Podcasts about egfr tkis

JCO Editorial Fellow Dr. Ece Cali Daylan and JCO Associate Editor Dr. Thomas Stinchcombe discuss the ASCO 2025 Simultaneous Publication paper "Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non-Small-Cell Lung Cancer." Transcript The guest on this podcast episode has no disclosures to declare. Dr. Ece Cali: Hello, and welcome to our 2025 ASCO Annual Meeting series, where we cover some of the top JCO papers published simultaneously with their abstract presentation at this year's meeting. I'm your host, Dr. Ece Cali, JCO Editorial Fellow, and I am joined by JCO Associate Editor, Dr. Tom Stinchcombe. In this episode, we will discuss the Journal of Clinical Oncology article and abstract presentation "Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non–Small-Cell Lung Cancer.” NeoADAURA is a randomized global phase III study investigating the efficacy of neoadjuvant osimertinib-containing regimens in patients with resectable EGFR-mutated stage II to IIIB non–small-cell lung cancer. 358 patients were randomized 1:1:1 to receive osimertinib plus chemotherapy, osimertinib monotherapy, or placebo plus chemotherapy in the neoadjuvant setting. The primary endpoint was major pathological response. Osimertinib plus chemotherapy and osimertinib alone demonstrated MPR rates of 26% and 25%, respectively, compared to 2% in the chemotherapy plus placebo arm with a p-value of less than 0.001. Tom, can you please explain to our listeners how you interpret this data? Dr. Thomas Stinchcombe: Great question. Yeah, I think to give a little context, obviously, chemotherapy and immunotherapies preoperatively is becoming the standard of care. However, patients with EGFR-mutant lung cancer generally have not responded to immunotherapy, and many of the trials excluded patients with known EGFR mutation. There have been smaller phase II trials that had looked at EGFR TKIs preoperatively, but none of these were definitive. So I think that this trial is a big trial, and I think some of the strengths are that it has osimertinib alone and chemotherapy with osimertinib arms as compared to the standard of chemotherapy. I think it's going to be really interesting at the meeting to see how this is discussed by the discussant and also what the reaction is to its public presentation. And I think that's largely because there's an alternative paradigm now, surgical resection adjuvant osimertinib, that's available to patients. So I think this will be interesting to see what the reaction is to the induction therapy. For patients with known N2 disease, I've generally given some form of induction therapy prior to surgical resection. So I think that's the subgroup of patients that I'm most likely to employ this approach with based on the results. Dr. Ece Cali: So, in this trial, more than 90% of the patients on the osimertinib-containing regimens underwent curative-intent surgery. So, this speaks to the feasibility of the approach, and the higher MPR rate with osimertinib-containing regimens is encouraging. Event-free survival data is currently immature. You have already touched upon some of the strengths of the trial, but what are the weaknesses and the strengths of this trial? Dr. Thomas Stinchcombe: So, I mean, I think there are some weaknesses. A major pathological response was chosen as an endpoint, and there could be an argument that path CR is more of a prognostic marker. However, the rates of path CR are relatively low, so it would have been very hard to design a trial such as that. And then I think the trial started off as a preoperative trial but effectively became a perioperative trial with preoperative EGFR-TKI, postoperative osimertinib. And so I think it's going to be very hard to determine what the contribution of the components are. And then you've hit on another part that I think is very important when we interpret the data that the maturity on the event-free survival is only 15%, and most people are still on therapy. So the event-free survival, which is an important endpoint, is very immature right now. Dr. Ece Cali: And this trial was designed to compare the neoadjuvant approaches, hence the comparator arm here is neoadjuvant chemotherapy followed by surgery. So, considering the ADAURA trial results with upfront surgery followed by osimertinib as adjuvant, so how do you see this trial's impact on the current clinical practice? Dr. Thomas Stinchcombe: Well, very good question, I think one that we're still struggling with as we kind of look at this data. I think, for me, stage II patients will most likely go to surgery and then get adjuvant osimertinib, and then maybe the N2 patients will get an osimertinib-containing regimen as an induction therapy. I think one of the questions is does it really matter when you get the osimertinib as long as you get it at some point? And I think that's going to be the critical interpretation of some of the data at this point. Dr. Ece Cali: And how do you think this trial shapes the future research for patients with resectable EGFR-mutated lung cancer? Dr. Thomas Stinchcombe: Well, I mean, I think it shows that chemotherapy was really modestly active with an MPR rate of 2%, no pathological responses. And then I think you're going to have to look at an osimertinib plus another targeted therapy component. I think, you know, when I looked at the osimertinib versus the chemo-osimertinib arm, I also was sort of surprised that the MPR rate and the path CR rate were very, very similar. So I think that the question is would a double targeted therapy approach or some other approach matter? And I think it also sets a safety standard. And you touched on this in your comments, that there was not a disparity in terms of the rate of going to surgery or R0/R1 resections. So patients were not having progressive disease events or toxicities that prevented surgery. So I think it does give us good safety data. Dr. Ece Cali: Tom, thank you so much for sharing your insights on the JCO article, "Neoadjuvant Osimertinib for Resectable EGFR-Mutated Non–Small-Cell Lung Cancer." Join us again for the latest simultaneous publications from the 2025 ASCO Annual Meeting, and please take a moment to rate, review, and subscribe to all ASCO podcast shows at asco.org/podcasts. Until then, enjoy the rest of ASCO 2025. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. John Sweetenham shares highlights from Day 3 of the 2025 ASCO Annual Meeting, including new research for the treatment of advanced renal cell carcinoma and 2 studies on novel approaches in non-small cell lung cancer. Transcript Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, the host of the ASCO Daily News Podcast, with my takeaways on selected abstracts from Day 3 of the 2025 ASCO Annual Meeting. Today's selection features studies addressing the treatment of advanced renal cell carcinoma and 2 studies exploring novel approaches in non-small cell lung cancer. My disclosures are available in the transcript of this episode. The first abstract is number 4505. This study, led by Dr. Toni Choueiri of the Dana-Farber Cancer Institute, describes the final analysis of the CheckMate 214 trial, which compared the combination of nivolumab and ipilimumab with sunitinib for the first-line treatment of advanced renal cell carcinoma. The ipi-nivo combination is approved for the frontline treatment of intermediate and poor-risk advanced renal cell carcinoma based on the primary analysis of the CheckMate 214 trial, which demonstrated a higher response rate and longer overall survival compared with sunitinib. Today's presentation provided the final safety and efficacy results for the trial with long-term follow-up of more than 9 years.  The intent-to-treat (ITT) population in this trial comprised 550 patients randomized to nivo and ipi versus 546 who received sunitinib. The final analysis showed sustained long-term benefit for the combination therapy. Patients given nivolumab plus ipi had a 29% reduction in the risk for death compared with sunitinib. For patients with intermediate or poor-risk disease, there was a 31% reduction in the risk of death.   The probability of remaining in response through 8 years was more than doubled with nivolumab plus ipilimumab versus sunitinib in the ITT population at 48% versus 19%, and in the intermediate and poor-risk population at 50% versus 23%. The other important observation is that patients with favorable-risk disease appeared to have a 20% reduction in the risk for death at 9 years and more durable responses. This suggests a possible delayed benefit for ipi and nivo in this group since these differences were not seen in the earlier analysis.   No new safety signals emerged with longer follow-up, and the results confirm the use of ipi and nivo as a standard front-line combination therapy in this disease. Since this combination has been in widespread use for some years, the results are not surprising although the subgroup analysis suggesting benefit in favorable-risk patients is likely to inform practice in the future.   Today's second abstract is number is 8506, which was presented by Dr. Tony Mok from the Chinese University of Hong Kong, describing results from the phase 3 HERTHENA-Lung02 trial. This trial compared the antibody-drug conjugate patritumab deruxtecan with platinum-based chemotherapy in patients with EGFR-mutated advanced non-small cell lung cancer following a third-generation tyrosine kinase inhibitor (TKI).  Patritumab deruxtecan, also known as HER3-DXd, comprises a fully human anti-HER3 IgG3 monoclonal antibody conjugated to a topoisomerase 1 inhibitor payload, and showed activity in a previous phase 2 trial in patients relapsing after EGFR TKI and chemotherapy.   In this phase 3 study, this agent was compared with platinum-based chemotherapy in eligible patients with an EGFR-activating mutation who had previously received 1 or 2 EGFR TKIs, at least one of which was a third-generation drug, with relapse or progression after this therapy. Five hundred and eighty-six patients were enrolled, with progression-free survival as the primary endpoint.  The primary analysis showed a 9-month progression-free survival of 29% for the experimental arm compared with 19% for platinum-based chemotherapy, for a hazard ratio of 0.77 and a P value of 0.011. With higher progression-free survival rates at 6 months and 12 months, HER3-DXd also had a better objective response rate (35.2% versus 25.3%) compared with platinum-based chemotherapy (PBC), and HER3-DXd also extended intracranial progression-free survival compared with PBC in patients with brain metastases, with a hazard ratio of 0.75. Grade 3 or more treatment-related adverse events occurred in 73% of patients treated with HER3-DXd and 57% of patients who received PBC. HER3-DXd had a higher rate of grade or more 3 thrombocytopenia, and drug-related interstitial lung disease occurred in 5% of patients in the HER3-DXd arm.   The follow-up will need more time to mature since no overall survival data are currently available, but definitely an agent to watch with interest. Moving on to today's final abstract, 8500, was presented by Dr. Pasi Jänne from the Dana-Farber Cancer Institute, describing results from the phase 2 portion of the KRYSTAL-7 study. This study is exploring the use of a potent KRAS inhibitor, adagrasib, in combination with pembrolizumab in patients with advanced or metastatic KRASG12C- mutated non-small cell lung cancer.  Adagrasib has already received accelerated approval in the U.S. for previously treated locally advanced or metastatic NSCLC with a KRASG12C mutation. A previous report from the KRYSTAL-7 study demonstrated encouraging activity in combination with pembrolizumab in the frontline setting for this patient group who also had more than 50% expression of PD-L1. The presentation today described efficacy and safety data for this drug combination across all PD-L1 expression levels.  One hundred and forty-nine patients with a median age of 67 years were treated with the combination, 104 of whom had PD-L1 expression level results available, representing the so-called biomarker population in this trial. The overall response rate for the entire study population was 44%. In the biomarker population, the overall response rate ranged from 36% in those with less than 1% PD-L1 expression to 61% for those with more than 50% expression. For all patients, the median response duration was just over 26 months, and the median progression-free and overall survival rates were 11 and 18.3 months respectively.    For the biomarker population, the median progression-free and overall survival were highest in those patients with more than 50% PD-L1. No new safety issues emerged from this analysis; the most frequent toxicities were nausea, diarrhea, and increases in transaminases. Immune-related toxicities included pneumonitis, hypothyroidism, and hepatitis. These are important results and the results of the phase 3 portion of KRYSTAL-7, which compares first-line therapy with adagrasib plus pembro versus pembro alone in the KRASG12C mutated/PD-L1 more than 50% group, will be informative. For those patients with lower levels of PD-L1 expression, the authors suggest that the treatment escalation may be beneficial, possibly including the addition of chemotherapy.  That concludes today's report. Thanks for listening and I hope you will join me again tomorrow to hear more top takeaways from ASCO25. If you value the insights that you hear on the ASCO Daily News Podcast, please remember to rate, review, and subscribe wherever you get your podcasts.  Disclaimer:  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  Find out more about today's speaker:    Dr. John Sweetenham    Follow ASCO on social media:     @ASCO on Twitter    @ASCO on Bluesky    ASCO on Facebook    ASCO on LinkedIn     Disclosures:   Dr. John Sweetenham:    No relationships to disclose

JCO PO author Dr. Hatim Husain at University of California San Diego, shares insights into his JCO PO article, “Adagrasib Treatment After Sotorasib-Related Hepatotoxicity in Patients With KRASG12C-Mutated Non–Small Cell Lung Cancer: A Case Series and Literature Review”, one of the top downloaded articles of 2024. Host Dr. Rafeh Naqash and Dr. Husain discuss how to utilize real-world and clinical trial data to discern the safety of adagrasib (another KRASG12C inhibitor), following sotorasib discontinuation due to hepatotoxicity. TRANSCRIPT Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations where we bring you engaging conversations with authors of clinically relevant and highly significant JCOPO articles. I'm your host, Dr. Rafeh Naqash, Podcast Editor for JCO Precision Oncology and Assistant Professor at the OU Stephenson Cancer Center.  Today, I'm very excited to be joined by Dr. Hatim Hussain, Professor of Medicine at the University of California, San Diego, and author of the JCO Precision Oncology article, “Adagrasib Treatment After Sotorasib-Related Hepatotoxicity in Patients With KRAS-G12C-Mutated Non-Small Cell Lung Cancer: A Case Series and Literature Review.” This was one of the top downloaded articles of 2024. And the other interesting thing is we generally don't do podcasts for case reports or case series, so this is one of the very few that we have selected for the podcast.  And at the time of the recording, our guest disclosures will be linked in the transcript.  Dr. Hussain, welcome to our podcast and thank you for joining us today. Dr. Hatim Husain: Thank you Dr. Naqash. Such a pleasure to be here and to speak with you all. Dr. Rafeh Naqash: And for the sake of this podcast, we'll refer to each other using our first names. So again, as I mentioned earlier that this is one of the very few case reports that we have selected for podcasts in JCOPO and the intention was very deliberate because it caters to something that is emerging where we are trying to treat more KRAS mutant patients with different KRAS inhibitors. And you tried to address one very unique aspect of it in this article which pertains to toxicity, especially hepatotoxicity. So for the sake of our listeners who tend to be community oncologists, trainees, academic faculty, can you tell us what are KRAS inhibitors? What is KRAS-G12C? And how do some of these approved KRAS inhibitors try to inhibit KRAS-G12C? Dr. Hatim Husain: Sure. For a long time actually we've not had a selective way to inhibit mutant KRAS. And over the last several years actually now, we've seen some dramatic advances here, particularly with the FDA approval of some of the selective inhibitors against the G12C variant. So KRAS-G12C is an isoform of KRAS that is most common in lung cancer and in fact actually is a transversion mutation in the KRAS gene that is a product of the carcinogen of tobacco. And in fact, the incidence of KRAS-G12C in lung cancer, it's quite astounding where as many KRAS-G12C patients there are, there can be, as you know, more than EGFR patients in certain populations and cohorts. The medicines sotorasib and adagrasib were rationally designed to be selective KRAS-G12C inhibitors. And the way that they do this is that they lock the KRAS protein in the OFF state. KRAS is a protein that oscillates between an ON and an OFF state and by virtue of locking the protein in an OFF state, it has shown inhibition of downstream signaling and mitigation of tumor growth and, in fact, tumor cell death. Dr. Rafeh Naqash: I absolutely love the way you describe the ON and OFF state, the oscillation where the ON is bound to the GTP and the OFF is bound to the GDP. The two KRAS inhibitors as currently FDA approved, as you mentioned, are RAS OFF inhibitors and they're emerging KRAS inhibitors that are RAS ON. So now, as we have known from previous data related to immunotherapy and EGFR TKIs such as osimirtinib where toxicity tends to be a compounded effect when you have osimertinib given within a certain timeline of previous checkpoint therapy, we've seen that in the clinic as the data for these KRAS inhibitors is emerging, you talk about some very interesting aspects and data about what has been published so far with regards to prior use of immunotherapy or chemo immunotherapy and the subsequent use of KRAS inhibitors. Could you elaborate upon that? Dr. Hatim Husain: Sure. So for this population of patients, the first line approved strategy is a strategy that most cases will incorporate immune therapy and chemotherapy. Immune therapy can have some important responses for patients with KRAS-G12C. This may be due to the fact that KRAS-G12C patients may have a higher incidence of prior smoking, perhaps higher mutation burdens in some patients, and perhaps immunogenicity is defined in that context. So the standard of care in the first line currently includes immune therapy or immune therapy and chemotherapy. Where the current FDA approvals for selective G12C inhibitors are are after the first line of therapy. There are a number of trials exploring these medicines in the first line to see if they may be incorporated into a future treatment paradigm. Dr. Rafeh Naqash: Thank you for that explanation. Now, going to what you published in this manuscript, can you help us understand the context of why you looked at this? Even though the data just comprises a case series of a handful of patients, but the observations are very interesting and these are real world scenarios where we often tend to be in situations where an individual has had toxicity on a certain drug and may have some response to that drug, but at the same time, the toxicity is challenging. And then you try to debate whether another drug in the same class might be beneficial without those toxicities. So you've tried to address that to some extent using this data set. So can you elaborate upon the question, the methodology, what you tried to look at, and important observations that you have? Dr. Hatim Husain: Yes, our paper was actually inspired by one of my patients. My patient was a patient who had received chemotherapy and immune therapy and actually in the past, even, you know, additional lines of immune therapies, it was really coming to the edge of where standard treatments would exist. It was right at the same time that these selective inhibitors had been approved and the patient had received sotorasib. And what was remarkable was, when given sotorasib, patient had a very high peak and spike in the transaminases. And we would do different trials of strategies around dose, around interruptions. And it was becoming quite difficult, actually, for the patient to proceed with additional therapy. It was around similar times, actually, and I do want to make a note that the patient was progressing, driven in large fact by the fact that we've had to interrupt the medicine. So we feel and believe that the patient had had inadequate dosing because of the level of toxicity that the patient was having with transaminase increase. So it was around the same time that adagrasib was first commercially available that we were at that point, and we did a trial of adagrasib post-sotorasib, largely driven by necessity, without having additional options to provide this patient in our environment. What was remarkable was when the patient received the adagrasib, there were no spikes in transaminases similar to what we had seen before. And that really led us thinking and to say, “Is this adverse event of transaminase increase or hepatotoxicity, is this a class effect with KRAS-G12C inhibitors, or is it more nuanced than that? Are there different, perhaps, mechanisms by which the medicines may work that may more or less differentially contribute to this adverse event?” And so that inspired us to kind of do a larger analysis, kind of really reach out to a larger network of physicians to gather insights and to gather responses in patients who had had a serial approach of sotorasib and then adagrasib.  What we found in this process was, in fact, actually there were many more cases of patients who resembled my patient, where the sequence of sotorasib going to adagrasib may have demonstrated differential contribution of hepatotoxicity in that context. And that really motivated us to put the publication together to due diligence, and in the publication spend a lot of time to kind of outline each patient case in detail around metrics surrounding time from last immune therapy, the number of days on sotorasib, the best response to sotorasib, the interval between sotorasib and adagrasib, the duration of adagrasib and then the grade of hepatotoxicity seen in each of the contexts, and particularly kind of the adagrasib and patient disease status as well. We were quite inspired by the effort to try to, if we do not have randomized data in comparison of one medicine to another, which we do not at this juncture, we do not have a randomized analysis to really diligently and rigorously compare the rates of AEs across each medicine, and even in sequence, we do not have that with immune therapy. But what we felt was trying to get more analysis of this sequential approach of, if patients had received a medicine, had to be taken off because of toxicity and then actually tried on a new medicine, what were those rates? We felt like that was at least some information to try to get at this question. Dr. Rafeh Naqash: And you bring forward a very important point, which is, a lot of times in the real world setting we don't have cross trial comparisons that can be fully applicable, or we don't have trials that compare two drugs of the same class with respect to the AE profile or efficacy. And observations like the one that you described that led to this study are extremely critical in trying to help answer these questions.  From a data standpoint, and you allude to it to some extent in your manuscript, the trials that are trying to address combination of KRAS-G12C with immunotherapy, especially sotorasib or adagrasib, can you elaborate on that data, what has been published so far and summarize it for our listeners? Dr. Hatim Husain: So there is data from clinical trials looking at patients actually who have received concomitant immune therapy and sotorasib. What was seen in this, in a real world analysis, was that some patients actually who had received sotorasib within a close proximity of immune therapy, as well as a larger study actually which showed in combination there were higher rates of hepatotoxicity in that context. In fact, there were rates of grade 3 hepatotoxicity. And I think built upon that data there's a recognition in the field that we have to be very diligent in terms of even the clinical trial designs in how to understand the pairing between immune therapy and selective G12C inhibitors. There are many trials that are ongoing, one of the studies that is ongoing is known as the KRYSTAL-7 study, which is evaluating adagrasib in combination with pembrolizumab in the first line. And we await more information on that strategy as well. In the context of sotorasib, because of some of the trials that have shown higher rates of hepatotoxicity, there are some additional trials now looking at sotorasib in combination with chemotherapy, and those also have some information that have been reported as well. Dr. Rafeh Naqash: From a drug development standpoint, as you mentioned, there's always a tendency to combine something with something else. And in my practice, and I'm sure in your practice too, when we do early phase trials, many trials are still focused on choosing the maximum tolerated dose, which may be something that we need to gradually move away from as we try to implement these combinations of multiple antibodies plus some of these target agents from maybe the biological optimal dose rather than the maximal tolerant dose is a better way to look at the drugs, the pharmacokinetic profile, and then see what is likely the safest combination with the most appropriate target engagement. Do you have any thoughts on that or insights on that from a drug development perspective? Dr. Hatim Husain: It's a wonderful question and I think it is a very insightful question and understanding of where we are in space right now. And I agree with you that historically, cancer drug development was really hinged upon medicines that perhaps required higher doses to see a benefit or to inch out kind of marginal increases upon where we were at. Now, in combination with medicines that have non-overlapping mechanisms of action, the concept is: Can there actually be more synergy across an approach using combinatorial strategies rather than just additive effects? And I think that in some cases this is being studied with immune therapy, in some cases actually even in the context of other novel mechanisms for cancer therapy. I think that in my practice, I will really try to see how a patient at an approved dose will respond. But definitely I'm open to the concept that there may be a dose that doesn't have to be the maximally tolerated dose, but rather the dose that responses can be seen and perhaps actually at a lower dose than what drives many toxicities. Dr. Rafeh Naqash: I often describe this to my patients as individual patient dose optimization outside of a clinical trial, where I'm sure you've probably done this, where in older adults maybe a lower dose of osimertinib is tolerated better, or a lower dose of sotorasib or adagrasib for that matter, tolerated better with perhaps a similar level of efficacy, since we don't have comparisons between doses and efficacy so far.  So I think in the bigger picture, as we discussed in a nutshell, what I would really like the listeners to understand is as we try to move towards this field of precision medicine targeting more and more of the undruggable genes, there's bound to be a certain level of toxicity patterns that we'll start observing. So I think these real world scenarios which may not be addressed using clinical trials because it is in the real world setting where you cycle one treatment after another after another, which may or may not be allowed in most trials and the real world setting can inform, in certain cases, subsequent trial designs. So I think the most important message, at least that I took from your manuscript, was that these real world observations can make a huge difference and inform practice, even though the data sets may be small. Of course, you want to validate some of these findings in a bigger, broader setting, but proof of concept is there. And I think next time I see an individual in my clinic where I see better toxicity, I'll definitely try to talk to them about subsequent treatment with another KRAS inhibitor, maybe adagrasib or something else, if and when appropriate.  Do you have any closing thoughts on some of these things that we discussed? Dr. Hatim Husain: I just want to leave the audience actually with this concept that sometimes we group targeted therapy side effects as being class effects unanimously. And I do think actually that each inhibitor may have different off target effects on where medicine may act. We don't truly understand the mechanism of hepatotoxicity in the context of selective KRAS-G12C inhibitors. One of the hypotheses may be due to off target cysteine reactivity in the numerous off target binding sites that certain medicines may have over others. And just even qualitatively which off target binding sites there may be, and how that may lead to either immunogenic responses and other organs or such. So I do think that we do need more research to understand the mechanism. But I think where we are at right now in this space is not assuming that all medicines are going to have the exact same toxicity. I think especially when patients may not have other options, this is something to consider as well. Dr. Rafeh Naqash: Thank you so much. Now, outside of the scientific insights, Hatim, I know you a little bit from before. And knowing the kind of work that you've done in precision medicine, I'm really interested to know about where you started, how you started, how things have been, and what kind of advice you have for junior faculty fellows who are interested in this field of precision medicine that is becoming more and more exciting as we progress in the oncology space. Dr. Hatim Husain: Thank you, Rafeh. I will say, actually as a medical student, I was actually very interested in oncology, partly because it was then and still remains one disease or a constellation of diseases that just has such a high psychological burden on patients. And through the experiences I've had, I really can understand and relate with that concept. I did my medical school at Northwestern, residency at the University of Southern California, and then my oncology fellowship at Johns Hopkins University.  And now I've been on faculty at University of California, San Diego, for about 12 years now. It's been a great experience paralleled with the fact that during these last 12 years, I've really seen how the developments in precision oncology, both targeted therapy as well as immune therapy, have really blossomed and unfolded. A large area of my research in my career has kind of focused on cancer genome and integration of novel technologies to really see how they may have clinical application. When I was in my fellowship and as a young faculty, the liquid biopsy was actually coming into development. And this was hinged upon information that had come forward in the prenatal space where some patients actually who were undergoing prenatal testing during pregnancy were found to have complex karyotypes and genomic alterations and then retrospectively found to have cancer.  And doing my fellowship at Johns Hopkins, some of the pioneers in liquid biopsy were my mentors and really kind of instilled in me that passion for really thinking through how cancer genomics can be integrated through time. And some of the research that I have been doing has been looking at clonal evolution of cancer, how cancer is changing over time, and how we can think through the right surveillance strategies to really understand how that change is occurring. The dynamics of ctDNA in retrospective cohorts have been studied and shown that, you know, there can be associations between progression-free survival and other clinical endpoints. The current paper that we are speaking about parallels that in a certain way where, rather than say, looking at clonal evolution and say, the efficacy answer of sotorasib first and then adagrasib and how frequently can adagrasib salvage patients, this looks at it from a different angle around toxicity. And I think that is a key point because, at my core, I really do enjoy the clinical aspect of complex decision making on behalf of patients weighing efficacy and toxicity that they may have as they try to get the best quality of life through this journey. Dr. Rafeh Naqash: Thank you again, Hatim, for all those insights, both from the scientific perspective as well as personal perspective. We appreciate that you chose JCOPO as the destination for your work.  And 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, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Dr. Hatem Husain Disclosures Consulting or Advisory Role: AstraZeneca, Foundation Medicine, Janssen, NeoGenomics Laboratories, Mirati Speakers' Bureau: AstraZeneca, Janssen Institution Research Funding: Pfizer, Bristol-Myers Squibb, Regeneron, Lilly Travel, Accommodations, Expenses: AstraZeneca, Janssen, Foundation Medicine  

The most enthralling conversation I've ever had with anyone on cancer. It's with Charlie Swanton who is a senior group leader at the Francis Crick Institute, the Royal Society Napier Professor in Cancer and medical oncologist at University College London, co-director of Cancer Research UK.Video snippet from our conversation. Full videos of all Ground Truths podcasts can be seen on YouTube here. The audios are also available on Apple and Spotify.Transcript with audio links and many external linksEric Topol (00:07):Well, hello, this is Eric Topol with Ground Truths, and I am really fortunate today to connect us with Charlie Swanton, who is if not the most prolific researcher in the space of oncology and medicine, and he's right up there. Charlie is a physician scientist who is an oncologist at Francis Crick and he heads up the lung cancer area there. So Charlie, welcome.Charles Swanton (00:40):Thank you, Eric. Nice to meet you.Learning from a FailureEric Topol (00:43):Well, it really is a treat because I've been reading your papers and they're diverse. They're not just on cancer. Could be connecting things like air pollution, it could be Covid, it could be AI, all sorts of things. And it's really quite extraordinary. So I thought I'd start out with a really interesting short paper you wrote towards the end of last year to give a sense about you. It was called Turning a failing PhD around. And that's good because it's kind of historical anchoring. Before we get into some of your latest contributions, maybe can you tell us about that story about what you went through with your PhD?Charles Swanton (01:26):Yeah, well thank you, Eric. I got into research quite early. I did what you in the US would call the MD PhD program. So in my twenties I started a PhD in a molecular biology lab at what was then called the Imperial Cancer Research Fund, which was the sort of the mecca for DNA tumor viruses, if you like. It was really the place to go if you wanted to study how DNA tumor viruses worked, and many of the components of the cell cycle were discovered there in the 80s and 90s. Of course, Paul Nurse was the director of the institute at the time who discovered cdc2, the archetypal regulator of the cell cycle that led to his Nobel Prize. So it was a very exciting place to work, but my PhD wasn't going terribly well. And sort of 18, 19 months into my PhD, I was summoned for my midterm reports and it was not materializing rapidly enough.(02:25):And I sat down with my graduate student supervisors who were very kind, very generous, but basically said, Charlie, this isn't going well, is it? You've got two choices. You can either go back to medical school or change PhD projects. What do you want to do? And I said, well, I can't go back to medical school because I'm now two years behind. So instead I think what I'll do is I'll change PhD projects. And they asked me what I'd like to do. And back then we didn't know how p21, the CDK inhibitor bound to cyclin D, and I said, that's what I want to understand how these proteins interact biochemically. And they said, how are you going to do that? And I said, I'm not too sure, but maybe we'll try yeast two-hybrid screen and a mutagenesis screen. And that didn't work either. And in the end, something remarkable happened.(03:14):My PhD boss, Nic Jones, who's a great guy, still is, retired though now, but a phenomenal scientist. He put me in touch with a colleague who actually works next door to me now at the Francis Crick Institute called Neil McDonald, a structural biologist. And they had just solved, well, the community had just solved the structure. Pavletich just solved the structure of cyclin A CDK2. And so, Neil could show me this beautiful image of the crystal structure in 3D of cyclin A, and we could mirror cyclin D onto it and find the surface residue. So I spent the whole of my summer holiday mutating every surface exposed acid on cyclin D to an alanine until I found one that failed to interact with p21, but could still bind the CDK. And that little breakthrough, very little breakthrough led to this discovery that I had where the viral cyclins encoded by Kaposi sarcoma herpes virus, very similar to cyclin D, except in this one region that I had found interactive with a CDK inhibitor protein p21.(04:17):And so, I asked my boss, what do you think about the possibility this cyclin could have evolved from cyclin D but now mutated its surface residues in a specific area so that it can't be inhibited by any of the control proteins in the mammalian cell cycle? He said, it's a great idea, Charlie, give it a shot. And it worked. And then six months later, we got a Nature paper. And that for me was like, I cannot tell you how exciting, not the Nature paper so much as the discovery that you were the first person in the world to ever see this beautiful aspect of evolutionary biology at play and how this cyclin had adapted to just drive the cell cycle without being inhibited. For me, just, I mean, it was like a dream come true, and I never experienced anything like it before, and I guess it's sizes the equivalent to me of a class A drug. You get such a buzz out of it and over the years you sort of long for that to happen again. And occasionally it does, and it's just a wonderful profession.Eric Topol (05:20):Well, I thought that it was such a great story because here you were about to fail. I mean literally fail, and you really were able to turn it around and it should give hope to everybody working in science out there that they could just be right around the corner from a significant discovery.Charles Swanton (05:36):I think what doesn't break you makes you stronger. You just got to plow on if you love it enough, you'll find a way forward eventually, I hope.Tracing the Evolution of Cancer (TRACERx)Eric Topol (05:44):Yeah, no question about that. Now, some of your recent contributions, I mean, it's just amazing to me. I just try to keep up with the literature just keeping up with you.Charles Swanton (05:58):Eric, it's sweet of you. The first thing to say is it's not just me. This is a big community of lung cancer researchers we have thanks to Cancer Research UK funded around TRACERx and the lung cancer center. Every one of my papers has three corresponding authors, multiple co-first authors that all contribute in this multidisciplinary team to the sort of series of small incremental discoveries. And it's absolutely not just me. I've got an amazing team of scientists who I work with and learn from, so it's sweet to give me the credit.Eric Topol (06:30):I think what you're saying is really important. It is a team, but I think what I see through it all is that you're an inspiration to the team. You pull people together from all over the world on these projects and it's pretty extraordinary, so that's what I would say.Charles Swanton (06:49):The lung community, Eric, the lung cancer community is just unbelievably conducive to collaboration and advancing understanding of the disease together. It's just such a privilege to be working in this field. I know that sounds terribly corny, but it is true. I don't think I recall a single email to anybody where I've asked if we can collaborate where they've said, no, everybody wants to help. Everybody wants to work together on this challenge. It's just such an amazing field to be working in.Eric Topol (07:19):Yeah. Well I was going to ask you about that. And of course you could have restricted your efforts or focused on different cancers. What made you land in lung cancer? Not that that's only part of what you're working on, but that being the main thing, what drew you to that area?Charles Swanton (07:39):So I think the answer to your question is back in 2008 when I was looking for a niche, back then it was lung cancer was just on the brink of becoming an exciting place to work, but back then nobody wanted to work in that field. So there was a chair position in thoracic oncology and precision medicine open at University College London Hospital that had been open, as I understand it for two years. And I don't think anybody had applied. So I applied and because I was the only one, I got it and the rest is history.(08:16):And of course that was right at the time when the IPASS draft from Tony Mok was published and was just a bit after when the poster child of EGFR TKIs and EGFR mutant lung cancer had finally proven that if you segregate that population of patients with EGFR activating mutation, they do incredibly well on an EGFR inhibitor. And that was sort of the solid tumor poster child along with Herceptin of precision medicine, I think. And you saw the data at ASCO this week of Lorlatinib in re-arranged lung cancer. Patients are living way beyond five years now, and people are actually talking about this disease being more like CML. I mean, it's extraordinary the progress that's been made in the last two decades in my short career.Eric Topol (09:02):Actually, I do want to have you put that in perspective because it's really important what you just mentioned. I was going to ask you about this ASCO study with the AKT subgroup. So the cancer landscape of the lung has changed so much from what used to be a disease of cigarette smoking to now one of, I guess adenocarcinoma, non-small cell carcinoma, not related to cigarettes. We're going to talk about air pollution in a minute. This group that had, as you say, 60 month, five year plus survival versus what the standard therapy was a year plus is so extraordinary. But is that just a small subgroup within small cell lung cancer?Charles Swanton (09:48):Yes, it is, unfortunately. It's just a small subgroup. In our practice, probably less than 1% of all presentations often in never smokers, often in female, never smokers. So it is still in the UK at least a minority subset of adenocarcinomas, but it's still, as you rightly say, a minority of patients that we can make a big difference to with a drug that's pretty well tolerated, crosses the blood-brain barrier and prevents central nervous system relapse and progression. It really is an extraordinary breakthrough, I think. But that said, we're also seeing advances in smoking associated lung cancer with a high mutational burden with checkpoint inhibitor therapy, particularly in the neoadjuvant setting now prior to surgery. That's really, really impressive indeed. And adjuvant checkpoint inhibitor therapies as well as in the metastatic setting are absolutely improving survival times and outcomes now in a way that we couldn't have dreamt of 15 years ago. We've got much more than just platinum-based chemo is basically the bottom line now.Revving Up ImmunotherapyEric Topol (10:56):Right, right. Well that actually gets a natural question about immunotherapy also is one of the moving parts actually just amazing to me how that's really, it's almost like we're just scratching the surface of immunotherapy now with checkpoint inhibitors because the more we get the immune system revved up, the more we're seeing results, whether it's with vaccines or CAR-T, I mean it seems like we're just at the early stages of getting the immune system where it needs to be to tackle the cancer. What's your thought about that?Charles Swanton (11:32):I think you're absolutely right. We are, we're at the beginning of a very long journey thanks to Jim Allison and Honjo. We've got CTLA4 and PD-1/PDL-1 axis to target that's made a dramatic difference across multiple solid tumor types including melanoma and lung cancer. But undoubtedly, there are other targets we've seen LAG-3 and melanoma and then we're seeing new ways, as you rightly put it to mobilize the immune system to target cancers. And that can be done through vaccine based approaches where you stimulate the immune system against the patient's specific mutations in their cancer or adoptive T-cell therapies where you take the T-cells out of the tumor, you prime them against the mutations found in the tumor, you expand them and then give them back to the patient. And colleagues in the US, Steve Rosenberg and John Haanen in the Netherlands have done a remarkable job there in the context of melanoma, we're not a million miles away from European approvals and academic initiated manufacturing of T-cells for patients in national health systems like in the Netherlands.(12:50):John Haanen's work is remarkable in that regard. And then there are really spectacular ways of altering T-cells to be able to either migrate to the tumor or to target specific tumor antigens. You mentioned CAR-T cell therapies in the context of acute leukemia, really extraordinary developments there. And myeloma and diffuse large B-cell lymphoma as well as even in solid tumors are showing efficacy. And I really am very excited about the future of what we call biological therapies, be it vaccines, an antibody drug conjugates and T-cell therapies. I think cancer is a constantly adapting evolutionary force to be reckoned with what better system to combat it than our evolving immune system. It strikes me as being a future solution to many of these refractory cancers we still find difficult to treat.Eric Topol (13:48):Yeah, your point is an interesting parallel how the SARS-CoV-2 virus is constantly mutating and becoming more evasive as is the tumor in a person and the fact that we can try to amp up the immune system with these various means that you just were reviewing. You mentioned the other category that's very hot right now, which is the antibody drug conjugates. Could you explain a bit about how they work and why you think this is an important part of the future for cancer?Antibody-Drug ConjugatesCharles Swanton (14:26):That's a great question. So one of the challenges with chemotherapy, as you know, is the normal tissue toxicity. So for instance, neutropenia, hair loss, bowel dysfunction, diarrhea, epithelial damage, essentially as you know, cytotoxics affect rapidly dividing tissues, so bone marrow, epithelial tissues. And because until relatively recently we had no way of targeting chemotherapy patients experienced side effects associated with them. So over the last decade or so, pioneers in this field have brought together this idea of biological therapies linked with chemotherapy through a biological linker. And so one poster chart of that would be the drug T-DXd, which is essentially Herceptin linked to a chemotherapy drug. And this is just the most extraordinary drug that obviously binds the HER2 receptor, but brings the chemotherapy and proximity of the tumor. The idea being the more drug you can get into the tumor and the less you're releasing into normal tissue, the more on tumor cytotoxicity you'll have and the less off tumor on target normal tissue side effects you'll have. And to a large extent, that's being shown to be the case. That doesn't mean they're completely toxicity free, they're not. And one of the side effects associated with these drugs is pneumonitis.(16:03):But that said, the efficacy is simply extraordinary. And for example, we're having to rewrite the rule books if you like, I think. I mean I'm not a breast cancer physician, I used to be a long time ago, but back in the past in the early 2000s, there was HER2 positive breast cancer and that's it. Now they're talking about HER2 low, HER2 ultra-low, all of which seem to in their own way be sensitive to T-DXd, albeit to a lower extent than HER2 positive disease. But the point is that there doesn't seem to be HER2 completely zero tumor group in breast cancer. And even the HER2-0 seem to benefit from T-DXd to an extent. And the question is why? And I think what people are thinking now is it's a combination of very low cell service expression of HER2 that's undetectable by conventional methods like immunohistochemistry, but also something exquisitely specific about the way in which HER2 is mobilized on the membrane and taken back into the cell. That seems to be specific to the breast cancer cell but not normal tissue. So in other words, the antibody drug conjugate binds the tumor cell, it's thought the whole receptor's internalized into the endosome, and that's where the toxicity then happens. And it's something to do with the endosomal trafficking with the low level expression and internalization of the receptor. That may well be the reason why these HER2 low tumors are so sensitive to this beautiful technology.Eric Topol (17:38):Now I mean it is an amazing technology in all these years where we just were basically indiscriminately trying to kill cells and hoping that the cancer would succumb. And now you're finding whether you want to call it a carry or vector or Trojan horse, whatever you want to call it, but do you see that analogy of the HER2 receptor that's going to be seen across the board in other cancers?Charles Swanton (18:02):That's the big question, Eric. I think, and have we just lucked out with T-DXd, will we find other T-DXd like ADCs targeting other proteins? I mean there are a lot of ADCs being developed against a lot of different cell surface proteins, and I think the jury's still out. I'm confident we will, but we have to bear in mind that biology is a fickle friend and there may be something here related to the internalization of the receptor in breast cancer that makes this disease so exquisitely sensitive. So I think we just don't know yet. I'm reasonably confident that we will find other targets that are as profoundly sensitive as HER2 positive breast cancer, but time will tell.Cancer, A Systemic DiseaseEric Topol (18:49):Right. Now along these lines, well the recent paper that you had in Cell, called embracing cancer complexity, which we've talking about a bit, in fact it's kind of those two words go together awfully well, but hallmarks of systemic disease, this was a masterful review, as you say with the team that you led. But can you tell us about what's your main perspective about this systemic disease? I mean obviously there's been the cancer is like cardiovascular and cancers like this or that, but here you really brought it together with systemic illness. What can you say about that?Charles Swanton (19:42):Well, thanks for the question first of all, Eric. So a lot of this comes from some of my medical experience of treating cancer and thinking to myself over the years, molecular biology has had a major footprint on advances in treating the disease undoubtedly. But there are still aspects of medicine where molecular biology has had very little impact, and often that is in areas of suffering in patients with advanced disease and cancer related to things like cancer cachexia, thrombophilia. What is the reason why patients die blood clots? What is the reason patients die of cancer at all? Even a simple question like that, we don't always know the answer to, on death certificates, we write metastatic disease as a cause of cancer death, but we have patients who die with often limited disease burden and no obvious proximal cause of death sometimes. And that's very perplexing, and we need to understand that process better.(20:41):And we need to understand aspects like cancer pain, for example, circadian rhythms affect biological sensitivity of cancer cells to drugs and what have you. Thinking about cancer rather than just sort of a single group of chaotically proliferating cells to a vision of cancer interacting both locally within a microenvironment but more distantly across organs and how organs communicate with the cancer through neuronal networks, for example, I think is going to be the next big challenge by setting the field over the next decade or two. And I think then thinking about more broadly what I mean by embracing complexity, I think some of that relates to the limitations of the model systems we use, trying to understand inter-organ crosstalk, some of the things you cover in your beautiful Twitter reviews. (←Ground Truths link) I remember recently you highlighted four publications that looked at central nervous system, immune cell crosstalk or central nervous system microbiome crosstalk. It's this sort of long range interaction between organs, between the central nervous system and the immune system and the cancer that I'm hugely interested in because I really think there are vital clues there that will unlock new targets that will enable us to control cancers more effectively if we just understood these complex networks better and had more sophisticated animal model systems to be able to interpret these interactions.Eric Topol (22:11):No, it's so important what you're bringing out, the mysteries that still we have to deal with cancer, why patients have all these issues or dying without really knowing what's happened no less, as you say, these new connects that are being discovered at a remarkable pace, as you mentioned, that ground truths. And also, for example, when I spoke with Michelle Monje, she's amazing on the cancer, where hijacking the brain cells and just pretty extraordinary things. Now that gets me to another line of work of yours. I mean there are many, but the issue of evolution of the tumor, and if you could put that in context, a hot area that's helping us elucidate these mechanisms is known as spatial omics or spatial biology. This whole idea of being able to get the spatial temporal progression through single cell sequencing and single cell nuclei, all the single cell omics. So if you could kind of take us through what have we learned with this technique and spatial omics that now has changed or illuminated our understanding of how cancer evolves?Charles Swanton (23:37):Yeah, great question. Well, I mean I think it helps us sort of rewind a bit and think about evolution in general. Genetic selection brought about by diverse environments and environmental pressures that force evolution, genetic evolution, and speciation down certain evolutionary roots. And I think one can think about cancers in a similar way. They start from a single cell and we can trace the evolutionary paths of cancers by single cell analysis as well as bulk sequencing of spatially separated tumor regions to be able to reconstruct their subclones. And that's taught us to some extent, what are the early events in tumor evolution? What are the biological mechanisms driving branched evolution? How does genome instability begin in tumors? And we found through TRACERx work, whole genome doubling is a major route through to driving chromosome instability along with mutagenic enzymes like APOBEC that drive both mutations and chromosomal instability.(24:44):And then that leads to a sort of adaptive radiation in a sense, not dissimilar to I guess the Cambrian explosion of evolutionary opportunity upon which natural selection can act. And that's when you start to see the hallmarks of immune evasion like loss of HLA, the immune recognition molecules that bind the neoantigens or even loss of the neoantigens altogether or mutation of beta 2 microglobulin that allow the tumor cells to now evolve below the radar, so to speak. But you allude to the sort of spatial technologies that allow us to start to interpret the microenvironments as well. And that then tells us what the evolutionary pressures are upon the tumor. And we're learning from those spatial technologies that these environments are incredibly diverse, actually interestingly seem to be converging on one important aspect I'd like to talk to you a little bit more about, which is the myeloid axis, which is these neutrophils, macrophages, et cetera, that seem to be associated with poor outcome and that will perhaps talk about pollution in a minute.(25:51):But I think they're creating a sort of chronic inflammatory response that allows these early nascent tumor cells to start to initiate into frankly tumor invasive cells and start to grow. And so, what we're seeing from these spatial technologies in lung cancer is that T-cells, predatory T-cells, force tumors to lose their HLA molecules and what have you to evade the immune system. But for reasons we don't understand, high neutrophil infiltration seems to be associated with poor outcome, poor metastasis free survival. And actually, those same neutrophils we've recently found actually even tracked to the metastasis sites of metastasis. So it's almost like this sort of symbiosis between the myeloid cells and the tumor cells in their biology and growth and progression of the tumor cells.Eric Topol (26:46):Yeah, I mean this white cell story, this seems to be getting legs and is relatively new, was this cracked because of the ability to do this type of work to in the past everything was, oh, it's cancer's heterogeneous and now we're getting pinpoint definition of what's going on.Charles Swanton (27:04):I think it's certainly contributed, but it's like everything in science, Eric, when you look back, there's evidence in the literature for pretty much everything we've ever discovered. You just need to put the pieces together. And I mean one example would be the neutrophil lymphocyte ratio in the blood as a hallmark of outcome in cancers and to checkpoint inhibitor blockade, maybe this begins to explain it, high neutrophils, immune suppressive environment, high neutrophils, high macrophages, high immune suppression, less benefit from checkpoint inhibitor therapy, whereas you want lymphocyte. So I think there are biomedical medical insights that help inform the biology we do in the lab that have been known for decades or more. And certainly the myeloid M2 axis in macrophages and what have you was known about way before these spatial technologies really came to fruition, I think.The Impact of Air PollutionEric Topol (28:01):Yeah. Well you touched on this about air pollution and that's another dimension of the work that you and your team have done. As you well know, there was a recent global burden of disease paper in the Lancet, which has now said that air pollution with particulate matter 2.5 less is the leading cause of the burden of disease in the world now.Charles Swanton (28:32):What did you think of that, Eric?Eric Topol (28:34):I mean, I was blown away. Totally blown away. And this is an era you've really worked on. So can you put it in perspective?Charles Swanton (28:42):Yeah. So we got into this because patients of mine, and many of my colleagues would ask the same question, I've never smoked doctor, I'm healthy. I'm in my mid 50s though they're often female and I've got lung cancer. Why is that doctor? I've had a good diet, I exercise, et cetera. And we didn't really have a very good answer for that, and I don't want to pretend for a minute we solved the whole problem. I think hopefully we've contributed to a little bit of understanding of why this may happen. But that aside, we knew that there were risk factors associated with lung cancer that included air pollution, radon exposure, of course, germline genetics, we mustn't forget very important germline variation. And I think there is evidence that all of them are associated with lung cancer risk in different ways. But we wanted to look at air pollution, particularly because there was an awful lot of evidence, several meta-analysis of over half a million individuals showing very convincingly with highly significant results that increasing PM 2.5 micron particulate levels were associated with increased risk of lung cancer.(29:59):To put that into perspective, where you are on the west coast of the US, it's relatively unpolluted. You would be talking about maybe five micrograms per meter cubed of PM2.5 in a place like San Diego or Western California, assuming there aren't any forest fires of course. And we estimate that that would translate to about, we think it's about one extra case of never smoking lung cancer per hundred thousand of the population per year per one microgram per meter cube rise in the pollution levels. So if you go to Beijing for example, on a bad day, the air pollution levels could be upwards of a hundred micrograms per meter cubed because there are so many coal fired power stations in China partly. And there I think the risk is considerably higher. And that's certainly what we've seen in the meta-analyses in our limited and relatively crude epidemiological analyses to be the case.(30:59):So I think the association was pretty certain, we were very confident from people's prior publications  this was important. But of course, association is not causation. So we took a number of animal models and showed that you could promote lung cancer formation in four different oncogene driven lung cancer models. And then the question is how, does air pollution stimulate mutations, which is what I initially thought it would do or something else. It turns out we don't see a significant increase in exogenous like C to A carcinogenic mutations. So that made us put our thinking caps on. And I said to you earlier, often all these discoveries have been made before. Well, Berenblum in 1947, first postulated that actually tumors are initiated through a two-step process, which we now know involves a sort of pre initiated cell with a mutation in that in itself is not sufficient to cause cancer.(31:58):But on top of that you need an inflammatory stimulus. So the question was then, well, okay, is inflammation working here? And we found that there was an interleukin-1 beta axis. And what happens is that the macrophages come into the lung on pollution exposure, engulf phagocytose the air pollutants, and we think what's happening is the air pollutants are puncturing membranes in the lung. That's what we think is happening. And interleukin-1 beta preformed IL-1 beta is being released into the extracellular matrix and then stimulating pre-initiated cells stem cells like the AT2 cells with an activating EGFR mutation to form a tumor. But the EGFR mutation alone is not sufficient to form tumors. It's only when you have the interleukin-1 beta and the activated mutation that a tumor can start.(32:49):And we found that if we sequence normal lung tissue in a healthy adult 60-year-old adult, we will find about half of biopsies will have an activating KRAS mutation in normal tissue, and about 15% will have an activating mutation in EGFR in histologically normal tissue with nerve and of cancer. In fact, my friend and colleague who's a co-author on the paper, James DeGregori, who you should speak to in Colorado, fascinating evolutionary cancer biologists estimates that in a healthy 60-year-old, there are a hundred billion cells in your body that harbor an oncogenic mutation. So that tells you that at the cellular level, cancer is an incredibly rare event and almost never happens. I mean, our lifetime risk of cancer is perhaps one in two. You covered that beautiful pancreas paper recently where they estimated that there may be 80 to 100 KRAS mutations in a normal adult pancreas, and yet our lifetime risk of pancreas cancer is one in 70. So this tells you that oncogenic mutations are rarely sufficient to drive cancer, so something else must be happening. And in the context of air pollution associated lung cancer, we think that's inflammation driven by these white cells, these myeloid cells, the macrophages.Cancer BiomarkersEric Topol (34:06):No, it makes a lot of sense. And this, you mentioned the pancreas paper and also what's going in the lung, and it seems like we have this burden of all you need is a tipping point and air pollution seems to qualify, and you seem to be really in the process of icing the mechanism. And like I would've thought it was just mutagenic and it's not so simple, right? But that gets me to this is such an important aspect of cancer, the fact that we harbor these kind of preconditions. And would you think that cancer takes decades to actually manifest most cancers, or do we really have an opportunity here to be able to track whether it's through blood or other biomarkers? Another area you've worked on a lot whereby let's say you could define people at risk for polygenic risk scores or various cancers or genome sequencing for predisposition genes, whatever, and you could monitor in the future over the course of those high-risk people, whether they were starting to manifest microscopic malignancy. Do you have any thoughts about how long it takes for the average person to actually manifest a typical cancer?Charles Swanton (35:28):That's a cracking question, and the answer is we've got some clues in various cancers. Peter Campbell would be a good person to speak to. He estimates that some of the earliest steps in renal cancer can occur in adolescence. We've had patients who gave up smoking 30 or so years ago where we can still see the clonal smoking mutations in the trunk of the tumor's evolutionary tree. So the initial footprints of the cancer are made 30 years before the cancer presents. That driver mutation itself may also be a KRAS mutation in a smoking cigarette context, G12C mutation. And those mutations can precede the diagnosis of the disease by decades. So the earliest steps in cancer evolution can occur, we think can precede diagnoses by a long time. So to your point, your question which is, is there an opportunity to intervene? I'm hugely optimistic about this actually, this idea of molecular cancer prevention.An Anti-Inflammatory Drug Reduces Fatal Cancer and Lung Cancer(36:41):How can we use data coming out of various studies in the pancreas, mesothelioma, lung, et cetera to understand the inflammatory responses? I don't think we can do very much about the mutations. The mutations unfortunately are a natural consequence of aging. You and I just sitting here talking for an hour will have accumulated multiple mutations in our bodies over that period, I'm afraid and there's no escaping it. And right now there's not much we can do to eradicate those mutant clones. So if we take that as almost an intractable problem, measuring them is hard enough, eradicating them is even harder. And then we go back to Berenblum in 1947 who said, you need an inflammatory stimulus. Well, could we do something about the inflammation and dampen down the inflammation? And of course, this is why we got so excited about IL-1 beta because of the CANTOS trial, which you may remember in 2017 from Ridker and colleagues showed that anti IL-1 beta used as a mechanism of preventing cardiovascular events was associated with a really impressive dose dependent reduction in new lung cancer primaries.(37:49):Really a beautiful example of cancer prevention in action. And that data weren't just a coincidence. The FDA mandated Novartis to collect the solid tumor data and the P-values are 0.001. I mean it's very highly significant dose dependent reduction in lung cancer incidents associated with anti IL-1 beta. So I think that's really the first clue in my mind that something can be done about this problem. And actually they had five years of follow-up, Eric. So that's something about that intervening period where you can treat and then over time see a reduction in new lung cancers forming. So I definitely think there's a window of opportunity here.Eric Topol (38:31):Well, what you're bringing up is fascinating here because this trial, which was a cardiology trial to try to reduce heart attacks, finds a reduction in cancer, and it's been lost. It's been buried. I mean, no one's using this therapy to prevent cancer between ratcheting up the immune system or decreasing inflammation. We have opportunities that we're not even attempting. Are there any trials that are trying to do this sort of thing?Charles Swanton (39:02):So this is the fundamental problem. Nobody wants to invest in prevention because essentially you are dealing with well individuals. It's like the vaccine challenge all over again. And the problem is you never know who you are benefiting. There's no economic model for it. So pharma just won't touch prevention with a barge pole right now. And that's the problem. There's no economic model for it. And yet the community, all my academic colleagues are crying out saying, this has got to be possible. This has got to be possible. So CRUK are putting together a group of like-minded individuals to see if we can do something here and we're gradually making progress, but it is tough.Eric Topol (39:43):And it's interesting that you bring that up because for GRAIL, one of the multicenter cancer early detection companies, they raised billions of dollars. And in fact, their largest trial is ongoing in the UK, but they haven't really focused on high-risk people. They just took anybody over age 50 or that sort of thing. But that's the only foray to try to reboot how we or make an early microscopic diagnosis of cancer and track people differently. And there's an opportunity there. You've written quite a bit on you and colleagues of the blood markers being able to find a cancer where well before, in fact, I was going to ask you about that is, do you think there's people that are not just having all these mutations every minute, every hour, but that are starting to have the early seeds of cancer, but because their immune system then subsequently kicks in that they basically kind of quash it for that period of time?Charles Swanton (40:47):Yeah, I do think that, I mean, the very fact that we see these sort of footprints in the tumor genome of immune evasion tells you that the immune system's having a very profound predatory effect on evolving tumors. So I do think it's very likely that there are tumors occurring that are suppressed by the immune system. There is a clear signature, a signal of negative selection in tumors where clones have been purified during their evolution by the immune system. So I think there's pretty strong evidence for that now. Obviously, it's very difficult to prove something existed when it doesn't now exist, but there absolutely is evidence for that. I think it raises the interesting question of immune system recognizes mutations and our bodies are replete with mutations as we were just discussing. Why is it that we're not just a sort of epithelial lining of autoimmunity with T-cells and immune cells everywhere? And I think what the clever thing about the immune system is it's evolved to target antigens only when they get above a certain burden. Otherwise, I think our epithelial lining, our skin, our guts, all of our tissues will be just full of T-cells eating away our normal clones.(42:09):These have to get to a certain size for antigen to be presented at a certain level for the immune system to recognize it. And it's only then that you get the immune predation occurring.Forever Chemicals and Microplastics Eric Topol (42:20):Yeah, well, I mean this is opportunities galore here. I also wanted to extend the air pollution story a bit. Obviously, we talked about particulate matter and there's ozone and nitric NO2, and there's all sorts of other air pollutants, but then there's also in the air and water these forever chemicals PFAS for abbreviation, and they seem to be incriminated like air pollution. Can you comment about that?Charles Swanton (42:55):Well, I can comment only insofar as to say I'm worried about the situation. Indeed, I'm worried about microplastics actually, and you actually cover that story as well in the New England Journal, the association of microplastics with plaque rupture and atheroma. And indeed, just as in parenthesis, I wanted to just quickly say we currently think the same mechanisms that are driving lung cancer are probably responsible for atheroma and possibly even neurodegenerative disease. And essentially it all comes down to the macrophages and the microglia becoming clogged up with these pollutants or environmental particulars and releasing chronic inflammatory mediators that ultimately lead to disease. And IL-1 beta being one of those in atheroma and probably IL-6 and TNF in neurodegenerative disease and what have you. But I think this issue that you rightly bring up of what is in our environment and how does it cause pathology is really something that epidemiologists have spent a lot of time focusing on.(43:56):But actually in terms of trying to move from association to causation, we've been, I would argue a little bit slow biologically in trying to understand these issues. And I think that is a concern. I mean, to give you an example, Allan Balmain, who works at UCSF quite close to you, published a paper in 2020 showing that 17 out of 20 environmental carcinogens IARC carcinogens class one carcinogens cause tumors in rodent models without driving mutations. So if you take that to a logical conclusion, in my mind, what worries me is that many of the sort of carcinogen assays are based on driving mutagenesis genome instability. But if many carcinogen aren't driving DNA mutagenesis but are still driving cancer, how are they doing it? And do we actually have the right assays to interpret safety of new chemical matter that's being introduced into our environment, these long-lived particles that we're breathing in plastics, pollutants, you name it, until we have the right biological assays, deeming something to be safe I think is tricky.Eric Topol (45:11):Absolutely. And I share your concerns on the nanoplastic microplastic story, as you well know, not only have they been seen in arteries that are inflamed and in blood clots and in various tissues, have they been seen so far or even looked for within tumor tissue?Charles Swanton (45:33):Good question. I'm not sure they have. I need to check. What I can tell you is we've been doing some experiments in the lab with fluorescent microplastics, 2.5 micron microplastics given inhaled microplastics. We find them in every mouse organ a week after. And these pollutants even get through into the brain through the olfactory bulb we think.Charles Swanton (45:57):Permeate every tissue, Eric.Eric Topol (45:59):Yeah, no, this is scary because here we are, we have these potentially ingenious ways to prevent cancer in the future, but we're chasing our tails by not doing anything to deal with our environment.Charles Swanton (46:11):I think that's right. I totally agree. Yeah.Eric Topol (46:15):So I mean, I can talk to you for the rest of the day, but I do want to end up with a topic that we have mutual interest in, which is AI. And also along with that, when you mentioned about aging, I'd like to get your views on these two, how do you see AI fitting into the future of cancer? And then the more general topic is, can we actually at some point modulate the biologic aging process with or without help with from AI? So those are two very dense questions, but maybe you can take us through them.Charles Swanton (46:57):How long have we got?Eric Topol (46:59):Just however long you have.A.I. and CancerCharles Swanton (47:02):AI and cancer. Well, AI and medicine actually in general, whether it's biomedical research or medical care, has just infinite potential. And I'm very, very excited about it. I think what excites me about AI is it's almost the infinite possibilities to work across scale. Some of the challenges we raised in the Cell review that you mentioned, tackling, embracing complexity are perfectly suited for an AI problem. Nonlinear data working, for instance in our fields with CT imaging, MRI imaging, clinical outcome data, blood parameters, genomics, transcriptomes and proteomes and trying to relate this all into something that's understandable that relates to risk of disease or potential identification of a new drug target, for example. There are numerous publications that you and others have covered that allude to the incredible possibilities there that are leading to, for instance, the new identification of drug targets. I mean, Eli Van Allen's published some beautiful work here and in the context of prostate cancer with MDM4 and FGF receptor molecules being intimately related to disease biology.(48:18):But then it's not just that, not just drug target identification, it's also going all the way through to the clinic through drug discovery. It's how you get these small molecules to interact with oncogenic proteins and to inhibit them. And there are some really spectacular developments going on in, for instance, time resolved cryo-electron microscopy, where in combination with modeling and quantum computing and what have you, you can start to find pockets emerging in mutant proteins, but not the wild type ones that are druggable. And then you can use sort of synthetic AI driven libraries to find small molecules that will be predicted to bind these transiently emerging pockets. So it's almost like AI is primed to help at every stage in scientific investigation from the bench all the way through to the bedside. And there are examples all the way through there in the literature that you and others have covered in the last few years. So I could not be more excited about that.Eric Topol (49:29):I couldn't agree with you more. And I think when we get to multimodal AI at the individual level across all their risks for conditions in their future, I hope someday will fulfill that fantasy of primary prevention. And that is getting me to this point that I touched on because I do think they interact to some degree AI and then will we ever be able to have an impact on aging? Most people conflate this because what we've been talking about throughout the hour has been age-related diseases, that is cancer, for example, and cardiovascular and neurodegenerative, which is different than changing aging per se, body wide aging. Do you think we'll ever changed body wide aging?Charles Swanton (50:18):Wow, what a question. Well, if you'd asked me 10 years ago, 15 years ago, do you think we'll ever cure melanoma in my lifetime, I'd have said definitely not. And now look where we are. Half of patients with melanoma, advanced melanoma, even with brain metastasis curd with combination checkpoint therapy. So I never say never in biology anymore. It always comes back to bite you and prove you wrong. So I think it's perfectly possible.Charles Swanton (50:49):We have ways to slow down the aging process. I guess the question is what will be the consequences of that?Eric Topol (50:55):That's what I was going to ask you, because all these things like epigenetic reprogramming and senolytic drugs, and they seem to at least pose some risk for cancer.Charles Swanton (51:09):That's the problem. This is an evolutionary phenomenon. It's a sort of biological response to the onslaught of these malignant cells that are potentially occurring every day in our normal tissue. And so, by tackling one problem, do we create another? And I think that's going to be the big challenge over the next 50 years.Eric Topol (51:31):Yeah, and I think your point about the multi-decade challenge, because if you can promote healthy aging without any risk of cancer, that would be great. But if the tradeoff is close, it's not going to be very favorable. That seems to be the main liability of modulation aging through many of the, there's many shots on goal here, of course, as you well know. But they do seem to pose that risk in general.Charles Swanton (51:58):I think that's right. I think the other thing is, I still find, I don't know if you agree with me, but it is an immense conundrum. What is the underlying molecular basis for somatic aging, for aging of normal tissues? And it may be multifactorial, it may not be just one answer to that question. And different tissues may age in different ways. I don't know. It's a fascinating area of biology, but I think it really needs to be studied more because as you say, it underpins all of these diseases we've been talking about today, cardiovascular, neurodegeneration, cancer, you name it. We absolutely have to understand this. And actually, the more I work in cancer, the more I feel like actually what I'm working on is aging.(52:48):And this is something that James DeGregori and I have discussed a lot. There's an observation that in medicine around patients with alpha-1 antitrypsin deficiency who are at higher risk of lung cancer, but they're also at high risk of COPD, and we know the associations of chronic obstructive pulmonary disease with lung cancer risk. And one of the theories that James had, and I think this is a beautiful idea, actually, is as our tissues age, and COPD is a reflection of aging, to some extent gone wrong. And as our tissues age, they become less good at controlling the expansion of these premalignant clones, harboring, harboring oncogenic mutations in normal tissue. And as those premalignant clones expand, the substrate for evolution also expands. So there's more likely to be a second and third hit genetically. So it may be by disrupting the extracellular matrices through inflammation that triggers COPD through alpha-1 antitrypsin deficiency or smoking, et cetera, you are less effectively controlling these emergent clones that just expand with age, which I think is a fascinating idea actually.Eric Topol (54:01):It really is. Well, I want to tell you, Charlie, this has been the most fascinating, exhilarating discussion I've ever had on cancer. I mean, really, I am indebted to you because not just all the work you've done, but your ability to really express it, articulate it in a way that hopefully everyone can understand who's listening or reading the transcript. So we'll keep following what you're doing because you're doing a lot of stuff. I can't thank you enough for joining me today, and you've given me lots of things to think about. I hope the people that are listening or reading feel the same way. I mean, this has been so mind bending in many respects. We're indebted to you.Charles Swanton (54:49):Well, we all love reading your Twitter feeds. Keep them coming. It helps us keep a broader view of medicine and biological research, not just cancer, which is why I love it so much.******************************************The Ground Truths newsletters and podcasts are all free, open-access, without ads.Please share this post/podcast with your friends and network if you found it informativeVoluntary paid subscriptions all go to support Scripps Research. Many thanks for that—they greatly helped fund our summer internship programs for 2023 and 2024.Thanks to my producer Jessica Nguyen and Sinjun Balabanoff tor audio and video support at Scripps Research.Note: you can select preferences to receive emails about newsletters, podcasts, or all I don't want to bother you with an email for content that you're not interested in. Get full access to Ground Truths at erictopol.substack.com/subscribe

Dr. Jyoti Patel discusses the latest update to the stage IV NSCLC with driver alterations living guideline, specifically for patients with EGFR or ROS1 alterations. She shares the latest recommendations based on recently published evidence, such as the FLAURA2, MARIPOSA-2, and TRIDENT-1 trials. Dr. Patel talks about how to choose between these new options and the impact for patients living with stage IV NSCLC, as well as novel drugs the panel is monitoring for future guideline updates. Read the full living guideline update “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.1” at www.asco.org/living-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/living-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.24.00762  Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Jyoti Patel from Northwestern University, co-chair on, “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.1.”  Thank you for being here today, Dr. Patel. Dr. Jyoti Patel: Thanks so much.   Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Patel, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.  So then to dive into the content of why we're here today, Dr. Patel, this living clinical practice guideline for systemic therapy for patients with stage four non-small cell lung cancer with driver alterations is being updated on a regular basis. So what prompted the update to the recommendations in this latest update?  Dr. Jyoti Patel: This recent update, I think, absolutely reflects how quickly the science is changing. The landscape of treatment options for patients with advanced non-small cell lung cancer is evolving so rapidly, and guidelines from even six months ago don't address some of the newest approvals and newest data and the newest clinical scenarios that we're presented with when we see patients. I think it's harder because before there was usually a single answer, and now there are a number of scenarios, and we hope that the guideline addresses this. Brittany Harvey: Absolutely. The panel's had a lot of data to review as you keep this guideline up to date.  So then this latest update addresses updates to both EGFR and ROS1 alterations. So starting with EGFR, what are the updated recommendations for patients with stage four non-small cell lung cancer and an EGFR exon 19 deletion or exon 21 L858R substitution?  Dr. Jyoti Patel: So for patients with classical driver mutations in EGFR, our recommendation remains that patients should be offered osimertinib. We now also have data to support intensification of therapy with osimertinib and chemotherapy. The FLAURA2 trial was a global randomized study in which patients with classical mutations were assigned to receive either osimertinib or osimertinib with doublet chemotherapy. The trial showed that progression free survival was longer with osimertinib plus chemotherapy with a hazard ratio that was pretty profound, 0.62. In patients who had CNS metastasis as well as patients with L858R mutations, this benefit remained and was perhaps even greater. Now the study remains immature in terms of OS. What we can say is that chemotherapy adds toxicity, so the inconvenience of 13 weekly infusions, expected toxicities from chemotherapy of myelosuppression and fatigue. I think this- we'll continue to watch as the study matures to really see the OS benefit, but certainly intensification in the frontline setting is an option for patients.  The other major update was for second and subsequent line therapy for these patients with EGFR mutations. Another important trial, a study called MARIPOSA-2, was published in the interim, and this was for patients who had received osimertinib in the frontline setting. Patients were randomized to one of three arms. The two arms that are most relevant for us to discuss are chemotherapy with amivantamab or chemotherapy alone. Chemotherapy with amivantamab was associated with an improvement in progression free survival with a hazard ratio of 0.48 as well as improvements in response rate with almost a doubling of response rate to the mid 60%. There was certainly an increase in AEs associated with amivantamab, primarily rash and lower extremity edema and importantly infusion reaction. Based on this data, though in the superior PFS and response rate, we've said that patients after osimertinib should be offered chemotherapy plus amivantamab. Patients may opt for chemotherapy alone because of the toxicity profile, but this recent update is reflective of that data. Brittany Harvey: Excellent. Thank you for reviewing those updated recommendations and the supporting evidence behind those recommendations. I think that's important to the nuance and the toxicity associated with these new recommendations as well.   So then, following those recommendations, what are the updated recommendations for patients with stage four non-small cell lung cancer and a ROS1 rearrangement? Dr. Jyoti Patel: ROS1 fusions have been noted in a small but important subset of patients. We now reflect multiple new options for patients. Traditionally, crizotinib was the primary drug that was recommended, but we now have two very active drugs, repotrectinib, and entrectinib, that have both been FDA approved. Repotrectinib was approved based on a study called the TRIDENT-1 trial. In this study, patients who were treatment naive, who had not received a prior TKI, had a response rate of 79% and a long duration of response over 34 months. For patients who had received prior TKIs, so primarily crizotinib, the response rate was lower at 38%. But again, very clinically meaningful. Repotrectinib has known CNS activity, so it would be the favored drug over crizotinib, which doesn't have CNS penetration. The decision between entrectinib and repotrectinib is one, I think, based on toxicity. Repotrectinib can cause things like dizziness and hypotension. Entrectinib can cause weight gain, and also has CNS effects. Brittany Harvey: Appreciate you reviewing those recommendations as well.  So then you've already talked a little bit about this in terms of deciding between some of the options. But in your view, what should clinicians know as they implement these new recommendations, and how do these new recommendations fit into the previous recommendations? Dr. Jyoti Patel: So there's an onslaught of new data, and certainly many of us want to remain at the front of our fields and prescribe the newest drug, our most effective drug, to all of our patients. But for the person living with cancer and in the practice of medicine, I think it's much more nuanced than that. For example, for a patient with an EGFR mutation exon deletion 19, the expectation is that osimertinib will have a deep and durable response. Certainly a patient will eventually have progression. I think the decision about intensification of therapy and chemotherapy on the onset really has to do with how much the patient is willing to deal with the inconvenience of ongoing chemotherapy, the uncertainty about what comes next after progression on chemotherapy. It may be, though, that a patient may very much fear progressive disease, and so that inconvenience is lessened because anxiety around feeling like they're doing everything for their cancer is diminished by intensification of therapy. Others who may have a large volume of disease or profoundly symptomatic, or who have L858R or brain metastasis it may make sense to give chemotherapy again, we're improving the time until progression significantly by combination therapy. Brittany Harvey: Definitely those nuances are important as we think about which options that patients should receive, along with shared decision making as well.  So then what do these new options mean for patients with EGFR or ROS1 alterations? Dr. Jyoti Patel: It's fantastic for patients that there are multiple options. It's also really hard for patients that there are multiple options, because then again, we have to really clarify aims of therapy, identify what's really important in patient experience and the lived importance of treatment delivery and the burden of treatment delivery. Now more than ever, oncologists have to know what's new and exciting. But patients have to be willing to ask and participate in the shared decision making - understanding their cancer and understanding that their options are absolutely important. As patients start making their decisions, we have the data just in terms of trial outcomes. I think we're now trying to understand the burden of treatment for patients. And so that piece of communicating financial toxicity, long term cumulative lower grade toxicity is going to be more important than ever. Brittany Harvey: Absolutely. It's great to have these new options, and those elements of communication are key to ensuring that patients meet their goals of care.  So then finally, as this is a living guideline, what ongoing research is the panel monitoring for future updates to these recommendations for patients with stage four non-small cell lung cancer with driver alterations? Dr. Jyoti Patel: It's certainly been an exciting time, and that's primarily because we've been able to build on years of foundational science and we have new drugs. Patients have been willing to volunteer to go on clinical trials and to think about what treatment options may be best. Now, the work really comes on seeing the longer term outcomes from these trials. So looking at these trials for overall survival, we want to also better identify which patients will benefit the most from these treatments and so that might be additional biomarker analysis. So it may be that we can identify patients that may need intensification of therapy based on tumor factors as well as patient factors as well in those patients in whom we can de-escalate treatment. I think there are a number of new compounds that are in the pipeline. So fourth generation EGFR TKIs are certainly interesting. They may be able to overcome resistance for a subset of patients who progress on osimertinib. We also think about novel drugs such as antibody drug conjugates and how they'll fit into our paradigm with osimertinib or after carboplatin-based doublets. Brittany Harvey: Definitely. We'll look forward to both longer term readouts from the current trials and new trials in this field to look at additional options for patients.  So I want to thank you so much for your time today, Dr. Patel, and thank you for all of your work to keep this living guideline up to date. Dr. Jyoti Patel: Great. Thanks so much, Brittany. It really is an exciting time for people who treat lung cancer and for patients who have lung cancer. We certainly have a long way to go, but certainly the rapid uptake of these guidelines reflect the progress that's being made.  Brittany Harvey: Absolutely. And just a final thank you to all of our listeners for tuning into the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/living-guidelines.  You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

Lung cancer is a significant global health issue, being the second most commonly diagnosed cancer and the leading cause of cancer-related death worldwide. Non-small-cell lung cancer (NSCLC) represents the majority of lung cancer cases and is often diagnosed at an advanced stage. Epidermal growth factor receptor (EGFR) mutations are more common in Asian NSCLC populations than in Western populations. Activating EGFR mutations, such as exon 19 deletions and L858R, are predictive of response to tyrosine kinase inhibitors (TKIs) and have revolutionized the treatment landscape for patients with EGFR-mutated NSCLC. However, most clinical trials tend to lack data for the elderly population, even though a significant proportion of lung cancer patients are aged 65 years and older. This underrepresentation of elderly patients in clinical trials limits our understanding of the effectiveness and safety of EGFR-TKIs in this specific population. In this new study, researchers Ling-Jen Hung, Ping-Chih Hsu, Cheng-Ta Yang, Chih-Hsi Scott Kuo, John Wen-Cheng Chang, Chen-Yang Huang, Ching-Fu Chang, and Chiao-En Wu from Chang Gung University and Taoyuan General Hospital conducted a multi-institute retrospective study to investigate the effectiveness and safety of afatinib, gefitinib, and erlotinib for treatment-naïve elderly patients with EGFR-mutated advanced NSCLC. On January 8, 2024, their research paper was published in Aging's Volume 16, Issue 1, entitled, “Effectiveness and safety of afatinib, gefitinib, and erlotinib for treatment-naïve elderly patients with epidermal growth factor receptor-mutated advanced non-small-cell lung cancer: a multi-institute retrospective study.” Full blog - https://aging-us.org/2024/01/efficacy-and-safety-of-egfr-tkis-for-elderly-patients-with-nsclc/ Paper DOI - https://doi.org/10.18632/aging.205395 Corresponding author - Chiao-En Wu - 8805017@cgmh.org.tw Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.205395 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, elderly patients, epidermal growth factor receptor, tyrosine kinase inhibitor, non-small-cell lung cancer, real-world evidence About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com​​ and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ X - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

Drs. Vamsi Velcheti and Jack West discuss ADAURA, KEYNOTE-671, and KEYNOTE-789 trials in NSCLC and the first pivotal study of sunvozertinib for the treatment of NSCLC with EGFR exon 20 insertion mutations. TRANSCRIPT Dr. Vamsi Velcheti: Hello, I'm Dr. Vamsi Velcheti, your guest host for the ASCO Daily News Podcast. I'm a professor of medicine and director of thoracic medical oncology at the Perlmutter Cancer Center at NYU Langone Health. My guest today is Dr. Jack West, a thoracic oncologist and associate professor in medical oncology at City of Hope Comprehensive Cancer Center. Today, we'll be discussing practice-changing studies and other key advances in lung cancer that were featured at the 2023 ASCO Annual Meeting.   Our full disclosures are available in the transcript of this episode and disclosures of all guests on the ASCO Daily News podcast are available at asco.org/DNpod.   Jack, there was a lot of exciting new data that emerged from the ASCO Annual Meeting, and it's great to have you back on our podcast today to talk about all the key updates in lung cancer.   Dr. Jack West: Absolutely. Thanks so much. It's always a high-energy meeting, and there was a lot to talk about in the lung cancer sessions this year for sure.  Dr. Vamsi Velcheti: Let's begin with LBA3, the ADAURA trial. This was presented in the Plenary Session at ASCO; we've heard previously the DFS updates from previous meetings, and overall survival updates were presented at the ASCO 2023 Annual Meeting. So, Jack, what was the highlight of the presentation for you? And could you put things in context for us? We have known about the DFS data for a while now. What gets you so excited about this study?  Dr. Jack West: Well, we've actually been focused on this trial for literally 3 years, since Dr. Herbst presented it at another Plenary presentation back in the ASCO Meeting in 2020 when we saw tremendous differences in the DFS data. Again, this was a trial of patients with resected stage 1b to 3a EGFR mutation-positive non-small cell lung cancer. Nearly 700 patients were randomized to after-surgery, and for many, but not all, patients undergoing chemotherapy, it wasn't mandated. But after that, they were randomized to get adjuvant, placebo, or osimertinib for up to 3 years. And we saw huge differences in the disease-free survival from the first presentation, with a hazard ratio in the range of 0.2.   We have notably seen significant improvements in disease-free survival before with other EGFR TKIs for this population after surgery, but nothing in this range. And it's also notable that in the various other trials of other EGFR inhibitors in the postoperative setting, we've seen a DFS benefit, but that didn't translate to an improvement in overall survival. So, seeing a press release that this was associated with a significant and, in fact, highly significant by report, improvement in overall survival, as well as DFS, was really notable.   What's also, I think, particularly important as a focus of this is that in the later presentations of this work, with longer follow-up last year, we saw that the DFS curves showed a drop in the DFS starting after these patients had completed 3 years of treatment. So, really suggesting that at least some, if not many or most of these patients who had been on adjuvant osimertinib were subject to a higher risk of relapse once they completed that. So, again, making the endpoint of overall survival particularly important. It's always been to me the endpoint we should care about most in a curative setting. Although the DFS was the primary endpoint of the study and it was powered and built around specifically focusing on the DFS difference, so overall survival was reassuring, I think, when we actually saw it, but not what the trial was centered around.    And what we saw was a very dramatic improvement in overall survival with a hazard ratio of 0.49. That was essentially the same for the patients with stage 2 to 3a disease, as well as the broader population with stage 1b to 3a disease. When we look at the absolute numbers for overall survival at 5 years, there was an improvement from 73% to 85% with osimertinib, and in the population from 1b to 3a, an improvement from 78% to 88%. So, many things to comment on here. Really remarkable to see an 88% 5-year survival in the osimertinib arm that includes patients with stage 3a disease.    I would say that there's still some controversy, some questions about this, and it really centers around a few things. One is, like many global trials, this one enrolled patients from many places that did not have the same standard of care staging that we follow in the U.S. There wasn't any specification or mandate for PET scans, which would be very routine in the U.S. And brain MRIs were not mandated either. And so there were almost certainly some patients with more advanced disease that was not detected that would be a big advantage for the osimertinib arm, but really not characterized. And also, the crossover was made possible to osimertinib starting in April of 2020, but only 38.5% of the patients on the control arm actually received osimertinib at the time of relapse. And even though many of the other patients who had a relapse did get another EGFR inhibitor, I don't think there's much question that osimertinib is the preferred and optimal EGFR TKI.   And so there were a couple of important factors kind of going for this trial. One is the long, long, long duration of treatment at 3 years, though with a drop-off, I think some questions about whether even that is enough, and we might be tempted to treat beyond 3 years. And then how much did the inability of most of the patients on the control arm to get osimertinib later contribute? My personal view is that it is a troubling aspect of this trial. But also so many other trials that they're run globally in places where we arguably perpetuate these disparities by running these trials that, in part, magnify the differences between the two arms because some patients just will not have access to what is our best standard of care in the U.S., or many other parts of the world, but weren't necessarily available to many of the patients on the control arm where it was conducted. So, I think that's always a concern. It's definitely an issue of this trial, but I would not say it's unique to this one.  Dr. Vamsi Velcheti: Very good points, Jack, and I completely agree with you. I think those certainly are concerns. But on the other hand, this is a pragmatic trial and that's the real-world scenario in terms of access issues, in terms of osimertinib globally, correct, in the stage 4 setting, even though we all agree that osimertinib is the best option for patients with metastatic EGFR-mutated lung cancer, I think that's obviously a reflection of global access issues and global disparities and changes in standard of care in terms of workup as well. So, it's somewhat of a pragmatic trial in some ways and I completely agree with you, I think that may have potentially had some impact on the overall survival.  Dr. Jack West: Well, I would clarify that I don't think that this really highly significant difference in overall survival is undermined completely by this. There's no question in my mind that with the huge difference in disease-free survival that we'd already seen for 3 years, it has become our standard of care really for this population at least to offer it, if not to strongly recommend it. But I would say that most of us have been quite inclined to recommend it, perhaps with caveats. And I would say that this overall survival benefit mostly corroborates that, even if there are some concerns about how these trials are done, but it's still an impressive difference that would lead me to only cement my practice of pursuing it in this setting. I just would love to re-examine how we conduct these trials and potentially potentiate disparities that exist and don't want to have our trials be more positive by capitalizing on that.   Dr. Vamsi Velcheti: Let's move on to the next abstract, LBA100; this is the KEYNOTE-671 trial. This was featured during the meeting's Clinical Science Symposium. This is a study of pembrolizumab or placebo plus platinum doublet followed by surgical resection and pembrolizumab or placebo for early-stage non-small cell lung cancer. Jack, what was the key message from this trial, and do you consider this as practice-changing?  Dr. Jack West: This has been an area where we've seen really dramatic evolution in our practice patterns, specifically, at least for patients who don't have a tumor harboring an EGFR mutation or ALK rearrangement. I would say that there has been some momentum toward preoperative neoadjuvant therapy, specifically based on the CheckMate-816 trial that gave chemo with nivolumab versus placebo and showed a significant improvement in the pathologic complete response rate at surgery as well as event-free survival. The overall survival looks encouraging but is still early and hasn't met the threshold for statistical significance, and that's FDA-approved.   But we still question whether there's a value to doing anything in the postoperative setting. And the CheckMate-816 trial did not include that as part of the trial. It allowed postoperative management at the judgment of the treating physician but didn't really prescribe anything. We now have the results of several trials in the last few months that have added a component in the postoperative setting in addition to three or four cycles of preoperative chemoimmunotherapy. And the first one that gave us a glimpse was the AEGEAN trial presented by Dr. John Heymach at AACR in April of this year that looked at chemo and durvalumab versus chemo placebo and then followed by a year of durvalumab versus placebo after surgery. That showed results in terms of major pathologic response and event-free survival that are significantly better with immunotherapy. Not clearly superior to what we would see with CheckMate-816.   And then even more recently, we saw a monthly Plenary presentation from ASCO with the Neotorch trial presented by Dr. Shun Lu of China. This was a Chinese trial only that presented results just for patients with stage 3 disease thus far. This included patients with stage 2 or stage 3, but what we saw is stage 3 results and that looked at chemo with toripalimab for 3 cycles versus placebo and then a year of checkpoint inhibitor or placebo. This also shows a benefit with the addition of immunotherapy, but not clear if that's better than what we can already achieve with neoadjuvant alone with the Checkmate-816 approach.   And then what we have now is a presentation and simultaneous publication by Dr. Heather Wakelee of KEYNOTE-671. And this is really almost the exact same trial design as AEGEAN. It's 4 cycles of platinum doublet chemotherapy and it is for patients with stage 2 to 3a disease. And this gave 4 cycles of chemotherapy with placebo or pembrolizumab. And then after surgery, patients would go on in the investigation arm to a year of pembrolizumab or to the additional year with placebo. And this shows a significant improvement in event-free survival with a hazard ratio of 0.58. It's most prominent in patients with high PD-L1, where the hazard ratio is 0.42. But there's still a benefit in patients with PD-L1 less than 1%, where it's 0.77. And there was a trend toward better overall survival here, hazard ratio of 0.73. It does not reach statistical significance at this early point. It's still preliminary but certainly looks encouraging. And there are also significant improvements in major pathologic response, where less than 10%, about a threefold difference from 30.2% with immunotherapy compared to 11% with placebo. And a very impressive improvement in pCR rate, which is 18.1% with the chemo and pembro compared to 4% with chemotherapy alone. Not surprisingly, when we look at event-free survival, it's best in the patients who achieve a pathologic complete response, but pembrolizumab improved outcomes in event-free survival even for those who didn't achieve a pCR.   The real question I would say is does the addition of a year of checkpoint inhibitor therapy postoperatively add to what we already achieve with those first three cycles with chemo-neo or 4 cycles with maybe one of these other options? And these trials can't answer that question because they just include them as a package deal. There's no way to tease apart right now the component of what incremental benefits you get from that. And it certainly adds a year of time coming in for every 3-week infusions. Even if you space that out, it's still a year of coming in and getting infusions, potential cumulative immune-related toxicities, and a lot of cost versus potentially being done. And I think that really is the big question at this point of do you want to recommend something when we don't really have a precedent for much benefit beyond the first 4 cycles? Perhaps. Certainly, we give maintenance pemetrexed and other immunotherapies and there can be benefit there. So, I wouldn't say you necessarily cap that. But if there is resistant disease after the first 4 cycles you've already given 3 cycles, how much benefit is there? How likely is it that you're going to eradicate the last cancer cells with more?   That said, I think many patients, and oncologists myself perhaps included, are going to be inclined to err on the side of possibly over-treating, but at least trying to give everything that is part of a widely studied, FDA-approved approach once these options become available. I just think it's going to end up as a careful discussion with each patient about whether they'd prefer to just say they're done or do that extra year and really feel that even if it comes back, they've done everything that made sense to try.  Dr. Vamsi Velcheti: Very good points, Jack. So let's move on to another abstract, which is the LBA9000. This is the KEYNOTE-789 trial. In my opinion, this is the most important negative phase 3 trial in lung cancer in a while. This is a trial looking at pemetrexed platinum with or without pembrolizumab in patients who have EGFR mutation-positive metastatic non-small cell lung cancer. So, what are your key takeaways, Jack?  Dr. Jack West: Well, I would say essentially we've been waiting to figure out what is the best treatment approach for patients with acquired resistance after osimertinib. And most of the patients had received osimertinib for their EGFR mutation-positive non-small cell. This is essentially KEYNOTE-189 being run in the EGFR mutation-positive patients after they've exhausted at least the major benefit of EGFR TKI therapy.   What we saw was a hazard ratio for progression-free survival of 0.8. It didn't quite make it across the threshold for efficacy, a significant difference. And so it missed that efficacy boundary. And overall survival, the hazard ratio is 0.84, also missing the efficacy boundary. When you look at the actual curves, they show modest separation, nothing eye-popping, certainly compared to some of the other trials we're talking about. But I wouldn't say they show no benefit. And I think that's, to me, why there's really still a role for a nuanced thought process and maybe some discussion about how negative this is. This is not, in my mind, stone-cold negative with no patients benefiting from immunotherapy. This is a trial that really suggests that there's a subset of patients who are benefiting from immunotherapy.   And we've also seen going back to subset analysis of the IMpower150 trial and also the ORIENT-31 trial with sintilimab and a bevacizumab biosimilar, another anti-VEGF inhibitor. These trials both really indicated a benefit in this population after EGFR TKI therapy of immunotherapy combined with VEGF. I think there could still be a value in there. I don't want to be a Pollyanna or too open-minded, but I think that there was at least a suggestion that this could still be a fruitful avenue. I think that this is still something we should do additional studies on that could bear fruit. I wouldn't close the door and categorically say this is just never going to translate to any benefit for any of these patients.   Dr. Vamsi Velcheti: The key thing, though, is, like in EGFR mutant patients I think in the previous studies as well, the response rates with single-agent PD-1 have been very minimal. And I think one of the things that's actually very important to highlight is in the operative setting, the early-stage setting, unfortunately, some of the trials with immunotherapy have included patients with an EGFR mutation. And now we have a treatment option for those patients within the adjuvant setting, especially osimertinib. We just heard from the ADAURA trial, which has a clear significant overall survival benefit. So I think it's really important to test for EGFR mutation in all stages. And if somebody with the early stage has an EGFR mutation, adjuvant immunotherapy, or perioperative immunotherapy may not be the best option for those patients.  Dr. Jack West: Right. I agree with that, although it is interesting that the KEYNOTE-671 trial did have some small population of patients with an EGFR mutation, and in that subset analysis, they seem to benefit from the pembrolizumab. I would not say that we should divert from ADAURA, but I'm just not as sure that our previous statement and mindset that immunotherapy just categorically doesn't work for patients with driver mutations is that simple.   First of all, there is some heterogeneity about which driver mutation, and the ALK-positive patients seem to really get no benefit. But I think there's still some questions about immunotherapy for EGFR. Certainly, patients with KRAS or BRAF V600E seem to benefit like the broader range of patients. And I would also say maybe it's different whether you're giving immunotherapy combined with chemotherapy versus as monotherapy. So that's why I'm just not that sure we really can characterize this that well yet.   The one additional point I would make about KEYNOTE-789 and the potential role of immunotherapy is that some experts in thoracic oncology and general oncologists alike may prefer to introduce chemotherapy at a time of progression, but keep the osimertinib going, maybe particularly for patients with brain metastases, whether current or a history of them, where we really feel that the osimertinib adds a critical component to CNS control. We don't want to ever give osimertinib or probably other EGFR TKIs concurrently with immunotherapy. So that's just a factor that we'd really want to consider when we're prioritizing where to fit in immunotherapy, if at all.  Dr. Vamsi Velcheti: Thank you, Jack. And let's move on to the next abstract, Abstract 9002. This is a pivotal study of results from the sunvozertinib, which is an EGFR exon 20 insertion site mutation drug. There's some very promising data. Jack, how do you feel this study is going to influence practice?  Dr. Jack West: Well, this is not an agent we have access to broadly yet, but I was quite impressed by it overall. I didn't mention it. We talked about it in the pre-ASCO discussion, and it was really one that I would mark as potentially practice-changing when we can get it. DZD 9008 or sunvozertinib is a potent inhibitor of exon 20 insertion mutations, and this was 97 patients, and the majority had had a couple of lines of prior therapy. They had to have gotten chemo, and the response rate was 60%, and it was really comparable efficacy with the different mutation subtypes.   I think that the main thing that I would want to clarify a little better in my own patient population is how well the drug is really tolerated. We talked about that there was not really much grade 3 toxicity and that's true, but diarrhea rates were 67%, even though it was grade 3 and just about 8%. But grade 2 diarrhea or grade 2 rash in patients who are on this therapy, we hope for a long time, I think is something we shouldn't minimize. And I think that particularly our mindset about toxicity needs to be different when we're talking about giving a treatment for 2 or 4 cycles and then being done with it versus something we hope we're going to be giving longitudinally. And we really don't want to minimize the potential impact on the quality of life of patients who are experiencing grade 2 rash, diarrhea, or paronychia for months and months, maybe more than a year at a time.   But that said, this is twice the response rate if not more than that of what we have already had for patients with this molecular aberration with an exon 20 insertion. So I think it's compelling and I think that it's going to be really valuable to offer to our patients. I just would like to clarify better how well patients who are actually on it are feeling when you incorporate the potentially chronic toxicity issues.  Dr. Vamsi Velcheti: Thank you, Jack. And let's move on to the last abstract. This the LUNAR study, LBA9005. This is a positive phase 3 study that looked at tumor-treating fields or TTF therapy with standard of care treatments in metastatic non-small-cell lung cancer following platinum failure. This has been talked about a lot at ASCO, and Jack I'm eager to hear your key takeaways about this study.  Dr. Jack West: Well, we knew from a press release several months ago, I think back in February, that there was a significant improvement in overall survival with the addition of tumor-treated fields. Again, this concept that electric fields can lead to antimitotic effect and potentially downstream induction of immunogenic cell death and enhanced immune response, that's at least the concept. And it's of course established, has utility in patients with glioblastoma, although kind of, I would say underutilized because it can be cumbersome. And I think that's one of the things we need to factor in is that this is not the easiest approach to pursue.   But we don't have that many therapies that improve overall survival significantly in previously treated patients with non-small cell lung cancer. So, I think there's good reason to focus on this and ask how beneficial it is. It was notable, it was pretty much an even split of patients enrolled on the trial, 276 patients total, but about half had gotten chemo but not gotten immunotherapy before. And then the other half, I would say the clear majority, had gotten immunotherapy as well as chemo and got docetaxel-based treatment.     And the overall survival benefit was significant for the intent to treat total population with a hazard ratio of 0.74 and a difference in 3-year survival of 18% favoring the addition of tumor-treating fields on the chest versus 7% in the patients who didn't. It really seemed to separate between the patients who had not had an immune checkpoint inhibitor and got tumor-treating fields with the checkpoint inhibitor where the hazard ratio is 0.63 and those who got tumor-treating fields with docetaxel where the hazard ratio was 0.81. So it really wasn't significant in this population.  Toxicity, no real surprises compared to what we already knew about tumor-treating fields. Mostly dermatitis, but I would say that one of the kind of unmeasured issues is that this is a device that people have to wear on their chest carrying a battery pack with them all day long. It's essentially all the waking day, and so I think that's at least cumbersome. I wouldn't call it prohibitive, but it's a challenge. And I think we need to really ask whether the juice is worth the squeeze, whether the benefit is that compelling. And I question that when we're talking about an agent that doesn't significantly move the needle against docetaxel alone.   Again, this is a population where in the U.S. we have ramucirumab to add to docetaxel. Not everyone does that. It's not uniform, but that has a statistically significant, though modest survival benefit associated with that. We don't do better than that with tumor treating fields. And so, I think that this is an option that merits discussion and some patients may opt for it, but I suspect that most of my patients would not find the absolute difference to be that compelling for the challenges it incurs. I don't know what your perspective is here.  Dr. Vamsi Velcheti: I completely agree, Jack. And I think the study design and just the fact that the standard of care has changed over the last 5, actually 6 years since the study has been open. And I'm not really so sure I could really make much sense of the data in terms of the standard of care combination with TTF providing more benefit. And I think there are more questions than answers here and I'm not so sure which populations would benefit the most. And I think, I hate to say this, but this is a nice proof of concept. I hate to say this because it's a phase 3 study and it's a positive phase 3 study, but it's clinical relevance with the current standard of care, I think, I'm not really sure how much of an impact this would really have.    Well, Jack, I've really enjoyed speaking with you about these key advances in lung cancer that were featured at the 2023 ASCO Annual Meeting. Our listeners will find links to all the studies discussed today in the transcript of this episode. Thank you so much, Jack, for joining us today.  Dr. Jack West: Always a pleasure. Thanks so much.  Dr. Vamsi Velcheti: And just like that, we've reached the end of another enriching episode. But remember, like all good things, this too must come to an end, but only until we meet again. We really would like your feedback on the podcast. If you enjoyed the podcast, please rate, review and subscribe wherever you get your podcasts.  Disclaimer:    The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Follow today's speakers:   Dr. Vamsidhar Velcheti   @VamsiVelcheti   Dr. H. Jack West   @JackWestMD   Follow ASCO on social media:    @ASCO on Twitter   ASCO on Facebook   ASCO on LinkedIn      Disclosures:    Dr. Vamsidhar Velcheti:   Honoraria: ITeos Therapeutics   Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine, AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen, Elevation Oncology, Taiho Oncology, Merus   Research Funding (Inst.): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline     Dr. Jack West:   Honoraria: AstraZeneca, Genentech/Roche, Merck, Takeda, Mirati, Regneron, Amgen, Abbvie   Consulting or Advisory Role: AstraZeneca, Genentech/Roche, Merck, Takeda, Mirati Therapeutics, Regneron, Amgen, Abbvie, Summit Therapeutics   Speakers' Bureau: Takeda, Merck, AstraZeneca        

With new Pod this week, we're re-releasing the 2nd episode from way back in 2017 that provides a historical overview of how the use of EGFR TKIs changed from their use in all NSLCLC to only with activating mutations.

Tim Fenton, Ph.D., University of Southampton, shares his work on the roles of APOBEC3 genes. Hear how he is investigating APOBEC regulation and function in keratinocytes. Series: "Stem Cell Channel" [Health and Medicine] [Show ID: 38724]

Tim Fenton, Ph.D., University of Southampton, shares his work on the roles of APOBEC3 genes. Hear how he is investigating APOBEC regulation and function in keratinocytes. Series: "Stem Cell Channel" [Health and Medicine] [Show ID: 38724]

Tim Fenton, Ph.D., University of Southampton, shares his work on the roles of APOBEC3 genes. Hear how he is investigating APOBEC regulation and function in keratinocytes. Series: "Stem Cell Channel" [Health and Medicine] [Show ID: 38724]

Tim Fenton, Ph.D., University of Southampton, shares his work on the roles of APOBEC3 genes. Hear how he is investigating APOBEC regulation and function in keratinocytes. Series: "Stem Cell Channel" [Health and Medicine] [Show ID: 38724]

Tim Fenton, Ph.D., University of Southampton, shares his work on the roles of APOBEC3 genes. Hear how he is investigating APOBEC regulation and function in keratinocytes. Series: "Stem Cell Channel" [Health and Medicine] [Show ID: 38724]

Tim Fenton, Ph.D., University of Southampton, shares his work on the roles of APOBEC3 genes. Hear how he is investigating APOBEC regulation and function in keratinocytes. Series: "Stem Cell Channel" [Health and Medicine] [Show ID: 38724]

Tim Fenton, Ph.D., University of Southampton, shares his work on the roles of APOBEC3 genes. Hear how he is investigating APOBEC regulation and function in keratinocytes. Series: "Stem Cell Channel" [Health and Medicine] [Show ID: 38724]

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.17.512459v1?rss=1 Authors: Shi, B. Abstract: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) positively affect the initial control of non-small cell lung cancer (NSCLC). The rapidly acquired TKIs resistance accounts for a major hurdle in successful treatment. However, the mechanisms controlling EGFR-TKIs resistance remain largely unknown. RNA structures have widespread and crucial roles in various biological processes; but, their role in regulating cancer drug resistance remains unclear. Here, the PARIS method is used to establish the higher-order RNA structure maps of EGFR-TKI resistant- and sensitive-cells of NSCLC. According to our results, RNA structural regions are enriched in UTRs and correlate with translation efficiency. Moreover, YRDC facilitates resistance to EGFR-TKIs in NSCLC cells, and RNA structure formation in YRDC 3'UTR suppress ELAVL1 binding leading to EGFR-TKIs sensitivity by impairing YRDC translation. A potential cancer therapy strategy is provided by using antisense oligonucleotide (ASO) to perturb the interaction between RNA and protein. Our study reveals an unprecedented mechanism in which the RNA structure switch modulates EGFR-TKIs resistance by controlling YRDC mRNA translation in an ELAVL1-dependent manner. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

We discuss a phase I study (CALM) of an allogeneic anti-CD19 CART-T product, using aprepitant (?) for pruritis from EGFR TKIs, and the widely discussed NordICC study on colonoscopy screening. CALM: https://doi.org/10.1016/S2352-3026(22)00245-9 Aprepitant vs. desloratidine: https://doi.org/10.1002/cncr.34474 NordICC: https://www.nejm.org/doi/full/10.1056/NEJMoa2208375 NordICC editorial: https://www.nejm.org/doi/full/10.1056/NEJMe2211595

Dr. Chul Kim gives a brief history of targeted therapies, and discusses EGFR-TKIs.

Guest host Dr. Nathan Pennell, of the Cleveland Clinic Taussig Cancer Institute, and Dr. Vamsi Velcheti, of the NYU Langone Perlmutter Cancer Center, discuss the ATLANTIS trial and other novel therapies in advanced SCLC, NSCLC, and malignant pleural mesothelioma featured at the 2022 ASCO Annual Meeting Poster Sessions.  Transcript   Dr. Nathan Pennell: Hello, I'm Dr. Nathan Pennell, your guest host for the ASCO Daily News Podcast, today. I'm the co-director of the Cleveland Clinic Lung Cancer Program and vice-chair of Clinical Research for the Taussig Cancer Institute.  My guest today is my friend Dr. Vamsidhar Velcheti, an associate professor and medical director of thoracic oncology at the Perlmutter Cancer Center at NYU Langone Health.  We'll be discussing key posters on lung cancer that will be featured at the 2022 ASCO Annual Meeting. Although the oral sessions tend to get the most press, we want to make sure you don't miss out on some high-impact abstracts that are presented in the poster session.  Our full disclosures are available in the show notes and disclosures of all guests on the podcast can be found on our transcripts at asco.orgpodcasts.  Vamsi, it's great to speak with you today.  Dr. Vamsidhar Velcheti: Thank you, Nate. It's a pleasure to discuss these 5 outstanding abstracts.  Dr. Nathan Pennell: Why don't we start with Abstract 9021, “Genomic correlates of acquired resistance to PD-(L)1 blockade in patients with advanced non—small cell lung cancer (NSCLC).” Vamsi, what were your key takeaways from this study?  Dr. Vamsidhar Velcheti: This is an important study in my opinion. This was a very large study of 1,700 patients from Dana Farber and the investigators looked at 45 specimens and matched pre- and post- immunotherapy treated patients. And they looked at the data mechanisms of resistance that were identified in 25 out of the 45 patients, that is 55% of the patients.  5 patients had acquired STK11 mutations. One patient had a KEAP1 alteration. There were several patients who had like KEAP1 SMARCA4 mutations. And interestingly, there were also some patients who developed KRAS-G12C mutation as well on the post-treatment specimens.  So, this is an interesting abstract. We typically don't do biopsies on patients progressing on immunotherapy. At this point, we don't have a standard clinical indication to do so. However, identifying these new novel mechanisms of genomic mechanisms of resistance is actually very important, because a lot of new therapy medications are being developed to target, for example, KEAP1, and could be approached to target microglobulin mutations. So, it's very important to kind of understand the mechanisms of resistance.  Dr. Nathan Pennell: Yeah, I completely agree. I mean, most of the benefits in second line in the refractory setting with targeted treatments came about through studies like this where there was broad sequencing of resistance and trying to understand and I think we're still kind of in the infancy of understanding resistance to immunotherapy, but it's a good start.  Abstract 9019 was another interesting study in non—small cell lung cancer. That was “A phase II study of AK112 (PD-1/VEGF bispecific) in combination with chemotherapy in patients with advanced non—small cell lung cancer.” Can you tell us a little bit about that study?  Dr. Vamsidhar Velcheti: Yeah, this is a multicenter phase-2 trial. This is an interesting agent. It's a PD-1/VEGF bispecific antibody developed by Akeso Bio. This is a single-arm study, and they did the study in 3 different cohorts.  One of the cohorts was patients with advanced non—small cell lung cancer who had wild-type EGFR/ALK, and they were treatment-naive. There was another cohort of patients where they enrolled patients with EGFR mutation who developed resistance to EGFR tyrosine kinase inhibitors (TKIs) and essentially progressed on osimertinib. And there was another cohort where patients were enrolled who were PD-1 refractory, they had prior PD-1or PD-1 chemo combination, and they had progressions. So, they enrolled a total of 133 patients, it was a decent-sized study, but a very early efficacy finding study.  In the cohort-1 which is the cohort that is enrolled with untreated patients with advanced non—small cell lung cancer. They had like 20 partial responses out of 26 patients that were evaluable and enrolled in the cohort, and there were 6 patients who had stable disease.  So, overall, the response rate was 76.9% and 100% disease control rate. So, this is a very small cohort and small data set. So, we have to interpret this with caution. But suddenly, a very interesting signal here for this VEGF/PD-1 bispecific antibody.  Dr. Nathan Pennell: The 40% response rate in the immunotherapy (IO) and chemo refractory patients, I thought was fairly interesting, although, as you said, very small numbers in these cohorts will have to be reproduced in larger trials.  Dr. Vamsidhar Velcheti: Right. I think there was a lot of excitement early on the IMpower150, right? With the combination of bevacizumab with chemo-theralizumab.  There seems to be some signal in terms of the addition of a VEGF inhibitor to immunotherapy. And we've seen that consistently in renal cells and other tumor types. So, I think this is a really intriguing signal. I think this definitely warrants further exploration.  So, the other interesting thing was cohort-2 where they enrolled patients who had progressed on EGFR TKIs. So, in that cohort, they had like 19 evaluable patients and 13 patients had a partial response and 5 had stable disease. So, a very respectable response rate of 68.4% and 94.7 disease control rate. So, again, very small numbers, but a nice signal here for the efficacy of the drug.  There was another cohort, which is the cohort-3 where they enrolled patients who progressed on PD-1 therapy, and they enrolled a total of 20 patients with 8 patients having a partial response, following progression on PD-1 therapy.  Dr. Nathan Pennell: Yeah, I look forward to seeing further follow-up on this. It definitely sounds interesting. Moving on to Abstract 8541. This was “Durvalumab (durva) after chemoradiotherapy (CRT) in unresectable, stage III, EGFR mutation-positive (EGFRm) NSCLC: A post hoc subgroup analysis from PACIFIC,' which of course was the study that led to the broad use of durvalumab, the anti-PD-L1 antibody after chemoradiotherapy for unresectable stage III non-small cell, but this was the post hoc subgroup analysis of the EGFR mutation-positive group. And this is a subgroup we've really been curious about whether there was a role for consolidation, immunotherapy, or not. And so, what are your thoughts on the study?  Dr. Vamsidhar Velcheti: I agree with you, Nate, that this is actually some data that I was really, really looking forward to. Before we actually talk about the abstract. What do you do for those patients? If you have an EGFR mutation patient who has stage IIIB, what do you do right now?  Dr. Nathan Pennell: It's a great question. I have a discussion with them about the potential pluses and minuses of doing consolidation durvalumab. But I actually don't always use durvalumab in this setting, because of concerns about if you're using durvalumab and they recur, perhaps there is a problem with toxicity with using osimertinib. Honestly, I go back and forth about what the right thing is to do in this subgroup.  Dr. Vamsidhar Velcheti: No, I think that's the right context. I think that's a good setup to kind of discuss the data from the trial. I'm really excited about this. And I'm glad that we have this data to look at.  So, as you pointed out, the Pacific trial, its U.S. Food and Drug Administration (FDA) approval for durvalumab in the consolidation setting for patients with stage III after chemoradiation. This has now been the standard of care for like a few years now. The problem with the study is that patients with EGFR/ALK were allowed to enroll in the study.  Typically, for most IO trials, we generally tend to see patients with EGFR/ALK being excluded. So, this trial was an exception. In this study, they actually presented a post-hoc exploratory analysis of efficacy and safety of patients who did consolidation with durvalumab, but there was a total of 35 patients of the 713 patients that were randomized in the trial. And out of the 35 patients with EGFR mutation, 24 received durvalumab and 11 received a placebo.  So, of course, you're going to interpret this data with a little bit of caution. This is a full stock analysis, not pre-planned in small numbers. In this dataset, essentially, the median progression-free survival (PFS) was not different among patients treated with durvalumab or placebo, and the median survival was also not statistically significant. Overall, there was not much benefit from adding durvalumab in this setting in patients who have EGFR mutation-positive stage III lung cancer.  Dr. Nathan Pennell: I think that tends to track along with what we who have been treating patients with EGFR mutations for years, and knowing the disappointing response rates, certainly in the advanced stage with immunotherapy, I think we were concerned that in this consolidation phase that it would also potentially be a relatively marginal benefit. I agree with you that 35 patients are too small to make any definitive conclusions, but it certainly isn't supportive of a large benefit.  Dr. Vamsidhar Velcheti: But I think I'm excited about the LAUREL study that's ongoing, hopefully, that'll give us a little bit more definitive answers as to what we should be doing for patients with EGFR mutation-positive disease. Suddenly this is a piece of information that's helpful for treating physicians to make some decisions on clinical management for these patients.  Dr. Nathan Pennell: I agree. Now moving beyond the non—small cell. Let's talk about “Final survival outcomes and immune biomarker analysis of a randomized, open-label, phase I/II study combining oncolytic adenovirus ONCOS-102 with pemetrexed/cisplatin (P/C) in patients with unresectable malignant pleural mesothelioma (MPM).” That's Abstract 8561. What were your takeaways here?  Dr. Vamsidhar Velcheti: Yeah, it's always good to see some new therapeutic options for patients with mesothelioma. This is somewhat of an orphan disease and we haven't seen a lot of advances. Granted, we have some new therapeutic options with immunotherapy now, like, there is now a standard of care in the frontline setting.  So, this particular approach with ONCOS-102 is an oncolytic adenovirus expressing GM-CSF. And this is intended to stimulate the local and systemic immune response and remodulate the tumor microenvironment.  This was a small phase 1 study where they had a CFT run-in of 6 patients and a total of 25 patients were randomly assigned to receive ONCOS-102 intratumorally with ultrasound guidance or CT guidance and they injected this oncolytic virus into the tumor directly.  They were also getting treatment with platinum pemetrexed which is the standard of care in the frontline setting. The control here was 6 cycles of platinum pemetrexed. So, they enrolled both the treatment-naive patients in the frontline setting and they also enrolled patients who will progress on a platinum doublet.  I should note that none of these patients were treated with immunotherapy. I think that's something that we'll kind of get back to and we'll discuss. Overall, from a safety standpoint, there were some expected toxicities like pyrexia and nausea which is seen in the experimental group. It's just kind of to be expected with an oncolytic virus. Overall, the 30-month survival rates were 34.3% and 18.2% in the control arm, and the median overall survival (OS) was 19.3 months and 18.3 in the controller.  So, for patients who were treated with the frontline chemotherapy, the survival rate was better with 30 months survival, it was 33.3 [months]. And in the experimental group, it was 0%.  So, overall, they also looked at tumor-infiltrating lymphocytes, they had CD4 around CD8 and granzyme B expressing CDA T-cells, and they had favorable PK from increased immune cell infiltration. So, this is very promising data but of course in a small study, and also in a population that hasn't had immunotherapy patients who are getting platinum doublet. In terms of safety, I think it looks promising. We need to see larger studies, especially with immunotherapy combinations.  Dr. Nathan Pennell: Yeah, I was impressed with the increased tumor infiltration of CD4 and CDA-positive T-cells, and the survival in the first line looked fairly impressive, although again, a very small subgroup of patients. But as you said, a standard of care these days is definitely going to involve immunotherapy. And so, I look forward to seeing combination trials in the future with this drug.  Shifting from mesothelioma over to small cell lung cancer, Abstract 8570 is “Stereotactic radiosurgery (SRS) versus whole brain radiation therapy (WBRT) in patients with small cell lung cancer (SCLC) and intracranial metastatic disease (IMD): A systematic review and meta-analysis.” Do you think that this would influence how we approach patients with brain metastases in the small cell?  Dr. Vamsidhar Velcheti: There are some in the community who kind of advocate for SRS in small cells if they have limited CNS disease. Certainly, I'm not one of them, but I think this is an interesting study in that light like we have never had any proper randomized trial. And we probably won't have randomized trials in that setting. So, at the end of the day, I think we all kind of customize our treatment approaches based on our patients and how much disease burden they have.  But having said that, the authors here have done a pretty large systemic analysis, and they looked at 3,700+ trials, they looked at random effects meta-analysis pooled hazard ratios for overall survival in patients who received SRS in the whole brain with or without SRS boost.  What they found was that overall survival following SRS was not inferior to whole brain RT. What do we really make out of this data? I think, given the heterogeneity, we have to see how the analysis was done and the kind of studies that went into the analysis. But however, I think the bigger question is, is there a population that we need to maybe—perhaps like, if somebody has an isolated brain met, you could potentially consider SRS with a whole brain RT for better local control.  So, the authors actually look at pooled data to look at local control versus intracranial distant control. So, this is a really interesting approach that asks the question, if patients had SRS and whole brain radiation, would it actually offer adequate intracranial distant control meaning like, do they develop new lesions?  So, it does look fairly decent. But again, it all depends on what kind of studies went into the analysis. And I don't think we should read too much into it. But at the same time, it kind of raises the question: is there a population of patients with small cell where it may be potentially appropriate to give SRS?  So, that's what I do in my day-to-day clinical practice. Sometimes there are situations where you kind of do the thing that we don't usually always do like in the small cell, we always think about whole brain radiation as something that we always have to offer, but I want to hear your perspectives too.  Dr. Nathan Pennell: No, I was always taught that you never did anything with whole brain radiation in the small cell even with a solitary metastasis. For a study like this, it's certainly interesting. You wonder how much selection bias there was towards people with fewer brain metastases and perhaps being in better health or better response to systemic disease that were referred for SRS, compared to whole brain radiation.  Part of the issue is the morbidity associated with whole brain radiation is significantly more than with SRS. And now that we are starting to, for the first time, see some patients with small cell [lung cancer] that are living substantially longer with immunotherapy, it might be worth exploring which patients might benefit from having that lower morbidity from whole brain radiation. But I agree with you that I'm not sure that we know who those patients are.  Dr. Vamsidhar Velcheti: Yeah, I think this is a difficult question to answer through a meta-analysis in my opinion. But having said that, your thought in terms of proving systemic therapies, then we kind of revisit the paradigm of offering SRS to some patients may be, especially with new BiTE T-cell engager studies that are ongoing, and hopefully, if you see some positive results, that might change what we do, but it's an important clinical question.  Dr. Nathan Pennell: And finally, in Abstract 8524, we have an interesting analysis of patients with relapsed small cell lung cancer, who received single-agent Lurbinectedin in the phase-3 Atlantis trial. What do you think about this poster, and why should this be on our radar?  Dr. Vamsidhar Velcheti: Yeah, I think this has been an interesting approval, of course, lurbinectedin FDA approved, as you know, like in June of 2020, based on data from a trial that uses 3.2 milligrams per meter square dosing every 21 days in second line setting post-chemotherapy.  What happened after that was there was a trial with the combination with doxorubicin in the second line setting comparative arm in that phase 3 trial topotecan or CAV.  In that trial, it was a negative trial, the primary endpoint was not met. The primary endpoint was overall survival, and it was a negative trial. And there were subgroup analyses done in the trial. The study that is presented now is actually a post-hoc analysis looking at patients who received treatment with this combination with doxorubicin that is like a lurbinectedin with doxorubicin, who had like a total of 10 cycles of the combination, and they switched to lurbinectedin monotherapy.  So, there were a total of 50 patients in that trial. They looked at the responses and the durability of responses in that population. It's a highly select population that made it to 10 cycles and they had stable disease or better and they switched to lurbinectedin monotherapy.  So, the highlight of the abstract is the median overall survival was 20.7 months. Of course, for small cell, that's really impressive. But I think we've got to be really careful in interpreting this data. This is like a small subgroup of highly selected patients who actually benefited from the trial. My question for you, Nate, is do you use lurbinectedin in the second line setting frequently or are you still treating them with topotecan?  Dr. Nathan Pannell: We still often use topotecan. I think lurbinectedin certainly seems to be an active drug, and it has some favorable schedule of administration pretty well tolerated from a tolerability standpoint, but from an efficacy standpoint, I still haven't really seen much that makes it stand out as significantly better than older options like topotecan or irinotecan.  That being said, it is intriguing that there is a subgroup of people who seem to have prolonged disease control with this. The problem, of course, is if you already select the people who make it 10 cycles without progression, then you're already picking the group of people who are doing extremely well. So, it's not surprising that they would continue to do extremely well.  Nonetheless, it's a sizable subgroup of people that seem to benefit and it would really be nice if there was, for example, a biomarker that might tell us which patients would truly benefit from this drug compared to our other options.  Dr. Vamsidhar Velcheti: Yeah, exactly. True. Right, I mean, like all of us have patients who have done exceedingly well on topotecan and I had a patient on paclitaxel for years. So, it's really important to kind of keep that in mind when we look at these sub-proof post hoc analyses.  Dr. Nathan Pennell: Well, thanks Vamsi for sharing these important advances in lung cancer that will be featured at the 2022 ASCO Annual Meeting.  Dr. Vamsidhar Velcheti: Thank you, Nate.  Dr. Nathan Pennell: And thank you to our listeners for joining us today. If you're enjoying the content on the ASCO Daily News podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.    Disclosures:  Dr. Nathan Pennell:   Consulting or Advisory Role: AstraZeneca, Lilly, Cota Healthcare, Merck, Bristol-Myers Squibb, Genentech, Amgen, G1 Therapeutics, Pfizer, Boehringer Ingelheim, Viosera, Xencor, Mirati Therapeutics, Janssen Oncology, Sanofi/Regeneron  Research Funding (Inst): Genentech, AstraZeneca, Merck, Loxo, Altor BioScience, Spectrum Pharmaceuticals, Bristol-Myers Squibb, Jounce Therapeutics, Mirati Therapeutics, Heat Biologics, WindMIL, Sanofi  Dr. Vamsidhar Velcheti:  Honoraria: ITeos Therapeutics  Consulting or Advisory Role: Bristol-Myers Squibb, Merck, Foundation Medicine , AstraZeneca/MedImmune, Novartis, Lilly, EMD Serono, GSK, Amgen  Research Funding (Institution): Genentech, Trovagene, Eisai, OncoPlex Diagnostics, Alkermes, NantOmics, Genoptix, Altor BioScience, Merck, Bristol-Myers Squibb, Atreca, Heat Biologics, Leap Therapeutics, RSIP Vision, GlaxoSmithKline  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.   

Guest: Joel Neal, MD, PhD Guest: Alexander Spira, MD, PhD, FACP With the recent approvals of mobocertinib and amivantamab, we now have targeted therapies for EGFR exon 20 insertion–positive locally advanced or metastatic NSCLC, following progression on or after platinum-based chemotherapy. To learn more about mobocertinib, Dr. Joel Neal (Stanford) speaks with Dr. Alexander Spira (Virginia Cancer Specialists Research Institute) about the historical unmet need for this patient population, how mobocertinib is different from classical EGFR TKIs, and the clinical data that led to its FDA approval. All trademarks are property of their respective owners.©2022 Takeda Pharmaceuticals U.S.A., Inc. All rights reserved.03/22 VV-MEDMAT-61581

CME credits: 0.50 Valid until: 15-12-2022 Claim your CME credit at https://reachmd.com/programs/cme/the-role-of-her3-expression-in-advanced-solid-tumors/12956/ HER3 is the new marker on the block, but is it diagnostic, predictive, or prognostic? Hear from the experts, Drs. Lauren Ritterhouse, Pasi Jänne, and Kanwal Raghav, as they explore the role of HER3 in oncogenesis and resistance to EGFR TKIs. Find out how we can now target HER3 signaling in metastatic solid tumors through the use of emerging HER3-targeted therapies along with novel and exciting antibody-drug conjugate studies and strategies.

CME credits: 0.50 Valid until: 15-12-2022 Claim your CME credit at https://reachmd.com/programs/cme/the-role-of-her3-expression-in-advanced-solid-tumors/12956/ HER3 is the new marker on the block, but is it diagnostic, predictive, or prognostic? Hear from the experts, Drs. Lauren Ritterhouse, Pasi Jänne, and Kanwal Raghav, as they explore the role of HER3 in oncogenesis and resistance to EGFR TKIs. Find out how we can now target HER3 signaling in metastatic solid tumors through the use of emerging HER3-targeted therapies along with novel and exciting antibody-drug conjugate studies and strategies.

Host: Lauren Ritterhouse, MD ,PhD Guest: Pasi Antero Jänne, MD, PhD Guest: Kanwal Raghav, MD HER3 is the new marker on the block, but is it diagnostic, predictive, or prognostic? Hear from the experts, Drs. Lauren Ritterhouse, Pasi Jänne, and Kanwal Raghav, as they explore the role of HER3 in oncogenesis and resistance to EGFR TKIs. Find out how we can now target HER3 signaling in metastatic solid tumors through the use of emerging HER3-targeted therapies along with novel and exciting antibody-drug conjugate studies and strategies.

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

Faculty panel moderated by Dr. Daniel Tan discusses the latest data on adjuvant use of EGFR TKIs in early-stage NSCLC. Earn Credit / Learning Objectives & Disclosures: https://www.medscape.org/viewarticle/940688?src=mkm_podcast_addon_940688

Biomarker Assessment and Targeted Treatment of Nonsquamous Non-Small Cell Lung Cancer — A roundtable discussion with clinical investigators Drs Justin F Gainor, Matthew Gubens, Geoffrey R Oxnard and Heather Wakelee and general medical oncologists Drs Isaac Levy and Estelamari Rodriguez regarding biomarker analysis and related treatment decision-making for patients with non-small cell lung cancer. Biomarker testing and therapeutic decision-making for patients with non-small cell lung cancer (NSCLC) (00:00) Case: A woman in her late 80s, a never smoker, is diagnosed with metastatic adenocarcinoma of the lung with an EGFR exon 21 L858R mutation (01:56) Therapeutic approach for patients with NSCLC and EGFR tumor mutations (04:14) Results of the Phase III FLAURA trial evaluating osimertinib versus gefitinib or erlotinib for untreated advanced NSCLC with EGFR tumor mutations (06:08) Pneumonitis and cardiotoxicity associated with osimertinib in patients with NSCLC (09:56) Second-line therapy for patients after disease progression on osimertinib (13:25) Efficacy and tolerability of immune checkpoint inhibitors in patients with NSCLC harboring an actionable genomic alteration (17:08) Resistance mutations in patients who experience disease progression on osimertinib (18:58) Genomic profiling for patients with metastatic nonsquamous NSCLC; optimal testing platforms (24:38) Evaluation of biomarkers in patients with squamous cell carcinoma of the lung (28:54) Targeting KRAS G12C and MET exon 14 splice mutations  (31:39) Case: A woman in her mid-50s who presents with cough, dyspnea and respiratory distress is diagnosed with metastatic adenocarcinoma of the lung with an EGFR exon 21 L858R mutation (36:15) Considerations for switching to an EGFR tyrosine kinase inhibitor (TKI) in a symptomatic patient initially started on chemotherapy prior to the identification of an EGFR tumor mutation (38:18) Role of liquid biopsy in monitoring patients who are receiving EGFR TKI therapy (40:56) Activity of immune checkpoint inhibitors in patients with NSCLC and targetable genomic alterations (44:35) Results of the IMpower150 and IMpower130 trials of atezolizumab with bevacizumab/chemotherapy and atezolizumab with chemotherapy, respectively, as first-line treatment for metastatic nonsquamous NSCLC (47:32) Immune checkpoint inhibitors for patients with advanced lung cancer with oncogenic driver alterations: Results from the IMMUNOTARGET registry (50:37) Toxicities associated with the use of targeted therapy after immunotherapy in patients with NSCLC; risk of pneumonitis with durvalumab and osimertinib (53:33) Increased hepatotoxicity associated with sequential immune checkpoint inhibitor and crizotinib therapy for patients with NSCLC (56:20) Therapeutic approach for patients with locally advanced NSCLC with EGFR tumor mutations who experience disease relapse after treatment with durvalumab (59:10) Cardiac toxicity associated with immune checkpoint inhibitors (1:03:56) Monitoring for and management of the cardiac side effects of immune checkpoint inhibitors (1:06:52) Case: A man in his late 70s with adenocarcinoma of the lung and brain metastases is found through next-generation sequencing to have an EGFR exon 21 L858R mutation, HER2 amplification and high PD-L1 expression (1:09:58) Use of liquid biopsy to detect genomic alterations in patients with NSCLC (1:11:22) FGFR alterations in patients with NSCLC (1:14:42) Targeting HER2 alterations in patients with lung cancer (1:16:27) Efficacy of EGFR TKIs in patients with lung cancer and CNS metastases; sequencing stereotactic radiosurgery and EGFR TKIs (1:18:22) Diagnosis and management of radiation necrosis in patients with lung cancer (1:22:26) Preservation of neurocognitive function during whole-brain radiation therapy with hippocampal sparing for patients with NSCLC and brain metastases (1:25:33) Case: A woman in her early 80s with adenocarcinoma of the lung with an EGFR exon 21 L858R mutation and metastases to the brain receives osimertinib as first-line therapy (1:27:11) Activity of EGFR TKIs in patients with brain metastases; CNS penetration and dosing of osimertinib (1:30:59) Results of the BLOOM study evaluating osimertinib for patients with leptomeningeal metastases from NSCLC with EGFR tumor mutations (1:34:34) Targeting EGFR exon 20 insertions with TAK-788 and poziotinib (1:36:12) Results of the Phase III ALEX study evaluating alectinib and the Phase III ALTA-1L study investigating brigatinib for patients with advanced NSCLC and ALK rearrangements (1:39:36) Sequencing ALK inhibitors for patients with NSCLC with ALK rearrangements (1:42:08) Tolerability of brigatinib, alectinib, ceritinib and lorlatinib in patients with NSCLC with ALK rearrangements (1:45:41) Emerging data with targeted therapies for patients with NSCLC in the (neo)adjuvant setting (1:50:16) Ongoing (neo)adjuvant trials of targeted therapies for patients with locally advanced NSCLC (1:52:38) Perspective on emerging data from studies evaluating adjuvant targeted therapy for advanced NSCLC (1:55:56) Risks associated with neoadjuvant therapy for patients with advanced NSCLC (1:59:02) Case: A woman in her late 50s with metastatic NSCLC with a RET rearrangement receives carboplatin/pemetrexed/bevacizumab followed by selpercatinib upon disease progression (2:01:04) Activity of the selective RET inhibitors selpercatinib and pralsetinib; detection of RET alterations in patients with NSCLC (2:05:48) Duration of response, CNS penetration and tolerability profile of RET inhibitors (2:08:56) Efficacy of pemetrexed-based chemotherapy regimens for patients with NSCLC with RET fusions (2:12:33) Case: A woman in her mid-50s with metastatic NSCLC with a BRAF V600E tumor mutation attains a good response to dabrafenib/trametinib after experiencing disease progression on multiple lines of therapy (2:15:05) Activity and tolerability of BRAF and MEK inhibitors in patients with NSCLC with BRAF tumor mutations (2:17:26) Duration of therapy with BRAF and MEK inhibitors (2:19:47) Biology, detection and management of NSCLC with MET exon 14 mutations (2:22:35) Significance of HER2 mutations in patients with lung cancer (2:26:43) Targeting NTRK gene fusions with larotrectinib and entrectinib (2:29:44) Therapeutic options for patients with NSCLC and ROS1 translocations (2:35:52) CME information and select publications

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

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

In this second episode of our new podcast series, Dr Tom Lynch, who began his position as director of the Fred Hutchinson Cancer Research Center as Seattle became the first epicenter of the COVID-19 pandemic in the United States, comments on the current status of oncology research and data soon to be presented from a Phase III trial evaluating the EGFR TKI osimertinib as adjuvant therapy for patients with non-small cell lung cancer and EGFR tumor mutations. Additional resources: * Lynch TJ et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350(21):2129-39. Abstract (https://pubmed.ncbi.nlm.nih.gov/15118073/) * AstraZeneca. [Osimertinib] Phase III ADAURA trial will be unblinded early after overwhelming efficacy in the adjuvant treatment of patients with EGFR-mutated lung cancer [press release (https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2020/tagrisso-phase-iii-adaura-trial-will-be-unblinded-early-after-overwhelming-efficacy-in-the-adjuvant-treatment-of-patients-with-egfr-mutated-lung-cancer.html)]. April 10, 2020. * National Comprehensive Cancer Network. Short-term recommendations for non-small cell lung cancer management during the COVID-19 pandemic. COVID-19 NCCN guidelines (https://www.nccn.org/covid-19/pdf/COVID_NSCLC.pdf).

Consensus or Controversy? The Integration of Novel Therapies into the Interdisciplinary Management of Non-Small Cell Lung Cancer with CNS Metastases: Our most recent one-on-one interview with Dr Riely as a supplement to a CME symposium held during the 24th Annual Meeting and Education Day of the Society for Neuro-Oncology featuring expert comments on the application of emerging research to patient care. Improved treatment outcomes and impact on the incidence of brain metastases in patients with non-small cell lung cancer (NSCLC) (00:00) Case (Dr Gubens): A man in his mid-50s with adenocarcinoma of the lung with an EGFR exon 19 deletion mutation, asymptomatic brain lesions and significant systemic burden (03:43) Clinical care of patients with NSCLC brain metastases alone and no systemic disease (06:23) Diagnosis of radiation necrosis (11:42) Activity of the third-generation EGFR tyrosine kinase inhibitor (TKI) osimertinib in patients with NSCLC and CNS metastases (13:17) Mechanism of action of osimertinib in the brain and effect on CNS disease progression (15:43) Risks of whole-brain radiation therapy; role of hippocampus sparing and memantine administration in minimizing the adverse effects of whole-brain radiation therapy (17:42) Comparison of survival outcomes with stereotactic radiation therapy and EGFR TKIs (22:24) Case (Dr Gubens): A man in his late 40s with metastatic NSCLC with an ALK rearrangement and large asymptomatic brain metastases (24:46) Role of other TKIs (ie, BRAF, MET, HER2 inhibitors) in NSCLC with CNS metastases (28:15) Antitumor effect of ALK inhibitors in patients with CNS metastases (31:58) Practical issues in the management of CNS metastases: edema, symptomatic CNS metastases and oligoprogression (33:21) Managing CNS metastases with leptomeningeal involvement (36:44) Case (Dr Gubens): A man in his early 40s with metastatic adenocarcinoma of the lung with an EGFR L858R mutation responds to first-line osimertinib for 2 years but then develops 2 new asymptomatic punctate parenchymal metastases and extensive leptomeningeal involvement (39:01) Symptoms of CNS metastases with leptomeningeal involvement; challenges in diagnosis (43:13) Case (Dr Gubens): A woman in her late 60s with metastatic adenocarcinoma of the lung, no targetable tumor mutations and a PD-L1 tumor proportion score (TPS) of 80% (44:53) Outlook on the use of TKIs for patients with CNS metastases (48:42) Potential for combining TKIs with chemotherapy in the management of CNS metastases (50:19) Activity and safety of EGFR TKIs in combination with anti-PD-1/PD-L1 antibodies (52:14) CME information and select publications

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

Go online to PeerView.com/PPF860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Central nervous system (CNS) metastases occur commonly in patients with lung cancer, and those patients with epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancer (NSCLC) are particularly prone to their development. Treatment of brain metastases is challenging, and there are varied perspectives among different specialists about the best approach—if, when, and how to use local therapies, systemic therapies, or different treatment modalities in combination or sequence, etc. Clinical trials are underway to try to answer some of these critical questions about which treatment strategies yield the best results for these patients. This PeerView Live MasterClass and Practicum on-demand educational activity features a panel of multidisciplinary experts in EGFR-mutant lung cancer and CNS metastases who discuss the evolving evidence, clinical challenges, and practicalities of patient care. Real cases are debated from multiple perspectives, with an emphasis on information and guidance relevant for radiation oncologists. Upon completion of this activity, participants should be better able to: Describe molecular pathways that drive malignancy in lung cancer and the oncogenic activation of tyrosine kinases, such as mutations in EGFR, and the epidemiology and presentation of CNS metastases in EGFR-mutant lung cancer, Discuss the mechanisms of action, characteristics, and safety/efficacy profiles of the various EGFR TKIs available for the treatment of EGFR-mutant NSCLC throughout the continuum of advanced disease, including in patients with CNS metastases, Summarize the efficacy and safety data of available and emerging treatment strategies used in the management of brain or leptomeningeal metastases in patients with EGFR-mutant NSCLC, including the use of local therapies such as radiation, systemic therapies such as EGFR TKIs, and sequential/combination treatment approaches, Implement individualized treatment plans for patients with EGFR-mutant lung cancer with CNS metastases, including in the context of clinical practice or clinical trials, based on the latest evidence, recommendations, and effective multidisciplinary collaboration and coordination of care

Go online to PeerView.com/PPF860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Central nervous system (CNS) metastases occur commonly in patients with lung cancer, and those patients with epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancer (NSCLC) are particularly prone to their development. Treatment of brain metastases is challenging, and there are varied perspectives among different specialists about the best approach—if, when, and how to use local therapies, systemic therapies, or different treatment modalities in combination or sequence, etc. Clinical trials are underway to try to answer some of these critical questions about which treatment strategies yield the best results for these patients. This PeerView Live MasterClass and Practicum on-demand educational activity features a panel of multidisciplinary experts in EGFR-mutant lung cancer and CNS metastases who discuss the evolving evidence, clinical challenges, and practicalities of patient care. Real cases are debated from multiple perspectives, with an emphasis on information and guidance relevant for radiation oncologists. Upon completion of this activity, participants should be better able to: Describe molecular pathways that drive malignancy in lung cancer and the oncogenic activation of tyrosine kinases, such as mutations in EGFR, and the epidemiology and presentation of CNS metastases in EGFR-mutant lung cancer, Discuss the mechanisms of action, characteristics, and safety/efficacy profiles of the various EGFR TKIs available for the treatment of EGFR-mutant NSCLC throughout the continuum of advanced disease, including in patients with CNS metastases, Summarize the efficacy and safety data of available and emerging treatment strategies used in the management of brain or leptomeningeal metastases in patients with EGFR-mutant NSCLC, including the use of local therapies such as radiation, systemic therapies such as EGFR TKIs, and sequential/combination treatment approaches, Implement individualized treatment plans for patients with EGFR-mutant lung cancer with CNS metastases, including in the context of clinical practice or clinical trials, based on the latest evidence, recommendations, and effective multidisciplinary collaboration and coordination of care

Go online to PeerView.com/PPF860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Central nervous system (CNS) metastases occur commonly in patients with lung cancer, and those patients with epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancer (NSCLC) are particularly prone to their development. Treatment of brain metastases is challenging, and there are varied perspectives among different specialists about the best approach—if, when, and how to use local therapies, systemic therapies, or different treatment modalities in combination or sequence, etc. Clinical trials are underway to try to answer some of these critical questions about which treatment strategies yield the best results for these patients. This PeerView Live MasterClass and Practicum on-demand educational activity features a panel of multidisciplinary experts in EGFR-mutant lung cancer and CNS metastases who discuss the evolving evidence, clinical challenges, and practicalities of patient care. Real cases are debated from multiple perspectives, with an emphasis on information and guidance relevant for radiation oncologists. Upon completion of this activity, participants should be better able to: Describe molecular pathways that drive malignancy in lung cancer and the oncogenic activation of tyrosine kinases, such as mutations in EGFR, and the epidemiology and presentation of CNS metastases in EGFR-mutant lung cancer, Discuss the mechanisms of action, characteristics, and safety/efficacy profiles of the various EGFR TKIs available for the treatment of EGFR-mutant NSCLC throughout the continuum of advanced disease, including in patients with CNS metastases, Summarize the efficacy and safety data of available and emerging treatment strategies used in the management of brain or leptomeningeal metastases in patients with EGFR-mutant NSCLC, including the use of local therapies such as radiation, systemic therapies such as EGFR TKIs, and sequential/combination treatment approaches, Implement individualized treatment plans for patients with EGFR-mutant lung cancer with CNS metastases, including in the context of clinical practice or clinical trials, based on the latest evidence, recommendations, and effective multidisciplinary collaboration and coordination of care

Go online to PeerView.com/PPF860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Central nervous system (CNS) metastases occur commonly in patients with lung cancer, and those patients with epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancer (NSCLC) are particularly prone to their development. Treatment of brain metastases is challenging, and there are varied perspectives among different specialists about the best approach—if, when, and how to use local therapies, systemic therapies, or different treatment modalities in combination or sequence, etc. Clinical trials are underway to try to answer some of these critical questions about which treatment strategies yield the best results for these patients. This PeerView Live MasterClass and Practicum on-demand educational activity features a panel of multidisciplinary experts in EGFR-mutant lung cancer and CNS metastases who discuss the evolving evidence, clinical challenges, and practicalities of patient care. Real cases are debated from multiple perspectives, with an emphasis on information and guidance relevant for radiation oncologists. Upon completion of this activity, participants should be better able to: Describe molecular pathways that drive malignancy in lung cancer and the oncogenic activation of tyrosine kinases, such as mutations in EGFR, and the epidemiology and presentation of CNS metastases in EGFR-mutant lung cancer, Discuss the mechanisms of action, characteristics, and safety/efficacy profiles of the various EGFR TKIs available for the treatment of EGFR-mutant NSCLC throughout the continuum of advanced disease, including in patients with CNS metastases, Summarize the efficacy and safety data of available and emerging treatment strategies used in the management of brain or leptomeningeal metastases in patients with EGFR-mutant NSCLC, including the use of local therapies such as radiation, systemic therapies such as EGFR TKIs, and sequential/combination treatment approaches, Implement individualized treatment plans for patients with EGFR-mutant lung cancer with CNS metastases, including in the context of clinical practice or clinical trials, based on the latest evidence, recommendations, and effective multidisciplinary collaboration and coordination of care

Go online to PeerView.com/PPF860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Central nervous system (CNS) metastases occur commonly in patients with lung cancer, and those patients with epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancer (NSCLC) are particularly prone to their development. Treatment of brain metastases is challenging, and there are varied perspectives among different specialists about the best approach—if, when, and how to use local therapies, systemic therapies, or different treatment modalities in combination or sequence, etc. Clinical trials are underway to try to answer some of these critical questions about which treatment strategies yield the best results for these patients. This PeerView Live MasterClass and Practicum on-demand educational activity features a panel of multidisciplinary experts in EGFR-mutant lung cancer and CNS metastases who discuss the evolving evidence, clinical challenges, and practicalities of patient care. Real cases are debated from multiple perspectives, with an emphasis on information and guidance relevant for radiation oncologists. Upon completion of this activity, participants should be better able to: Describe molecular pathways that drive malignancy in lung cancer and the oncogenic activation of tyrosine kinases, such as mutations in EGFR, and the epidemiology and presentation of CNS metastases in EGFR-mutant lung cancer, Discuss the mechanisms of action, characteristics, and safety/efficacy profiles of the various EGFR TKIs available for the treatment of EGFR-mutant NSCLC throughout the continuum of advanced disease, including in patients with CNS metastases, Summarize the efficacy and safety data of available and emerging treatment strategies used in the management of brain or leptomeningeal metastases in patients with EGFR-mutant NSCLC, including the use of local therapies such as radiation, systemic therapies such as EGFR TKIs, and sequential/combination treatment approaches, Implement individualized treatment plans for patients with EGFR-mutant lung cancer with CNS metastases, including in the context of clinical practice or clinical trials, based on the latest evidence, recommendations, and effective multidisciplinary collaboration and coordination of care

Go online to PeerView.com/PPF860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Central nervous system (CNS) metastases occur commonly in patients with lung cancer, and those patients with epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancer (NSCLC) are particularly prone to their development. Treatment of brain metastases is challenging, and there are varied perspectives among different specialists about the best approach—if, when, and how to use local therapies, systemic therapies, or different treatment modalities in combination or sequence, etc. Clinical trials are underway to try to answer some of these critical questions about which treatment strategies yield the best results for these patients. This PeerView Live MasterClass and Practicum on-demand educational activity features a panel of multidisciplinary experts in EGFR-mutant lung cancer and CNS metastases who discuss the evolving evidence, clinical challenges, and practicalities of patient care. Real cases are debated from multiple perspectives, with an emphasis on information and guidance relevant for radiation oncologists. Upon completion of this activity, participants should be better able to: Describe molecular pathways that drive malignancy in lung cancer and the oncogenic activation of tyrosine kinases, such as mutations in EGFR, and the epidemiology and presentation of CNS metastases in EGFR-mutant lung cancer, Discuss the mechanisms of action, characteristics, and safety/efficacy profiles of the various EGFR TKIs available for the treatment of EGFR-mutant NSCLC throughout the continuum of advanced disease, including in patients with CNS metastases, Summarize the efficacy and safety data of available and emerging treatment strategies used in the management of brain or leptomeningeal metastases in patients with EGFR-mutant NSCLC, including the use of local therapies such as radiation, systemic therapies such as EGFR TKIs, and sequential/combination treatment approaches, Implement individualized treatment plans for patients with EGFR-mutant lung cancer with CNS metastases, including in the context of clinical practice or clinical trials, based on the latest evidence, recommendations, and effective multidisciplinary collaboration and coordination of care

Go online to PeerView.com/PPF860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Central nervous system (CNS) metastases occur commonly in patients with lung cancer, and those patients with epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancer (NSCLC) are particularly prone to their development. Treatment of brain metastases is challenging, and there are varied perspectives among different specialists about the best approach—if, when, and how to use local therapies, systemic therapies, or different treatment modalities in combination or sequence, etc. Clinical trials are underway to try to answer some of these critical questions about which treatment strategies yield the best results for these patients. This PeerView Live MasterClass and Practicum on-demand educational activity features a panel of multidisciplinary experts in EGFR-mutant lung cancer and CNS metastases who discuss the evolving evidence, clinical challenges, and practicalities of patient care. Real cases are debated from multiple perspectives, with an emphasis on information and guidance relevant for radiation oncologists. Upon completion of this activity, participants should be better able to: Describe molecular pathways that drive malignancy in lung cancer and the oncogenic activation of tyrosine kinases, such as mutations in EGFR, and the epidemiology and presentation of CNS metastases in EGFR-mutant lung cancer, Discuss the mechanisms of action, characteristics, and safety/efficacy profiles of the various EGFR TKIs available for the treatment of EGFR-mutant NSCLC throughout the continuum of advanced disease, including in patients with CNS metastases, Summarize the efficacy and safety data of available and emerging treatment strategies used in the management of brain or leptomeningeal metastases in patients with EGFR-mutant NSCLC, including the use of local therapies such as radiation, systemic therapies such as EGFR TKIs, and sequential/combination treatment approaches, Implement individualized treatment plans for patients with EGFR-mutant lung cancer with CNS metastases, including in the context of clinical practice or clinical trials, based on the latest evidence, recommendations, and effective multidisciplinary collaboration and coordination of care

Go online to PeerView.com/PPF860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. Central nervous system (CNS) metastases occur commonly in patients with lung cancer, and those patients with epidermal growth factor receptor (EGFR)-mutant non–small cell lung cancer (NSCLC) are particularly prone to their development. Treatment of brain metastases is challenging, and there are varied perspectives among different specialists about the best approach—if, when, and how to use local therapies, systemic therapies, or different treatment modalities in combination or sequence, etc. Clinical trials are underway to try to answer some of these critical questions about which treatment strategies yield the best results for these patients. This PeerView Live MasterClass and Practicum on-demand educational activity features a panel of multidisciplinary experts in EGFR-mutant lung cancer and CNS metastases who discuss the evolving evidence, clinical challenges, and practicalities of patient care. Real cases are debated from multiple perspectives, with an emphasis on information and guidance relevant for radiation oncologists. Upon completion of this activity, participants should be better able to: Describe molecular pathways that drive malignancy in lung cancer and the oncogenic activation of tyrosine kinases, such as mutations in EGFR, and the epidemiology and presentation of CNS metastases in EGFR-mutant lung cancer, Discuss the mechanisms of action, characteristics, and safety/efficacy profiles of the various EGFR TKIs available for the treatment of EGFR-mutant NSCLC throughout the continuum of advanced disease, including in patients with CNS metastases, Summarize the efficacy and safety data of available and emerging treatment strategies used in the management of brain or leptomeningeal metastases in patients with EGFR-mutant NSCLC, including the use of local therapies such as radiation, systemic therapies such as EGFR TKIs, and sequential/combination treatment approaches, Implement individualized treatment plans for patients with EGFR-mutant lung cancer with CNS metastases, including in the context of clinical practice or clinical trials, based on the latest evidence, recommendations, and effective multidisciplinary collaboration and coordination of care

Go online to PeerView.com/CXH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The best practices for management of patients with EGFR-mutant NSCLC continue to evolve as a result of advances in molecular testing and targeted treatment. Understanding what, when, and how to test, as well as how to select therapy, throughout the continuum of advanced NSCLC is paramount. In this activity, based on a recent live symposium held in San Diego, California, experts in EGFR-mutant NSCLC provide a concise but comprehensive overview of all the recent key evidence and new research directions and provide practical guidance for how to navigate clinical decisions in EGFR-mutant NSCLC in different settings and patient populations. Upon completion of this activity, participants will be able to: Discuss the latest recommendations for tissue- and blood-based molecular testing to evaluate EGFR mutation status in patients with advanced/metastatic NSCLC, Assess the characteristics, safety/efficacy profiles, and indications of the different EGFR inhibitors available for the treatment of EGFR-positive NSCLC in different settings and patient populations, including those with brain or leptomeningeal metastases, Evaluate the current evidence related to the mechanisms of acquired resistance to the various EGFR TKIs used in the first line and subsequent therapy of advanced EGFR-mutant NSCLC, Implement best practices related to molecular testing for EGFR mutations through the continuum of advanced NSCLC, and interpret results to guide treatment selection, Implement evidence-based, individualized treatment plans for patients with EGFR-mutant NSCLC.

Go online to PeerView.com/CXH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The best practices for management of patients with EGFR-mutant NSCLC continue to evolve as a result of advances in molecular testing and targeted treatment. Understanding what, when, and how to test, as well as how to select therapy, throughout the continuum of advanced NSCLC is paramount. In this activity, based on a recent live symposium held in San Diego, California, experts in EGFR-mutant NSCLC provide a concise but comprehensive overview of all the recent key evidence and new research directions and provide practical guidance for how to navigate clinical decisions in EGFR-mutant NSCLC in different settings and patient populations. Upon completion of this activity, participants will be able to: Discuss the latest recommendations for tissue- and blood-based molecular testing to evaluate EGFR mutation status in patients with advanced/metastatic NSCLC, Assess the characteristics, safety/efficacy profiles, and indications of the different EGFR inhibitors available for the treatment of EGFR-positive NSCLC in different settings and patient populations, including those with brain or leptomeningeal metastases, Evaluate the current evidence related to the mechanisms of acquired resistance to the various EGFR TKIs used in the first line and subsequent therapy of advanced EGFR-mutant NSCLC, Implement best practices related to molecular testing for EGFR mutations through the continuum of advanced NSCLC, and interpret results to guide treatment selection, Implement evidence-based, individualized treatment plans for patients with EGFR-mutant NSCLC.

Go online to PeerView.com/CXH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The best practices for management of patients with EGFR-mutant NSCLC continue to evolve as a result of advances in molecular testing and targeted treatment. Understanding what, when, and how to test, as well as how to select therapy, throughout the continuum of advanced NSCLC is paramount. In this activity, based on a recent live symposium held in San Diego, California, experts in EGFR-mutant NSCLC provide a concise but comprehensive overview of all the recent key evidence and new research directions and provide practical guidance for how to navigate clinical decisions in EGFR-mutant NSCLC in different settings and patient populations. Upon completion of this activity, participants will be able to: Discuss the latest recommendations for tissue- and blood-based molecular testing to evaluate EGFR mutation status in patients with advanced/metastatic NSCLC, Assess the characteristics, safety/efficacy profiles, and indications of the different EGFR inhibitors available for the treatment of EGFR-positive NSCLC in different settings and patient populations, including those with brain or leptomeningeal metastases, Evaluate the current evidence related to the mechanisms of acquired resistance to the various EGFR TKIs used in the first line and subsequent therapy of advanced EGFR-mutant NSCLC, Implement best practices related to molecular testing for EGFR mutations through the continuum of advanced NSCLC, and interpret results to guide treatment selection, Implement evidence-based, individualized treatment plans for patients with EGFR-mutant NSCLC.

Go online to PeerView.com/CXH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The best practices for management of patients with EGFR-mutant NSCLC continue to evolve as a result of advances in molecular testing and targeted treatment. Understanding what, when, and how to test, as well as how to select therapy, throughout the continuum of advanced NSCLC is paramount. In this activity, based on a recent live symposium held in San Diego, California, experts in EGFR-mutant NSCLC provide a concise but comprehensive overview of all the recent key evidence and new research directions and provide practical guidance for how to navigate clinical decisions in EGFR-mutant NSCLC in different settings and patient populations. Upon completion of this activity, participants will be able to: Discuss the latest recommendations for tissue- and blood-based molecular testing to evaluate EGFR mutation status in patients with advanced/metastatic NSCLC, Assess the characteristics, safety/efficacy profiles, and indications of the different EGFR inhibitors available for the treatment of EGFR-positive NSCLC in different settings and patient populations, including those with brain or leptomeningeal metastases, Evaluate the current evidence related to the mechanisms of acquired resistance to the various EGFR TKIs used in the first line and subsequent therapy of advanced EGFR-mutant NSCLC, Implement best practices related to molecular testing for EGFR mutations through the continuum of advanced NSCLC, and interpret results to guide treatment selection, Implement evidence-based, individualized treatment plans for patients with EGFR-mutant NSCLC.

Go online to PeerView.com/CXH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The best practices for management of patients with EGFR-mutant NSCLC continue to evolve as a result of advances in molecular testing and targeted treatment. Understanding what, when, and how to test, as well as how to select therapy, throughout the continuum of advanced NSCLC is paramount. In this activity, based on a recent live symposium held in San Diego, California, experts in EGFR-mutant NSCLC provide a concise but comprehensive overview of all the recent key evidence and new research directions and provide practical guidance for how to navigate clinical decisions in EGFR-mutant NSCLC in different settings and patient populations. Upon completion of this activity, participants will be able to: Discuss the latest recommendations for tissue- and blood-based molecular testing to evaluate EGFR mutation status in patients with advanced/metastatic NSCLC, Assess the characteristics, safety/efficacy profiles, and indications of the different EGFR inhibitors available for the treatment of EGFR-positive NSCLC in different settings and patient populations, including those with brain or leptomeningeal metastases, Evaluate the current evidence related to the mechanisms of acquired resistance to the various EGFR TKIs used in the first line and subsequent therapy of advanced EGFR-mutant NSCLC, Implement best practices related to molecular testing for EGFR mutations through the continuum of advanced NSCLC, and interpret results to guide treatment selection, Implement evidence-based, individualized treatment plans for patients with EGFR-mutant NSCLC.

Go online to PeerView.com/CXH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The best practices for management of patients with EGFR-mutant NSCLC continue to evolve as a result of advances in molecular testing and targeted treatment. Understanding what, when, and how to test, as well as how to select therapy, throughout the continuum of advanced NSCLC is paramount. In this activity, based on a recent live symposium held in San Diego, California, experts in EGFR-mutant NSCLC provide a concise but comprehensive overview of all the recent key evidence and new research directions and provide practical guidance for how to navigate clinical decisions in EGFR-mutant NSCLC in different settings and patient populations. Upon completion of this activity, participants will be able to: Discuss the latest recommendations for tissue- and blood-based molecular testing to evaluate EGFR mutation status in patients with advanced/metastatic NSCLC, Assess the characteristics, safety/efficacy profiles, and indications of the different EGFR inhibitors available for the treatment of EGFR-positive NSCLC in different settings and patient populations, including those with brain or leptomeningeal metastases, Evaluate the current evidence related to the mechanisms of acquired resistance to the various EGFR TKIs used in the first line and subsequent therapy of advanced EGFR-mutant NSCLC, Implement best practices related to molecular testing for EGFR mutations through the continuum of advanced NSCLC, and interpret results to guide treatment selection, Implement evidence-based, individualized treatment plans for patients with EGFR-mutant NSCLC.

Go online to PeerView.com/CXH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The best practices for management of patients with EGFR-mutant NSCLC continue to evolve as a result of advances in molecular testing and targeted treatment. Understanding what, when, and how to test, as well as how to select therapy, throughout the continuum of advanced NSCLC is paramount. In this activity, based on a recent live symposium held in San Diego, California, experts in EGFR-mutant NSCLC provide a concise but comprehensive overview of all the recent key evidence and new research directions and provide practical guidance for how to navigate clinical decisions in EGFR-mutant NSCLC in different settings and patient populations. Upon completion of this activity, participants will be able to: Discuss the latest recommendations for tissue- and blood-based molecular testing to evaluate EGFR mutation status in patients with advanced/metastatic NSCLC, Assess the characteristics, safety/efficacy profiles, and indications of the different EGFR inhibitors available for the treatment of EGFR-positive NSCLC in different settings and patient populations, including those with brain or leptomeningeal metastases, Evaluate the current evidence related to the mechanisms of acquired resistance to the various EGFR TKIs used in the first line and subsequent therapy of advanced EGFR-mutant NSCLC, Implement best practices related to molecular testing for EGFR mutations through the continuum of advanced NSCLC, and interpret results to guide treatment selection, Implement evidence-based, individualized treatment plans for patients with EGFR-mutant NSCLC.

Go online to PeerView.com/CXH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The best practices for management of patients with EGFR-mutant NSCLC continue to evolve as a result of advances in molecular testing and targeted treatment. Understanding what, when, and how to test, as well as how to select therapy, throughout the continuum of advanced NSCLC is paramount. In this activity, based on a recent live symposium held in San Diego, California, experts in EGFR-mutant NSCLC provide a concise but comprehensive overview of all the recent key evidence and new research directions and provide practical guidance for how to navigate clinical decisions in EGFR-mutant NSCLC in different settings and patient populations. Upon completion of this activity, participants will be able to: Discuss the latest recommendations for tissue- and blood-based molecular testing to evaluate EGFR mutation status in patients with advanced/metastatic NSCLC, Assess the characteristics, safety/efficacy profiles, and indications of the different EGFR inhibitors available for the treatment of EGFR-positive NSCLC in different settings and patient populations, including those with brain or leptomeningeal metastases, Evaluate the current evidence related to the mechanisms of acquired resistance to the various EGFR TKIs used in the first line and subsequent therapy of advanced EGFR-mutant NSCLC, Implement best practices related to molecular testing for EGFR mutations through the continuum of advanced NSCLC, and interpret results to guide treatment selection, Implement evidence-based, individualized treatment plans for patients with EGFR-mutant NSCLC.

Go online to PeerView.com/CXH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The best practices for management of patients with EGFR-mutant NSCLC continue to evolve as a result of advances in molecular testing and targeted treatment. Understanding what, when, and how to test, as well as how to select therapy, throughout the continuum of advanced NSCLC is paramount. In this activity, based on a recent live symposium held in San Diego, California, experts in EGFR-mutant NSCLC provide a concise but comprehensive overview of all the recent key evidence and new research directions and provide practical guidance for how to navigate clinical decisions in EGFR-mutant NSCLC in different settings and patient populations. Upon completion of this activity, participants will be able to: Discuss the latest recommendations for tissue- and blood-based molecular testing to evaluate EGFR mutation status in patients with advanced/metastatic NSCLC, Assess the characteristics, safety/efficacy profiles, and indications of the different EGFR inhibitors available for the treatment of EGFR-positive NSCLC in different settings and patient populations, including those with brain or leptomeningeal metastases, Evaluate the current evidence related to the mechanisms of acquired resistance to the various EGFR TKIs used in the first line and subsequent therapy of advanced EGFR-mutant NSCLC, Implement best practices related to molecular testing for EGFR mutations through the continuum of advanced NSCLC, and interpret results to guide treatment selection, Implement evidence-based, individualized treatment plans for patients with EGFR-mutant NSCLC.

Go online to PeerView.com/CXH860 to view the activity, download slides and practice aids, and complete the post-test to earn credit. The best practices for management of patients with EGFR-mutant NSCLC continue to evolve as a result of advances in molecular testing and targeted treatment. Understanding what, when, and how to test, as well as how to select therapy, throughout the continuum of advanced NSCLC is paramount. In this activity, based on a recent live symposium held in San Diego, California, experts in EGFR-mutant NSCLC provide a concise but comprehensive overview of all the recent key evidence and new research directions and provide practical guidance for how to navigate clinical decisions in EGFR-mutant NSCLC in different settings and patient populations. Upon completion of this activity, participants will be able to: Discuss the latest recommendations for tissue- and blood-based molecular testing to evaluate EGFR mutation status in patients with advanced/metastatic NSCLC, Assess the characteristics, safety/efficacy profiles, and indications of the different EGFR inhibitors available for the treatment of EGFR-positive NSCLC in different settings and patient populations, including those with brain or leptomeningeal metastases, Evaluate the current evidence related to the mechanisms of acquired resistance to the various EGFR TKIs used in the first line and subsequent therapy of advanced EGFR-mutant NSCLC, Implement best practices related to molecular testing for EGFR mutations through the continuum of advanced NSCLC, and interpret results to guide treatment selection, Implement evidence-based, individualized treatment plans for patients with EGFR-mutant NSCLC.

Lung Cancer Update – Part 1: Our interview with Dr Ramalingam highlights the following topics as well as cases from his practice: Mechanisms of resistance to osimertinib and management of non-small cell lung cancer (NSCLC) with EGFR tumor mutations in patients who experience disease progression on first-line osimertinib: 0m0s Results of the Phase III IMpower150 trial: Atezolizumab and chemotherapy with or without bevacizumab versus bevacizumab and chemotherapy for chemotherapy-naïve metastatic nonsquamous NSCLC: 3m55s Role of bevacizumab in combination with EGFR tyrosine kinase inhibitors (TKIs) for patients with NSCLC and EGFR tumor mutations: 5m22s Emerging data with novel TKIs for patients with NSCLC and MET gene amplifications: 8m0s Incidence and clinical significance of MET amplifications and MET exon 14 mutations: 10m22s Use of liquid biopsies to detect mutations in patients with lung cancer: 13m52s FLAURA study results: Osimertinib versus erlotinib or gefitinib as first-line therapy for advanced NSCLC with an EGFR tumor mutation: 17m11s Ongoing evaluation of EGFR TKIs for Stage III NSCLC: 19m4s Perspective on the use of osimertinib in the adjuvant setting: 21m52s Case: A 62-year-old man and never smoker with Stage IV NSCLC and an EGFR exon 19 deletion receives osimertinib as first-line treatment: 23m30s Response to osimertinib in patients with brain metastases: 27m5s Case: A 44-year-old man and never smoker with metastatic NSCLC and an ALK rearrangement receives alectinib after disease progression on crizotinib with an anti-PD-1 antibody: 31m3s ALTA-1L: A Phase III trial evaluating brigatinib versus crizotinib for advanced NSCLC with an ALK rearrangement: 35m44s Efficacy and tolerability of lorlatinib in patients with NSCLC and an ALK rearrangement: 39m43s Case: A 52-year-old woman and nonsmoker with metastatic NSCLC and a BRAF V600E tumor mutation receives dabrafenib and trametinib as second-line therapy: 42m13s Use of targeted therapy as first-line treatment for patients with NSCLC: 44m42s Case: A 58-year-old man with locally advanced squamous cell carcinoma of the lung receives durvalumab as consolidation therapy after chemoradiation therapy: 46m59s Overall survival with the addition of durvalumab to chemoradiation therapy for patients with Stage III NSCLC: 48m45s Pulmonary toxicity associated with durvalumab: 50m47s Ongoing investigation of immune checkpoint inhibitors in the adjuvant setting: 55m30s Management of metastatic small cell lung cancer: 58m5s Novel agents under investigation for small cell lung cancer: 1h0m15s Emerging research aimed at enhancing the efficacy of immune checkpoint inhibitors: 1h5m2s Select publications

Go online to PeerView.com/GPR860 to view the entire programme with slides. In this activity, an expert in oncology discusses the evolving evidence on molecular testing and treatment of EGFR mutation-positive NSCLC, including new data from real-world studies, and provides practical guidance for nuanced, individualized decision-making related to selection and sequencing of EGFR-targeted therapies throughout the continuum of advanced NSCLC. Upon completion of this activity, participants will be able to: Review the current understanding of the biology of EGFR mutation-based heterogeneity in NSCLC and the clinical roles of EGFR TKIs in the newly diagnosed setting, Assess mechanisms of acquired resistance to EGFR TKIs and their implications for treatment selection in first-line and later lines of therapy in advanced EGFR mutation-positive NSCLC, Discuss real-world evidence on the efficacy and safety of EGFR TKIs and its impact on long-term treatment planning for patients with advanced NSCLC exhibiting EGFR mutations, Employ effective strategies to prevent, mitigate, and manage adverse effects of EGFR TKI therapy to optimize patient outcomes.

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

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

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

Drs. Ben Solomon, Leora Horn, & Jack West compare the clinical data with the third generation EGFR TKIs so active in acquired resistance and consider whether there are significant differences between them.

Drs. Ben Solomon, Leora Horn, & Jack West compare the clinical data with the third generation EGFR TKIs so active in acquired resistance and consider whether there are significant differences between them.

Drs. Ben Solomon, Leora Horn, & Jack West compare the clinical data with the third generation EGFR TKIs so active in acquired resistance and consider whether there are significant differences between them.

Drs. Ben Solomon, Leora Horn, & Jack West review whether the data and clinical experience suggest any clinically significant differences among the first and second generation EGFR TKIs (Iressa, Tarceva, Gilotrif/Giotrif).

Drs. Ben Solomon, Leora Horn, & Jack West review whether the data and clinical experience suggest any clinically significant differences among the first and second generation EGFR TKIs (Iressa, Tarceva, Gilotrif/Giotrif).

Drs. Ben Solomon, Leora Horn, & Jack West review whether the data and clinical experience suggest any clinically significant differences among the first and second generation EGFR TKIs (Iressa, Tarceva, Gilotrif/Giotrif).

Drs. Leora Horn, Ben Solomon, & Jack West consider whether third generation EGFR TKIs, so active in patients with acquired resistance, might be best used prior to development of acquired resistance.

Drs. Leora Horn, Ben Solomon, & Jack West consider whether third generation EGFR TKIs, so active in patients with acquired resistance, might be best used prior to development of acquired resistance.

Drs. Leora Horn, Ben Solomon, & Jack West consider whether third generation EGFR TKIs, so active in patients with acquired resistance, might be best used prior to development of acquired resistance.

Medical oncologist Dr. Greg Riely, MSKCC, summarizes the development of acquired resistance after a good initial response to EGFR inhibitor therapy and the clinical patterns of progression commonly seen.

Medical oncologist Dr. Greg Riely, MSKCC, summarizes the development of acquired resistance after a good initial response to EGFR inhibitor therapy and the clinical patterns of progression commonly seen.

Medical oncologist Dr. Greg Riely, MSKCC, summarizes the development of acquired resistance after a good initial response to EGFR inhibitor therapy and the clinical patterns of progression commonly seen.

For patients with wild type EGFR, meaning there is no EGFR mutation, drugs like Tarceva (erlotinib) can have a small benefit, but Dr. Joan Schiller wants research to do better. February 2014

For patients with wild type EGFR, meaning there is no EGFR mutation, drugs like Tarceva (erlotinib) can have a small benefit, but Dr. Joan Schiller wants research to do better. February 2014

For patients with wild type EGFR, meaning there is no EGFR mutation, drugs like Tarceva (erlotinib) can have a small benefit, but Dr. Joan Schiller wants research to do better. February 2014

Drs. Jack West, Mary Pinder, and Nate Pennell discuss options for managing acquired resistance to EGFR TKIs and ALK inhibitors in patients with advanced NSCLC and a driver mutation.

Drs. Jack West, Mary Pinder, and Nate Pennell discuss options for managing acquired resistance to EGFR TKIs and ALK inhibitors in patients with advanced NSCLC and a driver mutation.

Drs. Jack West, Mary Pinder, and Nate Pennell discuss options for managing acquired resistance to EGFR TKIs and ALK inhibitors in patients with advanced NSCLC and a driver mutation.

Current Developments and Perspectives in Targeted Therapies Many different approaches for improving the prognosis of patients with advanced non-small-cell lung cancer (NSCLC) are currently being investigated. This article discusses the significance of maintenance therapy after primary chemotherapy and reviews study data on second-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), inhibitors of insulin-like growth factor receptors (IGFR), vascular-disrupting agents (VDAs) and multi-TKIs of vascular endothelial growth factor receptors (VEGFR). The article also looks at the future prospects of using genetic markers in the field of NSCLC.