would have short term plans for the other areas that we haven't gone into detail here. And again, I would remind listeners that they can go through our whole list of ideas in terms of areas of focus at asco.org/cca. Right? Absolutely. And when they do that, what they'll find are that we are calling for increased research in precision medicine and pediatric cancer. We're calling for increased research that's necessary to optimize the care of older adults with cancer. We're calling for research on how to ensure more equitable access to cancer clinical trials, so that all patients can benefit from those studies, and we can make progress more quickly. And then finally, of course, we're very interested in learning more about how to reduce the long term consequences of cancer treatment. The pediatric oncologists have actually been quite successful at this, because first of all, they've been very successful at curing children. And now, they've been able to show that they can begin to pull back on certain components of therapy in a very thoughtful and well studied way, so as to not diminish the chance of cure, but to diminish the risk of long term side effects of treatment. We, of course, want to have more research done, addressing the challenge of obesity in this country and its link to cancer risk, cancer progression, and cancer treatment, and then finally, to identify strategies to better understand the biology of so-called pre-malignant lesions, so that we can understand which pre-malignant cancers are the ones that are destined, in fact, to become invasive cancer. That latter touches on a theme we could talk about another day which is the building, the emerging drive to rename some of those cancers, as something less than cancer, because of their lack of at least acute life threatening potential, right? We could talk about that another day, and we should. Yes. So one of the things that I think is always important to point out is we can do all of this work, but of course, we are part of society, and we're dependent upon various sources of funding and other resources in terms of public policy. We are dependent on government ultimately for support, as well as private support. And I think this clinical cancer advances report highlights that there are policies that would help us improve and accelerate clinical cancer research. Some of them are obvious. We talk about them in other podcasts, increasing access to clinical trials, covering the routine quest of care for trial participants, and indeed, increasing overall federal funding, not in an unpredictable way, but in a steady way, that allows us to make multi-year plans across our community. Given all of that, what steps do you think ASCO members, specifically, could take to support us? And I would take it a step further. What should they be telling their representatives in Congress in terms of these policies? What should they be telling them in terms of supporting these critical areas of cancer research and how can they make an impact? It's clear that essentially all progress that we make in developing new treatments for cancer ultimately gets linked back to federally funded support for basic science research. All of the insights that we've developed in terms of what causes cancer, how it progresses, which are the high risk populations, so much of that information comes from data sets and other basic laboratory studies, funded by the NIH or the National Cancer Institute. Of course, the NCI has in place a robust national clinical trials network publicly funded that supports clinical trials that would never be done by a commercial sponsor. In fact, three of the rare cancer studies that I mentioned earlier during this podcast were done with support from federal funding. Those studies, because they are rare cancer, small populations are not studying tumors that represent a large market for a new pharmaceutical product. They're not going to be done by a commercial sponsor. We need federal support. And we need our members to point out these kinds of examples when they go to talk to their representatives in Congress. And I would urge our members to not only go to talk to your representative, but to bring a patient with you. The patient tells a story far better than we can. And having the patient at your side and having the patient tell their own story about how they benefited from federally funded research is very powerful. In order to reach your member of Congress, ASCO's trying to make that as easy as possible, and you can do that by going to ASCO's Act network at asco.org/actnetwork. That's great. I mean, we've covered a lot of exciting progress, I think, this year. And readers who take the time can dive far more deeply into this discussion with our publication. But what would you say is the main takeaway, the thematic takeaway that you hope people will get from this year's clinical cancer advances report? To me, I think what we continue to see this year, and we have seen in recent years is that the more deeply we understand cancer biology, the more that will quickly lead us to new therapeutic approaches that will be far more effective, and hopefully, less toxic, and maybe most importantly, more enduring than the common therapies that we've had available to us in the past. Our field is clearly moving to a day when immunotherapy will be central to cancer care, when every patient will have their cancer genotype well understood, and where therapy decisions will be informed by that deeper understanding of each patient's biology. So you almost did this, but I'm going to push you a little more. In the same way that we're now calling for what should be done next in terms of research, if you could actually look into the future, what areas of progress against cancer would you expect or maybe hope to see, just 12 months from now, when we do this report again? I hope that one of the things we'll see is rapid progress in developing, not necessarily novel biomarkers as unique tests, but novel biomarkers signatures. I think it's becoming increasingly clear that in order to select patients optimally to receive immunotherapy, and even to select patients to receive certain precision medicines, that a single biomarker is not necessarily the optimal selection strategy. For immunotherapy, we may need to see a signature that represents some characteristics of the tumor, some characteristics of the patient, maybe even some characteristics of that patient's microbiome in order to figure out who is most likely to be susceptible to which immunotherapy approach, and the same is going to be true, I think, for even the now common precision medicine approaches with small molecules. We're trying to understand how molecular pathways and networks work inside the cell can suggest to us not which single targeted therapy to use, but which combination of targeted therapies to use for each individual person. This kind of work is on the horizon. It's complicated, involves lots of complex algorithms. But my hope is that this will move us to a future where we can take the results of a test on a patient's tumor and integrate information of various sorts and come out with a more precise estimate of what's likely to be the best treatment for that person. And you think that we could see some of those results even as soon as just 12 months from now, or is this a longer term hope? I think we will begin to see some of these types of approaches appearing at an ASCO meeting in 2020. Well, that's really exciting. I think it's really both uplifting, and I think challenging to hear where we are, because of course, as is always true in science, every answer begets many more questions. And in our world, every bit of progress identifies new challenges. And I think that's what's summed up in a lot of what's in this report now, right? Absolutely. But you know, I think for the first time, you know, ASCO is trying to articulate where we see the greatest opportunity. And we hope to be able to do this each year in the coming years. As you said earlier, it may not always be nine research priorities. Some of that might even be repeated year to year, because we won't solve every one of these in a year from now. But we will modify these. We will improve upon them, and they will change as the science advances, as the questions evolve, and as the opportunities continue to develop. Well, rich I want to thank you for joining me today for this ASCO in Action podcast. I'll remind everybody, we have a mission at ASCO to conquer cancer through research, education, and promotion of the highest quality cancer care. And this clinical cancer advances report really does help us meet that mission, by increasing awareness of the progress we're making, but also, as you point out, identifying the critical importance of the entire community's engagement in research and high quality care. That is pointing out just how important all that is in terms of delivering on the promise of all of our progress. I encourage listeners, again, to read the full report by visiting asco.org/cca. And until next time, I thank everyone for listening to this ASCO in Action podcast.

出品：中国科普博览 SELF格致论道讲坛导语：我们平时身体出小毛病，吃的是经过证实有效的“仿制药”，但事实上还有好多未满足的临床需求，像是癌症患者，因为没有得到有效的治疗而丧生。所以这势必需要研究、开发“创新药”来解决医学治疗的困境，在SELF论坛上，让中科院药物研究所的沈竞康带我们看看未来的创新药可以做到什么？---嘉宾介绍---沈竞康中科院上海药物研究所研究员 以下内容为沈竞康演讲实录：各位朋友下午好，首先请允许我问你们一个问题，至今为止，在你的一生中，从来没有吃过药、从来没有接触过药的有没有？请举手。一个都没有，那么我们的缘分就有了，我们从药作为缘分来共同讲解今天的故事。白求恩同志是加拿大共产党员，不远万里来到中国，帮助中国人民的抗日战争。大家很熟悉这个故事，但是，大家知道他最后讲了一句什么话？他最后讲的一句话是“我不能亲眼看到新中国成立了，但是我相信新中国是一定会成功的。”为什么？原因是他在当时治疗伤员的时候，没带手套把手指割破了，如果今天没戴手套，在外科手术室里边是违规的。但是，在那个特殊年代割破了手指，接下来还有一系列的病员等着治疗，这些伤员又都有感染，其中还有一个链球菌的感染。接下来这一系列的感染造成白求恩医生感染，得了败血症，最后生命垂危离开了我们，所以有了这么一个故事。如果说在当时有足够的青霉素，白求恩就能够看到新中国的成立。这是我想讲的第一段。我们在很多的电视连续剧或者故事中，看到过去有很多的地下党、地下交通站，地下交通站干什么？三件事情，第一个送人，把我们的抗日青年、地下人员送到解放军区；第二个送武器，武器问题还不大，我们可以从敌人手里夺；第三件事情要运送我们的药物。在农村缺医少药的年代，我们因为没有药会碰到很多的问题，我自己手上至今还有这个伤疤，也是和白求恩当初得的同样的病，败血症，就是一个小小的感染，整个右手臂里边，全部变成化脓。我比白求恩幸运，我能够回到上海，那个年代在上海的话还能够得到治疗。那么我们看前十几年，2003年SARS爆发的时候，这种大规模的、传染性的疾病，带来多大的困难、带来多大的恐慌，所以药物对于我们来说，是维护我们的健康、维护我们的民生、维护国家的安全、维护社会稳定不可或缺的一样非常重要的物资。说了这么多药物，药物有多少种？我现在简单地说，药物只有两类：一类是仿制药，一类是创新药。何为仿制药？就是这个药已经存在，不管它在哪里销售、在哪里上市、在哪里使用，但是它已经存在。这样的药在它的专利到期以后，合法把它制造出来，然后通过药品监管部门批准，把它推向市场、推向临床给病人使用，这样的药就是仿制药。那另一类药呢？是和仿制药不同的，就是说这个药从来不存在，我把它创造出来提供临床使用，推向市场。这一类药和前面的仿制药在功能上有什么根本的区别呢？仿制药是已经经过证实的、非常有效的一种药物，可以治疗疾病，所以我们用这样的药非常的放心，也非常的价廉物美，可以满足今天的临床需求。但是今天的临床需求都满足了吗？当每一个病人到了医院的时候，都想得到最好的治疗，每一个人都想长生不老、都想起死回生，但是事实是严峻的、是不可能的。为什么？其中有一条，我觉得是我们的责任，因为我们没有给医生提供足够的武器，医生没有武器让他怎么上战场？让他怎么把病治好？那么解决这样的问题就是我们现在不断要追求的──去研究创新的药物，去解决临床还没有满足的需求。我们来看看在全球这些年新兴的市场──中国排在新兴市场的第一位──我们在整个药物的产值和需求上面有大量的上升，我们大概占了全球的30%左右，但是我们不要忘记发达国家占了60%以上。在我们的30%中间，仿制药物占了大概65%；而发达国家在70%左右的医疗市场上面，仿制药占了18%。这是两个完全不同的数字。美国现在仿制药也在不断的增加，他们这些年由于品牌药的专利到期，所以原来一些品牌药现在变成了仿制药，这些仿制药能够解决临床今天的问题，所以被继续的使用。而且美国大家也知道，不管是民主党还是共和党，始终都存在一个非常严峻的问题，就是它要解决健康的问题，因此经济承受着巨大的压力，所以要降低它的医疗的成本。美国现在仿制药占处方量的88%，创新药即品牌药还在专利保护期的只有12%，但是从价值来讲，六百五十亿美元的是仿制药，那是占处方量的88%；而3110亿美元的，是用于12%的处方量份额的。那么从这里，我们就看到了一个问题：就是创新药和仿制药有着不同的作用，创新药和仿制药有着不同的价值。那么你们又要问我问题了：我们为什么现在还要研究创新药呢？你刚才不是说白求恩当时如果有青霉素的话，他就能够看到新中国成立了吗？其实问题是在不断的变化，当青霉素很好的抗击那些病菌的时候，病菌在不断的变化，所以现在耐药的抗生细菌又产生了，我们就需要有新的抗耐药的抗生素去解决问题。那么我下面再举一个例子，大家比较熟悉的肿瘤，也是大家现在最恐慌的一件事情。当肿瘤发生的时候，过去用什么药？我们大量的用化疗、放疗、手术，手术继续需要使用化疗，化疗药也继续在使用。现在没有完全改变，但是那个时候的化疗带来一个什么问题？因为化疗是杀死那些长得特别快的细胞，肿瘤是我们的身上长得特别快的细胞，当到了我这个年龄的时候，不可能每年再长一寸，然后长到像姚明一样高。为什么？因为大部分的细胞不是快速分裂繁殖了，而肿瘤是快速生长的细胞，我们抓住了这个特点，在当时的科学的基础上的认识，就是消灭掉快速生长的细胞，来消灭肿瘤。但是我们不要忘记在我们的身上，除了肿瘤细胞之外，还有很多正常的细胞：比如说我们的血液系统、免疫系统、粘膜系统，都是快速生长的一些细胞，在杀死肿瘤的时候，这些细胞也受到了伤害。所以我们会看到在肿瘤化疗的时候，我们白血球下降，免疫力下降。而这样的疾病正是需要我们有更强的免疫力去进行自动防卫的时候，这样的损伤是对肿瘤的治疗不利。 所以在这样的研究基础上，不断的生命科学的发展、基础医学研究的发展给我们带来了启示，在这里边有一些和肿瘤非常密切相关的因素，这些我们叫它通路、机理。这些机理上面有一些物质，这些物质和肿瘤的增殖密切相关，在正常的细胞中间非常少或者不存在，如果我们把这样的路给它堵住了，那么它就不能走歪门邪道只能改邪归正，这样的治疗是否能带来更大的好处？在上个世纪的最后几年，上市了几个药物：格列卫、易瑞沙、赫赛汀。赫赛汀是一个抗体，前两个都是小分子药物。易瑞沙是它的商品名，吉非替尼是它的通用名，如果你是仿制这个药物，那你就仿制的不是易瑞沙，仿制的是吉非替尼。这类的药物上市给我们带来了什么机会？它所作用的是表皮生长因子受体，如果把这条通路给它堵住，一部分肿瘤不能够生长。美国2003年这个药批准上市，但批准上市以后，在美国卖得不好、效果不怎么样。深入研究发现：在亚洲不吸烟的女性中，有相当一部分的病人是EGFR──也就是表皮生长因子受体发生了突变，这一部分突变的病人，当她使用易瑞沙、使用吉非替尼的时候，它就变得特别有效。当然这是一个进步，进步以后还有新的挑战，新的挑战是──当这样的病人用了它两年以后或者用了一年半以后，相当一部分的人发生了其中一条道路的耐药──这个受体又发生了突变，就是EGFR又发生了突变。它的突变的50%以上的病人，是在T790M的位置上面发生了突变。这样突变以后的话，原来有效的药变成没有效，所以新的药物研究又要开始。那么前些年阿斯利康一个新的药物又上市了，叫奥希替尼，奥希替尼上市以后，对T790突变的这一部分病人变得有效，所以我们和肿瘤的斗争看来还是永远没有揭晓。今天已经讲创新药物这么有用，创新药物给我们带来这么大的变化、有这么大的价值，那接下去大家会又要问问题了──创新药物怎么来啊？怎么做啊？大家有很多的耳闻。那我想这里，我只能简单说一说，最早的是“神农遍尝百草”。神农尝百草就是以人去试药的毒性，最后得到了一些我们现在在用的中药。当然这些中药在现代的研究过程中，又在不断的发展，随着时代的进步，用人去尝的代价太大了。所以我们用动物去做研究，动物造成疾病的模型，以动物去试这个药的安全性，然后把这个药最后用到人身上去，这样的话减少伤害。所以我们在这里我们要向为人类健康做出了贡献的动物致敬，因为它们为我们做出了大量的贡献。随着分子生物学、细胞生物学的研究，再进一步的发展，就后来就发现了这些都是有很深入的机理的，光是用动物研究还不够，那么再深一步是什么？要用分子水平、细胞水平。在分子水平上，我们能够清掉一条通路，就按照这条通路里边的蛋白，药物怎么样起作用，然后我们再过渡到动物的进一步的验证，然后又通过人来确证。把一个确证了安全有效的药物再推向市场，让广大的病人来受益。这个就是药物研究从古代到现代发展的变化。现在我们已经不断地讲：作用到和疾病相关的一个通路上面的一个分子，这个分子是什么？这个分子就是我们今天说的靶标，也是我们在药物研究中间说的这个靶标，这个靶标可以是一个生命体内的一个大分子，也可以是致病源的一个大分子。所以我又想简单化地把我们的疾病分成两类，一类是内源性的；一类是外源性的。就造成疾病的因素，一类是外源的──刚才说白求恩是碰到了外源性的疾病，因为他是细菌对他的感染；而肿瘤是一个内源性的疾病，是内部的肌体发生了变化而产生。那么这两种疾病都有一些分子，这些分子和疾病相关，药物和它作用了以后，能够产生效应的，我们就称为靶标。这些靶标，我想用这张图来讲会非常生动，这张图中间的──别把它看成是一个平面的、是一张纸──这个靶心是一个电子的靶心，当击中靶心的时候，冰嘣！结果是什么？当冰嘣的时候，首先亮光闪起，每个人的眼睛开始注视这个，然后声音响起，整个环境中间都产生了一个效应──这个效应如果发生在身体体内，如果这个靶标是对着药物作用、和疾病相连的话，那么这样的效应就可以达到药物的治疗的效果。这个飞镖就是药物分子。那么我们怎么样去寻找它呢？寻找的过程，前半段是刚才邓博士说到的，我们生命科学的一些基础研究，这些基础的研究从DNA开始到RNA等等，是生命科学的一个前期的研究──发现靶标。我们真正的药物研究是和前面密切相关的，但是我今天要说的药物研究是从“靶标初步确认、一个潜在的靶标已经存在”开始，最后走到一个药物上市的过程。这样一个药物发现过程，我们首先是要让飞镖飞上去，这个飞镖不是一个，是一百万个、两百万个。最后打中的，我们再往后研究。所以这时候产生新药的第一步，在我们这个俗语中间叫“先导化合物”。这样的先导化合物它还不是药，它还没有很好的、能够成为药的特性，所以我们还要进行改造，改造完了以后，我们首先要在动物上面证明它的疗效、证明它的安全性，然后我们在临床上面一期一期的、按部就班的、循序渐进的来证明它的有效性和安全性，最后通过监管部门的批准来上市，所以这样一个过程就是我们药物研发的过程。我想大家可能已经听到过很多像是“10000个化合物出1个药”这种说法，10000个化合物出什么？就是从我们先导化合物的发现开始，可能总结下来统计意义是10000，不是每个药都是这样，但是统计意义是这样，然后在先导化合物的优化的时候，它就变成了200多个到500个，然后上了临床是5个到10个，最后上市的药是1个──这就是10000个到1个的故事。那么时间大家也都听了──十年到十五年的时间，前半段的大家看到了是三年到六年，后半段六年到七年，最后还有审批的半年到两年的时间，所以总的时间就是十年到十五年。我现在再举一个例子，刚才已经说到了EGFR的抑制剂，吉非替尼用了以后，一年半到两年这些很有效的这些病人又产生了耐药：其中一个是突变；另外一条路是旁路启动──原来不活跃的、不起主导作用的，因为主路被堵了，所以辅路开始拥挤。这个过程也是EGFR被药物使用以后，造成了耐药的一条途径。这部分的途径也就是干细胞生长因子受体被激活，而且是过度的表达，这部分的表达，用原来的药变得没有效。这是我们工作的一个例子，我们也是从大量的化合物中间首先发现了最小的一个分子，这个分子活性是不太强，然后我们用结构生物学、计算机辅助设计、化学合成，最后经生物活性的再测试，测试了以后把它活性提高了一千倍。提高了一千倍以后，它对着这个靶效果挺好，但是没有冰嘣的声音，打上去“懵”的一下。那么这个过程是什么？因为它的效应没有产生，所以这时候只能说还不是真正的先导化合物，在先导化合物和候选化合物之间。然后我们进一步的活性优化以后，得到了活性真正提高、在细胞上面有作用的。再进一步的在动物体内进行研究，在一系列的功能验证了确实是这么一种机理，把它临床前的工作全部做完，这个药才能够进入临床实验。进入临床实验有四个非常重要的要素：第一个“申办者”，如果我做研究，我申办；如果是一个企业做研究，他申办者要做这个研究；第二个是“有接受这个实验的志愿者”，在一期临床的话，除了肿瘤，都是正常人，然后肿瘤是病人，其他的二级、三级、四级，是病人来进行。其中还有“医学研究者”，这是由临床研究的。另外一个非常重要的部分是“伦理委员会”,要控制所有的实验在伦理上是不是合适的。这样的话，我们在一期的实验中，从小剂量到大剂量，从单次给药到多次给药，最后来证实了这个潜在的药物的耐受性和初步的安全性。然后第二期临床开始了，这一次伦理委员会要重新来批准，然后受试者重新的来自愿，然后填写知情通知书以后，精心的来参加到这样的研究中间来，然后这一期主要是来证明——你原来在动物上的有效性，是否在人身上也有同样的有效性？那么再进一步做完了以后，还要扩大临床、扩大人群，延长时间，来获得有效性、安全性的进一步的数据。还要观察，因为往往病人他不是只吃这种药，他除了这个病还可能有其他的病，那么和其他的药物在联用的时候，会有什么问题？这些问题都搞清楚了，充分的把所有应该解答的问题都解答完了，然后向监管部门提出申请，来批准成为一个药物，这样就是一个药物的全过程。这样一个全过程我们为什么失败这么多？因为在临床一期的时候，成功率——统计前十年的结果——全世界成功的只有百分之六十几；而我们通过二期临床的成功率是百分之三十几，加在一起的话，大概20%左右。这个20%在三期临床的时候，还要淘汰掉40%左右，那么剩下了大概还有10%左右。最后要申请上市的时候，还得要考虑它的风险和得到的利益——从现有的药物和新的药物之间，它得到了什么新的利益——以及对整个社会各方面的影响。所以最后上市的成功率——就是说我们临床的成功率不到10%。我们虽然大量研究的是肿瘤的药物，但肿瘤的药物至今为止也是成功率最低的——只有百分之五点几。那么临床失败的主要的原因来源于什么？是来源于“有效性是否真正证实了比现有的治疗手段更好？”、“安全性是否能够保障我们的病人在治疗的过程得到安全的有利因素？”那么，我想我们的有效性和安全性是从开始发现的时候一直走到最后。那么我在这里想举一个例子，讲一个丙肝。丙肝过去好像不太重视，我们只重视乙肝，但是丙肝其实在全世界是一个比较大的问题——有1亿多病人——中国占了3000病人，这些病人中间有相当一部分发生肝硬化，还有一部分发生肝硬化的代谢失常，这部分病人要比肝硬化带来对生命的危害更大。还有一部分是造成了肝细胞的肝癌，肝细胞肝癌平均第一年发现以后，他的死亡的可能性就有33%，那么这样一种严重的后果必须从源头上面开始治疗：丙肝有6种基因型，有50多种亚型，是一个非常复杂的疾病。在我们现在的药物发现之前，我们已经发现了这些靶点的研究，开始做这些药的时候，在2013年之前所有的这些药物都需要和干扰素合用，最好的是干扰素和利巴韦林的合用，要治疗48周到72周，有效率只有40%~70%，而且副作用很大。所以在这样的基础上，2013年12月批准了一个药叫索氟布韦，它是12周的治疗，虽然每片药要卖一千块美元一片，但是它12周的病毒学的应答率是90%，所以说这一部分病人在不用干扰素的情况下，能够得到的有效的治疗是非常大，所以它上市第一年就创造了年销售额100亿美元的一个奇迹。但是前面说的六种基因亚型中有两种基因型的病人治疗不好，是这个90%以外的部分，所以在下一个年度又有“哈维尼”，它就是把索氟布韦和另外一个药又做成了一个复方，这个复方在治疗了八周以后，它的有效率提高到94%，而且基因亚型的病人开始扩展。但是还是有一个问题，因为有一部分人即使在得到了初步的治疗以后，还是会有病毒继续感染，所以在这样的基础上又进行进一步的研究：在2016年的时候，“伊柯鲁沙”上市了，这样一个复方使得六种基因型的病人在12周的治疗以后，都能够得到清除，然后得到了有效治疗。它和我们现在的乙肝有一个很大不同，这个药的发现整体上可能我们就可以消灭未来的丙型病毒性肝炎，所以这是在治疗上面非常重要。从有效性上面来讲，是一个非常好的故事。那么从安全性来讲，也是一个非常重要的事情：临床前——在进入接触到人之前——我们再也不能以人来试毒、以人来试药了，所以就是从分子水平到动物水平不断的来进行研究，我们从小动物到大动物、从单次给药到多次给药，甚至是六个月到九个月连续的给药，在动物上面要看到它是安全的，我们也要明白我们加高剂量可能会发生毒性。这没关系，我们治疗剂量还是在安全范围内，但是在加高剂量发生毒性的时候，它毒性主要出现在什么地方？它的毒性靶器官是什么？它的机理是什么？这样的毒性是不是可逆的？如果是可逆的是我们是可以挽救的，这样的话我们在病人治疗的时候、在临床前的试用过程中间，我们是有手段的；不然我们这个化合物只能停止在这个阶段，它永远只是一个化合物，它不可能成为药物。那么我想告诉大家，即使一个药物上市以后，它还是有这样问题，所以我们也在不同程度的、不断的提高监管的水平和监管的质量。这是一个故事，1957年在德国发明了一种药叫反应停，反应停这个药在中国也曾经使用过，大家比较熟悉。大家想一想，当妇女妊娠的时候，妊娠反应恶心呕吐，把胆汁都吐出来的那种，不但是病人的痛苦，病人的家属在边上也受不了。这个时候如果有一个非常好的药，吃了以后让她能够顺顺利利的度过10月怀胎、产下来她的小baby，这是多么高兴。所以在当时这个药是孕妇的理想选择，多少病人感激涕零、多少家庭感恩戴德。但是事情很快的就发生了变化，三年以后就来状告这个公司了，说因为我产下的小baby缺胳膊少腿——我们叫海豹肢畸胎——这样一些畸胎的产生，在整个世界上当时就产生了1.2万人，所以这个药马上停下来了。而美国有过非常偶然的一个机会，有一个刚刚进入美国食品药品监督管理局工作不久的一位医生，叫凯尔西，她反复看了这个资料以后，认为提供的安全性资料不够充分，所以她迟迟拒绝在美国把反应停上市，也因为这样美国没有发现大规模的海豹肢畸形的儿童，只有个别的人直接从欧洲买了药，自己带回来到美国服用，这部分的病人中间产生了少数的海豹足的畸胎。所以这里也告诉我们一个非常重要的事情，我们千万千万别到国外去随便把一个药买回来，我们的药品是有专门的监管的。在中国监管部门监管的这个药物是安全的、有效的，如果有问题你是可以去追溯的。所以凡是没有得到它所管辖部门的药品监管部门批准的药物，都是伪药和假药，这是一个不能够否认的事实。也因为这样，凯尔西医生在1962年的时候得到了美国总统奖。当时美国总统肯尼迪启动了哈瑞森修正案。这个修正案就是在一个药品上市之前，必须要充分的披露药品的安全性、有效性，还必须在上市以后不断的让大家知道这个药品。但是在中国，我觉得我们每一位今天在这里听的人都有一个责任，当你使用一种药——如果这种药，在过去的说明书上面没有写清楚它有这样的副作用，而你身上发生了这样的副作用，你要报告。因为我们有一个不良反应的专门的报告制度，通过这样的报告制度，才能够不仅在一个药物上市之前经过严格的控制，药物在上市以后，我们还能够继续的跟踪，不让一个能够危害健康的药物继续的在市场上存在，然后让我们的健康得到更好的保障。最后我想用丙型肝炎的药物的发明人，也是药物化学家索非亚博士——索非亚博士去年得到了美国的拉斯克奖，得到拉斯克奖以后，中国的药明康德采访他，采访了他以后，他最后有了这么一段话：如果我们都有一点在大量的失败以后的、小小的幸运，我们能够对人类的健康、对人类的治疗带来福音，那这就是我们最大的安慰，我想也就是我们最大的能够奉献给今天所有在座的各位！谢谢！“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。

出品：中国科普博览 SELF格致论道讲坛导语：我们平时身体出小毛病，吃的是经过证实有效的“仿制药”，但事实上还有好多未满足的临床需求，像是癌症患者，因为没有得到有效的治疗而丧生。所以这势必需要研究、开发“创新药”来解决医学治疗的困境，在SELF论坛上，让中科院药物研究所的沈竞康带我们看看未来的创新药可以做到什么？---嘉宾介绍---沈竞康中科院上海药物研究所研究员 以下内容为沈竞康演讲实录：各位朋友下午好，首先请允许我问你们一个问题，至今为止，在你的一生中，从来没有吃过药、从来没有接触过药的有没有？请举手。一个都没有，那么我们的缘分就有了，我们从药作为缘分来共同讲解今天的故事。白求恩同志是加拿大共产党员，不远万里来到中国，帮助中国人民的抗日战争。大家很熟悉这个故事，但是，大家知道他最后讲了一句什么话？他最后讲的一句话是“我不能亲眼看到新中国成立了，但是我相信新中国是一定会成功的。”为什么？原因是他在当时治疗伤员的时候，没带手套把手指割破了，如果今天没戴手套，在外科手术室里边是违规的。但是，在那个特殊年代割破了手指，接下来还有一系列的病员等着治疗，这些伤员又都有感染，其中还有一个链球菌的感染。接下来这一系列的感染造成白求恩医生感染，得了败血症，最后生命垂危离开了我们，所以有了这么一个故事。如果说在当时有足够的青霉素，白求恩就能够看到新中国的成立。这是我想讲的第一段。我们在很多的电视连续剧或者故事中，看到过去有很多的地下党、地下交通站，地下交通站干什么？三件事情，第一个送人，把我们的抗日青年、地下人员送到解放军区；第二个送武器，武器问题还不大，我们可以从敌人手里夺；第三件事情要运送我们的药物。在农村缺医少药的年代，我们因为没有药会碰到很多的问题，我自己手上至今还有这个伤疤，也是和白求恩当初得的同样的病，败血症，就是一个小小的感染，整个右手臂里边，全部变成化脓。我比白求恩幸运，我能够回到上海，那个年代在上海的话还能够得到治疗。那么我们看前十几年，2003年SARS爆发的时候，这种大规模的、传染性的疾病，带来多大的困难、带来多大的恐慌，所以药物对于我们来说，是维护我们的健康、维护我们的民生、维护国家的安全、维护社会稳定不可或缺的一样非常重要的物资。说了这么多药物，药物有多少种？我现在简单地说，药物只有两类：一类是仿制药，一类是创新药。何为仿制药？就是这个药已经存在，不管它在哪里销售、在哪里上市、在哪里使用，但是它已经存在。这样的药在它的专利到期以后，合法把它制造出来，然后通过药品监管部门批准，把它推向市场、推向临床给病人使用，这样的药就是仿制药。那另一类药呢？是和仿制药不同的，就是说这个药从来不存在，我把它创造出来提供临床使用，推向市场。这一类药和前面的仿制药在功能上有什么根本的区别呢？仿制药是已经经过证实的、非常有效的一种药物，可以治疗疾病，所以我们用这样的药非常的放心，也非常的价廉物美，可以满足今天的临床需求。但是今天的临床需求都满足了吗？当每一个病人到了医院的时候，都想得到最好的治疗，每一个人都想长生不老、都想起死回生，但是事实是严峻的、是不可能的。为什么？其中有一条，我觉得是我们的责任，因为我们没有给医生提供足够的武器，医生没有武器让他怎么上战场？让他怎么把病治好？那么解决这样的问题就是我们现在不断要追求的──去研究创新的药物，去解决临床还没有满足的需求。我们来看看在全球这些年新兴的市场──中国排在新兴市场的第一位──我们在整个药物的产值和需求上面有大量的上升，我们大概占了全球的30%左右，但是我们不要忘记发达国家占了60%以上。在我们的30%中间，仿制药物占了大概65%；而发达国家在70%左右的医疗市场上面，仿制药占了18%。这是两个完全不同的数字。美国现在仿制药也在不断的增加，他们这些年由于品牌药的专利到期，所以原来一些品牌药现在变成了仿制药，这些仿制药能够解决临床今天的问题，所以被继续的使用。而且美国大家也知道，不管是民主党还是共和党，始终都存在一个非常严峻的问题，就是它要解决健康的问题，因此经济承受着巨大的压力，所以要降低它的医疗的成本。美国现在仿制药占处方量的88%，创新药即品牌药还在专利保护期的只有12%，但是从价值来讲，六百五十亿美元的是仿制药，那是占处方量的88%；而3110亿美元的，是用于12%的处方量份额的。那么从这里，我们就看到了一个问题：就是创新药和仿制药有着不同的作用，创新药和仿制药有着不同的价值。那么你们又要问我问题了：我们为什么现在还要研究创新药呢？你刚才不是说白求恩当时如果有青霉素的话，他就能够看到新中国成立了吗？其实问题是在不断的变化，当青霉素很好的抗击那些病菌的时候，病菌在不断的变化，所以现在耐药的抗生细菌又产生了，我们就需要有新的抗耐药的抗生素去解决问题。那么我下面再举一个例子，大家比较熟悉的肿瘤，也是大家现在最恐慌的一件事情。当肿瘤发生的时候，过去用什么药？我们大量的用化疗、放疗、手术，手术继续需要使用化疗，化疗药也继续在使用。现在没有完全改变，但是那个时候的化疗带来一个什么问题？因为化疗是杀死那些长得特别快的细胞，肿瘤是我们的身上长得特别快的细胞，当到了我这个年龄的时候，不可能每年再长一寸，然后长到像姚明一样高。为什么？因为大部分的细胞不是快速分裂繁殖了，而肿瘤是快速生长的细胞，我们抓住了这个特点，在当时的科学的基础上的认识，就是消灭掉快速生长的细胞，来消灭肿瘤。但是我们不要忘记在我们的身上，除了肿瘤细胞之外，还有很多正常的细胞：比如说我们的血液系统、免疫系统、粘膜系统，都是快速生长的一些细胞，在杀死肿瘤的时候，这些细胞也受到了伤害。所以我们会看到在肿瘤化疗的时候，我们白血球下降，免疫力下降。而这样的疾病正是需要我们有更强的免疫力去进行自动防卫的时候，这样的损伤是对肿瘤的治疗不利。 所以在这样的研究基础上，不断的生命科学的发展、基础医学研究的发展给我们带来了启示，在这里边有一些和肿瘤非常密切相关的因素，这些我们叫它通路、机理。这些机理上面有一些物质，这些物质和肿瘤的增殖密切相关，在正常的细胞中间非常少或者不存在，如果我们把这样的路给它堵住了，那么它就不能走歪门邪道只能改邪归正，这样的治疗是否能带来更大的好处？在上个世纪的最后几年，上市了几个药物：格列卫、易瑞沙、赫赛汀。赫赛汀是一个抗体，前两个都是小分子药物。易瑞沙是它的商品名，吉非替尼是它的通用名，如果你是仿制这个药物，那你就仿制的不是易瑞沙，仿制的是吉非替尼。这类的药物上市给我们带来了什么机会？它所作用的是表皮生长因子受体，如果把这条通路给它堵住，一部分肿瘤不能够生长。美国2003年这个药批准上市，但批准上市以后，在美国卖得不好、效果不怎么样。深入研究发现：在亚洲不吸烟的女性中，有相当一部分的病人是EGFR──也就是表皮生长因子受体发生了突变，这一部分突变的病人，当她使用易瑞沙、使用吉非替尼的时候，它就变得特别有效。当然这是一个进步，进步以后还有新的挑战，新的挑战是──当这样的病人用了它两年以后或者用了一年半以后，相当一部分的人发生了其中一条道路的耐药──这个受体又发生了突变，就是EGFR又发生了突变。它的突变的50%以上的病人，是在T790M的位置上面发生了突变。这样突变以后的话，原来有效的药变成没有效，所以新的药物研究又要开始。那么前些年阿斯利康一个新的药物又上市了，叫奥希替尼，奥希替尼上市以后，对T790突变的这一部分病人变得有效，所以我们和肿瘤的斗争看来还是永远没有揭晓。今天已经讲创新药物这么有用，创新药物给我们带来这么大的变化、有这么大的价值，那接下去大家会又要问问题了──创新药物怎么来啊？怎么做啊？大家有很多的耳闻。那我想这里，我只能简单说一说，最早的是“神农遍尝百草”。神农尝百草就是以人去试药的毒性，最后得到了一些我们现在在用的中药。当然这些中药在现代的研究过程中，又在不断的发展，随着时代的进步，用人去尝的代价太大了。所以我们用动物去做研究，动物造成疾病的模型，以动物去试这个药的安全性，然后把这个药最后用到人身上去，这样的话减少伤害。所以我们在这里我们要向为人类健康做出了贡献的动物致敬，因为它们为我们做出了大量的贡献。随着分子生物学、细胞生物学的研究，再进一步的发展，就后来就发现了这些都是有很深入的机理的，光是用动物研究还不够，那么再深一步是什么？要用分子水平、细胞水平。在分子水平上，我们能够清掉一条通路，就按照这条通路里边的蛋白，药物怎么样起作用，然后我们再过渡到动物的进一步的验证，然后又通过人来确证。把一个确证了安全有效的药物再推向市场，让广大的病人来受益。这个就是药物研究从古代到现代发展的变化。现在我们已经不断地讲：作用到和疾病相关的一个通路上面的一个分子，这个分子是什么？这个分子就是我们今天说的靶标，也是我们在药物研究中间说的这个靶标，这个靶标可以是一个生命体内的一个大分子，也可以是致病源的一个大分子。所以我又想简单化地把我们的疾病分成两类，一类是内源性的；一类是外源性的。就造成疾病的因素，一类是外源的──刚才说白求恩是碰到了外源性的疾病，因为他是细菌对他的感染；而肿瘤是一个内源性的疾病，是内部的肌体发生了变化而产生。那么这两种疾病都有一些分子，这些分子和疾病相关，药物和它作用了以后，能够产生效应的，我们就称为靶标。这些靶标，我想用这张图来讲会非常生动，这张图中间的──别把它看成是一个平面的、是一张纸──这个靶心是一个电子的靶心，当击中靶心的时候，冰嘣！结果是什么？当冰嘣的时候，首先亮光闪起，每个人的眼睛开始注视这个，然后声音响起，整个环境中间都产生了一个效应──这个效应如果发生在身体体内，如果这个靶标是对着药物作用、和疾病相连的话，那么这样的效应就可以达到药物的治疗的效果。这个飞镖就是药物分子。那么我们怎么样去寻找它呢？寻找的过程，前半段是刚才邓博士说到的，我们生命科学的一些基础研究，这些基础的研究从DNA开始到RNA等等，是生命科学的一个前期的研究──发现靶标。我们真正的药物研究是和前面密切相关的，但是我今天要说的药物研究是从“靶标初步确认、一个潜在的靶标已经存在”开始，最后走到一个药物上市的过程。这样一个药物发现过程，我们首先是要让飞镖飞上去，这个飞镖不是一个，是一百万个、两百万个。最后打中的，我们再往后研究。所以这时候产生新药的第一步，在我们这个俗语中间叫“先导化合物”。这样的先导化合物它还不是药，它还没有很好的、能够成为药的特性，所以我们还要进行改造，改造完了以后，我们首先要在动物上面证明它的疗效、证明它的安全性，然后我们在临床上面一期一期的、按部就班的、循序渐进的来证明它的有效性和安全性，最后通过监管部门的批准来上市，所以这样一个过程就是我们药物研发的过程。我想大家可能已经听到过很多像是“10000个化合物出1个药”这种说法，10000个化合物出什么？就是从我们先导化合物的发现开始，可能总结下来统计意义是10000，不是每个药都是这样，但是统计意义是这样，然后在先导化合物的优化的时候，它就变成了200多个到500个，然后上了临床是5个到10个，最后上市的药是1个──这就是10000个到1个的故事。那么时间大家也都听了──十年到十五年的时间，前半段的大家看到了是三年到六年，后半段六年到七年，最后还有审批的半年到两年的时间，所以总的时间就是十年到十五年。我现在再举一个例子，刚才已经说到了EGFR的抑制剂，吉非替尼用了以后，一年半到两年这些很有效的这些病人又产生了耐药：其中一个是突变；另外一条路是旁路启动──原来不活跃的、不起主导作用的，因为主路被堵了，所以辅路开始拥挤。这个过程也是EGFR被药物使用以后，造成了耐药的一条途径。这部分的途径也就是干细胞生长因子受体被激活，而且是过度的表达，这部分的表达，用原来的药变得没有效。这是我们工作的一个例子，我们也是从大量的化合物中间首先发现了最小的一个分子，这个分子活性是不太强，然后我们用结构生物学、计算机辅助设计、化学合成，最后经生物活性的再测试，测试了以后把它活性提高了一千倍。提高了一千倍以后，它对着这个靶效果挺好，但是没有冰嘣的声音，打上去“懵”的一下。那么这个过程是什么？因为它的效应没有产生，所以这时候只能说还不是真正的先导化合物，在先导化合物和候选化合物之间。然后我们进一步的活性优化以后，得到了活性真正提高、在细胞上面有作用的。再进一步的在动物体内进行研究，在一系列的功能验证了确实是这么一种机理，把它临床前的工作全部做完，这个药才能够进入临床实验。进入临床实验有四个非常重要的要素：第一个“申办者”，如果我做研究，我申办；如果是一个企业做研究，他申办者要做这个研究；第二个是“有接受这个实验的志愿者”，在一期临床的话，除了肿瘤，都是正常人，然后肿瘤是病人，其他的二级、三级、四级，是病人来进行。其中还有“医学研究者”，这是由临床研究的。另外一个非常重要的部分是“伦理委员会”,要控制所有的实验在伦理上是不是合适的。这样的话，我们在一期的实验中，从小剂量到大剂量，从单次给药到多次给药，最后来证实了这个潜在的药物的耐受性和初步的安全性。然后第二期临床开始了，这一次伦理委员会要重新来批准，然后受试者重新的来自愿，然后填写知情通知书以后，精心的来参加到这样的研究中间来，然后这一期主要是来证明——你原来在动物上的有效性，是否在人身上也有同样的有效性？那么再进一步做完了以后，还要扩大临床、扩大人群，延长时间，来获得有效性、安全性的进一步的数据。还要观察，因为往往病人他不是只吃这种药，他除了这个病还可能有其他的病，那么和其他的药物在联用的时候，会有什么问题？这些问题都搞清楚了，充分的把所有应该解答的问题都解答完了，然后向监管部门提出申请，来批准成为一个药物，这样就是一个药物的全过程。这样一个全过程我们为什么失败这么多？因为在临床一期的时候，成功率——统计前十年的结果——全世界成功的只有百分之六十几；而我们通过二期临床的成功率是百分之三十几，加在一起的话，大概20%左右。这个20%在三期临床的时候，还要淘汰掉40%左右，那么剩下了大概还有10%左右。最后要申请上市的时候，还得要考虑它的风险和得到的利益——从现有的药物和新的药物之间，它得到了什么新的利益——以及对整个社会各方面的影响。所以最后上市的成功率——就是说我们临床的成功率不到10%。我们虽然大量研究的是肿瘤的药物，但肿瘤的药物至今为止也是成功率最低的——只有百分之五点几。那么临床失败的主要的原因来源于什么？是来源于“有效性是否真正证实了比现有的治疗手段更好？”、“安全性是否能够保障我们的病人在治疗的过程得到安全的有利因素？”那么，我想我们的有效性和安全性是从开始发现的时候一直走到最后。那么我在这里想举一个例子，讲一个丙肝。丙肝过去好像不太重视，我们只重视乙肝，但是丙肝其实在全世界是一个比较大的问题——有1亿多病人——中国占了3000病人，这些病人中间有相当一部分发生肝硬化，还有一部分发生肝硬化的代谢失常，这部分病人要比肝硬化带来对生命的危害更大。还有一部分是造成了肝细胞的肝癌，肝细胞肝癌平均第一年发现以后，他的死亡的可能性就有33%，那么这样一种严重的后果必须从源头上面开始治疗：丙肝有6种基因型，有50多种亚型，是一个非常复杂的疾病。在我们现在的药物发现之前，我们已经发现了这些靶点的研究，开始做这些药的时候，在2013年之前所有的这些药物都需要和干扰素合用，最好的是干扰素和利巴韦林的合用，要治疗48周到72周，有效率只有40%~70%，而且副作用很大。所以在这样的基础上，2013年12月批准了一个药叫索氟布韦，它是12周的治疗，虽然每片药要卖一千块美元一片，但是它12周的病毒学的应答率是90%，所以说这一部分病人在不用干扰素的情况下，能够得到的有效的治疗是非常大，所以它上市第一年就创造了年销售额100亿美元的一个奇迹。但是前面说的六种基因亚型中有两种基因型的病人治疗不好，是这个90%以外的部分，所以在下一个年度又有“哈维尼”，它就是把索氟布韦和另外一个药又做成了一个复方，这个复方在治疗了八周以后，它的有效率提高到94%，而且基因亚型的病人开始扩展。但是还是有一个问题，因为有一部分人即使在得到了初步的治疗以后，还是会有病毒继续感染，所以在这样的基础上又进行进一步的研究：在2016年的时候，“伊柯鲁沙”上市了，这样一个复方使得六种基因型的病人在12周的治疗以后，都能够得到清除，然后得到了有效治疗。它和我们现在的乙肝有一个很大不同，这个药的发现整体上可能我们就可以消灭未来的丙型病毒性肝炎，所以这是在治疗上面非常重要。从有效性上面来讲，是一个非常好的故事。那么从安全性来讲，也是一个非常重要的事情：临床前——在进入接触到人之前——我们再也不能以人来试毒、以人来试药了，所以就是从分子水平到动物水平不断的来进行研究，我们从小动物到大动物、从单次给药到多次给药，甚至是六个月到九个月连续的给药，在动物上面要看到它是安全的，我们也要明白我们加高剂量可能会发生毒性。这没关系，我们治疗剂量还是在安全范围内，但是在加高剂量发生毒性的时候，它毒性主要出现在什么地方？它的毒性靶器官是什么？它的机理是什么？这样的毒性是不是可逆的？如果是可逆的是我们是可以挽救的，这样的话我们在病人治疗的时候、在临床前的试用过程中间，我们是有手段的；不然我们这个化合物只能停止在这个阶段，它永远只是一个化合物，它不可能成为药物。那么我想告诉大家，即使一个药物上市以后，它还是有这样问题，所以我们也在不同程度的、不断的提高监管的水平和监管的质量。这是一个故事，1957年在德国发明了一种药叫反应停，反应停这个药在中国也曾经使用过，大家比较熟悉。大家想一想，当妇女妊娠的时候，妊娠反应恶心呕吐，把胆汁都吐出来的那种，不但是病人的痛苦，病人的家属在边上也受不了。这个时候如果有一个非常好的药，吃了以后让她能够顺顺利利的度过10月怀胎、产下来她的小baby，这是多么高兴。所以在当时这个药是孕妇的理想选择，多少病人感激涕零、多少家庭感恩戴德。但是事情很快的就发生了变化，三年以后就来状告这个公司了，说因为我产下的小baby缺胳膊少腿——我们叫海豹肢畸胎——这样一些畸胎的产生，在整个世界上当时就产生了1.2万人，所以这个药马上停下来了。而美国有过非常偶然的一个机会，有一个刚刚进入美国食品药品监督管理局工作不久的一位医生，叫凯尔西，她反复看了这个资料以后，认为提供的安全性资料不够充分，所以她迟迟拒绝在美国把反应停上市，也因为这样美国没有发现大规模的海豹肢畸形的儿童，只有个别的人直接从欧洲买了药，自己带回来到美国服用，这部分的病人中间产生了少数的海豹足的畸胎。所以这里也告诉我们一个非常重要的事情，我们千万千万别到国外去随便把一个药买回来，我们的药品是有专门的监管的。在中国监管部门监管的这个药物是安全的、有效的，如果有问题你是可以去追溯的。所以凡是没有得到它所管辖部门的药品监管部门批准的药物，都是伪药和假药，这是一个不能够否认的事实。也因为这样，凯尔西医生在1962年的时候得到了美国总统奖。当时美国总统肯尼迪启动了哈瑞森修正案。这个修正案就是在一个药品上市之前，必须要充分的披露药品的安全性、有效性，还必须在上市以后不断的让大家知道这个药品。但是在中国，我觉得我们每一位今天在这里听的人都有一个责任，当你使用一种药——如果这种药，在过去的说明书上面没有写清楚它有这样的副作用，而你身上发生了这样的副作用，你要报告。因为我们有一个不良反应的专门的报告制度，通过这样的报告制度，才能够不仅在一个药物上市之前经过严格的控制，药物在上市以后，我们还能够继续的跟踪，不让一个能够危害健康的药物继续的在市场上存在，然后让我们的健康得到更好的保障。最后我想用丙型肝炎的药物的发明人，也是药物化学家索非亚博士——索非亚博士去年得到了美国的拉斯克奖，得到拉斯克奖以后，中国的药明康德采访他，采访了他以后，他最后有了这么一段话：如果我们都有一点在大量的失败以后的、小小的幸运，我们能够对人类的健康、对人类的治疗带来福音，那这就是我们最大的安慰，我想也就是我们最大的能够奉献给今天所有在座的各位！谢谢！“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。

The highlights are presented by Rolf A. Stahel, Universitätsspital Zürich, Onkologie, Zürich, Switzerland (rolf.stahel@usz.ch). A critical review of the highlights of the European Lung Cancer Conference (ELCC) 2016, held in April 2016 in Geneva, is presented in this podcast. Considering the most interesting and practice-changing trials reported at the meeting, the key trial on the use of osimertinib in patients with non-small cell lung cancer (NSCLC) with EGFR harbouring the T790M mutation who had progressed on first line tyrosine-kinase inhibitors (TKIs) was highlighted. The meeting also featured interesting studies on testing for the T790M mutation and highlighted the potential of liquid biopsies. Two areas of potentially valuable biomarker development were stressed: biomarkers in oncogenic-driven NSCLC, and, more controversially, immunotherapy-related biomarkers. New treatment strategies were highlighted by the presentation of the Heine H. Hansen Award to Professor Suresh Senan (Amsterdam) whose work on stereotactic radiotherapy of lung cancer has led to significant changes in practice. Further, immunotherapy of lung cancer, through the use of immune-checkpoint inhibitors is already in clinical practice, and the results of ongoing trials considering whether immunotherapy can replace chemotherapy in these settings are now eagerly waited. The podcast is conducted by Anna Berghoff, Medical University of Vienna Vienna, Austria.

Dr. Jack West, Swedish Cancer Institute, reviews trial evidence for the efficacy of rociletinib and osimertinib for EGFR acquired resistance not driven by a T790M mutation.

Dr. Jack West, Swedish Cancer Institute, reviews trial evidence for the efficacy of rociletinib and osimertinib for EGFR acquired resistance not driven by a T790M mutation.

Dr. Jack West, Swedish Cancer Institute, reviews trial evidence for the efficacy of rociletinib and osimertinib for EGFR acquired resistance not driven by a T790M mutation.

Dr. Jared Weiss, UNC Lineberger Comprehensive Cancer Center, describes the types of situations in which local therapy is appropriate for treating limited acquired resistance.

Dr. Jared Weiss, UNC Lineberger Comprehensive Cancer Center, discusses the genetic risk (or lack thereof) for lung cancer.

Dr. Jared Weiss, UNC Lineberger Comprehensive Cancer Center, discusses the genetic risk (or lack thereof) for lung cancer.

Dr. Jared Weiss, UNC Lineberger Comprehensive Cancer Center, describes the types of situations in which local therapy is appropriate for treating limited acquired resistance.

Dr. Jared Weiss, UNC Lineberger Comprehensive Cancer Center, describes the types of situations in which local therapy is appropriate for treating limited acquired resistance.

Dr. Jared Weiss, UNC Lineberger Comprehensive Cancer Center, discusses the genetic risk (or lack thereof) for lung cancer.

Dr. Nathan Pennell, Cleveland Clinic, discusses the concept of acquired resistance and new agents designed to address it, including Rociletinib and Merelitinib.

Dr. Nathan Pennell, Cleveland Clinic, discusses the concept of acquired resistance and new agents designed to address it, including Rociletinib and Merelitinib.

Dr. Nathan Pennell, Cleveland Clinic, discusses the concept of acquired resistance and new agents designed to address it, including Rociletinib and Merelitinib.

Drs. Jack West and Greg Riely field questions about which treatments should EGFR lung cancer patients consider when their cancers progress.

Drs. Jack West and Greg Riely field questions about which treatments should EGFR lung cancer patients consider when their cancers progress.

Drs. Jack West and Greg Riely field questions about which treatments should EGFR lung cancer patients consider when their cancers progress.

Dr. Jack West suggests that progression in T790M-negative EGFR lung cancer patients may not require a change in therapy. In this video he details what should go into the decision to modify treatment for those patients.

Dr. Jack West suggests that progression in T790M-negative EGFR lung cancer patients may not require a change in therapy. In this video he details what should go into the decision to modify treatment for those patients.

Dr. Jack West suggests that progression in T790M-negative EGFR lung cancer patients may not require a change in therapy. In this video he details what should go into the decision to modify treatment for those patients.

There are sub-types within the sub-type of EGFR mutation positive lung cancer. In this presentation, Dr. Jack West discuss the different activating mutations within EGFR positive tumors and how they impact treatment.

There are sub-types within the sub-type of EGFR mutation positive lung cancer. In this presentation, Dr. Jack West discuss the different activating mutations within EGFR positive tumors and how they impact treatment.

There are sub-types within the sub-type of EGFR mutation positive lung cancer. In this presentation, Dr. Jack West discuss the different activating mutations within EGFR positive tumors and how they impact treatment.