Podcasts about fgfr1

JCO PO author Dr. Jun Gong shares insights into his JCO PO articles, “Phase II Study of Erdafitinib in Patients with Tumors with FGFR Amplifications: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Sub-protocol K1" and “Phase II Study of Erdafitinib in Patients with Tumors with FGFR Mutations or Fusions: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Sub-protocol K2”. Host Dr. Rafeh Naqash and Dr. Gong discuss the limited activity of FGFR inhibition in solid tumors with FGFR amplifications and mutations or fusions in this NCI-MATCH phase II trial. TRANSCRIPT  Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations of clinically relevant and highly significant JCO PO articles. I'm your host, Dr. Rafeh Naqash, Social Media Editor for JCO Precision Oncology and Assistant Professor at the Stevenson Cancer Center at the University of Oklahoma.  Today, we are excited to be joined by Dr. Jun Gong, Associate Professor in the Division of Medical Oncology at Cedars-Sinai Medical Center and lead author of the JCO Precision Oncology article entitled "Phase II Study of Erdafitinib in Patients with Tumors Harboring FGFR Amplifications: Results from the NCI-MATCH ECOG-ACRIN Trial EAY131 Subprotocol K1" and "Phase II Study of Erdafitinib in Patients with Tumors with FGFR Mutations or Fusions: Results from the NCI-MATCH ECOG-ACRIN Trial EAY131 Subprotocol K2."   Our guest's disclosures will be linked in the transcript.   Dr. Gong, welcome to our podcast and thank you for joining us.  Dr. Jun Gong: Thank you, Dr. Naqash and JCO Precision Oncology for having me. Dr. Rafeh Naqash: We are excited to be discussing some interesting aspects that you have led and published on from the NCI-MATCH trial. We were trying to understand from a background perspective, since this master protocol has been going on for quite some time, could you give us a little bit of background for the sake of our listeners on what the NCI-MATCH is and what were the specific objectives for these two subprotocols?  Dr. Jun Gong: Yes, of course, Dr. Naqash. So, as you may all know, the importance of targeted therapies in the current era of precision oncology. And on that backdrop, the NCI-MATCH was a national multicenter study designed essentially to look for signals of efficacy across various solid tumor and hematologic malignancy types, with a focus on specific mutations. The master protocol is unique in that there are several arms to the trial, each targeting a specific potential targetable alteration using available agents in cancer today. Dr. Rafeh Naqash: Excellent. Thank you for that background. I know this master protocol has been going on for quite some time with different subprotocols. I believe some of them are immunotherapy-based. Also, you've led two important subprotocols, which are the FGFR amplification and the FGFR mutation or fusion. There are some differences, from what I gather, in responses for the fusions versus the amplifications or mutations versus the amplifications. Could you first delve into the first paper of the fusions, and describe what were the tumor types? As you mentioned in the paper, some tumors were excluded. What was the reason for the exclusion of some of those tumor types? Why did you want to study the fusions and mutations versus the amplifications separately? What was the background for that? Could you highlight some of those points for us? Dr. Jun Gong: Firstly, as a kind of a more background, FGFR has been a recognizable target for a couple of tumor types. And if you look at the broad landscape of FGFR alterations, they occur in about 5%-10% of cancers, with the majority being FGFR amplifications actually, and mutations and rearrangements following second and third respectively in most commonly identified alterations. With that being said, FGFR mutations and rearrangements have already been established in a couple of tumor types. Actually, the first FDA approval for an oral FGFR inhibitor was erdafitinib, which was the agent used in both of these back-to-back trials. However, erdafitinib was first approved in urothelial carcinoma, and since then, there has been an explosion in oral FGFR inhibitors targeting fusions and mutations in other cancer types, such as cholangiocarcinoma.   More recently, there was even an FDA approval in a myeloid malignancy as well. So, we used erdafitinib, being that it was the first FDA-approved, orally available agent to target this alteration. We conducted the two back-to-back studies in recognition that although rearrangements and mutations have already been established in certain tumor types, we were more interested in looking at the more common FGFR alteration, that being amplifications. However, the efficacy in that was a little unknown, and so these two separate subprotocols were developed: K2, which was to look at FGFR mutations and fusions in tumor types, excluding urothelial carcinoma, to look if there was a signal of efficacy beyond currently FDA-approved indications, and amplification as a separate cohort. Dr. Rafeh Naqash: That's a very good explanation of why you concentrated on the tumor types in these protocols.  Now, going back to subprotocol K1, could you tell us what were some of the tumor types that you did include, and what was the sample size, and what was the hypothesis for the sample size as a meaningful level of activity that you wanted to see and would have potentially led to a bigger, broader trial? Dr. Jun Gong: So, subprotocol K1 was the arm investigating erdafitinib in those with FGFR amplifications, and these were predefined on the NCI-MATCH protocol, looking at FGFR 1, 2, 3, and 4 amplifications essentially. These were allowed to have local testing through a local CLIA-certified assay, but then they needed to be confirmed on a central assay, which is the NCI-MATCH Oncomine assay. These statistics are uniform for the NCI-MATCH trials, and the goal was at least 31 patients, with the hypothesis that if the response rate was 16% or more, this was considered a signal of activity. However, there was an additional protocol specific requirement in that if the sample size was fewer than 31 patients, then the primary efficacy population would be assessed against a null hypothesis overall response rate of 5%. Meaning that if there were less than 31 subjects, an overall response rate of greater than 5% would be defined as positive. Again, the NCI-MATCH was uniform. Secondary objectives included progression-free survival, overall survival, and safety and toxicity. With that being said, K1 originally began accrual. The NCI-MATCH actually launched in 2015, but in the subprotocol K1, 35 patients were initially enrolled in the study. If you go down the eligibility criteria, however, a lot of these patients dropped out due to a lack of central tumor confirmation and various reasons. Ultimately, 18 patients were included in the pre-specified primary efficacy cohort. Dr. Rafeh Naqash: Thank you. I did see for subprotocol K1, you mostly had stable disease in a couple of patients, no responses, and I think one individual with breast cancer had a prolonged stable disease.   Now, from an FGFR amplification standpoint, did you or were you able to correlate - again, this is not objective responses, it's not a partial response or a complete response - was there any correlation from the level of amplification to the duration of stable disease?  Dr. Jun Gong: That's actually the core of our discussion about why K1, despite a variety basket of solid tumor types, somewhere, preclinical data had suggested FGFR amplifications could be targeted, that K1 was ultimately a negative trial with a 0% response rate. We dive in that although we included as an eligibility criteria a copy number variation of seven as the threshold for amplification, we realized that if you look at some of the literature out there, that even in the FGFR 1 and 2 amplification cohorts, where these are the more common cohorts of amplified tumor types that have been targeted, you really needed a high level of amplification, more than 99% of tumor cells being amplified in the previous studies, to actually generate a response.  The thought was that we assumed that FGFR amplification would lead to protein expression and dependence on FGFR signaling, providing sensitivity to FGFR inhibition. However, we realized that there is a certain degree where a high level of amplification needs to happen, and it may not be for all FGFR amplifications. We looked into the literature that FGFR 1 and 2 were the more commonly studied FGFR amplifications. FGFR 1, if you actually look at the amplicon structure, it tends to amplify a lot of other genes because it's such a huge amplicon structure. But FGFR 2 is shorter and centered on just FGFR 2 with a few other genes co-amplified. So, actually in the literature, they've already been seeing that maybe FGFR 2 amplification tumors are more readily targetable based on the robustness of evidence, rather than FGFR 1. But across all of these, the higher the level of amplification, seems the more targetable. Dr. Rafeh Naqash: Those are interesting discussions around protein expression on the tumor that could imply therapeutic vulnerability. So I've always thought about it, whether trials like NCI-MATCH trials or ASCO TAPUR, for example, would be perhaps more informative if, on a secondary analysis standpoint, proteomics is something that could be done on the tumor tissue, because similar to NCI-MATCH, ASCO TAPUR has other sub protocols where some of these mutations or amplifications don't necessarily result in antitumor responses. But I think from a biology standpoint, as you mentioned, a certain amplification might correspond to RNA expression and that might correspond to protein expression, which is downstream. So looking at that would be something interesting. Have you planned for something like that on these tumor specimens? If you have biobanked any of those specimens. Dr. Jun Gong: I think that's a great future direction. And I know you, Dr. Naqash, being involved in so many cooperative trials, I think it is possible, but it really depends on good trial planning from the onset. When designing such massive trials like this, I think the more important thing is if your trials are negative, but they are informative for the field to go back and have these postdoc available biobanks that you said. And I think having it integrated firstly, is way more efficient than to have kind of an amendment kind of going through halfway or when the trial is started. That could be a little bit more logistically difficult.  Dr. Rafeh Naqash: I completely agree. And you mentioned corporate groups, I think we've been discussing, and I'm pretty sure you have also, there's a lot to be learned from clinical trials that are negative. We often, in the academic or non-academic setting, end up not publishing some of those negative results, pharma or corporate group based studies. And I think the resources, the specimens, and the negative results could correlate to some other novel findings if some of those exploratory analyses are done in the appropriate manner.   Now, going to the drug itself or the erdafitinib here, it's a pan-FGFR inhibitor. Is that something that you think is a limitation in the drug development space? I do early phase trials, and I'm pretty sure you do a lot of these basket early phase trials. Is that something that you feel is a limitation when you have a drug that targets different mutations or different protein changes of the same gene or different amplifications? Could that be a reason why something like this doesn't necessarily work because it doesn't have as much specificity against the isoform as one might need to inhibit the downstream kinase activation?  Dr. Jun Gong: That is also a great point. The NCI-MATCH sub protocol K1 and K2 used erdafitinib, which was the first FDA-approved FGFR inhibitor. But as many of the listeners and yourself may know, there have been newer iterations in next-generation development of the FGFR inhibitors. And it's very fascinating, the tyrosine kinase inhibitors, with each iteration, you seem to have a little more potency and the ability to bypass some of the resistance mutations, almost paralleling the lung cancer space, where we kind of follow that, and they've been kind of the pioneers in that space. And to your point, yes, we consider– the NCI-MATCH was developed nearly a decade ago, and the available agents at that time, would it have changed the findings if we used a kind of a newer generation or more potent FGFR inhibitor? It's possible, I think, especially in the K1 cohort with the amplifications. We even suggested in the discussion of the paper future directions, is that one way to kind of bypass the amplification issue is to use more potent and specific FGFR inhibitors. And so I think it's very possible that you highlight this point.  Dr. Rafeh Naqash: And for the sake of our listeners, Jun, especially trainees, could you highlight what are currently some of the FDA-approved FGFR inhibitors, and what tumor types are they currently approved in?  Dr. Jun Gong: The first one, as we have hinted, was in treatment of refractory, essentially urothelial carcinoma with FGFR mutations and rearrangements, mainly 2 and 3. And this is where oral erdafitinib was approved. And it's interesting, I kind of teach my fellows and our health staff that erdafitinib is interesting in that its FDA label insert requires a starting dose of about 8 milligrams daily, and it's a 28-day cycle. But during the first 14 days, we're really looking at the serum phosphate levels. If they are within a certain level, if they are within 5.5 to 7, for example, you continue the current dose. But if they are less than 5.5, the FDA label actually mandates that you increase it to 9 milligrams oral daily, continuously. This is biologically logical to me. FGFR is located to the renal tubules, and so this is a major phosphate kind of metabolism pathway here. And so you're using that as a surrogate, essentially, if the right dosing is achieved. And so that's unique.  And then the subsequent kind of FGFR inhibitors that came about, you had a couple in cholangiocarcinoma, where, unlike urothelial carcinoma, where it's about 30% of the time, you'll find the FGFR alterations of target. It's about half of that 15% in cholangiocarcinoma, and it's mainly intrahepatic cholangiocarcinoma in that sense. And here you have pemigatinib, which is one of the FGFR inhibitors approved for cholangiocarcinoma. And then you also had infragatinib, which is approved. But however, infigratinib eventually had their FDA label culled. It was withdrawn by the company, I think it was in 2022. And then more recently, you had even a more potent FGFR inhibitor in cholangio approved and futibatinib. It's interesting that with these more later generations of FGFR inhibitors, they do show a correlation with phosphate levels, but they don't have that specific kind of dosing early on in the first cycle, like erdafitinib. And so it's interesting to see that with the later generations, you're seeing more potency as well. Dr. Rafeh Naqash: Thank you for that overview, which I'm sure most of the trainees appreciate since this is an up and coming field in the space of precision medicine, especially FGFR. From a side-effect profile standpoint, you mentioned phosphate issues. Do you think that is a drug class effect here, or is that an FGFR receptor subtype effect, depending on which FGFR receptor, 1 or 2 or 3, that is being targeted?  Dr. Jun Gong: I do think this is a class effect that you'll see across a lot of the trials where phosphorus elevations or decreases are going to be probably your most common treatment-related adverse event. And I actually emphasize this is probably one of the most trickier side effects of this class, where we're almost having to have to monitor the phosphorus levels pretty routinely, pretty closely. And you also have other class effects on the nails. There's some rare retinal ocular toxicities that's unique to the FGFR class as well. And so it's a very exciting class of compounds, but it does require some close monitoring of some unique class effects as you've hinted. Dr. Rafeh Naqash: Based on the results from your K1 sub protocol, are FGFR inhibitors still the approach within, let's say, within cholangio or urothelial with FGFR amplifications? Is that still something that has been established and seen from a clinical response standpoint? Dr. Jun Gong: The FDA approvals are really for mutations and fusions. So this K1 sub protocol, essentially, I think provides one answer that we've been all wondering about for the longest time, “Hey, could amplifications be targeted as well?” Unfortunately, we didn't include urothelial carcinomas in this study because of the FDA approval. But from a kind of a basket solid tumor perspective, I think this really dampens the enthusiasm. As of right now, it really is fusions and mutations that are targetable. Amplifications need further investigation before becoming established in solid tumors. Dr. Rafeh Naqash: Going to the discussion with the second K2 protocol, which is mutations and fusions, can you highlight again which tumor types there where you saw some clinical outcomes that you saw and any unique insights on certain mutations or protein changes that were a little more relevant than some others?  Dr. Jun Gong: Sure. So this is the parallel study to K1, in that now we are looking at fusions and mutations of FGFR1, 2, 3, and 4. And essentially, we, again, excluded those with urothelial carcinoma, given the FDA approval for erdafitinib in this trial. The trial actually opened then the FDA approvals for the FGFR inhibitors for cholangiocarcinoma happened. So this trial didn't really exclude those with FGFR mutated or rearranged cholangiocarcinoma as well. If you look at the breakdown of the cohort in K2, you saw a good mix of breast cancers or a couple of gynecologic malignancies. There were a couple of head and neck cancers. There were several brain tumors as well. There was one lung cancer. There were four noted intrahepatic cholangiocarcinomas. Again, we could not exclude those due to the fact that the trial had opened and was accruing when the FGFR inhibitors approved for cholangiocarcinoma happened. Similar design, with a phase II, single-arm, open-label of erdafitinib, and again, the same statistical design was implemented in that if it's higher than 31 patients, 16% overall response rate was a primary endpoint goal. If it was less than that, it was against the 5% overall response rate.   And here in K2, 35 patients were enrolled and 25 patients were ultimately included in the primary efficacy analysis. So because it was fewer than 31 in the primary efficacy cohort, it followed the NCI-MATCH to be specified with a primary endpoint goal of 5% or higher. And here, in a heavily pre-treated cohort of more than 50% of subjects who have received prior than 3 or higher lines of therapy, overall response rate essentially confirmed was 16% with the p value of 0.034, which met the positivity cutoff of 5%. However, an additional seven patients experienced stable disease as best confirmed response. And it's important to note that four of these were grade IV glioblastomas with prolonged progression-free survival. So ultimately, this trial was positive in reading the endpoint that outside of urothelial carcinoma, could FGFR inhibition be pursued in other tumor types that had FGFR rearrangements or fusions? Dr. Rafeh Naqash: You mentioned glioblastoma, which is an area of huge unmet need. Do you think a trial like this as an upfront approach in glioblastoma, perhaps maybe after Temodar, could be a more meaningful way using the strongest, more precise therapy earlier on when there are certain mechanisms that inhibition of which would result in anti-tumor responses? Do you think doing this earlier on rather than second, third, fourth line would be more intriguing in some ways?  Dr. Jun Gong: I think you've hit upon several key points there. Firstly, just a high unmet need in glioblastomas, in general. And then to us, although it was a stable disease it was quite noticeable that four of these occurred in IDH1 and 2 wild-type brain tumors. We kind of discussed that in the discussion as well. And of these, we actually realized that in the pre-clinical and other published literatures space that for some reason, IDH1 and wild-type tended to have more FGFR alterations, while 0% were found in IDH1 and 2 mutant high grade gliomas. So I think there is something hypothesis generating coming out of this study as well even though there were stable disease. And that you may be selecting for– We may be able to have future studies to select for a specific niche of glioblastomas. And as to your point, Dr. Naqash, I think  if we can have a design trial looking for these specific molecular subsets, I think it's wide open for trials of this nature in the first line, second line, or refractory space. Even piggybacking into cholangiocarcinoma, you see, they're now looking at these in the neoadjuvant and adjuvant space as well. So I think we can identify the subset - it's wide open out there. Dr. Rafeh Naqash: I completely agree. I remember my program director a few years back when immunotherapy was in the metastatic setting, it was very exciting. He gave a talk in which he said "Early, earlier, earliest," and the more early, the better it seems. So I'm guessing that it's probably something similar for precision medicine-based approaches like targeting FGFR perhaps earlier.   So what is next for some of these two studies, or these ideas that have come out of these two studies? Are you trying to develop something subsequently, or is NCI-MATCH looking at it from a certain perspective? Or what would you want to do as a next step, ideally if you had the funding and the pharma support? Dr. Jun Gong: That's the million dollar question. So just from the broad strokes, I think what these two back to back papers and studies comment is that amplifications may not be the more targetable of FGFR subset, but there is avenue for improvement there and further investigation. FGFR fusions and mutations however seem to go along with what we know in some of the FDA approved types now. Now the next step is in the area of precision oncology is could we expand the label indications now to other subtypes with FGFR fusions and mutations. And this is I think following precedent. You and the audience may know that there are a lot of different tumor agnostic approvals now for both immunotherapy and other targeted therapy types. So I think the goal of this study was to provide momentum for, perhaps, advancements into a tumor agnostic indication for FGFR inhibitors.  And we do cite in the K2 manuscript the results of a phase II study that was also published around the time we were writing the study up. It was the phase II RAGNAR study. And that enrolled patients, again, with FGFR fusions and mutations. And that trial was positive, too. That one was a larger study of 217 subjects. We highlight some differences in study populations as to why maybe the difference in responders were detected. Both were positive studies. It was reassuring that the overall survival impulse studies were about the same. And again, I think they don't compete. I rather think they complement each other in providing this body of evidence that  may meet- at one point, the FDA should be approached with this evidence for a tumor agnostic mutation so that more patients with this subset could be benefitting.  Dr. Rafeh Naqash: Excellent. Thank you so much, Jun.  Now, could you tell us briefly what your background is, where you've trained, and your interests, and how you balance clinical research with some of your personal interests?  Dr. Jun Gong: Sure. Thank you for that interest. I did my training in medical school in New York. I went to New York Medical College. And then I did my residency at Cedars-Sinai for medicine. And I went to City of Hope for fellowship where I was trained in GU by Dr. Monty Powell who maybe you folks are familiar with. And my GI training was with Dr. Fakih at City of Hope. And since then I returned back to Cedars-Sinai where I serve as a dual GI/GU focused medical oncologist. I do clinical trials in both and translational science, really focused on targeting tumor metabolism in both as well. My advice to the listeners and trainees and I tell my own fellows this, I think it's very rare now unless you're in phase I to do a dual focus. So I actually emphasized to my trainees that the more focused you can be, the better. Unless you are going into phase I, for example. With that, you can hone in, develop your craft. But then again, I have known several mentors who do multiple tumor types. But I think the more traditional mechanism is to focus as much as you can is my advice for the listeners.  Dr. Rafeh Naqash: Thank you again, Jun, for all those interesting scientific and personal insights. We appreciate you and working with JCO Precision Oncology for both of your manuscripts. This is the first time we have ever invited a lead author for two manuscripts at the same time. It's always good to be the first in something, and I learned a lot and hopefully, our audience would have learned a lot. Dr. Jun Gong: Thank you, Dr. Naqash, for having me. It was a pleasure speaking with you and the crew. Dr. Rafeh Naqash: Thank you.   Thank you for listening to JCO Precision Oncology Conversations. Don't forget to give us a rating or review, and be sure to subscribe so you never miss an episode. You can find all ASCO shows at asco.org/podcasts. 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, experiences, 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.  

Drs. Shaalan Beg and Rachna Shroff discuss key abstracts on GI cancers that were featured at the 2024 ASCO Gastrointestinal Cancers Symposium, including SKYSCRAPER-08, EMERALD-1, and NEST-1 in esophageal squamous cell carcinoma, hepatocellular carcinoma, and colorectal cancer, respectively. TRANSCRIPT Dr. Shaalan Beg: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, your guest host of the podcast today. I'm an adjunct associate professor at UT Southwestern's Simmons Comprehensive Cancer Center and vice president of oncology at Science 37. Today, we'll be discussing key abstracts and other exciting highlights from the 2024 ASCO Gastrointestinal Cancers Symposium. Joining me to discuss some key takeaways from the meeting is the chair of this year's Symposium, Dr. Rachna Shroff. Dr. Shroff is the division chief of Hematology Oncology and chief of GI Medical Oncology at the University of Arizona Cancer Center. She also serves as the associate dean for clinical and translational research at the University of Arizona College of Medicine – Tucson. Our full disclosures are available in the transcript of this episode, and disclosures related to all episodes of the podcast are available at asco.org/DNpod.  Dr. Shroff, welcome back to the ASCO Daily News Podcast, and congratulations on a great Symposium. The scientific advances and innovative, multidisciplinary approaches that were featured throughout the meeting were really inspiring and reflect the incredible strides we're making in GI cancer research. Dr. Rachna Shroff: Thank you so much for having me back. I am delighted to be here.  Dr. Shaalan Beg: Dr. Shroff, the theme of this year's symposium was "Taking Personalized Care to the Next Level." I'd love to hear your reflections on the sessions that you found most exciting and really resonated with the attendees.  Dr. Rachna Shroff: Yes, thank you. We were really excited about this theme because we really felt that “Taking Personalized Care to the Next Level” translated to thinking through personalized approaches to patient care, not just in the traditional ways that we think of with precision oncology and genomics driving our care, but also how we can think through multidisciplinary approaches and an individualized care plan. Thinking through how artificial intelligence and novel clinical trial designs can and should be implemented to meet the needs of our individual patients. And so we really highlighted that in what was a somewhat new reboot of a session called “Intersections,” which were every day and were really more cross-tumor; they were tumor agnostic but were thematic focused. As I mentioned, those themes were really based on feedback that we had from prior attendees, as well as from the program committee's feeling on what are really the questions that we are dealing with and that are burning in the clinic today and that includes the emerging role of artificial intelligence and machine learning and how we integrate that into our clinical care, approaches to oligometastatic disease, and it's not really just something that we think of in colorectal cancer but haven't fully used that paradigm to really apply it to other GI malignancies. And then the art and science of clinical trial design where, again, traditional randomized phase 3 trials might not be the best and most innovative and most expedient way of bringing novel therapeutics to our patients. And so, I thought that all of those sessions were really highlighting different important topics that we deal with day to day. Additionally, we had a really fantastic keynote lecture from Dr. Kimmie Ng of the Dana-Farber Cancer Institute. She is a world-renowned expert in the early-onset colorectal cancer space, and the timing of her keynote was perfect with the new cancer statistics that came out literally days before GI ASCO that demonstrated this just dramatic rise in early onset GI malignancies as a whole, not just colorectal. And she spoke really in a comprehensive manner not just on clinical approaches, screening approaches, and how to find these patients at an earlier stage, but also kind of gave us a call to action, if you will, in terms of public health initiatives, as well as like I said, clinical care and really thinking outside of the box for how to reach these patients.  And then, of course, we always have what I think is one of my favorite aspects of the meeting, which are the networking opportunities that include the Trainee and Early Career Networking Luncheon, the Women's Networking Reception, and the Meet the Experts Luncheon where, especially as junior career investigators, you have an opportunity to meet what we think of as the “big names” in GI cancer. Dr. Shaalan Beg: Absolutely, I remember my first couple of GI ASCO meetings and those were probably the most memorable sessions that I attended as junior faculty as well.   So let's take a deeper dive into some key abstracts from the meeting. I'd like to begin with Abstract 245. This is the SKYSCRAPER-08 study. It's first-line tiragolumab and atezolizumab with chemotherapy in an Asian patient population with esophageal squamous cell carcinoma. What are your key takeaways from this study?  Dr. Rachna Shroff: Yeah. This was an exciting study in my opinion in the sense that thinking through how we can build on immunotherapy backbones is obviously a pressing question across the GI cancer space. So this was a phase 3 randomized, double-blinded, placebo-controlled trial that looked specifically at patients with esophageal squamous cell carcinomas. And the study was enrolled fully with an Asian population. It looked at taking the traditional chemotherapy backbone and adding to it an anti-PD-L1 with atezolizumab and an anti-TIGIT with tiragolumab. Again, that proof of principle of using anti-TIGIT and PD-L1 has been looked at across a lot of different GI cancer spaces and we know that the esophageal squamous cell cancers tend to be very immunotherapy responsive. So this was a really important question.  This involved a number of patients, a little over 460 patients, who were randomized one-to-one to receive the tiragolumab with atezolizumab with the standard paclitaxel and cisplatin, that's used for esophageal squamous versus chemotherapy alone with placebo. And the primary endpoint was independent review of progression-free survival, and overall survival. And so, out of the 461 patients randomized, there was at the primary analysis, a median improvement in progression free survival, from 5.4 months in the control arm to 6.2 months with a tira-paclitaxel plus chemo arm with a hazard ratio of 0.56, highly statistically significant. Similarly the median overall survival was also improved from 11.1 months to 15.7 months again with a hazard ratio of 0.7 and some of the other key efficacy endpoints were also improved with the addition of the anti-TIGIT PD-L1 approach. And importantly, there was not really safety signals that jumped out at us.  And so, to me, what this means is that, in our patients with esophageal squamous cell carcinoma, we really should be thinking about chemotherapy with immunotherapy as a backbone and how we can build on it. And, you know, I would imagine that it's hard to argue with both the PFS and OS endpoint that adding anti-TIGIT won't necessarily be kind of the new approach to these patients. And importantly, I'll point out that it seems to be a benefit across the subgroups, including PD-1 status, which is always our big question here. I think the only thing to keep in mind is this was an all-Asian population and whether or not that kind of immune profile of the immune responsiveness is different in those patients, but regardless, a positive phase 3 trial. Dr. Shaalan Beg: It's really exciting to see immune checkpoint inhibitors or immunotherapy beyond PD-1 targeted, CTLA-4 targeted treatments making their way into GI Cancers.  Dr. Rachna Shroff: Absolutely. Dr. Shaalan Beg: Sticking with the immunotherapy theme, let's focus on hepatocellular carcinoma. So LBA432, the EMERALD-1 study of transarterial chemoembolization combined with durva with or without bevacizumab looked at people with unresectable hepatocellular carcinoma eligible for embolization. So really a highly anticipated study, I'm wondering what your thoughts are and whether it'll be practice-changing for this field.  Dr. Rachna Shroff: I was excited to see the press release when it showed that the study was positive, and I think it's because now that we're using immunotherapy in the advanced HCC space, our obvious question is, can we integrate it into multimodality approaches? There are a lot of smaller studies looking at neoadjuvant IO approaches, and in this intermediate stage, unresectable hepatocellular carcinoma patients. We wanted to know if there was a utility to liver directed therapy with immunotherapy.  So, this was a large study. It was a global study looking at unresectable HCC with preserved Child-Pugh function. But it was Child-Pugh A and up to B7, importantly. And there were 616 patients randomized in a 1:1:1 fashion, with the control arm being just TACE alone. But then, there was also an opportunity for durvalumab with TACE, as well as durvalumab plus bevacizumab with TACE. The patients would receive durvalumab during their TACE treatments and could receive up to four TACE treatments and then subsequently were either continued on durvalumab alone, durvalumab plus bevacizumab, or the placebo. The primary endpoint was progression-free survival, powered specifically to look at TACE versus durvalumab plus TACE. In this study, the primary endpoint was met with a significant improvement in PFS. Median PFS was 15 months versus 8.2 months, with a hazard ratio of 0.77. Most prespecified subgroups demonstrated this benefit.  Importantly, there was a secondary endpoint looking at durvalumab plus TACE versus TACE alone, and that actually did not show a statistically significant improvement in median PFS from 8.2 months in the control arm to 10.0 months. The overall response rates were slightly higher with the durvalumab plus bevacizumab approach at 43.6%. And importantly in these patients, who oftentimes have a higher burden of disease in the liver, median time to progression is a really important and clinically meaningful endpoint. That was 22 months with the durvalumab plus bevacizumab and TACE versus 10 months for TACE alone. I would just point out that the overall concern we always have with bevacizumab is the increased risk of bleeding and the treatment-related adverse event profile. Overall, there were no safety signals that emerged from this, with nothing that really, especially in that bleeding risk category, jumped out at us. Of course, we haven't seen the overall survival data yet because we have not seen enough follow-up to really see that number.  I do think that this is potentially practice-changing, and I think it just demonstrates that there's probably some synergy between anti-VEGF with anti-PD-1, and then the liver-directed treatments. The obvious question for us in the United States is that the vast majority of people are moving away from TACE and towards more radioembolization and what can we extrapolate from this? Does this really tell us much if people are using more of a Y90-based approach? I think those are a lot of the burning questions that most of us have.  Dr. Shaalan Beg: Yeah, and it's a very interesting direction that the HCC space is taking because we heard in previous meetings, the role of PD-1 inhibition as adjuvant therapy after resection. Now, we have data for local-regionally advanced disease over local-regional treatments. And of course, you already mentioned the data for more advanced disease. So it sounds like immunotherapy may be impacting the management of anyone diagnosed with hepatocellular carcinoma.  Let's talk about the MONET trial, Abstract 249, which compared thoracoscopic esophagectomy and open esophagectomy for thoracic esophageal cancer. Do you think this is a study which may influence the treatment of patients with thoracic esophageal cancer? Dr. Rachna Shroff: So, this was, again, I think, a really important question. It was a randomized, controlled phase 3 trial comparing a more minimally invasive approach with TE — thoracoscopic esophagectomy — versus an open approach. This had patients with clinical stage 1-3, excluding T4 thoracic esophageal squamous cell carcinomas. They were randomized 1:1 to the open versus the TE approach, with a primary endpoint of overall survival and an important secondary endpoint of relapse-free survival. 300 patients were randomized, and at the second planned interim analysis, the median follow-up was a little over two and a half years. The 3-year overall survival was 82% in the TE group versus 70.9% in the open group. The DSMC of this trial actually recommended early termination based on the non-inferiority, which is what they were specifically looking at. There was a very statistically significant one-sided p-value for non-inferiority.  Importantly, the 3-year recurrence-free survival was also markedly better in the TE group versus the open group, with no real notable differences in R0 resection, or a large percentage of patients who needed to be converted from a TE to an open approach, and really not any significant difference in overall postoperative morbidity. I think this just supports the concept that minimally invasive approaches for our patients with GI malignancies can and should be considered. Again, esophageal squamous because they tend to be seen a lot more in Asia, this study was conducted in Japan, but I think that being said, a lot of our surgeons in Europe and in the U.S. are also very amenable to minimally invasive approaches. And I think this just supports the fact that an open approach is not necessary. So, I would think again, that this is something that is implementable and I think will affect the field.  Dr. Shaalan Beg: Moving on to metastatic cholangiocarcinoma, there have been many FGFR inhibitors that have shown activity and promise and are approved for the management of cholangiocarcinoma with FGFR alteration. But at this ASCO GI, we heard the results of the safety and efficacy of an FGFR1, 2, and 3 inhibitor, tinengotinib, as monotherapy for advanced metastatic cholangiocarcinoma (Abstract 434). How do you see this fitting into the broad picture? Dr. Rachna Shroff: Yeah, so this was highly anticipated data, primarily because at this point, the FGFR space in cholangiocarcinoma is quite crowded. And so a lot of us were getting sick of the "me-too" drugs. What is really unique about tinengotinib is that, not only is it a selective multikinase inhibitor, but it also, in preclinical models as well as in early phase one trials, demonstrated potent inhibition of patients with FGFR2 fusions and rearrangements who had acquired resistance mutations. So, as we better understand the first generation of FGFR inhibitors and note the resistance mechanisms, these drugs are now being developed to try to circumvent or overcome those.  This study looked at 4 different cohorts: 1 cohort with FGFR2 fusion patients who had primary progression who never responded to FGFR inhibitors, a second cohort with FGFR2 fusion patients who had progression after primary response, so those with acquired resistance, and then there was non-fusion FGFR alterations because we do know that a number of cholangiocarcinoma patients have other FGFR alterations that are not fusions, and then those with FGFR wild-type. The primary endpoint was objective response rate, with a total of 48 patients enrolled across the four cohorts. And so the 40 patients who were evaluable in the group that had primary resistance, which was the first cohort, there was a response rate was 9.1% and that was partial response, and 31% had tumor reduction with tinengotinib. And similarly in those with acquired resistance, 37.5%, 3 out of 8 patients had a partial response and tumor reductions were noted with an overall disease control rate between those patients with FGFR2 fusions of 94.7%, between those with primary and secondary resistance.  In the patients who had FGFR alterations, there was 3 out of 9 patients with a partial response and again, tumor reductions were notable across the board and the disease control rate was 88.9%. The FGFR wild-type group, not surprisingly, did not see any partial responses, but interestingly, 75% of these patients had at least disease control, and the median progression-free survival was 5.26 months, again, kind of most notably impressive in the 2 cohorts that included FGFR2 fusions. The toxicity profiles are what we come to expect for FGFR inhibitors and we've gotten better at managing those and mitigating some of those so there was really nothing to jump out there. So there is now an ongoing randomized phase III trial specifically looking at tinengotinib versus physician's choice in patients with FGFR2-altered cholangiocarcinoma after having received prior FGFR inhibitors. So that's where I think it's in is for those of us who know that there are multiple drugs in the space, our big question is can we sequence through that? Can we offer multiple FGFR inhibitors in these patients? And I think we are all eagerly anticipating this data as well as the subsequent data to really justify the use of these novel second generation FGFR inhibitors.  Dr. Shaalan Beg: It's been fantastic to see the evolution of these compounds in precision medicine, or precision oncology at its finest, in terms of understanding mechanisms of resistance and treating refractory disease.   Let's focus on colorectal cancer. I'll tell you, there has been a lot of discussion, Dr. Shroff, on social media, on insurance companies sometimes rejecting one biologic or the other based on tumor sidedness. We have talked about tumor sidedness predicting response on this podcast based on data from previous studies. But this year in GI ASCO, Abstract 207 explored the role of tumor genomics and tumor sidedness and they said that it's tumor genomics, that tumor genomics better explains the differences on outcomes, and it explains it better than sidedness. What does this mean to the field? Because a lot of professional organizations have guidelines that are asking people to now incorporate sidedness. So how does that change based on these results? Dr. Rachna Shroff: I really commend these authors on leveraging real-world data, and I think we're getting better and better at recognizing that real world data actually informs our clinical decision making, possibly better than sometimes some of these studies that lead to the guidelines and algorithms that we develop. So this is a perfect example of a little bit cart before horse in trying to understand the way that sidedness and genomics may interplay.   So this was a study that basically leveraged both the Foundation Medicine and Flatiron Health clinical genomic database and looked at patients with microsatellite stable metastatic colorectal cancer. There were a total of 3,845 patients included in a kind of two-thirds one-third split between left sided and right-sided colorectal cancer. And they found the typical genomic alterations that historically have been thought of more with left-sided colorectal cancer like APC and then more of the RAS BRAF alterations in the right-sided patients. But I think what they really thought and what I think was remarkable is they really looked at the patients and how they received chemotherapy with anti-EGFR or bevacizumab therapies, and they did a multivariate analysis to really see what is driving outcomes. And like you mentioned, what they found was patients in the RAS pathway, those classified as having alterations in the RAS pathway, had less favorable outcomes, while those with APC altered group had more favorable outcomes. And that was regardless of treatment received and sidedness.  And so when they did an analysis of what was called a “likelihood ratio test,” they found that when genomics was added to the sidedness evaluation, there was an improvement in outcome prediction, but not when sidedness was added to genomics. Like you said, it kind of demonstrates, at least in this mining of real-world data from Flatiron that tumor genomics is probably a better driver and a more important driver in determining outcomes than sidedness.  I totally agree with you. I would push for us to really kind of bring a little bit of noise to this and to make insurance companies and other companies that are looking at this to think through this a little bit more and make sure that we're putting all of the data together in a comprehensive passion before making the treatment plans and determinations. Dr. Shaalan Beg: The last abstract I'd like to ask you about is Abstract 117, the NEST-1 trial. This study looked at neoadjuvant botensilimab and balstilimab for resectable mismatch repair proficient and deficient colorectal cancer, both MSS and MSI. What are your key takeaways from this study?  Dr. Rachna Shroff: This is another study that is demonstrating that there may potentially be a role for immunotherapy in microsatellite stable patients. I will make the caveat that this was a single-arm study that really was looking at feasibility safety, with efficacy as a secondary endpoint. The combination of bot-bal in the neoadjuvant space for colorectal cancer patients, they received one dose of boten and two fixed doses of bal two weeks apart and then were taken to surgery. They limited the number of patients and out of the 12 patients that were enrolled, they limited the number of mismatch repair deficient patients. So to your point, they allowed both, but they wanted to make sure it was not just MSI-high patients. What they basically found is that it was safe and did not delay surgery or increase risks of adverse events. But importantly, there was significant regression of tumor noted. And some interesting spatial biology analyses demonstrated potentially novel mechanisms of action, especially in the MSS population, and that ctDNA reductions correlated with pathologic response. There were a lot of different things that they were looking at, basically suggesting that bot-bal is safe and can be used in both mismatch repair–deficient and proficient patients with colorectal cancer. And now importantly, they've added some additional cohorts and expanding the study. As I mentioned, this is right now just 12 patients, but does definitely have a provocative result.  Dr. Shaalan Beg: Thanks so much, Dr. Shroff.  Finally, the role of cell-free DNA (cfDNA) in GI cancers has been an exciting and important development in our field. There's tremendous data that emerged at the GI meeting, and we have decided to do a separate ASCO Daily News Podcast dedicated to ctDNA. So listeners, please look out for our coverage of key studies on ctDNA in GI cancers very soon here on the ASCO Daily News Podcast.  Many thanks, Dr. Shroff, for sharing your insights with us today and for your great work in building a robust GI meeting this year. Thank you very much. Dr. Rachna Shroff: Thank you so much. Dr. Shaalan Beg: And thank you to all our listeners for your time today. You'll find links to the abstracts discussed on the transcript of this episode. Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and inform. It is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Our guests on this podcast express their own opinions, experiences, and conclusions. These statements do not necessarily reflect the views of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an endorsement by ASCO.   Find out more about today's speakers: Dr. Shaalan Beg @ShaalanBeg Dr. Rachna Shroff @rachnatshroff   Follow ASCO on social media:  @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn    Disclosures: Dr. Shaalan Beg: Employment: Science 37 Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals   Dr. Rachna Shroff: Consulting or Advisory Role: Exelixis, Merck, QED Therapeutics, Incyte, Astra Zeneca, Taiho Pharmaceutical, Boehringer Ingelheim, SERVIER, Genentech, Basilea Research Funding: Pieris Pharmaceuticals, Taiho Pharmaceutical, Merck, Exelixis, QED Therapeutics, Rafael Pharmaceuticals, Bristol-Myers Squibb, Bayer, Immunovaccine, Seagen, Novocure, Nucana, Loxo/Lilly, Faeth Therapeutics

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.18.516150v1?rss=1 Authors: Ursem, S. R., Diepenbroek, C., Kool, T., Eggels, L., Heijboer, A. C., la Fleur, S. E. Abstract: Fibroblast growth factor 23 (FGF23) is a key regulator of systemic phosphate homeostasis, but also an interplay with glucose metabolism has been suggested. Several studies implicate a function of FGF23 in the brain, and indeed we have recently identified FGF23 protein in several brain areas in rats, such as the hypothalamus, third ventricle and choroid plexus. In the current study, we aimed to determine the effect of an intracerebroventricular (icv) injection of FGF23 in the third ventricle of rats on hypothalamic genes involved in glucose regulation. In addition, we assessed whether glycerol can be used safely for icv injections as glycerol is used as a stabilizing compound for FGF23 protein. Adult Wistar rats received an icv injection of recombinant rat FGF23 or vehicle. Dose dependent behavioral changes, suggestive of stress, were observed directly after infusion of FGF23. After 60 min animals were sacrificed and the arcuate nucleus, lateral hypothalamus and choroid plexus were isolated. In these brain regions gene expression was determined of the FGF23 receptor complex (FGFR1, Klotho), NPY, POMC, phosphate transporters (SLC20 and SLC34 families) and markers of cellular ER stress (ATF4 and the ratio of spliced/unspliced XBP1). We showed that glycerol is well tolerated as stabilizer for icv injections. In FGF23-treated animals, cellular ER stress markers were increased in the arcuate nucleus. FGF23 injection did not affect expression of its receptor complex, NPY, POMC, or phosphate transporters. Future studies are warranted to investigate the effect of FGF23 in the brain on the protein level and on neuronal activation. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Featuring perspectives from Dr Carl Gay, including the following topics: Introduction: Journal Club with Carl M Gay, MD, PhD (0:00) Case: A woman in her early 60s with extensive-stage small cell lung cancer (ES-SCLC) and a small residual lung mass after carboplatin/etoposide/atezolizumab — Kapisthalam (KS) Kumar, MD (19:15) Case: A woman and heavy smoker in her early 70s who develops widespread ES-SCLC after chemotherapy/radiation therapy for limited-stage SCLC — Neil Morganstein, MD (24:24) Case: A man in his mid 60s with ES-SCLC and disease progression after carboplatin/etoposide/atezolizumab with central nervous system metastases (FGFR1 gain, tumor mutational burden 11 mut/Mb) who receives lurbinectedin/radiation to the brain — Adam R Miller, MD (38:36) Case: A man in his early 60s with progressive ES-SCLC s/p carboplatin/atezolizumab on lurbinectedin with dose adjustment — Rohit Gosain, MD (47:38) Case: A woman and current smoker in her early 70s with ES-SCLC who receives dose-attenuated chemoimmunotherapy due to multiple comorbidities — Minesh Dinubhai Patel, MD (58:09) CME information and select publications

Listen to a soundcast of the 8/24/22 and 8/26/22 FDA approvals of Imbruvica (ibrutinib) for pediatric patients with chronic graft versus host disease, including a new oral suspension, and Pemazyre (pemigatinib) for relapsed or refractory myeloid/lymphoid neoplasms with FGFR1 rearrangement.”

Dr Verstovsek discusses the FDA approval of pemigatinib in myeloid/lymphoid neoplasms with FGFR1 rearrangements, the transformative effects of pemigatinib, and the importance of identifying chromosomal abnormalities in patients with this aggressive disease.

This week, we're covering the FDA approval of pemigatinib for patients with myeloid or lymphoid neoplasms and an FGFR1 rearrangement. We'll also discuss a long-term update from the STAMPEDE trial of radiotherapy in prostate cancer.Coverage of stories discussed this week on ascopost.com:FDA Approves Pemigatinib for Patients With Myeloid/Lymphoid Neoplasms and FGFR1 RearrangementLong-Term Benefit of Radiotherapy Confirmed in Advanced Prostate Cancer: STAMPEDE Trial Follow-upTo listen to more podcasts from ASCO, visit asco.org/podcasts.

Dr. Diwakar Davar and Dr. Jason Luke, both of the University of Pittsburgh's Hillman Cancer Center, highlight key advances in early phase therapeutics and immunotherapy that were featured at the 2022 ASCO Annual Meeting and also address toxicities, including immune checkpoint inhibitor-associated myocarditis. TRANSCRIPT Dr. Diwakar Davar: Hello, and welcome to the ASCO Daily News Podcast. My name is Dr. Diwakar Davar, and I'm an assistant professor of Medical Oncology, specializing in melanoma and phase 1 therapeutics at the University of Pittsburgh's Hillman Cancer Center. I am the guest host of today's podcast. My guest today is Dr. Jason Luke, a colleague and the director of the Cancer Immunotherapeutics Center at the UPMC Hillman Cancer Center here.  Today, we'll be discussing advances in early-phase therapeutics and immunotherapy that were featured at the 2022 ASCO Annual Meeting.   You'll find our full disclosures in the show notes, and the disclosures of all guests on the podcast are available on our transcripts at asco.org/podcasts.  Jason, thank you for coming on the podcast today.  Dr. Jason Luke: Thanks so much for the invitation. It was a great ASCO, and I hope everyone had a good time.  Dr. Diwakar Davar: So, onto our abstracts. So, the first one that we'll be discussing, and Jason as you know we've done this before. We'll be rapidly transitioning between phase 1 therapeutics, melanoma, and advanced phase 2 and 3 trials, but you know this is something you do very well. So Abstract 2504, it's a phase 1 trial of TIM-3 inhibitor cobomilab immunotherapy and in combination with PD-1 inhibitors nivolumab and dostarlimab. The AMBER Trial that was presented recently, and in full disclosure, both you and I actually are on this abstract. So, what do you think of this abstract? What do you think of the data that is discussed, and how do we contextualize this in relation to what needs to be done in this space?  Dr. Jason Luke: So, I think this is an exciting abstract because it brings forward what may be the next high-priority immune checkpoint to try to target in clinical oncology. To level-set, I think everybody listening will know about PD-1 and CTLA-4 as immune checkpoints. In the last year, we've had LAG-3 come forward as now a standard of care element of armamentarium in melanoma, and we look forward to further studies of LAG-3 and other tumor types as we think it should be a good partner where PD-1 is otherwise approved.  So here now, we hear about TIM-3, which is another negative regulatory checkpoint on a number of different immune subsets. And in this abstract, the antibody targeting TIM-3 was cobolimab. So, TIM-3 is a very interesting molecule. It has, what you might call, pleiotropic effects in the immune system. So, while in the context of this abstract, it was being targeted as another immune checkpoint on T cells, it's important to point out that TIM-3 has other regulatory roles in other immune subsets such as myeloid cells and very particularly dendritic cells, and that's important because it might bring in another element of the innate immune system to try to drive anti-tumor responses. So, it's an exciting target because it might be able to expand the groups of patients who could benefit from immune checkpoint blockade.  So, in this abstract, we see initially the phase 1 data of combining cobolimab, anti-TIM-3 with anti-PD-1 of a couple of different flavors. And what you could take from this abstract is that in the phase 1 setting, the drug was well-tolerated and combined well, and had pharmacokinetic properties that would be consistent with what we'd expect for this kind of a monoclonal antibody. I think we have to marry this abstract, which is really the phase 1 data about safety in pharmacokinetic (PK) to another abstract presented in the melanoma session, which showed an expansion cohort of patients who got cobolimab plus nivolumab or dostarlimab.  And there we did see a 50% response rate, albeit that there was heterogeneity of patients being treatment naïve versus treatment-experienced. So, what I would say to this on a high level is that I think these data are preliminarily exciting, suggesting that further investigation into TIM-3 may be valuable in terms of expanding the population of patients initially in melanoma, but there will data coming soon in lung cancer and in other tumor types with another novel checkpoint. And I think if we think ahead into the future, the question is probably going to end up being, which combinations of checkpoints for which patients. That's pretty exciting to think about. We've seen a lot of data of PD-1 plus other molecules, and I think some future biomarker stratification really will be necessary to know which patient would benefit the most from which of these combos, but for the time being, this is exciting data to see where the field is going to go over the next couple of years.  Dr. Diwakar Davar: Great. And I guess, to your point, one important thing to highlight from the abstract is your point about the role of the different compartments. There was actually a very interesting dose-response relationship with the highest dose of the drug not necessarily being the most effective dose, suggesting that yes, as you escalate, you may have different effects in different compartments, and maybe therefore a broad selection of doses might be required to ensure that you have optimal engagement of the optimal target.  So, the next abstract is Abstract 3007. This is the tumor-agnostic efficacy and safety of erdafitinib. So, we now know that FGFR pathway aberrations are found from 77% of all malignancies, FGFR targets are now U.S. Food and Drug Administration (FDA) approved in cholangiocarcinoma with pemigatinib, infigratinib, and as well with erdafitinib metastatic urothelial cancer. We know that these agents are not necessarily effective tests in 1 tumor type because these alterations have risen in multiple tumor types. So, the RAGNAR trial, looking at this across multiple tumor types, what do you make of the interim analysis result presented by Dr. Loriot?  Dr. Jason Luke: So, I'd say that this is probably the future of targeted therapy. And so, I think that where we have activity in 1 disease, it's very likely we would have activity in others. So, the author has described this as the largest basket trial of a molecularly defined subset that's been pursued to date. There are upwards of more than 200 patients in the study. I think it's really important, as we think about the data, to realize, though, that all FGFR alterations are not exactly the same thing. And so, in this study, they gave erdafitinib to patients with solid tumors of any FGFR altered status. And so that's FGFR1, 2, 3, 4 mutations or gene fusions. And that's a lot of heterogeneity in there actually.  And in this study, there were two-thirds fusions and one-third mutations, mostly in FGFR2 and 3. That will become relevant as we start to think about the results. On a high level, I have to say that it is impressive in pan-cancer fashion, just selecting by FGFR alteration, there's about a 30% response rate observed. I think that no matter what, that's going to be valuable considering these were patients with refractory tumors with 3 lines of prior therapy on median. I think what we need to know more is the breakdown of which specific molecular alteration and FGFR in which tumor types drove most of the benefit.  So, for example, in bladder cancer where erdafitinib is already approved, that's almost entirely an FGFR3 fusion setting. So we know the drug is effective there. And so I think there will be a further breakdown of the data. As it matures more, you really start to tease out, is it really the case that any FGFR alteration can be treated or there are some that really ought to be the high priorities that we really ought to be going after. I think it would be remiss not to also note, however, that while there's excitement about this sort of pan-cancer approach, the current generation of FGFR inhibitors are not exactly the easiest drugs to take.  And so, the in-class, hypophosphatemia and stomatitis really does lead to dose reductions in a lot of the patients. And I think that that's probably really important to emphasize is that despite the pan-tumor activity, there's still a lot of potential in this field to refine further because it's almost certainly the case that if we had less off-target toxicity, so to say, we could improve the efficacy beyond that 30% that we saw here.  All the same, I think this is exciting for the concept of a pan-cancer tumor agnostic sort of approach, and we'll really look forward to more data to come from this study over the next, hopefully, few months.  Dr. Diwakar Davar: And I guess 1 corollary to that is that we now need to start looking for FGFR alterations in multiple tumor types. So, tests, tests, tests. All right, Abstract 3004, phase 1a/1b dose escalation and expansion study of the MDM2-p53 antagonist BI 907828 in patients with multiple solid tumors including advanced, metastatic, liposarcoma. So, we've recently had data of the previously undruggable KRAS, and now we've got previously undruggable p53, for which we now have targets. So, Jason, what do you make of the p53 targeting approach, in this case, using MDM2 and this particular drug from Boehringer Ingelheim?  Dr. Jason Luke: So, I think that this is an exciting abstract exactly for the reason that you mentioned, which is that p53 has been, and unfortunately, to some degree, still remains, one of those holy grails but undruggable targets in oncology. So MDM2, for those who are listening but might not be aware, is a negative regulator of p53. So, the concept here then is if you drug it, you might release p53 to reactivate activity in that pathway, and then p53 being the guardian of the genome, so to say, potentially leading to apoptosis of cancer cells.  And so, this drug binds MDM2 and MDM2 can be amplified as a resistance mechanism in p53 and several tumor types. And so here, they showed data for the early part of a clinical trial investigating the small molecule, BI 907828, but then they focus specifically in liposarcoma, which is a disease known to be an MDM2 amplified. And so, the results were pretty interesting. The toxicity of this kind of an approach, just to note, is really in class. It leads to some gastrointestinal (GI) toxicities as well as hematologic problems, and this goes again for most regulators of the cell cycle will have these effects, whether they're CDK inhibitors or MDM2 or p53 modulators.  But I think what was very interesting, this is a disease liposarcoma where chemotherapy, functionally speaking, has no role. We, unfortunately, give it to some patients sometimes, but it has almost no activity, and they observe that in poorly differentiated liposarcomas, the response rate was about 12%, but the stable disease was quite durable. And so, I think that really is potentially a big deal because this is an orphan disease. It really lacks any other treatment. But as you zoom out from that, if you start to think about targeting amplified MDM2 in other settings, I think the activity that we see here is intriguing, and potentially suggests that we may be coming to a future where we'll have multiple, sort of, orthogonal approaches after reactivating p53. There were actually other abstracts at ASCO Annual Meeting of other molecules that were less mature also along this line.  So, I think, very exciting to take away from this, one, a potential treatment for liposarcoma for all of those patients that anybody listening actually sees, but secondarily this concept of targeting p53, which I think we'll see a lot more of over the next couple of years.  Dr. Diwakar Davar: Excellent. Moving on to the Abstract 3002, this is a phase 1, two-part multicenter, first-in-human study of DS-6000a of an antibody-drug conjugate comprising the anti-CDH6 IgG1 monoclonal antibody that is attached to a topoisomerase I inhibitor payload via a cleavable linker. And so basically, a way in which you can give topoisomerase: (1) TOP1 inhibitor, (2) CDH6-expressing cells. This was studied in advanced renal cell carcinoma (RCC) and advanced ovarian cancer in this abstract presented by Dr. Hamilton. Jason, what do you think of the results and what do you think of this approach in general, this antibody-drug conjugate (ADC) approach using novel targets as well as novel payloads?  Dr. Jason Luke: I think this is one of those that you can't help but be pretty excited about, and I think in the context of the data shown at the plenary session in breast cancer for antibody-drug conjugates (LBA3), I think this is really where the field is going to start to go. So, you mentioned that this is an antibody-drug conjugate that targets cadherin 6 or CDH6, which people will remember from biochemistry class and medical school, or something is a cell-cell adhesion molecule, really a basement membrane protein. So, the concept of targeting it really is just to go after a latch mechanism to get the molecule into the tumor where you want. And CDH expression is very high in renal cell carcinoma, upwards of 80% of samples, also high in ovarian cancer, which is why they chose those 2 tumors to go after.  So, the ADCC, and you described its structure just a little bit, but it's essentially the same backbone as trastuzumab deruxtecan, which we saw this outstanding activity for HER2 and breast cancer on the plenary, with these 8 chemotherapies moieties attached to it, but here now, targeting it instead to HER2, with this molecule now to CDH6. And I think, again, you can't help but be impressed. There were treatment responses on almost every dose level of the dose escalation in this study. There's in fact only 1 patient whose tumor was not, at least, stable disease or a PR, and I think that that just goes to show the power of truly bringing the chemotherapy in a targeted manner into the tumor microenvironment. Responses were heterogeneous. They were not super deep responses per se, but the stable disease was quite durable in the study, and the patients were going out more than 7 months. And again, realizing this is at the lower dose levels as we're increasing the dose and move this in their earlier lives of therapy is likely to be even more effective.  They did show a waterfall plot of the reduction in CA 125 for the patients with ovarian cancer that really looked quite impressive. And given that that's our clinical biomarker that we commonly follow, it may actually even more indicative of the benefit we would see as opposed to resist.  Now, again, there is some toxicity. It is a chemotherapy moiety that's conjugated to the ADCs. So, the most common toxicities were nausea, vomiting, and low platelet counts, but these are kind of toxicities that we're quite accustomed to with chemotherapy. Just to summarize, I think there's a lot of promise for this kind of antibody-drug conjugate targeting, and I think it can only be impressive that they had this amount of activity in the dose escalation of the study. [I] very much look forward to the expansion cohorts in renal and ovarian, which we'll presumably expect to see later this year, early in the next year.  Dr. Diwakar Davar: And as you alluded to, this really was parallel that ASCO, by the standing ovation given to Dr. Modi when she presented the DESTINY04 data of trastuzumab deruxtecan in HER2-low breast cancer, basically now redefining breast cancer from 4 camps, now we have to think of not just HER2 amplified or HER2-high, but also HER2-low. So yes, really have to now rethink how we classify these diseases (LBA3).  So Abstract 2509, the efficacy of anti-PD-1/PD-L1 immunotherapy in non–small cell lung cancer dependent based on CD8 and PD-L1 status. So really Dr. Galon taking us into what he has now described as the immunoscore—really a way of characterizing tumors. A way of thinking about tumors that you've also championed, Jason, in terms of this T cell-inflamed and uninflamed hypothesis. So, tell us a little bit about how these jives with your work and how you would think about lung cancer patients responding and not responding to immune checkpoint inhibitors (ICI) therapy in this context?  Dr. Jason Luke: Yeah. I think the focus quickly here on the immunoscore, so the people are aware of that, I think is really important for diving into these specific results. You have to realize our fundamental underlying predicate for immune checkpoint blockade inhibitor response is that patients have mounted an adaptive immune response. So, CD8 T-cells have gone into the tumor where they elaborate chemokines and cytokines like interferon gamma, which upregulates the expression of PD-L1 in the tumor but also in the surrounding immune cells.  So, you realize that even though antibodies are targeting PD-1, it's really that we're targeting that tumor microenvironment. So, the more robustly we can measure that, and we understand it, the more likely we are to know whether or not the patient is going to benefit. So, this is where the immunoscore comes in. The immunoscore is actually a fairly simple test. It's one slide, immunohistochemistry slide where they can stain jointly for CD8 and PD-L1 on the same slide. And that allows them to do a number of different things beyond just testing the total level of PD-L1. They can test the CD8 density, the PD-L1 expression, but then also the interaction between CD8 T-cells, their distance from each other, from PD-L1 expressing cells, and so on and so forth.  And so really [this] can give us a much more robust analysis of what all is going on in the tumor microenvironment again, off of a single slide. So here then, in this abstract, for patients with non–small cell lung cancer receiving anti-PD-1, they then compared the utility of only PD-L1 testing versus doing the immunoscore. And so, it was actually quite a large set. They had about 250 patients in their analytical set and then split about 150 or 180 or something into the training and validation sets, and they compared the immunoscore against 2 different standard PD-L1 antibodies, the 22C3 as well as the SP263. And what they saw was a high concordance for expression between PD-L1 and the immunoscore.  That's good, because, again, they're measuring PD-L1 in both of those. And so that was a good, sort of, level set. The immunoscore, however, allows them to look to 7 different parameters, again, beyond just PD-L1, as I mentioned. So, CD8 density, interaction, distance, and this kind of thing. Then in these test and training cohorts, they were able to actually split out patients who are PD-L1 positive into further groups, those that were immunoscore low and that were high. And in so doing, they were actually able to sort of dramatically predict the likely progression-free survival on PD-1 checkpoint blockade in those different non–small cell lung cancer groups.  So why is this important? Selection of patients by PD-1 has been very useful in the field of non–small cell lung cancer, but it's hardly a panacea. You're not at all assured your patient is going to do well just because they're PD-L1. And here comes a second assay that can be done in a standard of care setting. So, the immunoscore is a test. You could just order it, and that really does give you much more predictive power about who's likely to do well and who isn't. And I think this test and more broadly multi-spectral imaging is really going to become a core component to how we risk stratify and predict outcomes to checkpoint blockade and lung cancer, but broadly in other tumor types over the next couple of years.  Dr. Diwakar Davar: Okay. Now, moving on from a biomarker for PD-L1 and PD-1 to a setting in which PD-1 was just recently U.S. Food and Drug Administration (FDA)-approved, so I'll give a brief background to the trial that you've actually developed and led. And so, this is KEYNOTE-716, the abstract in question is LBA9500 (late-breaking abstract) 9500, but this is the distant metastasis-free survival (DMFS) data readout. The DMFS, distant metastasis-free survival with pembrolizumab versus placebo in the adjuvant setting for patients with stage IIB or IIC, that is high-risk node-negative melanoma and the data from the phase 3 KEYNOTE-716 study.  So, this data, at least the recurrence-free survival (RFS) data was actually earlier published, you had presented it earlier last year and also more recently this year, but it was published recently in Lancet. And we know that 716 is a study in which, for the first time ever, we have an immune checkpoint inhibitor PD-1 that was studied against placebo with the high-risk node-negative setting in stage IIB and C melanoma, demonstrated a significant RFS benefit in the setting against placebo. And now we have the DMFS readout.  Maybe you could tell us a little bit about both the RFS and the DMFS data, and why this is such an important advance for these patients.  Dr. Jason Luke: Thanks. And I agree this really is a sea change in how we thought about stratification of patients with melanoma, but I think this broadly has implications for other tumor types as well. So, in melanoma, we've historically thought of its involvement of the lymph nodes—stage III as being the high-risk disease, but we also, if you look at the outcomes from the AJCC, we see the patients with stage IIB and IIC, so deep primary lesions, actually have similar bad outcomes as those patients with stage IIIA and IIIB. And so anti-PD1 and adjuvant therapy and melanoma were originally proved for stage III, but having understood that about 5 years ago actually, started to think, well, why not also treat the patients with stage II if they're at similar risk.  And we pursued KEYNOTE-716 as you mentioned, and it read out last year as a positive trial for recurrence-free survival. And the abstract here then was to look at the impact on distant metastasis-free survival. So, while the regulatory consideration for approval, and it is approved and it's available for patients now, was based on relapse, what we really want to be preventing is the development of metastatic disease because presumably that would correlate with the eventual death of the patient from cancer.  So, in the abstract here, we see the first update for DMFS, which also was positive on its first analysis, the hazard ratio at 0.64. And so, again, very similar to the RFS benefit, showing about a 35-36% reduction in distant metastasis-free survival. And this is a theme that we've seen across adjuvant studies in melanoma, all the adjuvant studies in fact, is that the RFS improvement, the relapse-free survival hazard ratio mirrors very closely the distant metastasis-free survival ratio. We saw that again here. I think it just emphasizes that anti-PD-1 immunotherapy is highly effective in melanoma no matter what stage it's in, but rather related to the risk of death for melanoma.  And so this really has a practice changing in the field of melanoma oncology. Patients need to be referred to medical oncology early for discussion around risk stratification and consideration of adjuvant therapy—I think even at the same time that they're having resection of their primary lesion, and it even calls into  question of whether or not we should even fully be doing procedures like sentinel lymph node biopsies any longer, considering we can make the decision to give adjuvant therapy now based on the primary—albeit that's a controversial area of discussion.  And I would just love for this to start to penetrate into other disease settings. We've seen more recently, approval for neoadjuvant therapy in lung cancer and we see in kidney cancer, bladder cancer. We see adjuvant therapy in—I think we're going to see immunotherapy starting to become an important part of the armamentarium in these hard-to-treat cancers, even at the time that perioperatively before or after surgery.  So definitely a major change in the way we're thinking about stratifying patients and emphasizes that you need to get those patients with melanoma in to have that discussion around adjuvant therapy probably at the time of the primary lesion resection.  Dr. Diwakar Davar: And finally, Abstract 2507, single-cell profiling of human heart and blood in patients with checkpoint inhibitor-associated myocarditis. So, this is data from the NGH Group, Dr. Villani and colleagues are presented by Dr. Blum. We know that myocarditis is an uncommon but very serious immune related adverse event (irAE), and here in this particular dataset, this group which has done a lot of underlying work to really uncover the role of certain key phenotypes, cellular phenotypes, in the development of myocarditis it's presenting the data in the context of ICI-related myocarditis. So, what do you think of this data, what do you think of the use of checkpoint inhibitors are now, as you've said, migrated linear in the lifecycle of the patient, what do we need to be thinking about and how does this improve our understanding of both the use of the drug and what we need to be worried about?  Dr. Jason Luke: I think the toxicities of immunotherapy, while, less frequent than, say, chemotherapy, can actually be more disastrous. In the rare patients, we have extreme immune-related adverse events, there is an incidence of actually life-threatening and fatal events. And so, myocarditis, associated with checkpoint blockade, is one of those things that could be seen, and here at ASCO Annual Meeting, we saw a couple of abstracts summarizing the experience from the National Cancer Institute following myocarditis events, and then this abstract in a translational level trying to better understand what is actually going on in terms of the immune response in those myocarditis cases.  And so, I thought this was actually a very interesting abstract. There was only a small number of patients. They had 13 samples from patients who had had endomyocardial biopsies in the context of immune-related myocarditis, and you might say, well, only 13 samples, but fortunately, this is quite a rare event, less than 1% of patients who get immune checkpoint inhibitors. And what they saw was relatively unsurprising, which is that in patients who were having myocarditis, they saw an increase in T cells and in K-cells, as well as activated CD8 and CD4 T-cells.  I think what was very interesting was when they started to dig into what were the phenotypes of the cells and what were the pathways that were turned on. Again, it was not especially surprising to see that they saw increased levels of interferon signaling and immune-receptor signaling as well as motility and adhesion, but this really, I think emphasizes that there are potentially interventions beyond just the general immune-suppression approaches that we give. They could be more nuanced but perhaps more efficacious because sadly, patients do pass away when they develop this. And in their cohort of 13 patients, 3 of those patients died. And specifically, in looking in those 3 patients, they actually saw that all 3 patients had a shared T cell cluster. And they can't exactly say what it is exactly yet, but I think it's very interesting to see that because it suggests that there's probably something about the T cell response in those patients that disproportionately triggered a fatal event.  And if we can understand that better, we then may be able to really tailor our interventions in a way that is more useful. Because, frankly, the way these patients usually present is they show up in the emergency room (ER), and they're seen by an ER doctor who thinks they're having acute coronary. They ship them off to the catheterization (cath) lab. They open him up, and then they get in there, and there's nothing going on. There's no plaque. And so now, all of a sudden, everyone is quite confused. And so, if we had better ways to search for that ahead of time to be aware of it, we might have better interventions because usually what happens right at that moment is everybody gets very confused and starts calling the oncologist, and we start slapping on steroids and other immunomodulatory agents, but sometimes it's late.  So, I think this is a great abstract. It's really starting to preliminary give us an idea of what is the actual biology that underpins these terrible events, and we can hope that we can build off that over time hopefully to eventually come up with better predictors and then obviously better interventions to try to avoid these outcomes in a small but real number of patients.  Dr. Diwakar Davar: Excellent. One other point is you and I are both involved in drug development, and as we start thinking of side effects. Side effects are really on the flip side of responses in drug development. So really 1 point to make of this is that when people start developing side effects rather than, as you say, putting your hands up in the air and waving them around, 1 of the things that we should be doing in drug development is possibly biopsying these patients because we could get new PD insights into how these drugs work, why they work, and particularly which sub-populations themselves they work on, particularly in the early-drug development setting when you oftentimes don't have that many responses.  With that, thank you, Jason, for sharing your insights with us today.  Dr. Jason Luke: Thank you.  Dr. Diwakar Davar: And thank you to our listeners for your time today. If you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. So, thank you for your attention, and we will sign out.      Disclosures:  Dr. Diwakar Davar:   Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences  Consulting or Advisory Role: Instil Bio, Vedanta Biosciences  Consulting or Advisory Role (Immediate family member): Shionogi  Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences  Research Funding (Inst.): Zucero Therapeutics  Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy  Dr. Jason Luke:   Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical , Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX  Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine  Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure  Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof)  Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio  Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.     

Listen to a blog summary of a trending research paper published by Oncotarget, entitled, "Proteomic analysis reveals dual requirement for Grb2 and PLCγ1 interactions for BCR-FGFR1-Driven 8p11 cell proliferation." ___________________________________________ Chromosomes are found in the nucleus of cells and consist of proteins and tightly coiled strands of DNA. During cell division, chromosomal translocations can occur while the chromosomes are being copied. This type of mutation can mean that an entire chromosome has moved to another location, or that a chromosome has broken, usually into two pieces, and moved to another site. Some translocations are harmless, but others can lead to aberrant cell proliferation and cancer. “Over the last half century, chromosomal translocations encoding functional oncogenic proteins have been identified as drivers of multiple cancers, and account for 20% of all malignant neoplasms [1, 2].” For example, the t(8;22)(p11;q11) chromosomal translocation leads to the initiation of an oncogenic fusion protein called the Breakpoint Cluster Region Fibroblast Growth Factor Receptor 1 (BCR-FGFR1). BCR-FGFR1 is a single driver of 8p11 myeloproliferative syndrome, which is also known as stem cell leukemia/lymphoma (SCLL). “Stem cell leukemia/lymphoma (SCLL) exhibits distinct clinical and pathological features characterized by chromosomal translocations involving the FGFR1 gene at chromosome 8p11.” In a trending new study, researchers from the University of California San Diego and Sanford Burnham Prebys Medical Discovery Institute examined mutations in PLCγ1 and Grb2 binding sites individually and when combined together in a double mutant within BCR-FGFR1. On May 11, 2022, the research paper was published in Oncotarget and entitled, “Proteomic analysis reveals dual requirement for Grb2 and PLCγ1 interactions for BCR-FGFR1-Driven 8p11 cell proliferation.” Full blog - https://www.oncotarget.org/2022/05/12/trending-with-impact-dual-requirement-in-stem-cell-leukemia-lymphoma/ DOI - https://doi.org/10.18632/oncotarget.28228 Correspondence to - Daniel J. Donoghue - ddonoghue@ucsd.edu Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28228 Keywords - oncogenic fusion protein, chromosomal translocation, protein interactome, phosphoproteome, stem cell leukemia/lymphoma About Oncotarget Oncotarget is a peer-reviewed, open access biomedical journal covering research on all aspects of oncology. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/OncotargetYouTube LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Oncotarget is published by Impact Journals, LLC: https://www.ImpactJournals.com Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

FDA 批准首个用于治疗晚期尿路上皮癌的FGFR激酶抑制剂Nature Medicine 免疫检查点抑制剂PD-L1联合CTLA-4单抗治疗高危尿路上皮癌前沿医学 多功能天然高分子纳米颗粒作为抗纤维化基因载体用于治疗CKD厄达替尼（erdafitinib）我们的节目曾在《消化科星期三 Episode 3》中介绍过培米加替尼，治疗成纤维细胞生长因子受体编码基因（FGFR）基因融合或重排的局部晚期胆管癌，胆管癌中约有20%的患者存在这种基因突变。研究人员发现FGFR突变在尿路上皮癌中也很常见，并且可能与对免疫干预的敏感性降低相关。厄达替尼（erdafitinib）是一种FGFR1-4的酪氨酸激酶抑制剂，2019年4月，FDA已经批准厄达替尼（erdafitinib）用于治疗局部晚期或转移性尿路上皮癌。《BLC2001研究：厄达替尼治疗局部晚期或转移性尿路上皮细胞癌的2期临床研究》New England Journal of Medicine，2019年8月 (1) 在这项开放标签的2期研究中，纳入了FGFR基因突变的、局部晚期和不可切除或转移性尿路上皮细胞癌的患者99人，所有患者既往均接受过化疗，并在化疗12个月内发生疾病进展。最初将患者随机分组，随后根据中期分析，将连续用药方案的起始剂量设定为8mg/d，并可在药效学指导下，将剂量增加至9mg/d。经过平均5个周期的厄达替尼治疗后，缓解率为40%（3%完全缓解，37%部分缓解）。在既往接受过免疫治疗患者中，缓解率为59%。中位无进展生存期为5.5个月，中位总生存期为13.8个月。结论：在既往接受过治疗的、有FGFR基因突变的、且患局部晚期和不可切除或转移性的尿路上皮细胞癌的患者中，厄达替尼治疗后肿瘤客观缓解率达40%。膀胱尿路上皮癌膀胱癌是最常见的泌尿系统恶性肿瘤，其中尿路上皮癌（也称移行细胞癌）是主要的组织学类型，占所有膀胱癌的90%。膀胱尿路上皮癌可表现为非肌肉浸润癌、肌肉浸润癌和转移癌，病变的程度可以反映自然病程，并决定了治疗和预后。膀胱癌通常表现为肉眼血尿或镜下血尿，刺激性或梗阻性排尿困难也可以 是首发症状。非肌肉浸润性膀胱癌的治疗对于非肌肉浸润性膀胱癌的患者，采用经尿道膀胱肿瘤切除术（TURBT），并联合膀胱内辅助治疗等保守治疗方式有可能保留膀胱功能。膀胱内辅助治疗主要包括卡介苗（牛结合分支杆菌的减毒活疫苗）和丝裂霉素C、表柔比星、吉西他滨等化疗药物。《系统回顾：膀胱治疗非肌肉浸润性膀胱癌的疗效》European Urology，2020年9月 (2)研究的目的是评价在卡介苗治疗后，保留膀胱功能的患者的疾病完全缓解率和无复发率。研究系统地回顾了42项研究，包括24种治疗方案、2254名患者。包含原位癌在内的肿瘤治疗中位完全缓解率，6个月时为26%，12个月时为17%，24个月时为8%。相比，乳头状癌的平均无进展率，6个月时为67%，12个月时为44%，24个月时为10%。特别是在卡介苗无效的、接受草分枝杆菌细胞壁-核酸复合物的患者中，6个月和12个月的完全缓解率分别为45%和27%；6、12、24个月中位不带病生存率分别为43%、35%和18%。总的中位无进展率为91%，原位癌的研究中为95%，乳头状癌的研究中为89%。膀胱内给药的不良反应少，且轻微。结论：卡介苗治疗后的、保留膀胱疗法，在非肌肉浸润性膀胱癌患者中取得了适度的疗效。《NIMBUS研究：卡介苗标准剂量和数量灌注治疗重度非肌肉浸润性膀胱癌的3期临床研究》European Urology，2020年11月 (3)膀胱内灌注卡介苗治疗是一种被广泛接受的预防非肌肉浸润性膀胱癌复发的策略，但是具有显著的毒性。研究的目的是评估了降低标准剂量卡介苗灌注的次数是否可以达到同样的疗效。研究纳入了345名非肌肉浸润性膀胱癌的患者，分别接受标准治疗（诱导6周，在第3、6和12个月时各治疗3周，共15次灌注），或低频率治疗（第1、2和6周诱导，在第3、6和12个月时各治疗2周，共9次灌注）。中位随访12个月后，标准治疗组复发率12%，低频率治疗组复发率27%。安全性分析达到了预先定义的、无效停止标准。结论：在预防膀胱癌复发方面，标准治疗方案更好，目前研究已经停止对参与者的招募。《国家质量指标项目：提高非肌肉浸润性膀胱癌经尿道膀胱肿瘤切除术的质量和有效性》European Urology，2020年8月 (4)非肌肉浸润性膀胱癌的临床预后部分取决于初始干预。为了改善和标准化癌症治疗，苏格兰实施了一项针对膀胱癌的国家质量指标项目。研究中纳入了2689例患者，标准干预包括：（1）使用膀胱图；（2）经尿道膀胱肿瘤切除术后单次膀胱内灌注丝裂霉素C一次；（3）逼尿肌活检；（4）高危膀胱癌患者中，早期行二次手术。研究中，67%患者接受了术后一次膀胱灌注；复发率、残余癌比例和继发肿瘤的比例分别为13%、33%和2.9%。术后一次膀胱灌注复发率降低相关；逼尿肌活检则癌症残留的可能性减半。结论：在苏格兰实施国家质量指标计划似乎有助于向患者提供高质量的经尿道膀胱肿瘤切除术，且降低了术后的复发率、肿瘤分期更准确。《DaBlaCa-13研究：短期强化化疗与标准辅助膀胱内灌注治疗非肌肉浸润性膀胱癌》European Urology，2020年8月 (5)膀胱灌注治疗非肌肉浸润性膀胱癌可减少复发。术前灌注化疗副作用更少，甚至一些患者在治疗后都无需接受肿瘤切除术了。研究旨在比较术前丝裂霉素C短期强化化疗治疗复发性非肌肉浸润性膀胱癌的效果。研究纳入120例患者，短期强化化疗组，膀胱灌注化疗每周3次，共2周；对照组先行经尿道膀胱肿瘤切除术，术后6周每周进行一次膀胱灌注辅助治疗。在短期强化化疗组中，有33名参与者（57%）出现了肿瘤完全缓解，且不良事件少。结论：术前短期强化化疗使一半以上的患者避免肿瘤切除术，但长期疗效仍需随访观察。肌肉浸润性膀胱癌的治疗对于肌肉浸润性膀胱癌，需行根治性膀胱切除术+尿流改道术，以及辅助化疗、免疫治疗。化疗方案中的MVAC方案（甲氨蝶呤、长春碱、多柔比星、顺铂）被认为是一线化疗方案，临床实践中多在这个方案上增减。目前已有几个免疫检查点抑制剂被获批用于膀胱尿路上皮癌的治疗：阿替利珠单抗（atezolizumab），帕博利珠单抗（pembrolizumab），纳武利尤单抗（nivolumab），阿伟鲁单抗（avelumab），德瓦鲁单抗（durvalumab）。《回顾性综述：FGFR3的水平变化与膀胱癌对铂化疗的敏感性有关》European Urology，2020年8月(6)大约15%的膀胱癌存在成纤维细胞生长因子受体3 （FGFR3）基因突变。研究人员回顾性的比较和综述三个队列的患者：（1）新辅助化疗治疗肌肉侵袭性膀胱癌患者的数据；（2）一线铂类化疗治疗转移性尿路上皮癌患者的数据；（3）来自癌症基因组图谱中的肌肉侵袭性膀胱癌患者的数据。队列一：72例新辅助化疗的肌肉侵袭性膀胱炎癌患者中有13%具有FGFR3突变，均没有达到病理完全缓解，且无复发生存期短。队列三：来自癌症基因组图谱中的肌肉侵袭性膀胱癌的患者，接受辅助化疗、且伴有FGFR3突变的无复发生存期也更短。相反，在未接受化疗的患者中，FGFR3突变与无复发生存期更长、总生存率更高。队列二：转移性尿路上皮癌的患者中，FGFR3突变虽然药物反应低，但不影响无进展生存率和总生存率。结论：肌肉浸润性膀胱癌中，FGFR3突变可能与围手术期铂类药物化疗反应差、易复发有关。《IMvigor130研究：化疗联合阿替利珠单抗治疗转移性尿路上皮癌的3期临床研究》Lancet，2020年5月 (7)这个多中心、3期、随机研究的目的是，比较阿替利珠单抗与安慰剂加铂类化疗在一线转移性尿路上皮癌的疗效。研究纳入未经治疗的、≥18岁的、局部晚期或转移性尿路上皮细胞癌患者共1213人。随机接受阿替利珠单抗+铂类化疗，或阿替利珠单抗单药治疗，或安慰剂+铂类化疗，随访11.8个月。中位无进展生存期，在阿替利珠单抗联合化疗组为8·2个月，在安慰剂联合化疗组为6.3个月（p = 0·007）。中位生存期，在阿替利珠单抗联合化疗组为16·0个月，安慰剂联合化疗组为13·4个月（p = 0·027）。阿替利珠单抗单药治疗组中位总生存期为15·7个月，与安慰剂联合化疗组无差异。结论：阿替利珠单抗联合铂类化疗延长了转移性尿路上皮癌患者的无进展生存，研究支持使用阿替利珠单抗联合铂类化疗作为转移性尿路上皮癌的潜在的、一线治疗选择。《JAVELIN Bladder200研究：PD-L1单抗阿伟鲁单抗维持治疗局部晚期、或转移性尿路上皮癌》New England Journal of Medicine，2020年9月 (8)这项3期临床试验中，研究人员纳入无法手术的局部晚期、或转移性尿路上皮癌患者共700人，在接受一线化疗后，随机给予阿伟鲁单抗维持治疗、或仅给予支持治疗。阿伟鲁单抗维持治疗能显著延长了患者的总生存期。阿伟鲁单抗组和对照组的，1年总生存率分别为71.3%和58.4%，中位总生存期分别为21.4个月和14.3个月（死亡风险比 0.69，P = 0.001）。阿伟鲁单抗也显著延长了PD-L1阳性的患者的总生存率，两组分别为79.1%和60.4%（风险比 0.56，P < 0.001）。在总体人群中，阿伟鲁单抗组的中位无进展生存期为3.7个月，对照组为2.0个月（疾病进展或死亡的风险比为0.62）；在PD-L1阳性的人群中，阿伟鲁单抗组的中位无进展生存期为5.7个月，对照组为2.1个月（风险比 0.56）。结论：一线化疗+阿伟鲁单抗维持治疗，能进一步延长了患者的总生存期。《随机对照研究：卡博替尼和纳武利尤单抗联合或不联合伊匹木单抗治疗转移性尿路上皮癌的1期临床研究》Journal of Clinical Oncology，2020年10月 (9)卡博替尼（cabozantinib）是一种酪氨酸激酶受体抑制剂 ，纳武利尤单抗（nivolumab）是一种PD-1单抗，伊匹木单抗（ipilimumab）是一种CTLA-4单抗。研究的目的是评估了卡博替尼联合纳武利尤单抗的CaboNivo方案，以及CaboNivo联合伊匹木单抗的CaboNivoIpi方案在转移性尿路上皮癌和其他泌尿生殖系统恶性肿瘤患者中的安全性和有效性，共入组54人。平均随访时间为44.6个月，转移性尿路上皮癌的客观缓解率为38.5%，平均缓解持续时间尚未达到，中位无进展生存期达12.8个月，中位总生存期为25.4个月。CaboNivo和CaboNivoIpi治疗组中，严重不良事件发生率分别为75%和87%，主要包括疲劳、腹泻、高血压、肝炎、结肠炎。II期临床研究推荐剂量为卡博替尼40 mg/d、纳武利尤单抗3 mg/kg，伊匹木单抗1 mg/kg。结论：CaboNivo方案（卡博替尼+纳武利尤单抗）和CaboNivoIpi（卡博替尼+纳武利尤单抗+伊匹木单抗）方案均显示了良好的耐受性和持久的疗效，多项II期和III期临床研究正在进行中。《随机对照临床研究：新辅助PD-L1加CTLA-4阻滞治疗顺铂化疗无法耐受的、可手术切除的、高危、尿路上皮癌的1期临床研究》Nature Medicine，2020年10月 (10)这是首个抗PD-L1单抗（德瓦鲁单抗，durvalumab）联合抗CTLA-4单抗（曲美木单抗，tremelimumab）。研究纳入在顺铂化疗无法耐受的、具有高危特征的、尿路上皮癌患者共28人（高危特征为肿块大、组织学变异、淋巴血管侵犯、肾盂积水和/或高度上尿路疾病）。在完成手术的患者中，病理完全缓解为37.5%，58%的患者达到无残余侵袭性占位。21%的患者出现免疫相关不良事件，包括无症状实验室异常、肝炎和结肠炎结论：研究提供了抗PD-L1单抗联合抗CTLA-4单抗新辅助治疗的初步安全性、有效性和生物标志物数据，这对于局限性尿路上皮癌患者，特别是具有高危特征且目前没有建立标准护理新辅助治疗的顺铂不合格患者，值得进一步发展。《NABUCCO研究：术前CTLA-4联合PD-1抑制剂治疗局部晚期尿路上皮癌的1期临床研究》Nature Medicine，2020年10月 (11)伊匹木单抗（ipilimumab）是一种CTLA-4单抗，纳武利尤单抗（nivolumab）是一种PD-1单抗，在NABUCCO研究中，纳入了24名III期、尿路上皮癌患者，术前接受两次伊匹木单抗联合纳武利尤单抗治疗后，然后在12周内接受手术切除。研究中46%的患者达到病理学完全缓解，58%达到无残余侵袭性占位。与单独使用PD-1/PD-L1抑制剂的研究相比，伊匹木单抗联合纳武利尤单抗的疗效与基线时CD8+ T细胞活性无关。3-4级免疫相关不良事件发生率分别为55%和41%。结论：在局部晚期尿路上皮癌患者中，CTLA-4联合PD-1阻断可能提供一个有效的术前治疗策略，而不用考虑先前的CD8+ T细胞的活性。纳米颗粒作为抗纤维化基因载体治疗CKD《基础研究：多功能天然高分子纳米颗粒作为抗纤维化基因载体用于治疗慢性肾脏病》J American Society of Nephrology，2020年8月 (12)预防或逆转促纤维化的细胞的基因表型是治疗慢性肾脏病的一个方向，来自南开大学的研究人员开发了一种纳米颗粒，作为抗纤维化的基因的载体，为损伤组织和常驻细胞提供抗纤维化治疗，以限制促纤维化表型的表现。研究人员将表达骨形态发生蛋白7（BMP7）或肝细胞生长因子（HGF）-NK1（HGF/NK1）的质粒DNA包裹在有一层透明质酸壳的聚糖纳米颗粒内，安全地将含有质粒DNA的多功能纳米粒导入肾脏，用于抗纤维化因子的局部和持续表达。在小鼠模型中，静脉注射后，这些纳米颗粒约有10-45%的基因被肾脏摄取，减轻了纤维化的发展，并挽救了肾功能。BMP7基因逆转了纤维化进展、促进肾小管再生；HGF/NK1基因减少胶原纤维沉积。结论：纳米颗粒作为BMP7基因和HGF-NK1基因的载体，提供了今后靶向基因治疗慢性肾脏病的基础。参考文献1.Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, et al. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. New England Journal of Medicine. 2019;381(4):338-48.2.Li R, Sundi D, Zhang J, Kim Y, Sylvester RJ, Spiess PE, et al. Systematic Review of the Therapeutic Efficacy of Bladder-preserving Treatments for Non-muscle-invasive Bladder Cancer Following Intravesical Bacillus Calmette-Guerin. Eur Urol. 2020;78(3):387-99.3.Grimm MO, van der Heijden AG, Colombel M, Muilwijk T, Martinez-Pineiro L, Babjuk MM, et al. Treatment of High-grade Non-muscle-invasive Bladder Carcinoma by Standard Number and Dose of BCG Instillations Versus Reduced Number and Standard Dose of BCG Instillations: Results of the European Association of Urology Research Foundation Randomised Phase III Clinical Trial "NIMBUS". Eur Urol. 2020;78(5):690-8.4.Mariappan P, Johnston A, Padovani L, Clark E, Trail M, Hamid S, et al. Enhanced Quality and Effectiveness of Transurethral Resection of Bladder Tumour in Non-muscle-invasive Bladder Cancer: A Multicentre Real-world Experience from Scotland's Quality Performance Indicators Programme. Eur Urol. 2020.5.Lindgren MS, Bue P, Azawi N, Blichert-Refsgaard L, Sundelin MO, Dyrskjøt L, et al. The DaBlaCa-13 Study: Short-term, Intensive Chemoresection Versus Standard Adjuvant Intravesical Instillations in Non-muscle-invasive Bladder Cancer-A Randomised Controlled Trial. Eur Urol. 2020.6.Teo MY, Mota JM, Whiting KA, Li HA, Funt SA, Lee CH, et al. Fibroblast Growth Factor Receptor 3 Alteration Status is Associated with Differential Sensitivity to Platinum-based Chemotherapy in Locally Advanced and Metastatic Urothelial Carcinoma. Eur Urol. 2020.7.Galsky MD, Arija JÁ A, Bamias A, Davis ID, De Santis M, Kikuchi E, et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. 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FDA 批准首个用于治疗晚期尿路上皮癌的FGFR激酶抑制剂Nature Medicine 免疫检查点抑制剂PD-L1联合CTLA-4单抗治疗高危尿路上皮癌前沿医学 多功能天然高分子纳米颗粒作为抗纤维化基因载体用于治疗CKD厄达替尼（erdafitinib）我们的节目曾在《消化科星期三 Episode 3》中介绍过培米加替尼，治疗成纤维细胞生长因子受体编码基因（FGFR）基因融合或重排的局部晚期胆管癌，胆管癌中约有20%的患者存在这种基因突变。研究人员发现FGFR突变在尿路上皮癌中也很常见，并且可能与对免疫干预的敏感性降低相关。厄达替尼（erdafitinib）是一种FGFR1-4的酪氨酸激酶抑制剂，2019年4月，FDA已经批准厄达替尼（erdafitinib）用于治疗局部晚期或转移性尿路上皮癌。《BLC2001研究：厄达替尼治疗局部晚期或转移性尿路上皮细胞癌的2期临床研究》New England Journal of Medicine，2019年8月 (1) 在这项开放标签的2期研究中，纳入了FGFR基因突变的、局部晚期和不可切除或转移性尿路上皮细胞癌的患者99人，所有患者既往均接受过化疗，并在化疗12个月内发生疾病进展。最初将患者随机分组，随后根据中期分析，将连续用药方案的起始剂量设定为8mg/d，并可在药效学指导下，将剂量增加至9mg/d。经过平均5个周期的厄达替尼治疗后，缓解率为40%（3%完全缓解，37%部分缓解）。在既往接受过免疫治疗患者中，缓解率为59%。中位无进展生存期为5.5个月，中位总生存期为13.8个月。结论：在既往接受过治疗的、有FGFR基因突变的、且患局部晚期和不可切除或转移性的尿路上皮细胞癌的患者中，厄达替尼治疗后肿瘤客观缓解率达40%。膀胱尿路上皮癌膀胱癌是最常见的泌尿系统恶性肿瘤，其中尿路上皮癌（也称移行细胞癌）是主要的组织学类型，占所有膀胱癌的90%。膀胱尿路上皮癌可表现为非肌肉浸润癌、肌肉浸润癌和转移癌，病变的程度可以反映自然病程，并决定了治疗和预后。膀胱癌通常表现为肉眼血尿或镜下血尿，刺激性或梗阻性排尿困难也可以 是首发症状。非肌肉浸润性膀胱癌的治疗对于非肌肉浸润性膀胱癌的患者，采用经尿道膀胱肿瘤切除术（TURBT），并联合膀胱内辅助治疗等保守治疗方式有可能保留膀胱功能。膀胱内辅助治疗主要包括卡介苗（牛结合分支杆菌的减毒活疫苗）和丝裂霉素C、表柔比星、吉西他滨等化疗药物。《系统回顾：膀胱治疗非肌肉浸润性膀胱癌的疗效》European Urology，2020年9月 (2)研究的目的是评价在卡介苗治疗后，保留膀胱功能的患者的疾病完全缓解率和无复发率。研究系统地回顾了42项研究，包括24种治疗方案、2254名患者。包含原位癌在内的肿瘤治疗中位完全缓解率，6个月时为26%，12个月时为17%，24个月时为8%。相比，乳头状癌的平均无进展率，6个月时为67%，12个月时为44%，24个月时为10%。特别是在卡介苗无效的、接受草分枝杆菌细胞壁-核酸复合物的患者中，6个月和12个月的完全缓解率分别为45%和27%；6、12、24个月中位不带病生存率分别为43%、35%和18%。总的中位无进展率为91%，原位癌的研究中为95%，乳头状癌的研究中为89%。膀胱内给药的不良反应少，且轻微。结论：卡介苗治疗后的、保留膀胱疗法，在非肌肉浸润性膀胱癌患者中取得了适度的疗效。《NIMBUS研究：卡介苗标准剂量和数量灌注治疗重度非肌肉浸润性膀胱癌的3期临床研究》European Urology，2020年11月 (3)膀胱内灌注卡介苗治疗是一种被广泛接受的预防非肌肉浸润性膀胱癌复发的策略，但是具有显著的毒性。研究的目的是评估了降低标准剂量卡介苗灌注的次数是否可以达到同样的疗效。研究纳入了345名非肌肉浸润性膀胱癌的患者，分别接受标准治疗（诱导6周，在第3、6和12个月时各治疗3周，共15次灌注），或低频率治疗（第1、2和6周诱导，在第3、6和12个月时各治疗2周，共9次灌注）。中位随访12个月后，标准治疗组复发率12%，低频率治疗组复发率27%。安全性分析达到了预先定义的、无效停止标准。结论：在预防膀胱癌复发方面，标准治疗方案更好，目前研究已经停止对参与者的招募。《国家质量指标项目：提高非肌肉浸润性膀胱癌经尿道膀胱肿瘤切除术的质量和有效性》European Urology，2020年8月 (4)非肌肉浸润性膀胱癌的临床预后部分取决于初始干预。为了改善和标准化癌症治疗，苏格兰实施了一项针对膀胱癌的国家质量指标项目。研究中纳入了2689例患者，标准干预包括：（1）使用膀胱图；（2）经尿道膀胱肿瘤切除术后单次膀胱内灌注丝裂霉素C一次；（3）逼尿肌活检；（4）高危膀胱癌患者中，早期行二次手术。研究中，67%患者接受了术后一次膀胱灌注；复发率、残余癌比例和继发肿瘤的比例分别为13%、33%和2.9%。术后一次膀胱灌注复发率降低相关；逼尿肌活检则癌症残留的可能性减半。结论：在苏格兰实施国家质量指标计划似乎有助于向患者提供高质量的经尿道膀胱肿瘤切除术，且降低了术后的复发率、肿瘤分期更准确。《DaBlaCa-13研究：短期强化化疗与标准辅助膀胱内灌注治疗非肌肉浸润性膀胱癌》European Urology，2020年8月 (5)膀胱灌注治疗非肌肉浸润性膀胱癌可减少复发。术前灌注化疗副作用更少，甚至一些患者在治疗后都无需接受肿瘤切除术了。研究旨在比较术前丝裂霉素C短期强化化疗治疗复发性非肌肉浸润性膀胱癌的效果。研究纳入120例患者，短期强化化疗组，膀胱灌注化疗每周3次，共2周；对照组先行经尿道膀胱肿瘤切除术，术后6周每周进行一次膀胱灌注辅助治疗。在短期强化化疗组中，有33名参与者（57%）出现了肿瘤完全缓解，且不良事件少。结论：术前短期强化化疗使一半以上的患者避免肿瘤切除术，但长期疗效仍需随访观察。肌肉浸润性膀胱癌的治疗对于肌肉浸润性膀胱癌，需行根治性膀胱切除术+尿流改道术，以及辅助化疗、免疫治疗。化疗方案中的MVAC方案（甲氨蝶呤、长春碱、多柔比星、顺铂）被认为是一线化疗方案，临床实践中多在这个方案上增减。目前已有几个免疫检查点抑制剂被获批用于膀胱尿路上皮癌的治疗：阿替利珠单抗（atezolizumab），帕博利珠单抗（pembrolizumab），纳武利尤单抗（nivolumab），阿伟鲁单抗（avelumab），德瓦鲁单抗（durvalumab）。《回顾性综述：FGFR3的水平变化与膀胱癌对铂化疗的敏感性有关》European Urology，2020年8月(6)大约15%的膀胱癌存在成纤维细胞生长因子受体3 （FGFR3）基因突变。研究人员回顾性的比较和综述三个队列的患者：（1）新辅助化疗治疗肌肉侵袭性膀胱癌患者的数据；（2）一线铂类化疗治疗转移性尿路上皮癌患者的数据；（3）来自癌症基因组图谱中的肌肉侵袭性膀胱癌患者的数据。队列一：72例新辅助化疗的肌肉侵袭性膀胱炎癌患者中有13%具有FGFR3突变，均没有达到病理完全缓解，且无复发生存期短。队列三：来自癌症基因组图谱中的肌肉侵袭性膀胱癌的患者，接受辅助化疗、且伴有FGFR3突变的无复发生存期也更短。相反，在未接受化疗的患者中，FGFR3突变与无复发生存期更长、总生存率更高。队列二：转移性尿路上皮癌的患者中，FGFR3突变虽然药物反应低，但不影响无进展生存率和总生存率。结论：肌肉浸润性膀胱癌中，FGFR3突变可能与围手术期铂类药物化疗反应差、易复发有关。《IMvigor130研究：化疗联合阿替利珠单抗治疗转移性尿路上皮癌的3期临床研究》Lancet，2020年5月 (7)这个多中心、3期、随机研究的目的是，比较阿替利珠单抗与安慰剂加铂类化疗在一线转移性尿路上皮癌的疗效。研究纳入未经治疗的、≥18岁的、局部晚期或转移性尿路上皮细胞癌患者共1213人。随机接受阿替利珠单抗+铂类化疗，或阿替利珠单抗单药治疗，或安慰剂+铂类化疗，随访11.8个月。中位无进展生存期，在阿替利珠单抗联合化疗组为8·2个月，在安慰剂联合化疗组为6.3个月（p = 0·007）。中位生存期，在阿替利珠单抗联合化疗组为16·0个月，安慰剂联合化疗组为13·4个月（p = 0·027）。阿替利珠单抗单药治疗组中位总生存期为15·7个月，与安慰剂联合化疗组无差异。结论：阿替利珠单抗联合铂类化疗延长了转移性尿路上皮癌患者的无进展生存，研究支持使用阿替利珠单抗联合铂类化疗作为转移性尿路上皮癌的潜在的、一线治疗选择。《JAVELIN Bladder200研究：PD-L1单抗阿伟鲁单抗维持治疗局部晚期、或转移性尿路上皮癌》New England Journal of Medicine，2020年9月 (8)这项3期临床试验中，研究人员纳入无法手术的局部晚期、或转移性尿路上皮癌患者共700人，在接受一线化疗后，随机给予阿伟鲁单抗维持治疗、或仅给予支持治疗。阿伟鲁单抗维持治疗能显著延长了患者的总生存期。阿伟鲁单抗组和对照组的，1年总生存率分别为71.3%和58.4%，中位总生存期分别为21.4个月和14.3个月（死亡风险比 0.69，P = 0.001）。阿伟鲁单抗也显著延长了PD-L1阳性的患者的总生存率，两组分别为79.1%和60.4%（风险比 0.56，P < 0.001）。在总体人群中，阿伟鲁单抗组的中位无进展生存期为3.7个月，对照组为2.0个月（疾病进展或死亡的风险比为0.62）；在PD-L1阳性的人群中，阿伟鲁单抗组的中位无进展生存期为5.7个月，对照组为2.1个月（风险比 0.56）。结论：一线化疗+阿伟鲁单抗维持治疗，能进一步延长了患者的总生存期。《随机对照研究：卡博替尼和纳武利尤单抗联合或不联合伊匹木单抗治疗转移性尿路上皮癌的1期临床研究》Journal of Clinical Oncology，2020年10月 (9)卡博替尼（cabozantinib）是一种酪氨酸激酶受体抑制剂 ，纳武利尤单抗（nivolumab）是一种PD-1单抗，伊匹木单抗（ipilimumab）是一种CTLA-4单抗。研究的目的是评估了卡博替尼联合纳武利尤单抗的CaboNivo方案，以及CaboNivo联合伊匹木单抗的CaboNivoIpi方案在转移性尿路上皮癌和其他泌尿生殖系统恶性肿瘤患者中的安全性和有效性，共入组54人。平均随访时间为44.6个月，转移性尿路上皮癌的客观缓解率为38.5%，平均缓解持续时间尚未达到，中位无进展生存期达12.8个月，中位总生存期为25.4个月。CaboNivo和CaboNivoIpi治疗组中，严重不良事件发生率分别为75%和87%，主要包括疲劳、腹泻、高血压、肝炎、结肠炎。II期临床研究推荐剂量为卡博替尼40 mg/d、纳武利尤单抗3 mg/kg，伊匹木单抗1 mg/kg。结论：CaboNivo方案（卡博替尼+纳武利尤单抗）和CaboNivoIpi（卡博替尼+纳武利尤单抗+伊匹木单抗）方案均显示了良好的耐受性和持久的疗效，多项II期和III期临床研究正在进行中。《随机对照临床研究：新辅助PD-L1加CTLA-4阻滞治疗顺铂化疗无法耐受的、可手术切除的、高危、尿路上皮癌的1期临床研究》Nature Medicine，2020年10月 (10)这是首个抗PD-L1单抗（德瓦鲁单抗，durvalumab）联合抗CTLA-4单抗（曲美木单抗，tremelimumab）。研究纳入在顺铂化疗无法耐受的、具有高危特征的、尿路上皮癌患者共28人（高危特征为肿块大、组织学变异、淋巴血管侵犯、肾盂积水和/或高度上尿路疾病）。在完成手术的患者中，病理完全缓解为37.5%，58%的患者达到无残余侵袭性占位。21%的患者出现免疫相关不良事件，包括无症状实验室异常、肝炎和结肠炎结论：研究提供了抗PD-L1单抗联合抗CTLA-4单抗新辅助治疗的初步安全性、有效性和生物标志物数据，这对于局限性尿路上皮癌患者，特别是具有高危特征且目前没有建立标准护理新辅助治疗的顺铂不合格患者，值得进一步发展。《NABUCCO研究：术前CTLA-4联合PD-1抑制剂治疗局部晚期尿路上皮癌的1期临床研究》Nature Medicine，2020年10月 (11)伊匹木单抗（ipilimumab）是一种CTLA-4单抗，纳武利尤单抗（nivolumab）是一种PD-1单抗，在NABUCCO研究中，纳入了24名III期、尿路上皮癌患者，术前接受两次伊匹木单抗联合纳武利尤单抗治疗后，然后在12周内接受手术切除。研究中46%的患者达到病理学完全缓解，58%达到无残余侵袭性占位。与单独使用PD-1/PD-L1抑制剂的研究相比，伊匹木单抗联合纳武利尤单抗的疗效与基线时CD8+ T细胞活性无关。3-4级免疫相关不良事件发生率分别为55%和41%。结论：在局部晚期尿路上皮癌患者中，CTLA-4联合PD-1阻断可能提供一个有效的术前治疗策略，而不用考虑先前的CD8+ T细胞的活性。纳米颗粒作为抗纤维化基因载体治疗CKD《基础研究：多功能天然高分子纳米颗粒作为抗纤维化基因载体用于治疗慢性肾脏病》J American Society of Nephrology，2020年8月 (12)预防或逆转促纤维化的细胞的基因表型是治疗慢性肾脏病的一个方向，来自南开大学的研究人员开发了一种纳米颗粒，作为抗纤维化的基因的载体，为损伤组织和常驻细胞提供抗纤维化治疗，以限制促纤维化表型的表现。研究人员将表达骨形态发生蛋白7（BMP7）或肝细胞生长因子（HGF）-NK1（HGF/NK1）的质粒DNA包裹在有一层透明质酸壳的聚糖纳米颗粒内，安全地将含有质粒DNA的多功能纳米粒导入肾脏，用于抗纤维化因子的局部和持续表达。在小鼠模型中，静脉注射后，这些纳米颗粒约有10-45%的基因被肾脏摄取，减轻了纤维化的发展，并挽救了肾功能。BMP7基因逆转了纤维化进展、促进肾小管再生；HGF/NK1基因减少胶原纤维沉积。结论：纳米颗粒作为BMP7基因和HGF-NK1基因的载体，提供了今后靶向基因治疗慢性肾脏病的基础。参考文献1.Loriot Y, Necchi A, Park SH, Garcia-Donas J, Huddart R, Burgess E, et al. Erdafitinib in Locally Advanced or Metastatic Urothelial Carcinoma. New England Journal of Medicine. 2019;381(4):338-48.2.Li R, Sundi D, Zhang J, Kim Y, Sylvester RJ, Spiess PE, et al. Systematic Review of the Therapeutic Efficacy of Bladder-preserving Treatments for Non-muscle-invasive Bladder Cancer Following Intravesical Bacillus Calmette-Guerin. Eur Urol. 2020;78(3):387-99.3.Grimm MO, van der Heijden AG, Colombel M, Muilwijk T, Martinez-Pineiro L, Babjuk MM, et al. Treatment of High-grade Non-muscle-invasive Bladder Carcinoma by Standard Number and Dose of BCG Instillations Versus Reduced Number and Standard Dose of BCG Instillations: Results of the European Association of Urology Research Foundation Randomised Phase III Clinical Trial "NIMBUS". Eur Urol. 2020;78(5):690-8.4.Mariappan P, Johnston A, Padovani L, Clark E, Trail M, Hamid S, et al. Enhanced Quality and Effectiveness of Transurethral Resection of Bladder Tumour in Non-muscle-invasive Bladder Cancer: A Multicentre Real-world Experience from Scotland's Quality Performance Indicators Programme. Eur Urol. 2020.5.Lindgren MS, Bue P, Azawi N, Blichert-Refsgaard L, Sundelin MO, Dyrskjøt L, et al. The DaBlaCa-13 Study: Short-term, Intensive Chemoresection Versus Standard Adjuvant Intravesical Instillations in Non-muscle-invasive Bladder Cancer-A Randomised Controlled Trial. Eur Urol. 2020.6.Teo MY, Mota JM, Whiting KA, Li HA, Funt SA, Lee CH, et al. Fibroblast Growth Factor Receptor 3 Alteration Status is Associated with Differential Sensitivity to Platinum-based Chemotherapy in Locally Advanced and Metastatic Urothelial Carcinoma. Eur Urol. 2020.7.Galsky MD, Arija JÁ A, Bamias A, Davis ID, De Santis M, Kikuchi E, et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020;395(10236):1547-57.8.Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020;383(13):1218-30.9.Apolo AB, Nadal R, Girardi DM, Niglio SA, Ley L, Cordes LM, et al. Phase I Study of Cabozantinib and Nivolumab Alone or With Ipilimumab for Advanced or Metastatic Urothelial Carcinoma and Other Genitourinary Tumors. J Clin Oncol. 2020;38(31):3672-84.10.Gao J, Navai N, Alhalabi O, Siefker-Radtke A, Campbell MT, Tidwell RS, et al. Neoadjuvant PD-L1 plus CTLA-4 blockade in patients with cisplatin-ineligible operable high-risk urothelial carcinoma. Nat Med. 2020.11.van Dijk N, Gil-Jimenez A, Silina K, Hendricksen K, Smit LA, de Feijter JM, et al. Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial. Nat Med. 2020.12.Midgley AC, Wei Y, Zhu D, Gao F, Yan H, Khalique A, et al. Multifunctional Natural Polymer Nanoparticles as Antifibrotic Gene Carriers for CKD Therapy. J Am Soc Nephrol. 2020.

Featuring perspectives from Dr Shirish M Gadgeel on the later-line management of metastatic squamous cell carcinoma of the lung. Recent advances in the management of advanced non-small cell lung cancer (NSCLC) (0:00) Case: A woman in her early 70s with metastatic squamous cell carcinoma (SCC) of the lung receives carboplatin/paclitaxel and pembrolizumab as first-line therapy on the KEYNOTE-021 trial (02:25) Response to pembrolizumab and chemotherapy in advanced SCC of the lung (04:34) Efficacy of pembrolizumab alone or in combination with chemotherapy for advanced NSCLC (07:41) Choice of immune checkpoint inhibitor/chemotherapy regimen as first-line therapy for metastatic SCC of the lung (12:22) Results of the Phase III CheckMate 227 trial evaluating nivolumab alone, with ipilimumab or with chemotherapy as first-line therapy for metastatic NSCLC (15:43) Interim overall survival analysis of the Phase III IMpower110 study investigating atezolizumab versus platinum-based chemotherapy for metastatic NSCLC in the first-line setting (18:32) Cancer site and adverse events induced by immune checkpoint inhibitors (20:05) Genetic alterations in patients with SCC of the lung; rationale for targeting the ERBB signaling pathway (22:18) Results of the Phase III LUX-Lung 8 trial of afatinib versus erlotinib as second-line treatment for advanced SCC of the lung (25:53) Secondary analysis of LUX-Lung 8: Association of ERBB mutations with clinical outcomes among patients with afatinib- or erlotinib-treated SCC of the lung (28:04) Role of HER2 mutations and HER2 amplification in patients with NSCLC; incidence of HER2 alterations in patients with SCC of the lung (30:14) Targeting HER2 alterations with the tyrosine kinase inhibitors afatinib and dacomitinib in patients with NSCLC (34:15) Efficacy of the antibody-drug conjugate trastuzumab deruxtecan (DS-8201) in patients with NSCLC and HER2 alterations (36:11) Activity of T-DM1 in patients with NSCLC and HER2 mutations (38:04) Management of gastrointestinal side effects associated with afatinib (40:22) Activity of afatinib in heavily pretreated ERBB2 mutation-positive advanced NSCLC (43:01) Afatinib in patients with metastatic or recurrent lung cancer with HER2 mutations  (45:15) Case: A man in his early 80s develops metastases to the liver during treatment with durvalumab after chemoradiation therapy for Stage III SCC of the lung and is found to have FGFR1 amplification (47:15) FGFR signaling as a target for NSCLC therapy; outcomes with the FGFR inhibitor AZD4547 in patients with metastatic SCC of the lung and FGFR alterations (51:04) SWOG-S1400 Lung Cancer Master Protocol (Lung-MAP) — Biomarker-targeted therapy for patients with previously treated Stage IV SCC of the lung (56:02) Case: A woman in her early 50s with ALK-rearranged metastatic lung adenocarcinoma experiences a dramatic response to crizotinib on the PROFILE 1014 study (1:02:39) Response to ALK inhibitors for ALK-rearranged metastatic NSCLC (1:06:54) CME information and select publications

ONCE UPON A GENE - EPISODE 010 My Pfeiffer Pfamily Synthiea Kaldi was the first person I knew to call when I was told something was wrong with Ford. I admire her so much and would be lost without her humor and understanding. Finding someone like Synthiea, someone who lives with a lot of hard stuff but can also find the humor in it, is a really valuable resource for your mental health and general outlook. It's not easy being a parent, especially when your child has a complex medical need. Synthiea is further ahead in this unplanned detour along a dirt road with a lot of potholes and I'm constantly learning from her. It's impossible not to feel the light that radiates from her and I'm excited to share our conversation about her beautiful daughter and their experience with Pfeiffer Syndrome so far. Today we're talking about Mallory, Sythiea's little girl.  EPISODE HIGHLIGHTS Mallory was born with a genetic disorder called Pfeiffer Syndrome, which is caused by a mutation in one of two genes- either the FGFR1 or FGFR2. These genes control bone growth in utero, signaling them when to grow and stop growing. When Mallory was born, all the sutures in her skull were fused except one. Usually you have skull plates floating around the baby's head and they fuse much later, some not even until teen years. Because Mallory's plates where fused, her brain didn't have the room it needed to grow, so it started growing places it doesn't normally grow. It pinched her ear canals completely shut, so she wears hearing aids. It also grew behind her eyes and started pushing them out, so there were quite a few surgeries she had very early in order to protect her eyes. A lot of times, kids with fusions have fused fingers and toes. With Mallory's specific type of Pfeiffer Syndrome, most have fused elbows. Mallory also has fused knees.  When Mallory was born, I remember looking across the room and her head was huge, the shape of the Planter's peanut guy, one of here eyes looked like it was ready to pop out and I remember thinking she was going to die. It wasn't the best birth experience, but Mallory didn't die. She had much bigger plans. They transported her to NICU and the doctors were pretty sure of her diagnosis when she was born, but had to do the genetic testing to confirm. In the course of about two weeks that she was in the hospital, she had a bunch of surgeries. They had to go in and perform a strip craniectomy when she was only five days old, where they cut open the skull and give the brain room to grow and relieve the pressure.  We were very fortunate in that when Mallory was born, the Medical Director of Craniofacial told the hospital to arrange for us to meet another family in the area whose daughter also has Pfeiffer Syndrome. He knew her mom and I would hit it off and so he made it happen. That family is now some of our closest friends. We can laugh about things with each other because we're not afraid to and when you talk to people who aren't going through the same thing, they probably don't find it funny, but also don't think it's okay to laugh about it.  Mallory has a trach, which is a little tube that goes into the base of your throat to help you breath. She got that when she was about four months old because she wasn't breathing right and wasn't breathing well. A big part of the problem was that when that lovely big brain was growing wherever it could to protect itself, it really squished a lot of her throat and airway. If she got sick at all, it made it impossible for her to breath. We got the trach and with that came home nursing. The trach is not necessarily permanent, but we don't know at this point if or when she can get it out. Mallory is just another kid. Yes, she looks different and she talks different and she's in a wheelchair, but at the end of the day she likes princesses just like most kids her age. She likes watching funny YouTube videos of babies and cats, playing games, reading, all the same stuff. I appreciate when parents encourage their children to say hello and if they have a question to ask. Treating us as normal as possible is the best thing you can do and teaching your kids to do that as well is the best thing you can do for your kids.  CONNECT WITH SYNTHIEA Synthiea Kaldi on Facebook: https://www.facebook.com/skaldi TUNE INTO THE ONCE UPON A GENE PODCAST Spotify Apple Podcasts Stitcher Overcast CONNECT WITH EFFIE PARKS Website Twitter Instagram

Dr Formisano talks to ecancertv at SABCS 2015 about the critical interaction between the estrogen receptor (ER) and amplification of the fibroblast growth factor receptor 1 (FGFR1) gene in endocrine resistant breast cancer. In the interview, Dr Formisano explains how targeting the FGFR1 gene in combination with anti-estrogen therapy may abrogate resistance and is worthy of further clinical investigation. Specifically he describes the findings of a study in which whole exome sequencing was used to evaluate tumour biopsies taken from 130 women with an operable ER-positive/HER2-negative breast cancer who had received endocrine treatment with an aromatase inhibitor for 10 to 21 days before surgery.

Dr. Ross Camidge discusses a clinical trial studying patients with advanced stage lung cancer to identify those who may respond to a drug called ponatinib. Both small cell and non small cell lung cancer patients may be eligible. http://bit.ly/UCponatinib

Dr. Ross Camidge discusses a clinical trial studying patients with advanced stage lung cancer to identify those who may respond to a drug called ponatinib. Both small cell and non small cell lung cancer patients may be eligible. http://bit.ly/UCponatinib

Dr. Ross Camidge discusses a clinical trial studying patients with advanced stage lung cancer to identify those who may respond to a drug called ponatinib. Both small cell and non small cell lung cancer patients may be eligible. http://bit.ly/UCponatinib

In Part 2 of 2 videos about squamous lung cancer, Dr. Chad Pecot explains the value of patients receiving molecular profiling of their tumor, the vital role of clinical trials, and the promise of immunotherapy for treating this type of lung cancer.

In Part 2 of 2 videos about squamous lung cancer, Dr. Chad Pecot explains the value of patients receiving molecular profiling of their tumor, the vital role of clinical trials, and the promise of immunotherapy for treating this type of lung cancer.

In Part 2 of 2 videos about squamous lung cancer, Dr. Chad Pecot explains the value of patients receiving molecular profiling of their tumor, the vital role of clinical trials, and the promise of immunotherapy for treating this type of lung cancer.

Michael Simons describes how signaling through the receptor FGFR1 prevents endothelial-to-mesenchymal transition by inhibiting TGF-β signaling.