Podcasts about braf v600e

In this JCO Precision Oncology Article Insights episode, Jiasen He summarizes “Midline Low-Grade Gliomas of Early Childhood: Focus on Targeted Therapies.” by Dr. Ludmila Papusha et al. published on July 08, 2024. TRANSCRIPT  Jiasen He: Hello and welcome to JCO Precision Oncology Article Insights. I'm your host Jiasen He, a JCO Journal's Editorial Fellow. Today, I will provide a summary on “Midline Low-Grade Gliomas of Early Childhood: Focus on Targeted Therapies.” This is an observational study by Dr. Ludmila Papusha and colleagues that investigated the use of target therapies in early childhood with midline low grade glioma. Low grade glioma located in the hypothalamic chiasmatic region, thalamus and the brain stem are classified as midline low grade gliomas. Due to their unique locations, complete surgical resection is usually not able to be achieved. In young children with low grade glioma, radiation therapy is generally not favored. Traditionally, chemotherapy regimens such as carboplatin and vincristine have been used. However, as Dr. Papusha noted, this population often exhibits poor response to chemotherapy. With a growing understanding of the RAS-RAF-MEK pathways in low grade glioma, targeted therapy has emerged as a promising treatment option for this group. However, limited data is available regarding the mutation status of midline low grade glioma in early childhood and real world evidence on their response to targeted therapy remains scarce. Dr. Papusha's research aimed to address this critical gap by evaluating the effectiveness of targeted therapy in midline gliomas of early childhood. In this observational study, 40 patients under the age of three with midline low grade glioma were enrolled. Somatic genetic aberrations associated with activation of RAS-RAF signaling pathway were identified in 95% of the cohort with BRAF fusion being the most common aberration followed by the BRAF V600E mutation. These findings confirm the presence of targetable mutations in this specific population and provide a foundation for the use of targeted therapy. Diencephalic syndrome is a rare neurologic disorder typically affecting infants and young children with tumors located in the diencephalon. In this cohort, 43% of the optic pathway and hypothalamic gliomas manifested diencephalic syndrome. Among 30 patients who received first line chemotherapy, primary carboplatin and vincristine, the two-year and five-year progression-free survival rate were only 24% and 6.4% respectively, indicating that most patients experience disease progression with chemotherapy. Targeted therapy was administered to 27 patients of whom 22 experienced disease progression during or after chemotherapy. A total of 26 patients were available for evaluation. Dr. Papusha reported that all patients benefited from targeted therapy with 12 achieving a partial response, 2 showing a minor response and 12 maintaining stable disease. The median duration of targeted therapy was 16 months. These findings demonstrate the efficacy of targeted therapy in this population. Regarding toxicity from targeted therapy in this population, the most common adverse event was grade 1 to 2 skin toxicity observed in 52% of patients. Severe toxicity occurred in 36% of patients treated with trametinib including grade 3 skin toxicity, mucositis and hematuria. Additionally, grade 3 gastrointestinal toxicity was reported. Interestingly, all three patients who experienced grade 3 gastrointestinal toxicity had diencephalic syndrome at the time of targeted therapy initiation. The author also noted cases of disease progression during treatment breaks. However, tumor response was restored in all affected patients upon resumption of targeted therapy. The two-year progression-free survival rate was 59%. In conclusion, Dr. Papusha states the unique characteristics of infantile midline low grade glioma, including the high prevalence of diencephalic syndrome and resistance to chemotherapy. The study contributes valuable information on the targetable mutation profile in this population and provides further evidence supporting the use of targeted therapy while emphasizing the need for low monitoring of severe adverse events. As the author notes, important questions remain regarding the long term side effects of kinase inhibitors in infants and children as well as optimal duration of therapy. Thank you for listening to JCO Precision Oncology Article Insights and please tune in for the next topic. 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. Shaalan Beg and Dr. David Wang discuss key abstracts in GI cancers from the 2025 ASCO Gastrointestinal Cancers Symposium, including major advances in CRC, neoadjuvant approaches in esophageal cancer, and innovative studies on ctDNA. TRANSCRIPT Dr. Shaalan Beg: Hello and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg. I'm a medical oncologist and an adjunct associate professor at UT Southwestern Medical Center in Dallas. Today, we're bringing you some key highlights from the 2025 ASCO Gastrointestinal Cancers Symposium, and I'm delighted to be joined by the chair of GI25, Dr. David Wang. Dr. Wang is a GI medical oncologist at the University of Michigan. Our full disclosures are available in the transcript of this episode.  Dr. Wang, thanks for coming on the podcast today. Dr. David Wang: Well, thank you. It's a pleasure to be here. Dr. Shaalan Beg: GI25 featured major therapeutic advances across the spectrum of GI malignancies, and it was exciting to hear about innovations and novel approaches that are shaping the future of our field. Before we start talking about specific abstracts, could you share some of your key highlights from the meeting? Dr. David Wang: Sure. Our theme this year was “Breaking Boundaries to Enhance Patient Centered Care.” Past years' themes have focused more on precision oncology, but we wanted to broaden our focus on patients and to be more holistic, which kind of led us into some of the Intersection [sessions] that we had. Each day started with a different Intersection. The first one was “Emerging Therapies in GI Cancers”, where invited speakers talked about bispecific antibody drug conjugates, theranostics, CAR T and other cell-based therapies. The second day was on “Personalized Risk Assessment for GI Cancers,” and this included looking at polygenic risk scores for colorectal cancer, microRNAs and liquid biopsies such as exosomes and pancreatic cancer and non-endoscopic screening modalities in esophageal cancer. And on our final day, we wanted to talk about “Integrative Oncology and Integrative Medicine,” looking at evidence-based uses of acupuncture and supplements in patients who are receiving treatment for cancer, mindfulness-based practices and exercise. And of course, we had a fantastic keynote talk by Dr. Pamela Kunz from the Yale School of Medicine titled, “Disrupting Gastrointestinal Oncology: Shattering Barriers with Inclusive Science.” She highlighted the intersection of science, patient care, and health and gender equity. And I would encourage your podcast listeners to access the lecture in ASCO's Meeting Library if they haven't yet had a chance to hear Dr. Kunz's wonderful lecture.  We were really happy this year because the attendance hit a new record. We had over 5,000 people attend either in person or virtually from their home or office, and we had almost 1,000 abstracts submitted to the meeting, so these were either record or near record numbers. We offered a lot of different networking opportunities throughout the meeting, and attending found these to be incredibly rewarding and important and this will continue to be an area of emphasis in future meetings. Dr. Shaalan Beg: Let's take a deeper dive into the exciting studies presented at GI25. The late breaking abstract LBA143 was CheckMate-8HW. This was the first results of NIVO + IPI versus NIVO monotherapy for MSI-high metastatic colorectal cancer. What are your thoughts about this study? Dr. David Wang: Yeah, so we know that colorectal cancer patients with MSI-high tumors don't necessarily respond well to chemotherapy. And we were fortunate because last year CheckMate-8HW actually looked at two different arms – so this was NIVO + IPI compared to standard of care chemotherapy and showed its very significant improvement in median progression-free survival. And that was actually published in the New England Journal of Medicine back in November of 2024. This year's presentation actually focused now on NIVO + IPI versus NIVO monotherapy. And as you know IPI+NIVO can be quite toxic. So this was an important analysis to be done. So we know that NIVO is definitely more easily tolerated. So what was interesting was that the 2-year and 3-year progression-free survival not surprisingly favored IPI+NIVO and this was statistically significant. And the overall response rate was also better with IPI+NIVO versus NIVO alone. I know we're always concerned about toxicities and there were higher grade 3 and 4 toxicity incidences in the combination arm versus the monotherapy arm, but overall, only about 28 additional events in several hundred patients treated. So I think that's well-tolerated. Our discussant Dr. Wells Messersmith actually said that, with this new data, he would consider doing combination immunotherapy in any patient that presented in the front line with MSI-high or deficient mismatch repair colorectal cancer that was metastatic. Dr. Shaalan Beg: One of the focuses for directing first-line therapy for colorectal cancer has been right and left sided colon cancer because we know these are two different cancers with their own unique molecular subtypes. We heard on Abstract 17, the DEEPER trial, the final analysis of modified FOLFOXIRI plus cetuximab versus bevacizumab for RAS wild-type and left sided metastatic colorectal cancer. How do you summarize the findings of this study and what should our readers be aware of? Dr. David Wang: Interestingly, this was a phase 2 study and the emphasis of the abstract was actually a subgroup analysis of those patients with RAS wild-type and BRAF wild-type as well as left sided cancers. So, I think the entire study enrolled 359 patients, but the analysis that was discussed at the meeting really focused on 178 patients that fit that characteristic. Very similar to what we've seen in prior studies, left-sided tumors have better response to cetuximab versus bevacizumab. And if you flip it so that you now are looking at right sided tumors, targeting EGFR is actually detrimental. The depth of response was better with cetuximab in these left sided RAS and BRAF mutant tumors. And so the lead author actually suggested that this could be a new first-line standard of care. And the question is, is there a benefit of doing this triple agent regimen with modified FOLFIRINOX? We know there's a lot more toxicity with that. Not clear that there's a benefit for that over FOLFOX, maybe in younger patients that could tolerate it. When our discussant, again Dr. Wells Messersmith, spoke about this, he said that, in his practice he would, again, favor cetuximab over bevacizumab in combination with chemo, these left-sided RAS and BRAF wild-type tumors, but that he would actually prefer a doublet versus a triplet chemo regimen, and that is consistent with the current NCCN guidelines. Dr. Shaalan Beg: Another area where colorectal cancer has been a wonderful model to study new technology has been in the area of circulating tumor DNA (ctDNA). And the BESPOKE CRC trial is looking to see if ctDNA can inform adjuvant treatment decisions for stage II and III colorectal cancer. And in Abstract 15, we heard final results of the BESPOKE CRC sub-cohort. What were the findings there? Dr. David Wang: BESPOKE CRC is another one of these important ctDNA studies. It was an observational study, not a randomized trial, but it did provide a lot of different insights to us. We know that there were over 1,700 patients enrolled, and so it was reported that this is the largest ctDNA study in colorectal cancer performed in the United States. And they were able to analyze over 1,100 patients.  Some of the key findings were that postoperative adjuvant therapy management decisions actually changed in 1 out of 6 patients, so that's pretty significant. In terms of surveillance, we know that patients who have ctDNA positivity, this is prognostic of recurrence. In terms of patients who have positive ctDNA post-surgery, it looked like, at least in this observational study, the majority of patients who received any benefit were those who had positive ctDNA. So adjuvant therapy, even in stage II and stage III patients seemed to only benefit those patients who have positive ctDNA. I think that does raise the question, and this also was brought up in the discussion, which is “Can we de-escalate adjuvant therapy in terms of patients who are ctDNA-negative post-op?” And Dr. Richard Kim from Moffitt felt that we are not yet there. Obviously, we need randomized control trials where we are taking ctDNA results and then randomizing patients to receive adjuvant or non-adjuvant to really know the difference.  Other questions that come up with use of ctDNA include: What do you do with these patients who turn positive? This study for BESPOKE actually followed patients out to two years after surgery. So what you do with a positive ctDNA result wasn't really clear. It seems to suggest that once you turn positive, patients go on to more intensive surveillance. You know, again as an observation, patients who did turn positive were able to go to metastasis-directed therapy much more quickly. And again, this was supposedly to improve their curative intent therapy. And I think the other question that has been brought up all the time is, is this really cost effective? Patients want to know, and we want to give patients that information, but I think we're still stuck with what to do with a positive ctDNA level in a patient that's on surveillance because no randomized control studies have actually suggested that we need to start systemic therapy right away. Dr. Shaalan Beg: Yeah. And I guess in terms of practice informing or practice changing, these results may not give us a clear answer. But because a lot of patients are asking for these tests, it does give us some real world experiences on what to expect in terms of conversion of these positive into negative and the outcome so we can have a shared decision making with our patients in the clinic and then come up with a determination on whether ctDNA for molecular residual disease is something which would be worthwhile for the care of our patient. But more to come, I guess, in coming years to answer different problems around this challenge. Dr. David Wang: Yes, I agree. Dr. Shaalan Beg: The BREAKWATER trial looked at the use of encorafenib, cetuximab and chemotherapy for BRAF V600E-mutant metastatic colorectal cancer. We've covered this combination for a second- third-line treatment in metastatic colorectal cancer previously. Abstract 16 from GI25 was evaluating the use of this regimen in the first-line space. Everyone was looking forward to these results, and what did the investigators present? Dr. David Wang: I think this is, as you mentioned, a nice follow up to later lines of therapy where Dr. Kopetz from MD Anderson pioneered use of encorafenib, cetuximab and binimetinib in the BEACON trial. Everybody was kind of curious what would happen now if you use encorafenib plus cetuximab plus chemotherapy in the first-line setting. And so this is an interim analysis that was pre-planned in the phase 3 open label BREAKWATER trial. And even though there were three arms, and so the three arms were encorafenib plus cetuximab, encorafenib plus cetuximab plus FOLFOX, or standard of care chemo, only two arms were presented in the abstract. So basically looking at encorafenib plus cetuximab and FOLFOX-6 versus standard of care therapy, and the overall response rate was statistically significant with a 60.9% overall response rate encorafenib plus cetuximab plus chemo arm versus standard of care chemo was only 40%. The interim overall survival also was different. It was 92% versus 87% at 6 months and 79% versus 66% at 12 months, again favoring the chemotherapy plus encorafenib plus cetuximab. In terms of the statistics, the p was 0.0004. However, the pre-plan analysis required the p-value to be 1x10 to the -8. And so even though this looks really good, it hasn't quite met its pre-specified significance level. The good thing is that this is only interim analysis and the study is ongoing with future analysis planned.  So the real question is: Does it matter when we actually use this regimen? We know that the regimen's approved in the second third-line setting. What about in the first line? And there was some preclinical data that the discussant reviewed that shows that patients actually benefit if this is done in the first-line setting. For example, there was some preclinical data showing that even FOLFIRI, for example, can upregulate RAS, which would make tumors more resistant to this combination. This was thought to be practice-changing in a patient that has B600E showing up treatment naive that we should probably consider this regimen. And actually this did receive accelerated FDA approval about a month ago. Dr. Shaalan Beg: Yeah, and for what it's worth, I put up a Twitter poll asking my Twitter followers on how the BREAKWATER trial results will change their approach for newly diagnosed BRAF mutated colorectal cancer. We got 112 responses; 72% said that they will incorporate encorafenib, cetuximab, FOLFOX for their frontline BRAF mutated patients. But 23% said that they would like to wait for overall survival results. Dr. David Wang: Wow, that's interesting. They really want that 1x10 to the -8. Dr. Shaalan Beg: I guess so. All right. Let's change gears and talk about esophageal cancer. LBA329 was the SCIENCE study which presented preliminary results from a randomized phase 3 trial comparing sintilimab and chemoradiotherapy plus sintilimab versus chemoradiotherapy for neoadjuvant resectable locally advanced squamous esophageal cancer. Where are we in this space? Dr. David Wang: Okay. So, yeah, this was an interesting trial. Again, just to set the context, esophageal squamous cell carcinoma is more prevalent in Asia. And the study sites as well as the patients were mostly from Asia. So this was again a phase 3 trial with interim results. They only rolled 146 out of the planned 420 for this interim analysis. And yeah, they're using immune checkpoint inhibitor that we don't use in the United States, sintilimab, combined with their two standards of neoadjuvant therapy, either chemotherapy, which is more common in Asia, or or chemoradiation, which is more common in the US and Western Europe, versus chemoradiation. And so they actually had two primary endpoints, but only were reporting one. So their two primary endpoints were pathCR and the other one was event-free survival. The event-free survival, again, was not reported at the meeting.  What they found was that in terms of pathCR rate, if you take the two arms that are really informative about that, chemoradiation plus sintilimab versus chemoradiation alone, the pathCR rate was 60% versus 47%. We know that chemo alone doesn't induce as much of a pathCR rate, and that was 13%. So it was found that the delta in terms of pathCR between the chemoradiation arms, one with sintilimab and one without, was significant. And this actually confirms data again from Asia, like for the ESCORT-NEO trial where it used another immune checkpoint inhibitor pembrolizumab in addition to neoadjuvant chemo.  So as our discussant for this abstract said, yes, we know that radiation combined with chemotherapy improves pathCR rates, but we have recent data from the ESOPEC trial, we don't know that that necessarily will translate to overall survival. So again, waiting for additional enrollments and longer term follow up before incorporating this into clinical care here. Dr. Shaalan Beg: So David, how do the results of the SCIENCE trial compare with our practice in the United States and ongoing studies asking questions for neoadjuvant therapy for esophageal carcinoma in the United States? Dr. David Wang: I think obviously immune checkpoint inhibitor in the new adjuvant setting is important. Jennifer Eads at UPenn is running that EA2174 which is looking at chemoradiation plus or minus nivolumab, and then in non-pathCR responders randomized to adjuvant nivolumab per CheckMate 577 or nivolumab with intensification adding ipilimumab. We know that the ESOPEC trial just came out, and was published actually during the meeting, and that really focuses on adenocarcinomas. So adenocarcinomas of the GE junction, distal esophagus, now, we would probably treat very similarly to gastric using perioperative FLOT. However, the standard in the US for esophageal squamous cell carcinoma remains neoadjuvant chemoradiation. We know that squamous cell carcinomas are more exquisitely sensitive to radiotherapy. And then obviously in those patients who don't achieve a pathologic complete response, the expectation would be that they would go on to receive nivolumab per CheckMate 577. Again, the thought is that these tumors are more sensitive to immunotherapy given their higher incidences of mutational changes. And so again, this kind of goes along with the positive results seen in the SCIENCE trial that we just discussed with sintilimab but also EFFECT-neo with pembrolizumab. Obviously, we await the results of Jennifer's trial. Dr. Shaalan Beg: And the last abstract I was hoping we could get your perspective on was Abstract 652, which is a Phase 3 study of everolimus plus lanreotide versus everolimus monotherapy for unresectable or recurrent gastroenteropancreatic neuroendocrine tumors, the STARTER-NET trial. What were the results of this study? Dr. David Wang: So, I just want to give a shout out because we did have a session at this year's GI ASCO that looked at more rare tumors. So appendiceal tumors, neuroendocrine tumors, those kinds of things. So again, I would encourage your listeners to listen to that session if they have interest in that. Another type of rare tumor was adenosquamous tumors.  But in terms of the STARTER-NET trial, this was again an interim analysis of his phase 3trial and it was looking at combining everolimus plus lanreotide versus everolimus. So we know that in pancreatic-gastric neuroendocrine tumors, if you have low Ki-67, a well differentiated tumor, that the standard of care really is a somatostatin analog, and sometimes if they're more aggressive, we kind of consider molecular targeted therapy with everolimus. This was asking the question of whether we should do the combination on the frontline. And what was interesting is in this study, the patients were actually more of a poor prognostic set. So they had Ki-67 up to 20% or these were patients that actually had multiple liver lesions. And what they found was a median for progression free survival was improved with a combination out to 29.7 months versus 11.5 months with the somatostatin analog alone, and that the overall response rate was 23% versus 8.3%, again, favoring the combination. If you looked at subgroup analysis, it was actually those patients who had Ki-67 greater than 10%, so the more aggressive tumors, or those with diffuse liver lesions that had the most benefit. So I think that would be the patient population I would consider this new combination with using would be those patients again with poorer prognosis neuroendocrine tumor phenotype. Dr. Shaalan Beg: Thank you very much, Dr. Wang, for sharing your insights with us today and your great work to build a robust GI Cancers Symposium this year. Dr. David Wang: Well, thank you. I mean that really is a cooperative effort. We appreciate all the members of the GI25 Program Committee as well as the ASCO staff that just made it an outstanding meeting. Dr. Shaalan Beg: And thank you to all our listeners for your time today. You'll find links to the abstracts discussed today on the transcript of this episode.  Finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review and subscribe wherever you get your podcasts. Disclaimer: The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement. Find out more about today's speakers:  Dr. Shaalan Beg @ShaalanBeg  Dr. David Wang Follow ASCO on social media:   @ASCO on Twitter  @ASCO on BlueSky ASCO on Facebook   ASCO on LinkedIn   Disclosures:  Dr. Shaalan Beg:  Employment: Science 37  Consulting or Advisory Role: Ipsen, Array BioPharma, AstraZeneca/MedImmune, Cancer Commons, Legend Biotech, Foundation Medicine  Research Funding (Inst.): Bristol-Myers Squibb, AstraZeneca/MedImmune, Merck Serono, Five Prime Therapeutics, MedImmune, Genentech, Immunesensor, Tolero Pharmaceuticals  Dr. David Wang: Honoraria:  Novartis Consulting or Advisory Role: Novartis, Cardinal Health, Bristol-Myers Squibb, BeiGene, Eisai  

Welcome to another episode of the Oncology Brothers podcast! In this episode, Drs. Rahul and Rohit Gosain are joined by Dr. Alok Khorana, a GI medical oncologist from the Cleveland Clinic, to discuss the latest highlights from the GI ASCO 2025 conference. We dive into four key studies that are practice-informing and potentially practice-changing: 1. BREAKWATER: We explore the implications of using Encorafenib and Cetuximab in combination with FOLFOX for patients with BRAF V600E mutations, which are associated with poor prognosis. 2. CheckMate-8HW: This study investigates whether dual checkpoint inhibition is more effective than single-agent immunotherapy for MSI-high patients, revealing promising results in progression-free survival. 3. Aspirin in Adjuvant Settings: We discuss the role of low-dose aspirin in reducing recurrence rates for patients with PI3K alterations, highlighting its potential as a practice-changing intervention. 4. STARTER-NET: Finally, we review the findings from the study on Everolimus combined with Lanreotide for neuroendocrine tumors, noting the lack of overall survival benefit. Tune in for an insightful discussion on these important topics in oncology, and learn how these findings could impact treatment strategies in your practice. Don't forget to like, subscribe, and check out our other episodes for more conference highlights and treatment discussions! YouTube: https://youtu.be/YOToz3hKYTg Follow us on social media: •⁠  ⁠X/Twitter: https://twitter.com/oncbrothers •⁠  ⁠Instagram: https://www.instagram.com/oncbrothers #OncologyBrothers #GIASCO2025 #ColorectalCancer #Immunotherapy #NeuroendocrineTumors #CancerResearch #Podcast

BUFFALO, NY- October 29, 2024 – A new #casereport was #published in Oncotarget's Volume 15 on October 11, 2024, entitled “Complete response to encorafenib plus binimetinib in a BRAF V600E-mutant metastasic malignant glomus tumor.” As highlighted in the abstract, glomus tumors (GT) are rare mesenchymal neoplasms originating in dermal arteriovenous structures involved in thermoregulation. While generally benign, some can exhibit malignant features, leading to aggressive behavior, metastasis, and limited response to standard chemotherapy. The identification of the BRAF V600E mutation in certain malignant GT cases offers a promising therapeutic target. In their paper, researchers Marta Arregui, Antonio Calles, María del Mar Galera, Ana Gutiérrez, Carlos López-Jiménez, Carolina Agra, Adriana Fernández, Natalia Gutiérrez, María de Toro and Rosa Álvarez from Gregorio Marañón University Hospital and Fundación Jiménez Díaz University Hospital in Madrid, Spain, document a remarkable clinical and metabolic response in a case of metastatic BRAF V600E-mutated glomangiosarcoma treated with the combination of encorafenib and binimetinib. They report on a 45-year-old male patient with stage IV malignant GT carrying a BRAF V600E mutation, who was treated systemically with encorafenib and binimetinib. This approach led to a swift clinical and radiological improvement. “To our knowledge, our patient represents the first reported case of a metastatic malignant GT successfully treated with BRAF and MEK inhibitors, achieving a long-lasting complete morpho-metabolic response.” DOI - https://doi.org/10.18632/oncotarget.28654 Correspondence to - Carlos López-Jiménez - clopezjimenez@atbsarc.org Video short - https://www.youtube.com/watch?v=xjbj3Iu16P4 Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28654 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, malignant glomus tumor, glomangiosarcoma, BRAF V600E, agnostic treatment, targeted therapy About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

En esta cápsula de ESMO 2024 EXPRESS, el Dr. Javier de Castro, oncólogo médico adscrito al Hospital Universitario La Paz en Madrid, España, nos comenta los progresos clave en el manejo del cáncer de pulmón, consolidando tendencias recientes en la terapia adyuvante y el uso de terapias dirigidas. Algunos de los puntos más relevantes incluyen: Terapia neoadyuvante en estadios II y III resecables: Los resultados recientes presentados en el Congreso destacan el uso de la combinación de quimioterapia e inmunoterapia en el contexto neoadyuvante. Un elemento adicional de relevancia es la monitorización de la enfermedad mínima residual mediante biopsia líquida. Los pacientes que logran un aclaramiento del ADN tumoral circulante tras la combinación de quimioterapia e inmunoterapia tienden a presentar mejores resultados clínicos. Aquellos que no alcanzan este aclaramiento podrían beneficiarse de tratamientos adicionales o modificados antes de la cirugía para optimizar los resultados. Avances en terapias dirigidas para EGFR y ALK: En pacientes con mutaciones de EGFR, se consolidó el uso de amivantamab en combinación con quimioterapia, mostrando mejoras significativas en la supervivencia libre de progresión y la respuesta objetiva. Para aquellos con mutaciones en ALK, se presentaron datos sobre inhibidores de cuarta generación, los cuales demostraron eficacia en pacientes que progresaron tras el uso de inhibidores de segunda y tercera generación como alectinib, brigatinib y lorlatinib. Mutaciones BRAF: En pacientes con mutaciones BRAF V600E, la combinación de encorafenib y binimetinib mostró una tasa de respuesta del 75% en pacientes naive y una supervivencia libre de progresión que alcanza hasta 40 meses, consolidándose como una opción eficaz para esta población. Estos avances subrayan la importancia de la personalización del tratamiento en cáncer de pulmón, especialmente en el uso combinado de terapias dirigidas y el monitoreo molecular mediante tecnologías como la biopsia líquida. Fecha de grabación: 16 de septiembre de 2024

BUFFALO, NY- August 14, 2024 – A new #casereport was #published in Oncotarget's Volume 15 on July 17, 2024, entitled, “Rapid but nondurable response of a BRAF exon 15 double-mutated spindle cell sarcoma to a combination of BRAF and MEK inhibitors.” As noted in the introduction of the Abstract, the BRAF V600E substitution predicts a cancer's sensitivity to BRAF inhibitor therapy, though the mutation is rarely found in soft-tissue sarcomas. Researchers Kseniya Sinichenkova, Iliya Sidorov, Nataliya Kriventsova, Dmitriy Konovalov, Ruslan Abasov, Nataliya Usman, Alexander Karachunskiy, Galina Novichkova, Dmitriy Litvinov, and Alexander Druy from the Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology, Immunology (Ministry of Healthcare of Russian Federation) and the Research Institute of Medical Cell Technologies in Yekaterinburg, Russia, describe a case of undifferentiated spindle cell sarcoma that exhibited primary insensitivity to standard chemotherapy and a pronounced but non-sustained response to BRAF/MEK inhibitors at recurrence. The case presentation involved a 13-year-old girl that was diagnosed with low-grade spindle cell sarcoma of pelvic localization, BRAF exon 15 double-mutated: c.1799T>A p.V600E and c.1819T>A p.S607T in cis-position. “This is the first report of spindle cell sarcoma BRAF V600E/S607T double-mutated, responding to a combination of B-Raf and MEK inhibitors.” DOI - https://doi.org/10.18632/oncotarget.28606 Correspondence to - Kseniya Sinichenkova - ksinichenkova@gmail.com Video short - https://www.youtube.com/watch?v=QWEAaaixPxE Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28606 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, undifferentiated sarcoma, BRAF V600E mutation, low grade spindle cell sarcoma, abdominal cocoon About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

CME credits: 0.75 Valid until: 26-04-2025 Claim your CME credit at https://reachmd.com/programs/cme/optimizing-therapeutic-selection-for-a-patient-with-newly-diagnosed-braf-v600e-mutated-metastatic-melanoma/24365/ This activity focuses on improving clinician awareness and knowledge of LAG-3-based immunotherapy in metastatic melanoma. We aim to identify patients with metastatic melanoma who can benefit from LAG-3/PD-1 combination therapy and enhance the competence of the multidisciplinary team in managing these patients.

In this JCO PO Article Insights episode, Fergus Keane provides a summary on "Microsatellite Instability Is Insufficiently Used as a Biomarker for Lynch Syndrome Testing in Clinical Practice", by Papadopoulou, et al published January 25, 2024 TRANSCRIPT The guest on this podcast episode has no disclosures to declare. Fergus Keane: Hello and welcome to JCO Precision Oncology Article Insights. I'm your host, Fergus Keane, an ASCO Editorial Fellow. Today, I will be providing a summary of the article entitled "Microsatellite Instability Is Insufficiently Used as a Biomarker for Lynch Syndrome Testing in Clinical Practice" by Dr. Eirini Papadopoulou. The mismatch repair pathway has gained interest in recent years due to advances in precision oncology, the widespread use of immune checkpoint blockade, and next-generation sequencing-based assays to identify microsatellite instability. The mismatch repair pathway has a key role in DNA repair and maintaining genomic stability. Tumor cells, which are MMR deficient are prone to mismatch errors in the microsatellite regions during DNA replication. Microsatellite instable, referred to as MSI-High tumors are observed across a variety of tumor types, most commonly colorectal and endometrial cancers.  Germline Lynch syndrome is caused by inactivating variants in one of five primary MMR genes, namely MSH2, MLH1, MSH6, PMS2, and EPCAM, and is associated with an autosomal dominant pattern of inheritance. Mismatch repair deficiency is observed in most tumors in individuals with Lynch syndrome and can also occur sporadically. In mismatch repair deficient colorectal cancer, sporadic cases are identified by BRAF V600E mutations or MLH1 gene promoter hypermethylation. The absence of both of these findings should raise suspicion for germline Lynch syndrome. The aim of this study was to report the prevalence of microsatellite instability in a large cohort of patients in Europe, specifically Greek patients. In addition, the authors aimed to evaluate the proportion of patients with microsatellite instability referred for germline testing and what factors appeared to influence clinician decision to refer for germline testing. 4553 patients with metastatic cancer were included between January 2020 and April 2023. All patients were referred for MSI analysis, and at physician discretion, BRAF V600E and MLH1 gene methylation analyses were available. Approximately half of patients included had colorectal cancer. 5.27% of patients exhibited MSI-High in total, of whom 58% were female and 42% were male.  The rates of MSI-High cancers varied according to tumor type, but the highest rates observed in patients with endometrial cancer at 15.69%, gastric cancer at 8.54%, colorectal cancer at 7.4%, and urinary tract cancers at 4.55%. Of the MSI-High patients, with colorectal cancer identified, 24.85% had a BRAF V600E. Excluding these patients, 198 were eligible for genetic testing with a hereditary cancer panel. Of these, only 22.7% were actually referred for a hereditary panel. The median age at diagnosis in this group was 59 years, compared with 66 years for those who were not referred for germline analyses. The age at diagnosis and referral for genetic analyses were significantly correlated.  Beyond colorectal cancer, patients with other cancer types who were also referred for germline testing included nine patients with endometrial cancer, four with gastric cancer, two with ovarian cancer, one with breast cancer, and one with gallbladder cancer, and referral patterns differed by tumor type. Of patients with colorectal and endometrial cancer, 24.4% had a positive germline mismatch repair variant identified. Of note, while the median age of patients with a pathogenic or likely pathogenic germline result was 48.5 years, over 40% of patients with a pathogenic germline result were aged over 50 years, highlighting that age alone should not be the only criterion for consideration of a referral for germline analysis in such patients.  This study highlights some important points. First, MSI analysis is an important biomarker for a variety of tumor types, including colorectal, gastric, and endometrial cancer, but also less commonly associated cancer types. Second, only 22.73% of patients eligible for germline analyses were referred in this patient cohort, despite recommendations from international guidelines indicating that a proportion of patients with a possible familial predisposition syndrome may not be tested for same. Third, key features such as age at diagnosis and tumor type influence the clinical decision for referral for genetic analysis.  The authors conclude that the value of MSI testing as a potential screening tool for identification of patients with a higher risk for germline pathogenic variants may be underappreciated and highlights this important biomarker. Thank you for listening to JCO Precision Oncology Article Insights, and please tune in for the next topic. Don't forget to give us a rating and review, and be sure to subscribe so that you don't 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. Natash Leighl and Dr. Jyoti Patel are back on the podcast to discuss the update to the living guideline on stage IV NSCLC with driver alterations. This guideline includes recommendations for first-, second-, and subsequent-line therapy for patients with driver alterations including: EGFR, ALK, ROS1, BRAFV600E, MET exon skipping mutation, RET rearrangement, NTRK rearrangement, HER2, and KRAS G12C. They highlight the key changes to the recommendations, addition of recent trials, the importance of biomarker testing, and the impact of this guideline for clinicians and patients living with advanced NSCLC. Stay tuned for future updates to this continuously updated guideline. Read the full update, “Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.3” at www.asco.org/living-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/living-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.02744.    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 am interviewing Dr. Jyoti Patel and Dr. Natasha Leighl, co-chairs on “Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.3.” Thank you for being here, Dr. Patel and Dr. Leighl.  And before we discuss this guideline, I would 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 and Dr. Leighl, who have 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, to start us off on this living clinical practice guideline, Dr. Leighl, this guideline for systemic therapy for patients with stage four non-small cell lung cancer with driver alterations is being routinely updated. What new data was reviewed in this full update to the living guideline? Dr. Natasha Leighl: Thanks so much, Brittany. So, we looked through the literature for publications between February and the end of October 2023, and also any novel agents that were approved, in particular by the United States FDA, to really incorporate this update in the current guidelines. In particular, we had updates in EGFR-driven tumors, BRAF and RET-driven tumors. And we also worked very hard to make this more digestible. In particular, it was turning into a bit of a laundry list of all of the things that we had ever recommended. So we really wanted to shorten things, pare them down, and really make them helpful and very, very current for the treatment of people with lung cancer in 2023 and 2024. Brittany Harvey: Excellent. Thank you for providing that overview of the evidence reviewed and the key updates that we will address in this guideline. So then I would like to talk about some of those key updated recommendations from the expert panel. You mentioned both EGFR, BRAF, and RET. So starting with patients with stage IV non-small cell lung cancer with EGFR alterations, Dr. Leighl, what are the key changes to those recommendations? Dr. Natasha Leighl: So, as I said, we really started to get quite a long list of things we recommended, including drugs that, to be honest, we no longer think are what we should lead with first-line. So we updated the recommendation to recommend first-line osimertinib in patients with sensitizing mutations. We were also able to capture in this update for patients with EGFR exon 20 insertion mutant lung cancer, the data from the randomized PAPILLON trial, recommending amivantamab plus chemotherapy for progression-free survival benefit. Not yet an overall survival benefit, but we will see how these data mature.  The other thing that we did was we moved all of the- I don't want to call them "legacy agents" because, in many countries, these are still very important. But older agents such as gefitinib, approaches such as gefitinib plus chemotherapy, and drugs like dacomitinib and other agents where we truly believe as an international panel that we would prefer a third-generation kinase inhibitor like osimertinib. We moved all of those to our discussion, just to recognize that, around the world, not everybody may have access. And we also specified that things are different in different countries. So, for example, in China, there are other third-generation kinase inhibitors with randomized data to support their use. And those are approved and used in China. And also, for example, in Korea, there are other agents that are used. So, we have really tried to be both inclusive and yet keep things simple at the same time. And hopefully, we have succeeded.  One of the challenges was that, with all of the updates that we made, we did not have all of the publications out yet at the end of October to make recommendations about moving beyond osimertinib in the first-line setting. So, please stay tuned for the next guideline update, where we're going to tackle whether we should give osimertinib alone or combination therapy. Brittany Harvey: Excellent. Thank you for providing those updates and clarifications for those patients with non-small cell lung cancer and an EGFR alteration. And we will look forward to the guideline panel's review of that evidence and future updates as well. So then, Dr. Leighl, you had previously mentioned that additional recommendations were updated, such as those for patients with BRAF alterations and RET alterations. So, Dr. Patel, what are the other key updated recommendations from the expert panel? Dr. Jyoti Patel: Thanks so much, Brittany. So certainly, I think we have seen many of these trials mature over time, which has been fantastic. I think one remarkable achievement was the reporting of a phase III selpercatinib trial. This was a trial in the front-line setting, in which patients who were RET-positive were randomized to selpercatinib versus carboplatin-based chemotherapy. And the selpercatinib significantly outperformed platinum-based chemotherapy, and I think really demonstrated a significant improvement in progression-free survival. So, based on that phase III trial, the recommendation for selpercatinib was elevated. Many of these agents that are used in clinical practice are approved initially on smaller phase I or phase II trials. And so, seeing the maturity of these phase III trials gives clinicians and patients greater certainty that these agents are really effective. And so, the evidence was increased for that, and that's now a preferred agent over another TKI, pralsetinib, in which there is only phase II data. So, certainly, those kinds of real things that we can explain to patients are important in these guidelines.  Another thing that we were able to update was another doublet for BRAF V600E non-small cell lung cancer. So, the combination of the two TKIs, encorafenib and binimetinib, was also included in the guidelines.  One thing that we tried to help was really identifying the best therapy post-progression on these first-generation TKIs. And again, there is a paucity of data, but often we went back to carboplatin-based doublets, and there is some data regarding whether or not patients with driver alterations should get immunotherapy in the second-line setting. And so, certainly, I think we have a number of randomized studies for patients with classical EGFR mutations, and our recommendation is generally avoidance of immunotherapy for these patients and treating many of these patients with carboplatin and pemetrexed when appropriate. I do not think we have the data for a lot of other subsets of patients. So, again, stay tuned as these data evolve. Brittany Harvey: Thank you for reviewing those updated recommendations and the supporting evidence. I think it's helpful for our listeners to understand the level of evidence behind these recommendations as well.  So then, Dr. Leighl, what should clinicians know as they implement these new and updated recommendations? Dr. Natasha Leighl: It's really important, first of all, to make sure that you have the information that you need to get your patients to these great new treatments as part of the shared decision-making process. So your patients need biomarker testing. You need to get that as quickly as you can. As Dr. Patel has highlighted, you really want to get that before they start their first-line therapy, if at all possible. We also really tried to bring out in this guideline that when things are delayed, I mean, this is the real world that we live in, just to be very cautious of immunotherapy with chemotherapy for that first cycle. That obviously, again, is a discussion with your patient, but this concept that the approach of a cycle of chemotherapy while you wait for the next-generation sequencing testing. And then if the patient does not have a driver alteration, adding any other therapy as appropriate is okay. It's something that people do. We believe it's important as we talk about the balance between benefits and harms. And so I think that's in there for clinicians, and I hope that they and patients can really benefit from that to avoid toxicity and also to really improve the ability to get molecular testing results first line.  Also, I think it's really important that when people read the wording of the guidelines, that this really follows GRADE, which is a type of system that we use to develop our recommendations. And so things like "may" do not mean that you shouldn't do it. So sometimes we'll hear back from clinicians and say, "Well, you said that they may use alectinib or lorlatinib, for example, with ALK, and I can only get coverage for one or the other." And so I think it's really important that clinicians and patients recognize that all of the things that we do recommend, even if we do use the word "may" or the recommendation is more conditional, we do think that these agents should be available for patients and clinicians, and that they go through this shared decision-making process together.  And so I think that's something that clinicians, we hope, can help take forward as they advocate for their patients to get access to these different and new and emerging treatments that have clearly shown benefit. Even when we say patients and clinicians may use this or that, there may be excellent reasons for using something newer, that's emerged, perhaps for toxicity benefits or benefits in terms of efficacy, even though we can't compare directly. And so we really want clinicians and patients to be empowered to access these new compounds and these new exciting agents that are in our guidelines. Brittany Harvey: Absolutely. Thank you for reviewing those key points. And, yes, that's a great comment that the level of obligation in the recommendations may be based on the evidence quality, but that doesn't mean that clinicians and patients shouldn't have access to all of the recommended treatment options to offer patients based off their individual patient and clinical characteristics.  So then, Dr. Patel, in your view, how will these changes affect patients with non-small cell lung cancer, with driver alterations?  Dr. Jyoti Patel: A lot of this echoes the points made by Dr. Leighl. I think there are opportunities for patients to assess toxicity or what it means for intensification of therapy. So, particularly for EGFR patients, for example, we have data that chemotherapy with osimertinib can improve progression-free survival, or the incorporation of a bispecific antibody, amivantamab, can improve progression-free survival over the TKI alone. It certainly comes with increased toxicity. And so how we weigh this in the absence of a known survival benefit at this juncture is one that, again, really gives patients the opportunity to prioritize what's important for them. And so I think this guideline affects patients and that we have multiple options, we help with the weight of the evidence so they may be able to better discern what treatment makes sense for them. Brittany Harvey: Understood. Yes, this guideline provides lots of options for different patients based off their driver alterations. So it's helpful to have that information for shared decision-making with their clinicians.  So then finally, to wrap us up, Dr. Leighl, what current research is the living guideline expert panel monitoring for updates to the guideline recommendations? Dr. Natasha Leighl: This process of the living guidelines has really been to help us stay on top of the amazing and incredibly rapid progress that we're making in lung cancer and other cancers. And even with this process, where we're trying to stay up-to-the-minute, there have already been some changes in the literature between the start of November and now. And so we're already working on some additional commentary and options for the first-line treatment of patients with EGFR-mutant lung cancer. Also, the subsequent treatment of patients with EGFR-mutant lung cancer, depending on what they've had before. Also, a great new study in patients with ROS1 fusion-driven lung cancer. And so these are some of the things that we're looking at.   Also, a bit more discussion about the importance of molecular testing. In our companion article, the Journal of Oncology Practice, along with Dr. Patel, we're going to be talking a bit more about new ways to genotype, for example, using both liquid biopsy and tumor tissue at the same time, and some of the support for that and how it gets us with our patients to the answers that they need faster.  Brittany Harvey: Absolutely. The pace of research in non-small cell lung cancer has moved quite quickly. So we definitely appreciate the panel's efforts to review all of this evidence on a continuous basis and take the time to develop these guideline recommendations for both clinicians and patients with non-small cell lung cancer.  So I want to thank you so much for your work to update these guidelines, and thank you for your time today, Dr. Patel and Dr. Leighl. Dr. Natasha Leighl: Thanks so much. It's a real pleasure to be here. Dr. Jyoti Patel: Thank you.  Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.  The purpose of this podcast is to educate and 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.      

BUFFALO, NY- January 29, 2024 – A new #research perspective was #published in Oncotarget's Volume 15 on January 24, 2024, entitled, “Genetic alterations in thyroid cancer mediating both resistance to BRAF inhibition and anaplastic transformation.” In this new paper, researchers Mark Lee and Luc GT Morris from New York Presbyterian Hospital and Memorial Sloan Kettering Cancer Center discuss thyroid cancer. A subset of thyroid cancers present at advanced stage or with dedifferentiated histology and have limited response to standard therapy. Tumors harboring the BRAF V600E mutation may be treated with BRAF inhibitors; however, tumor response is often short-lived due to multiple compensatory resistance mechanisms. “One mode of resistance is the transition to an alternative cell state, which on rare occasions can correspond to tumor dedifferentiation.” DNA sequencing and RNA expression profiling show that thyroid tumors that dedifferentiate after BRAF inhibition are enriched in known genetic alterations that mediate resistance to BRAF blockade, and may also drive tumor dedifferentiation, including mutations in the PI3K/AKT/MTOR (PIK3CA, MTOR), MAP/ERK (MET, NF2, NRAS, RASA1), SWI/SNF chromatin remodeling complex (ARID2, PBRM1), and JAK/STAT pathways (JAK1). Given these findings, recent investigations have evaluated the efficacy of dual-target therapies; however, continued lack of long-term tumor control illustrates the complex and multifactorial nature of these compensatory mechanisms. Transition to an immune-suppressed state is another correlate of BRAF inhibitor resistance and tumor dedifferentiation, suggesting a possible role for concurrent targeted therapy with immunotherapy. “Investigations into combined targeted and immunotherapy are ongoing, but early results with checkpoint inhibitors, viral therapies, and CAR T-cells suggest enhanced anti-tumor immune activity with these combinations.” DOI - https://doi.org/10.18632/oncotarget.28544 Correspondence to - Luc GT Morris - morrisl@mskcc.org Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28544 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, thyroid cancer, drug resistance, anaplastic transformation, BRAF inhibitors, PIK3CA About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957

During an overview of the current standard of care for patients with colorectal cancer (CRC), Tanios S. Bekaii-Saab, MD noted that as molecular testing becomes more important, researchers are looking into how to best personalize therapy for optimal outcomes. He spoke with CancerNetwork® as part of an Around the Practice® program focused on testing and treatment options for patients with metastatic CRC.  When discussing the future direction of CRC care strategies, it is possible that treatment will be tailored to the individual based on mutation status, such as BRAF V600E, said Bekaii-Saab, leader of the Gastrointestinal Cancer Program and medical director of the Cancer Clinical Research Office, and vice chair and section chief for Medical Oncology in the Department of Internal Medicine at the Mayo Clinic.  Bekaii-Saab noted that his institution is investigating select treatments in earlier lines of therapy, as chemotherapy plus or minus a biologic is the current standard of care. He also highlighted the importance of a multidisciplinary team approach, as he knows working with radiologists, and surgeons is important to provide patients with the best care.  At the time of the interview, fruquinintib (Fruzaqla) was pending approval for patients with previously treated metastatic CRC. On November 8, 2023, fruquintinib was granted approval based on results from the phase 3 FRESCO-2 trial (NCT04322539).1,2 Investigators of the trial reported a median overall survival of 7.4 months (95% CI, 6.7-8.2) in the fruquintinib arm vs 4.8 months (95% CI, 4.0-5.8) in the placebo arm (HR, 0.66; 95% CI, 0.55-0.80; P

Kristen K. Ciombor, MD, MSCI, an assistant professor in the Division of Hematology/Oncology in the Department of Medicine at the Vanderbilt University Medical Center, recently spoke at an Around the Practice discussion regarding updates in the world of metastatic colorectal cancer (CRC). In this episode of the ONCOLOGY® On the Go Podcast, she discusses treatment updates, molecular testing options, and emerging targets in CRC. Ciombor also highlighted ongoing research in the space, including the phase 3 BREAKWATER (NCT04607421)1 trial and the phase 3 MOUNTAINEER-03 (NCT05253651)2 trial. She also discussed some of the most important presentations from the 2023 European Society for Medical Oncology (ESMO) Congress, including those covering the phase 2 MOUNTAINEER study (NCT03043313)3 and the phase 3 KEYNOTE-811 trial (NCT03615326).4 Additionally, she spoke about her work in the phase 2 ECOG-ACRIN trial (NCT04751370) assessing neoadjuvant nivolumab (Opdivo) plus ipilimumab (Yervoy) in patients with microsatellite instability-high or mismatch repair deficient rectal cancer.5 “I'm hoping that we see more treatment options for patients [and that] we identify more patient subtypes that we can target and find actionable alterations for,” Ciombor said. References 1. Kopetz S, Grothey A, Yaeger R, et al. BREAKWATER: randomized phase 3 study of encorafenib (enco) + cetuximab (cetux) ± chemotherapy for first-line (1L) treatment (tx) of BRAF V600E-mutant (BRAFV600E) metastatic colorectal cancer (mCRC). J Clin Oncol. Published online May 28, 2021. doi:10.1200/jco.2021.39.15_suppl.tps3619 2. Bekaii-Saab TS, Van Cutsem E, Tabernero J, et al. MOUNTAINEER-03: phase 3 study of tucatinib, trastuzumab, and mFOLFOX6 as first-line treatment in HER2+ metastatic colorectal cancer—Trial in progress. J Clin Oncol. Published online January 24, 2023. doi:10.1200/jco.2023.41.4_suppl.tps261 3. Strickler JH, Cercek A, Siena S, et al. Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer (MOUNTAINEER): a multicentre, open-label, phase 2 study. Lancet Oncol. Published online May 24, 2023. doi:10.1016/S1470-2045(23)00150-X  4. Janjigian YY, Kawazoe A, Bai Y, et al. embrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Survival results from the phase III, randomized, double-blind, placebo-controlled KEYNOTE-811 study. Ann Oncol. 2023;34(suppl 2):S851-S852. doi:10.1016/j.annonc.2023.09.1424 5. Ciombor KK, Hong SC, Eng C, et al. EA2201: An ECOG-ACRIN phase II study of neoadjuvant nivolumab plus ipilimumab and short course radiation in MSI-H/dMMR rectal tumors. J Clin Oncol. Published online June 2, 2022. doi:10.1200/jco.2022.40.16_suppl.tps3644

In this podcast, host Dr. Stephen Liu moderates a discussion a recent FDA approval and a specific molecular subtype of NSCLC. On October 11, 2023, the US FDA granted approval to encorafenib and binimetinib for advanced NSCLC harboring a BRAF V600E mutation based on the phase II PHAROS trial.

Check out our free downloads at nascentmc.com: Implementing AMA Style – 8 Things to Get Right in Your Next Project Needs Assessments – 7 Essentials for Getting Funded Working With Your Medical Writer – 8 Ways to Get the Most out of Them See the full write ups for today's episode at nascentmc.com/podcast Here are the highlights:  Velsipity (Etrasimod) for UC: The FDA has approved Velsipity (etrasimod) for treating moderate to severe active ulcerative colitis (UC) in adults. Etrasimod, an oral medication manufactured by Pfizer, was based on safety and efficacy data from the ELEVATE UC 52 and ELEVATE UC 12 trials, making it the second S1P class agent approved for UC in the United States. The first agent, ozanimod (Zeposia), received FDA approval in May 2021. Braftovi (encorafenib) and Mektovi (binimetinib) for NSCLC:The FDA has granted approval for the combination of encorafenib and binimetinib to treat BRAF V600E–mutant, metastatic non–small cell lung cancer (NSCLC). The approval, supported by the phase 2 PHAROS study, showed a 75% objective response rate (ORR) in treatment-naive patients. This combination was previously approved for unresectable or metastatic melanoma with a BRAF mutation. Edison System for Non-Invasive Destruction of Liver Tumors:The FDA has authorized the marketing of the HistoSonics Inc. Edison System for non-invasive destruction of liver tumors. The system utilizes a non-thermal, mechanical process of focused ultrasound to create small, vapor-filled cavities (cavitation) without heat, mechanically destroying and liquefying targeted liver tissue, including tumors. This technology is suitable for patients with sufficient functional liver reserve. Complete Response Letter for Patisiran ATTR amyloidosis:The FDA declined to approve patisiran for ATTR amyloidosis despite a favorable recommendation from advisers. The FDA noted that patisiran did not significantly improve the condition of patients with heart muscle issues or cardiomyopathy caused by ATTR amyloidosis. Patisiran, branded as Onpattro, is already approved to treat nerve damage in adult patients with hereditary ATTR amyloidosis. FDA Creates a Digital Health Advisory Committee:The FDA has established a Digital Health Advisory Committee to address complex issues related to digital health technologies, including AI/ML, augmented reality, virtual reality, and more. This committee will provide expertise and perspective to improve the FDA's understanding of the benefits, risks, and clinical outcomes associated with digital health technologies and is expected to be fully operational in 2024. Intro and outro music Garden Of Love by Pk jazz Collective  

Encorafenib + binimetinib gets FDA-approval for metastatic NSCLC, but how does it compare to dabrafenib/trametinib? Plus, a new pediatric approval for dabrafenib/trametinib means more dosage form options.

Featuring perspectives from Dr Kristen K Ciombor and Dr J Randolph Hecht, including the following topics: Introduction (0:00) Case: A woman in her early 80s with KRAS-mutated, HER2-positive metastatic colorectal adenocarcinoma — Zanetta S Lamar, MD (14:29) Case: A man in his late 70s with metastatic KRAS G12C-mutated rectal adenocarcinoma treated with third-line sotorasib/panitumumab — Georges Azzi, MD (26:03) Cases: A man in his late 50s with KRAS-mutated metastatic colon cancer and very slow disease progression on second-line FOLFIRI/bevacizumab, and a man in his mid 40s with KRAS wild-type metastatic colon cancer and disease progression on third-line treatment — Priya Rudolph, MD, PhD, and Ina J Patel, DO (30:41) Case: A man in his early 80s with right-sided microsatellite-stable (MSS), KRAS G12D-mutated metastatic colorectal cancer (mCRC), tumor mutational burden 10 mut/Mb, currently receiving third-line TAS-102 — Warren S Brenner, MD (37:11) Case: A man in his late 70s with microsatellite instability-high, BRAF V600E-mutated recurrent cecal adenocarcinoma — Nikesh Jasani, MD (50:09) Cases: A woman in her late 50s with MSS BRAF V600E-mutated mCRC with brain and bone metastases who experiences a good response to dose-reduced FOLFOX after disease progression on first-line encorafenib/cetuximab, and a woman in her mid 60s with RAS wild-type, BRAF V600E-mutated, MSS mCRC, now receiving encorafenib/cetuximab after disease progression on FOLFOX/bevacizumab — Farshid Dayyani, MD, PhD, and Dr Azzi (59:05) CME information and select publications

Featuring perspectives from Prof Georgina Long, including the following topics: Introduction: (0:00) Journal Club with Prof Long – Part 1 (7:56) Case: A man in his mid 70s presents with bilateral painfully inflamed red ears and is diagnosed with BRAF V600E-mutated metastatic melanoma — Joanna Metzner-Sadurski, MD (27:19) Case: A man in his early 70s with past medical history of diabetes, hypertension, chronic obstructive pulmonary disease and several skin cancers is diagnosed with BRAF wild-type Stage IIIA melanoma — Helen H Moon, MD (32:52) Case: A man in his late 50s with past medical history of Stage III melanoma and multiple metastatic recurrences responds to single-agent pembrolizumab — Warren S Brenner, MD (43:02) Case: A man in his mid 70s develops metastatic recurrence of melanoma after relatlimab/nivolumab on clinical trial and pembrolizumab therapy for Stage III BRAF V600K-mutated melanoma — Priya Rudolph, MD (50:48) Case: A woman in her mid 30s with a personal and family history of melanoma develops multiple axillary nodes with BRAF-mutated melanoma without a primary lesion — Dr Moon (58:18) CME information and select publications

A new case report was published in Oncotarget's Volume 14 on July 7, 2023, entitled, “Intrathoracic synovial sarcoma with BRAF V600E mutation.” Synovial sarcoma (SS) is a highly malignant mesenchymal tumor that occurs mainly in adolescents and young adults. The treatment of SS is multimodal, involving surgery, radiotherapy and chemotherapy. The overall prognosis is generally quite satisfactory in children and adolescents with localized SS at diagnosis. However, the outcome remains poor for patients who relapse, with a reported 5-year post-relapse survival of around 30%. In this new paper, researchers Ida Russo, Sabina Barresi, Pier Luigi Di Paolo, Valentina Di Ruscio, Giada Del Baldo, Annalisa Serra, Silvia Vallese, Evelina Miele, Angela Mastronuzzi, Rita Alaggio, Andrea Ferrari, and Giuseppe Maria Milano from Italy's Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) report the case of a 15-year-old boy with intrathoracic synovial sarcoma who relapsed after standard chemotherapy, surgery and radiotherapy. The molecular analysis of the tumor identified a BRAF V600E mutation at time of progression of relapsed disease under third line systemic treatment. This mutation is commonly seen in melanomas and papillary thyroid cancers, but less prevalent (typically

Dr. Navneet Singh highlights the latest evidence-based recommendation updates from the ASCO living guideline on stage IV non-small cell lung cancer with driver alterations. This update focuses on new second-line options for patients with advanced NSCLC and an EGFR exon 20 insertion, including amivantamab and mobocertinib. Dr. Singh also discusses updated results from CodeBreaK 200 and the option of second-line therapy with sotorasib for patients with advanced NSCLC and a KRAS-G12C mutation. Read the update, “Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.2” and view all recommendations 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 disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.01055  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 am joined by Dr. Navneet Singh from the Postgraduate Institute of Medical Education and Research in Chandigarh, India, co-chair on “Therapy for Stage IV Non-Small Cell Lung Cancer with Driver Alterations: ASCO Living Guideline, Version 2023.2.” Thank you for being here, Dr. Singh.  Dr. Navneet Singh: Thank you for having me, Brittany. Brittany Harvey: 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. Singh, 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 this living clinical practice guideline, Dr. Singh, this living guideline for systemic therapy for stage IV non-small cell lung cancer with driver alterations is being routinely updated. What new studies were reviewed by the panel to prompt an update to the recommendations in this version? Dr. Navneet Singh: So for this 2023 version 2 update, three trials were included. These include two studies which involved patients with exon 20 insertion mutations, who had received prior platinum-based chemotherapy and subsequently were treated with either amivantamab in the CHRYSALIS trial or with mobocertinib in the EXCLAIM trial. The third trial which formed the basis for this update was one which involved patients with KRAS G12C mutation who had previously received systemic therapy and subsequently were treated with sotorasib. And this was the CodeBreaK 200 trial. Brittany Harvey: Understood. So then, based on these three new trials that you've just mentioned, what are the updated recommendations from the expert panel for patients with advanced non-small cell lung cancer? Dr. Navneet Singh: For patients with advanced NSCLC with an EGFR exon 20 insertion mutation and an ECOG performance status of 0 to 2 who have received prior platinum-based chemotherapy, clinicians may offer amivantamab or mobocertinib as monotherapy. It is important to mention here that in the absence of head-to-head comparison of amivantamab or mobocertinib with each other or with other standard second-line therapies, no recommendation for sequencing can be made and therefore treatment should be individualized. Now, use of either of the two drugs is based on low-quality evidence and has a weak strength of recommendation. And the updates for treating KRAS G12C-mutated NSCLC is largely similar; that patients who have received prior systemic therapy may be offered sotorasib.  Brittany Harvey: Thank you for reviewing those updated recommendations. So what should clinicians know as they implement these new recommendations and how do they interface with the existing recommendations? Dr. Navneet Singh: It is important for clinicians involved in the management of EGFR mutant lung cancer to realize that exon 20 insertions are the third most common group of EGFR mutations and comprise approximately 5% of all EGFR mutations. Now, historically, the EGFR targeted drugs which have been the first, second, or third generation tyrosine kinase inhibitors have largely shown efficacy for the two common types of EGFR mutations, namely the exon 19 deletions and the exon 21 L858R point mutation. Exon 20 insertion mutations thus did not have any effective targeted therapy so far. But now, both of these drugs, amivantamab and mobocertinib, have shown very promising results for pretreated patients with this molecular aberration and therefore may be used in view of standard second line therapy. Similarly, in the case of KRAS G12C mutation, before this, there was no effective targeted therapy, but now sotorasib, based on the CodeBreaK 200 trial, appears to be a very valid option in view of standard second-line therapy.  Brittany Harvey: Excellent. So then, what do these new treatment options mean for patients with stage IV non-small cell lung cancer and an exon 20 insertion or a KRAS G12C mutation?  Dr. Navneet Singh: For patients with stage IV NSCLC and harboring an EGFR exon 20 insertion, the availability of two specific targeted drugs will improve the treatment options available following standard first-line therapy. Furthermore, ongoing trials for these agents in the treatment-naive setting may eventually lead to a scenario wherein such patients may be treated upfront with targeted therapy rather than chemotherapy or chemoimmunotherapy, analogous to how patients with the common EGFR mutations are treated. The ultimate aim of precision medicine is to offer the most effective treatment based on biomarker expression and targeted therapies in comparison to chemotherapy because these lead to better treatment outcomes and lesser side effects. Brittany Harvey: Absolutely. The goal of better outcomes with less side effects is what we're looking to achieve here. So then, finally, as this is a living guideline, what emerging therapies or targets is the panel monitoring for future guideline updates? Dr. Navneet Singh: As was already said, the expert panel eagerly awaits data from ongoing trials which are assessing the efficacy of drugs targeting the EGFR exon 20 insertion mutations, namely amivantamab and mobocertinib as first-line therapy, as also the drugs which target the KRAS G12C mutations which is sotorasib and adagrasib in the treatment-naïve setting. Ultimately, the optimal sequencing of therapies needs to be established in advanced and metastatic non-small cell lung cancer for several of the oncogenic driver alterations other than classical EGFR mutations and ALK and ROS-1 rearrangements. These include the EGFR exon 20 insertions and other uncommon EGFR mutations, the BRAF V600E, KRAS G12C, the HER2, and the MET exon 14 skipping mutations as well as the RET and NTRK fusions.  Brittany Harvey: It sounds like the living guideline expert panel will be busy moving forward then. So I want to thank you so much for your work to update this living guideline and thank you for your time today, Dr. Singh.  Dr. Navneet Singh:  Thank you so much, it was a pleasure being here. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/living-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  

CME credits: 1.00 Valid until: 29-06-2024 Claim your CME credit at https://reachmd.com/programs/cme/axis-nsclc-cme-broadcast-replay/15338/ Capitalizing on the advances in the identification of oncogenic driver mutations, genetic testing, and therapeutic approaches that target actionable mutations, targeted therapies are the current standard of care for eligible patients with advanced non–small cell lung cancer (NSCLC). Many targeted therapies are approved for the treatment of metastatic NSCLC with oncologic therapy decisions based on the presence of mutations and gene rearrangements. The National Comprehensive Cancer Center (NCCN) Clinical Practice Guidelines for metastatic NSCLC outline recommendations for molecular testing, now including EGFR mutation (for examples, exon 19 deletion or L858R), EGFR exon 20 insertion mutation, KRAS G12C mutation, ALK rearrangement, ROS1 rearrangement, BRAF-V600E mutation, NTRK1/2/3 gene fusion, METex14 skipping mutation, and RET rearrangement, along with PD-L1 expression level in patients with advanced or metastatic NSCLC. The development of these newer and other investigational targeted therapies provides unprecedented opportunities for improving outcomes for patients with targetable mutations. This educational activity will address the incorporation of appropriate and timely use of guideline-recommended biomarker testing and optimization of targeted and personalized treatment of patients with NSCLC. =

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        

Featuring perspectives from Dr Michael J Overman, including the following topics: Introduction (0:00) Case: A woman in her mid 40s with microsatellite instability-high (MSI-H) colorectal adenocarcinoma metastatic to the brain receives pembrolizumab; KRAS G13D and somatic BRCA exon 11 mutations — Warren S Brenner, MD (16:27) Case: A woman in her late 50s with MSI-H Stage IIIB adenocarcinoma of the colon, BRAF V600E mutation — Eric H Lee, MD, PhD (23:20) Case: A woman in her early 70s with past medical history of diverticulitis and partial colectomy diagnosed with T1, microsatellite stable (MSS) cecal colon adenocarcinoma, minimum residual disease-negative after resection — Farshid Dayyani, MD, PhD (32:37) Case: A woman in her late 60s with past medical history of hypothyroidism has mass in right lung consistent with colorectal adenocarcinoma but no evidence of primary or other distant disease — Swati Vishwanathan, MD (42:58) Case: A woman in her mid 60s with multiregimen-relapsed RAS wild-type, HER2-positive metastatic rectal cancer, now receiving trastuzumab/tucatinib — Sunil Gandhi, MD (46:51) Case: A man in his mid 60s with MSS metastatic cecal adenocarcinoma and progressive disease on FOLFIRINOX/bevacizumab and capecitabine/bevacizumab maintenance — Dr Brenner (50:13) Case: A woman in her mid 60s with metastatic BRAF V600E-mutant colorectal adenocarcinoma, with circulating tumor DNA positivity after FOLFOX, heated intraperitoneal chemotherapy and colectomy/debulking surgery — Jeremy Lorber, MD (54:31) CME information and select publications

Dr. John Sweetenham and Dr. Neeraj Agarwal discuss advances across the spectrum of malignancies, including key studies in precision oncology and disparities in cancer care in advance of the 2023 ASCO Annual Meeting.  TRANSCRIPT Dr. John Sweetenham: Hello, I'm Dr. John Sweetenham, now the associate director for cancer network clinical affairs at UT Southwestern's Harold C. Simmons Comprehensive Cancer Center, and host of the ASCO Daily News Podcast. I'm delighted to welcome Dr. Neeraj Agarwal, director of the Genitourinary Oncology Program and a professor of medicine at the University of Utah Huntsman Cancer Institute, who is editor-in-chief of the ASCO Daily News.  Today we'll be discussing some key advances across the spectrum of malignancies, as well as novel approaches in precision medicine and cancer disparities that will be 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 podcast can be found on our transcripts at asco.org/DNpod.  Neeraj, it's great to have you back on the podcast today. Dr. Neeraj Agarwal: Thank you so much, John, for having me. Dr. John Sweetenham: Neeraj, let's begin by discussing some practice-changing phase 3 trials, starting with Abstract 5500, the KEYNOTE-826 study. This study reports the final overall survival results from a randomized, double-blind, phase 3 study of pembrolizumab plus chemotherapy versus placebo plus chemotherapy for first-line treatment of persistent, recurrent, or metastatic cervical cancer, which will be presented by Dr. Bradley Monk.  Dr. Neeraj Agarwal: I'd be happy to. The initial analysis of the KEYNOTE-826 study revealed that first-line pembrolizumab plus chemotherapy provided significant improvements in the overall survival and progression-free survival compared to placebo plus chemotherapy in patients with metastatic, persistent, or recurrent cervical cancer who had not previously received systemic chemotherapy and were not candidates for curative treatments such as surgery or radiation. In this study, patients were randomly assigned in a 1:1 ratio to receive pembrolizumab or placebo at 200 milligrams every three weeks for up to 35 cycles, along with chemotherapy with paclitaxel, plus a platinum therapy with or without bevacizumab.   From November 2018 to January 2020, 617 patients were enrolled with 308 receiving pembrolizumab plus chemotherapy and 309 patients receiving placebo plus chemotherapy. At the data cutoff of October 3, 2022, the median follow-up was 39 months. At this protocol-specified final overall survival analysis, pembrolizumab plus chemotherapy treatment continues to show a significant improvement in overall survival and progression-free survival, regardless of whether patients receive bevacizumab or not. The incidence of grade 3 or more adverse events was higher in the pembrolizumab plus chemotherapy arm than the placebo plus chemotherapy arm, with the most common adverse event being anemia, neutropenia, and hypertension. Dr. John Sweetenham: These are exciting data, Neeraj. So the main message from this trial is that pembrolizumab plus chemotherapy, with or without bevacizumab, can now be considered as standard of care for first-line treatment of persistent, recurrent, or metastatic cervical cancer. Dr. Neeraj Agarwal: Yes, I agree, John. Now, moving on to a different common type of cancer, let's discuss Abstract 1001, titled “Second-Line Endocrine Therapy with or without Palbociclib Maintenance in Patients with Hormone Receptor-Positive/HER2-Negative Advanced Breast Cancer: Results from the PALMIRA Trial,” which will be discussed by Dr. Antonio Llombart-Cussac. So, John, based on this abstract, can you please tell us about the role of palbociclib after prior progression on this drug? Dr. John Sweetenham: Yes. In this study, the authors aimed to determine if palbociclib maintenance with an alternative endocrine therapy improves the anti-tumor activity of second-line treatment in patients with endocrine-sensitive hormone receptor-positive and HER2-negative advanced breast cancer who had disease progression to first-line treatment with palbociclib in combination with endocrine therapy. After including 198 patients in the trial with a 2:1 randomization, 136 patients received palbociclib with endocrine therapy and 62 patients received endocrine therapy alone. And at a median follow-up of 8.7 months, the primary endpoint of progression-free survival was not met with a median progression-free survival of 4.2 months in the palbociclib-containing combination versus 3.6 months in the control arm. Also, higher grade 3 to 4 adverse events were reported in patients treated in the palbociclib arm. Dr. Neeraj Agarwal: Thanks, John. So you are saying that continuing the CDK4/6 inhibitor palbociclib after prior disease progression on palbociclib, even when the primary endocrine therapy has been changed, doesn't seem to be beneficial, therefore, this practice may be discouraged in the clinical setting? Dr. John Sweetenham: Yes, that's correct. Neeraj, I think that's the conclusion from this study. Dr. Neeraj Agarwal: So, John, now let's switch gears and highlight some precision oncology studies.  Dr. John Sweetenham: Well, Abstract 3602, titled “Real World Rates of FDA-Approved Targeted Therapy and Immunotherapy Prescriptions for Metastatic Colorectal Cancer Patients in the VA's National Precision Oncology Program” will be presented by Dr. Alice Nono Djosta. Can you tell us more about this abstract, Neeraj? Dr. Neeraj Agarwal: Well, comprehensive genomic profiling has the potential to guide the administration of FDA-approved biomarker-directed therapies and improve outcomes among patients with metastatic colorectal cancer. So, in this study, Abstract 3602, investigators sought to determine the rates of actionable biomarkers and prescription of associated FDA-approved therapies among veterans in the National Precision Oncology Program. Patients with metastatic colorectal cancer who had undergone comprehensive genomic profiling via tissue or liquid biopsy were included between 2019 and 2022 and had 1 of the following 5 actionable biomarker profiles including: NRAS, KRAS, BRAF wild-type, BRAF V600E mutation, MSI-high, TMB-high, NTRK fusion or rearrangements.  Prescription data for seven FDA-approved biomarker-directed therapies were extracted and rates of comprehensive genomic profiling (CGP)-directed therapy prescriptions were assessed by the investigators. A total of 908 patients with metastatic colorectal cancer underwent comprehensive genomic profiling, with 80% patients having colon adenocarcinoma and 20% with rectal adenocarcinoma. The combined rates of any actionable variants were 47% in patients with colon adenocarcinoma and 45% in patients with rectal adenocarcinoma. After including 424 eligible patients for FDA-approved biomarker therapy, only 70% patients with MSI-high, 48% patients with TMB-high, 38% patients with NRAS, KRAS, and BRAF wild-type, and only 17% of patients with BRAF V600E mutation received FDA-approved CGP-directed therapies.  Dr. John Sweetenham: Very important data, Neeraj. What's the main conclusion of this study? Dr. Neeraj Agarwal: So, in conclusion, this study found that almost 30% of patients with MSI-high metastatic colorectal cancer did not receive effective immune checkpoint inhibitors. And overall, a significant number of eligible patients did not receive FDA-approved biomarker-directed therapies. So, it is crucial that we evaluate the barriers to prescribing comprehensive genomic profiling-directed therapies in our patients with metastatic colorectal cancers.  So, John, let's move on to lung cancer, where the use of single-gene testing is still common in the community practice. Can you please tell us about Abstract 6506, titled “The Impact of Single-Gene Testing on Subsequent Comprehensive Genomic Profiling Success in Community Oncology Practice for Advanced Non–small Cell Lung Cancer”? These are results from a prospective observational reference laboratory testing program and these results will be presented by Dr. Mary Nesline. Dr. John Sweetenham: Yes, definitely. In this study, researchers aim to investigate the impact of prior single-gene testing on comprehensive genomic profiling success and therapeutic opportunities for patients with non–small cell lung cancer in community settings. They included patients who underwent at least 1 single gene testing for guideline recommending genomic variants in non–small cell lung cancer such as BRAF, EGFR, KRAS, MET exon 14 skipping mutations, ALK, RET, and ROS1 rearrangements as well as PD-L1 immunohistochemistry.  And they offered comprehensive genomic profiling either before or after receipt of a negative single gene test. Of 580 patients with non–small cell lung cancer with the comprehensive genomic profiling ordered between 2021 and 2022, around 30% of the patients had at least 1 single-gene testing ordered prior to the comprehensive testing, with a median of 5 prior single-gene tests. Compared to CGP-only cases. CGP per cases with prior negative single gene testing was canceled twice as often at tissue review, had a higher DNA extraction failure, and a lower DNA sequencing success. CGP also identified guideline-recommended variants in genes with no single-gene testing offered during the study period, such as ERBB2 mutations, or NTRK2/3 fusions, as well as variants targeted in ongoing clinical trials in 28% of patients. Dr. Neeraj Agarwal: Very interesting. So John, what is your key takeaway message from this? Dr. John Sweetenham: The main message is that in a community oncology setting, the practice of ordering single gene testing prior to comprehensive genomic profiling for patients with non–small cell lung cancer is common. Prior negative single-gene testing led to a higher rate of CGP test cancellation due to tissue insufficiency and increased CGP DNA extraction failures. The practice of single-gene testing does not align with practice guideline recommendations and may negatively impact the potential benefits of CGP testing for patients with non–small cell lung cancer.  Now, let's move on to another important abstract that our fellow clinicians should hear about. This is Abstract 1534 titled “Real-World Experience of an In-House Dihydropyrimidine Dehydrogenase Genotype Test to Guide Fluoropyrimidine Dosing at a Multi-Site Cancer Hospital” that will be presented by Dr. Jai Patel. Can you tell us more about this abstract, Neeraj? Dr. Neeraj Agarwal: Sure. Fluoropyrimidines, such as 5-fluorouracil and capecitabine, are commonly used to treat solid tumor cancers such as gastrointestinal and breast cancers. We know that severe toxicity occurs in one-third of patients, which delays the timely completion of treatments and result in prolonged hospitalization of these patients. These toxicities may be due in part to genetic variation in the DPYD gene. Five variants are known to have moderate to strong evidence according to the Clinical Pharmacogenetics Implementation Consortium. So, in this observational study, the authors describe the implementation of an in-house DPYD test and its impact on the dosing of these fluoropyrimidines, which include capecitabine and 5-fluorouracil.  From March 2020 to December 2022, 491 patients received DPYD genotyping testing, and 90% of them had gastrointestinal cancers. The median lab turnaround time was only 3 days. Pre-treatment testing was ordered in 80% of patients, and 93% of patients had results before starting cycle 1. Overall, 6% of patients were heterozygous carriers. Fluoropyrimidine dose was reduced, avoided, or discontinued in 90% of these patients. Moreover, in pre-treatment carriers, 90% of patients received an upfront dose reduction, avoidance, or they even declined chemotherapy. Dr. John Sweetenham: Thanks, Neeraj. So what do you think is the key takeaway message here? Dr. Neeraj Agarwal: So, DPYD genotype-guided dosing of fluoropyrimidine, including 5-fluorouracil and capecitabine, is logistically feasible with a rapid turnaround time and can result in treatment dose modifications for most carriers, potentially avoiding or mitigating severe toxicities, especially in those patients who received pre-treatment testing. Dr. John Sweetenham: Thanks again. Now let's transition to studies that focus on disparities in cancer care. Dr. Neeraj Agarwal: Definitely. Let's discuss Abstract 6530, titled “Impact of Free Hospital-Provided Rideshare Service on Radiation Therapy Completion Rates: A Matched Cohort Analysis.” In this study, Dr. Eric Chen and colleagues assess the potential of rideshare services in facilitating timely radiation therapy for patients facing barriers, such as limited transportation, financial constraints, and lack of adequate social support. So the authors analyzed data from about 2,900 patients who underwent radiation therapy and found that 58 of them utilized a free hospital-provided rideshare service.  These free hospital-provided rideshare service utilizers had a lower median age and were more likely to identify as Black or African American compared to those who did not utilize these services. They also had higher socioeconomic disadvantages and traveled shorter distances for treatment. Interestingly, more rideshare utilizers underwent radiation therapy with curative intent, had longer treatment course duration, and a higher number of fractions prescribed. In the matched-cohort analysis, the study found that radiation therapy completion rates were significantly higher for rideshare utilizers compared to non-rideshare utilizers, especially for patients who were undergoing radiation therapy with curative intent.  Dr. John Sweetenham: So what's the key take-home message from this abstract? Dr. Neeraj Agarwal: This study highlights the potential benefit of utilizing hospital-provided free ride-share services, particularly for patients facing barriers to timely treatment. So, using these services were associated with higher radiation therapy completion rates, especially in the curative setting.  So, John, there is another study, Abstract 1606, titled “Trends and Disparities in Oncology Telehealth after the Initial Pandemic Era” that will be presented by Dr. Michael Lee and colleagues. They evaluated whether telehealth utilization continued after the pandemic and if demographic differences in its users persist. So John, please tell us more about this abstract. Dr. John Sweetenham: Yes, the authors conducted a retrospective cohort study in 22 Kaiser Permanente Northern California hematology and oncology clinics between October 1, 2020, and June 1, 2022. The study investigated the use of office, video, and telephone visits, analyzing more than 340,000 hematology oncology visits with MD or DO providers. Of these visits, 25% were in-office, 37% were video visits, and 39% were telephone visits. Monthly telehealth visits peaked in January 2021, representing around 86% of total visits, and decreased to 69% of the total visits by June 2022. Video visits were more common for new appointments, whereas telephone visits were more common for return appointments. Moving to the post-pandemic period, telehealth visits remained popular, with video visits being the most commonly utilized. However, telehealth use varied among demographic populations. Video visits were a significantly higher proportion of all visits among individuals less than 45 years old, primary English speakers, patients with commercial insurance, non-Hispanic Whites and Asians, compared with Hispanic, Whites, and Blacks, and patients living in the deprived neighborhoods. Dr. Neeraj Agarwal: Interesting data, John. So what is the key takeaway message from this abstract? Dr. John Sweetenham: Well, overall, it's encouraging to see that even after the pandemic, telehealth continued to be widely used. However, the concerning issue is that telehealth is less utilized in patients who may need it most. The next step, in my view, will be to work on barriers to access telehealth by underprivileged populations.   And that brings our discussion to a close today. Before we wrap up the podcast, Neeraj, do you have any final thoughts to share? Dr. Neeraj Agarwal: Yes, thanks, John. I would urge our listeners to come and join us at the ASCO Annual Meeting, not only to celebrate these successes but also to help disseminate these cutting-edge data to practitioners and patients across the world. Dr. John Sweetenham: Absolutely. I'd like to thank our listeners for joining us today, and thank you, Neeraj, for sharing your insights with us as well.  You will find links to the abstracts discussed today on the transcripts of this episode. Finally, if you value the insights that you hear on ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts.  Disclaimer:  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.  Find out more about today's speakers: Dr. John Sweetenham Dr. Neeraj Agarwal @neerajaiims Follow ASCO on social media:   @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn   Disclosures: Dr. John Sweetenham: Consulting or Advisory Role: EMA Wellness Dr. Neeraj Agarwal:  Consulting or Advisory Role: Pfizer, Bristol-Myers Squibb, AstraZeneca, Nektar, Lilly, Bayer, Pharmacyclics, Foundation Medicine, Astellas Pharma, Lilly, Exelixis, AstraZeneca, Pfizer, Merck, Novartis, Eisai, Seattle Genetics, EMD Serono, Janssen Oncology, AVEO, Calithera Biosciences, MEI Pharma, Genentech, Astellas Pharma, Foundation Medicine, and Gilead Sciences   Research Funding (Institution): Bayer, Bristol-Myers Squibb, Takeda, Pfizer, Exelixis, Amgen, AstraZeneca, Calithera Biosciences, Celldex, Eisai, Genentech, Immunomedics, Janssen, Merck, Lilly, Nektar, ORIC Pharmaceuticals, Crispr Therapeutics, Arvinas

Dr. Shaalan Beg and Dr. Mohamed Salem discuss novel therapies in gastrointestinal cancers, including CAR T therapy and the CodeBreak-101 trial in mCRC, new advances in uHCC in the HIMALAYA trial, and an exciting update from the NAPOLI-3 trial in pancreatic cancer, ahead of the 2023 ASCO Annual Meeting.  TRANSCRIPT Dr. Shaalan Beg: Hello, and welcome to the ASCO Daily News Podcast. I'm Dr. Shaalan Beg, your guest host of the podcast today. I'm the vice president of oncology at Science 37 and an adjunct associate professor at UT Southwestern Simmons Comprehensive Cancer Center. My guest today is Dr. Mohamed Salem, a GI oncologist at the Levine Cancer Institute at Atrium Health. We'll be discussing key posters and oral abstracts in GI oncology that will be 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 podcast can be found in our transcripts at asco.org/DNpod. Mohamed, thanks for coming on the podcast today.  Dr. Mohamed Salem: Thanks, Shaalan.  Dr. Shaalan Beg: There's some interesting studies in colorectal cancer that I'd like to get us started with today. Abstract 3547 is titled “A Phase I Dose-escalation Study of GCC19 CAR T: A Novel Coupled CAR Therapy for Patients with Metastatic Colorectal Cancer.” What are your thoughts on the study? Dr. Mohamed Salem: Actually, this was a very exciting study to see coming out in GI cancer, especially colorectal cancer. As you know, CAR T made its way to the treatment of lymphoma and other heme malignancies. In fact, we saw a fascinating response and outcome using that technique and that niche in the immunotherapy module. The challenge we had was that we could not replicate this in solid tumors until very recently. I'm sure you had the same thing in your clinic, too. A lot of patients with GI cancer or colorectal cancer come to you and say, "Okay, why can't I have CAR T?" And the response was, "We don't know if it's effective or if it's going to work yet." Here at our center, we had a phase 1 study, I think that was looking also at CAR T and solid tumors, particularly prostate cancer. So that I think was very exciting to see that technology is making its way to the solid tumor. I was very pleased to see this CAR T study coming out from the work of our Chinese colleagues looking into this in the CRC space.  Obviously, as you know, in colorectal cancer, we made a significant advancement, but I don't think we made enough advancement yet, and especially for refractory patients, patients with refractory disease who have underwent multiple lines of therapy. And this study actually addressed the need for those patients. So in this study, that was a phase I escalation dose, very much is we looked at about 13 patients who had metastatic CRC, they had at least two lines of therapy. So in what we say is a "refractory setting," unfortunately for those patients, we don't have large treatment options. And they used two doses, the first dose and the second dose that was a little bit higher. And the interesting part is that they were able to see very nice responses on this patient population. In the lower dose, I think the response was the PFS was about 1.9 months. But when they went up on the dose, actually the PFS was 6.3 months, which I think in the refractory setting is very meaningful.   And also the median overall survival for the first group was 13 months, which in the refractory setting is something we don't see often, and the higher dose was 18 months, which was even better. So there was a trend that higher doses are perhaps more effective or have better efficacies than lower doses, but also in terms of side effects, actually patients were relatively able to tolerate it well, and there were no surprising adverse events. So again, yes, that's 13 patients in total. So it's a very small study, but like everything else, the proof of concept sometimes is the first step and it's very important to see that data to suggest that this technology now can be utilized in solid tumors and CRC, especially now there is an unmet need for those patient populations. I'm sure you and I will see a lot of patients at the clinic with good progress status, and just looking for the next option, and I'm glad to see that. Hopefully, we can continue to build on that work.  Dr. Shaalan Beg: Another key abstract in colorectal cancer is Abstract 3513, the CodeBreak 101 study. This is a phase 1b safety efficacy trial of sotorasib plus panitumumab and chemotherapy with FOLFIRI for previously treated KRAS-G12C mutated colorectal cancer. And this is a really important study because even though KRAS-G12C represents a minority of KRAS mutated colorectal cancer, we know that this treatment can cause meaningful improvement in disease for other cancers like non-small cell lung cancer. And when sotorasib was tested as monotherapy in colorectal cancer, it saw an objective response rate of 9.7% that increased to 30% when added to panitumumab.   So in this trial, they took sotorasib plus panitumumab and added it to chemotherapy to see how it's tolerated and what its effectiveness is going to look like. And they enrolled people who had more than one or more lines of prior therapy for metastatic disease. They treated 33 patients. The most common side effect was dermatologic, which is probably related to EGFR-based therapy, and they saw a confirmed overall response rate of 58%. Side effects are those that we look to expect with this specific regimen. I don't see any additional safety concerns here, but this can be a big step forward for KRAS-G12C-altered colorectal cancer. What do you think? Dr. Mohamed Salem: I totally agree. And again, it was very exciting to see that abstract and that result. I totally believe now, and I'm sure you would agree with me too, Shaalan, that we're moving from an era of one size fits all to a precision oncology and tailored treatment. And the fact now we have a treatment option for patients with a KRAS mutation is very exciting because before, we didn't have much that we can do about that mutation. So now it's not just a proof of concept. Now you're hitting that target with the chemotherapy and you're getting a 50% response rate. That's something interesting also to see for this patient population and as you highlighted as safety also, and the adverse event was not high and patients were able to tolerate it, which makes it more doable for us to use it. Dr. Shaalan Beg: Yeah. And one of the challenges in the precision oncology space, which I'm sure you're experiencing in clinic as well, are the real-world applications of precision oncology and the drop-offs that happen that are preventing us from universal precision oncology - meaning the drop-offs that we see on eligible patients receiving the appropriate genomic testing, those who have genomic testing receiving the appropriate treatment. And we've seen a couple of fairly high-profile studies that are describing this in non-small cell lung cancer where the rates are not as encouraging as we would want it to be, which to me, as a physician, makes me worried that there are people out there who we don't know are carrying these mutations or have these mutations, and it hasn't been acted upon.   And related to that, there is an abstract at ASCO23, which is Abstract 3602, that looked at the real-world rates of FDA-approved targeted therapy and immunotherapy for people with metastatic colorectal cancer. They used the VA's National Precision Oncology Program data to study the prevalence of these mutations and how many of the folks ended up receiving the treatment that would be appropriate for those mutations. And this is a very exciting study. They looked at 908 metastatic colorectal cancer patients who underwent genomic profiling, 81% were colon and the rest were rectal. They found that 34% of patients harbored NRAS, KRAS, BRAF mutations, 9.6% were TMB-high, 7.7% had BRAF V600E, and 5.6% were MSI-high, which kind of puts the overall actionable variant prevalence in colon cancer at 47% and for rectal cancer at 44%.  And then they went down to see amongst those 424 eligible patients, how many ended up on appropriate therapy. And these were their numbers: for MSI-high 70%, TMB-high 47%, NRAS, KRAS, BRAF, wild-type 38%, BRAF V600E 17%. So nearly 30% of patients with MSI-high colorectal cancer did not receive immune checkpoint inhibitor therapy, and again, other aspects in terms of EGFR use, and I know that there are other challenges that may affect the use of EGFR inhibitors in colorectal cancer, but it really begs the point on aspects related to implementation science, on getting the testing and acting on those results. And I'm curious to what you're seeing that's being done on these initiatives nationally.  Dr. Mohamed Salem: I totally agree with you, Shaalan. This is a big problem we're facing day in and day out because we struggle to find treatment options for our patients. And I think if we're missing patient with targetable or actionable mutations and we're not utilizing that, I don't think that's a good situation to be in. And I think that's just a group effort. You have to work with the pathologist, you have to work with your team at the clinic. And as an oncologist treating this patient, we have to pay close attention to those markers. And frankly, just look for them. At least  the ones that you know are going to have therapeutic implications.  I do also think patient advocacy has a huge role here and huge opportunities that they can contribute. I am sure you are familiar with the pancreatic study that was published by our colleague Mike Pishvaian in Lancet a year or two ago. I think he named it the Know Your Tumor Type. I think that should be the way forward now, not just for pancreatic but for any cancer. Patients should ask their oncologists what my tumor is. Is it MSI-high, is it KRAS-G12C, is it BRAF? Because it will affect the treatment. I think it's multi-layer and all of us should work in a cohesive manner to be able to not ever miss those markers which carry therapeutic potential.   Dr. Shaalan Beg: So moving on to hepatocellular carcinoma, Dr. George Lau and colleagues, they'll be sharing data from the phase 3 HIMALAYA study with hepatocellular carcinoma in the Annual Meeting that's Abstract 4004. And he looked at outcomes by occurrence of immune-related events for people who received tremelimumab and durvalumab. What are your thoughts on this study?  Dr. Mohamed Salem: This was a very interesting abstract to see. For a long time, we didn't have many treatment options in hepatocellular carcinoma. So, over the last two or three years now, I think we've made nice advancements in the therapeutic landscape. So, we have multiple options including immunotherapy which is very exciting for all of us to be able to utilize those powerful drugs in that disease. The question that comes out is who actually responds? Obviously, in HCC you don't have a lot of biomarkers like the immune therapy biomarkers like MSI-high and PDL-1, and TMB. It isn't really playing a huge role in HCC. So, as you know, the HIMALAYA study is a phase 3 study and examined the STRIDE regimen which is treme plus durva in the first line of patients with metastatic or unresectable HCC against sorafenib. And the outcome was in favor of the STRIDE regimen with improvement in OS response rate and duration of response and because of that, it became one of the standards of care for that disease. But Abstract 4004 is actually asking a very interesting question - whether immune-related adverse events can predict outcomes. Meaning like those patients who experience immune-related adverse events will likely do better compared to those patients who didn't experience immune-related adverse events or not. The idea of adverse events as a biomarker if you will, for efficacy is not new. I mean we saw that back in the renal carcinoma TKI, hypertension. People who had hypertension were more likely to have a better response. In the GI also there was some data suggesting that rash might be a biomarker in predicting response to EGFR. So the same question we're applying here - immune-related adverse events can function as a biomarker for efficacy for the immune system.  And there are some data out there in other tumors that may be the case, but I think at least to my knowledge in the HCC or GI, this was the first study to address that question. So just to remind our audience that the HIMALAYA was a phase 3 study using the STRIDE regimen as a frontline for patients with hepatocellular carcinoma, either unresectable or metastatic disease. And they compared the STRIDE which is durva-treme compared to the standard of care at that time was sorafenib. The primary endpoint was overall survival and they had secondary endpoint duration of response, response rate, and obviously adverse event.  The study was positive, it met its primary endpoint and OS was in favor of the STRIDE regimen compared to sorafenib. But that part of the abstract now is focusing mainly on those patients who had immune therapy and whether that was a STRIDE regimen or the third arm that durva alone treatment. And they're looking at those patients who had immune-related adverse events, and those who didn't have immune-related adverse events. So basically four groups of patients, the patient who had a STRIDE regimen, about 139 patients had immune-related adverse events, and about 249 didn't have immune-related adverse events. For the cohort who had durva alone, about 64 patients had immune-related adverse events, almost 300 patients had no immune-related adverse events.  And it was very interesting that at least in the STRIDE arm, those patients who experienced immune-related adverse events, their outcome was better than those patients who did not have immune-related adverse events. It's the same trend seen on the durva alone arm, but I think the number was very small to make a statistical value out of it. But I think at least in the STRIDE arm there was a suggestive trend toward the outcome of those patients who experienced immune-related adverse events. So I think this is in a way very interesting because we're always wondering if we give the same dose at least in immunotherapy like for everyone.   What I was wondering is if it's too much, too little, or just right. It's hard to know for sure. But perhaps in my opinion and just me trying to understand why, in my theory, maybe that's just an indication of patients receiving enough drugs and effective drugs that will translate into efficacy. But at the same time, I also wanted to just put a word of caution here because we don't want to see side effects as a good thing. I think we want to make sure that us as oncologists treating these patients and patients also don't see like it's good to have a side effect. Side effects associated with especially those grade 3 or 4 can be associated with significant problems and decreased quality of life. So, definitely should be looking at those side effects and be careful interpreting those data. But I think that is very interesting and I will look for more work on that.   Dr. Shaalan Beg: Let's move on to pancreatic cancer. We heard the results of the NAPOLI-3 clinical trial at GI ASCO and this year in ASCO 2023 we will hear the results of Abstract 4006 by Dr. O'Reilly that are presenting results of the 12 and 18-month survival rates from the study that compared NALIRIFOX or nano-liposomal irinotecan, 5-fluoro/leucovorin, and oxaliplatin versus nab-paclitaxel/gemcitabine for newly diagnosed pancreatic cancer patients. I'm interested to hear what you think about that study. Dr. Mohamed Salem: Thank you, Shaalan. So this also is a very exciting abstract to see, and anyone who treats pancreatic cancer patients realizes that, unfortunately, even in 2023, we don't have a lot of treatment options. And yes, I think over the last decade we're now talking about second-line and third-line, but yet we still don't have a lot of treatment options. So, having more options is always good. But the question now is how do you sequence those chemotherapy options? Most of us obviously use FOLFIRINOX in the first line or gemcitabine and paclitaxel in the first line. Until very recently– because we didn't have a head-to-head comparison– we couldn't tell patients for sure if one is better than the other. I think we had some assumptions, but it wasn't really proven. It was just a cross-trial comparison.  So, the fact is that now we have that phase 3 trial looking at liposomal irinotecan, 5-fluoro/leucovorin and the oxaliplatin comparing to nab-paclitaxel/gemcitabine. To me, that was actually very exciting because now, at least, I can see a triplet chemotherapy drug compared to a doublet chemotherapy drug. And as you mentioned, Shaalan, the first initial read was positive in favor of the triplet regimen compared to the doublet, which I think was an important message to give to our colleagues and all of us that if you can, obviously, the triplet comes with side effects, but if you can deliver the triplet, that's perhaps a better starting point for the treatment. But the study here, we're trying to get more read after more mature or more time-lapsing. So the initial study was initial read was positive. And I think this is good to see, too because it translates that even with a longer follow-up, we're still seeing the same benefit. So the OS rate in 12 months for the triplet was about 45% compared to 39.5% for the doublet, and the 18 months, a year and a half, was 26% compared to 19%. So, definitely, you can see an improvement in every single endpoint. OS in general was 11.1 months compared to 9.2 months, and PFS was also in favor of the triplet. So I think it's a message here to reinforce what we saw a few months ago in the initial presentation that, in fact, the triplet is associated with better outcomes if you can safely manage the toxicity and guide the patient through the process. Dr. Shaalan Beg: Well, thank you very much, Mohamed. This was a lot of fun. Thanks for sharing your valuable insights with us on the ASCO Daily News Podcast. Dr. Mohamed Salem: Thank you for having me and looking forward to the full presentation at the meeting. And please, if you haven't registered for the meeting yet, make sure you attend. It's a wonderful opportunity to learn from an expert in the field and also meet your colleagues and make new friends. I also want to take this opportunity to thank the ASCO Daily News Podcast team for taking the time, and also for our colleagues who reviewed these abstracts. This takes a lot of time and effort, and I think they're doing a wonderful job. So, thank you to all of them, and I'll see you all at ASCO.  Dr. Shaalan Beg: And thank you to our listeners for your time today. You'll find links to the abstracts discussed today in the transcript of this episode. I'll be back to cover late-breaking abstracts and other key advances in GI oncology after the annual meeting, so please join us for more key insights from ASCO 23 on the ASCO Daily News Podcast.  Finally, if you value the insights that you hear on the podcast, please take a moment to rate, review, and subscribe wherever you get your podcast.  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, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.   Find out more about today's speakers: Dr. Shaalan Beg @ShaalanBeg Dr. Mohamed Salem @SalemGIOncDoc   Follow ASCO on social media: @ASCO on Twitter  ASCO on Facebook  ASCO on LinkedIn   Disclosures:  Dr. Shaalan Beg: Consulting or Advisory Role:  Ispen, Cancer Commons, Foundation Medicine, Genmab/Seagen Speakers' Bureau: Sirtex Research Funding (An Immediate Family Member): ImmuneSensor Therapeutics Research Funding (Institution): Bristol-Myers Squibb, Tolero Pharmaceuticals, Delfi Diagnostics, Merck, Merck Serono, AstraZeneca/MedImmune  Dr. Mohamed Salem: Consulting or Advisory Role: Taiho Pharmaceutical, Exelixis, Bristol-Myers Squibb, Exelixis, QED Therapeutics, Novartis, Pfizer, Daiichi Sankyo/Astra Zeneca Speakers' Bureau: Genentech/Roche, Taiho Pharmaceutical, Daiichi Sankyo/Astra Zeneca, BMS, Merck

Dr. Diwakar Davar and Dr. Jason Luke discuss advances in melanoma, including targeted therapy and the addition of LAG-3 inhibitors to checkpoint therapy, as well as promising checkpoint inhibitors in cutaneous squamous cell carcinoma and Merkel cell carcinoma in advance of the 2023 ASCO Annual Meeting.  TRANSCRIPT Dr. Diwakar Davar: Hello, and welcome to the ASCO Daily News Podcast. I'm your guest host, Dr. Diwakar Davar, and I'm an associate professor of medicine and the clinical director of the Melanoma and Skin Cancer Program at the University of Pittsburgh's Hillman Cancer Center. I'm delighted to welcome my colleague and friend, Dr. Jason Luke. Dr. Luke is an associate professor of medicine and the director of the Cancer Immunotherapeutic Center at the University of Pittsburgh's Hillman Cancer Center. He is a very, very well-renowned physician-scientist who has done fundamental work in developmental therapeutics and also in melanoma.  Today, we'll be discussing some key oral abstracts highlighting advances in immunotherapy in the cutaneous malignancy space that will be featured at the 2023 ASCO Annual Meeting.   You will find our full disclosures in the transcript of this episode and the disclosures of all guests on the ASCO Daily News Podcast are available in our transcripts at asco.org/DNpod.  Jason, thank you for coming on the podcast today. Dr. Jason Luke: Well, thanks so much for the opportunity. Dr. Diwakar Davar: So, we will go right ahead into the abstracts and the first one we thought we'd discuss is Abstract 9502, which is the RELATIVITY-047 study, specifically the 2-year results. This is the update. This has also been concurrently published at the New England Journal of Medicine Evidence online. And so in this publication and oral presentation, Hussein Tawbi, Georgina Long, and colleagues are talking about the nivo-rela data in the context of metastatic melanoma. So what is your take on this? What is your take on the data both presented and published and how would you contextualize this for the audience? Dr. Jason Luke: Right, so the RELATIVITY-047 study, as people will remember, randomized treatment-naive patients with metastatic melanoma to either receive nivolumab as standard treatment as a monotherapy or the combination of nivolumab and the anti-LAG-3 antibody relatlimab. And that study reported out a couple of years ago showing the improvement in progression-free survival as the primary endpoint. And at the time we saw that difference was approximately a 6-month absolute difference. And eventually, we saw there was an increase in the overall response rate also, again, approximately on the order of about a 10% change. What was interesting was that the overall survival initially was immature and that was an interesting follow-up point that we wanted to see. So I think what's important in seeing now this 2-year update of these data are the maintenance of the benefit for nivolumab plus relatlimab as compared to nivolumab alone across those measurements of progression-free survival and overall response rate.  Interestingly, the overall survival in the clinical trial actually did not meet the pre-specified threshold for statistical significance. That being said, when you look at the data presented in the Kaplan-Meier plots and you think about the difference, it really does appear that there's a clinically meaningful difference between these 2 groups. And the statistical cut point only missed by about .01. And so this is one of those areas where one wonders whether or not subsequent therapies may have impacted on the overall survival calculation because obviously, patients in this trial had not received ipilimumab or a PD-1 CTLA-4 combination. So the take-home message from me in this data set was that the benefit of nivolumab and relatlimab was sustained over time and there was no suggestion of any late toxicities that might make us concerned.   One advantage of this combination of nivolumab and relatlimab is the dramatically improved side effect profile relative to nivolumab and ipilimumab. So whereas immune-related adverse events that were serious, grade 3-4 is approximately 50% for nivolumab and ipilimumab, in the RELATIVITY-047 study, we see that the incidence of grade 3-4 toxicities for nivolumab and relatlimab is 17.2%, so that's less than half. So that's pretty attractive. And when we think about frontline management of patients, I think these data really support that nivolumab plus relatlimab is a reasonable consideration for some patients. And now I think the future question is really going to be, okay, well then who should get nivolumab and relatlimab versus who should still get nivolumab plus ipilimumab? Obviously, these data do not address that, and I think that that's probably the most important question for metastatic disease that's probably on the horizon. Dr. Diwakar Davar: Thank you, Jason, those are all fantastic points. It is interesting to note that as a result of the data, or really the lack thereof, the combination is actually not being launched in certain countries. So, for example, the German Health Authority, GBA, the Federal Joint Committee in Germany has decided against the acceptance of this agent because it does not accept event-free survival (EFS) as a patient-relevant endpoint. So it's interesting that we have an agent that is now going to be FDA-approved. It's already FDA-approved and available in the United States, but it will not be at least available in Germany and there may be other countries that decide favorably or unfavorably depending on how this OS data is viewed.   So pivoting to another LAG-3 inhibitor in this case fianlimab, we're going to discuss Abstract 9501. So Abstract 9501 essentially is describing a phase II trial that evaluated the LAG-3 inhibitor, fianlimab, along with the anti-PD-1 inhibitor, cemiplimab from Regeneron. The data is slightly different from what we have seen with RELATIVITY-047, the Opdualag combination. So Jason, how would you contextualize the fian-cemi combination in advanced melanoma in the context of what we've seen with RELATIVITY-047? If you could help us with that, please. Dr. Jason Luke: Yeah, absolutely. So before we dive into this specific abstract, it's, like you mentioned, probably useful to just put all of this in context. Targeting LAG-3 as an immunomodulatory approach has actually been in clinic for a decade approximately. And so the relatlimab phase 1 started quite a long time ago. And there was data for nivolumab and relatlimab in PD-1 refractory patients with melanoma that showed not a tremendously obvious level of activity. And so it was thought there that the only place they would see that activity was to go to a frontline randomized phase 2 and then phase 3 trial, as we just discussed.  In contrast to that, given all the data that had come forward about LAG-3 targeting with relatlimab, the group developing fianlimab took a different approach and rather treated a cohort of patients with treatment-naive melanoma to try to get an initial assessment right away of the activity as read out by overall response rate for this PD-1 plus LAG-3 combination, which is cemiplamab plus fianlimab.   And these authors have previously presented data about this combination from cohorts of patients who are treatment-naive who received this combination and described approximately a 64% overall response rate. And that's an impressive number in the treatment-naive setting. There's sort of a tension there to sort of say, well, wait a minute, the response rate in this single-arm study is 64%, but in RELATIVITY-047, the response rate was lower for the LAG-3 combination and I think that's not a fair comparison. We have to realize this is a much smaller group of patients that has the potential to have been somewhat biased towards a better cohort just because of where and when they were recruited to participate in this trial. All the same, I think that number does look impressive and suggest that this combination is active in the frontline.   Specific to this abstract, though, what the authors presented here was to update those previous data and then specifically also to focus on a cohort of patients who are allowed to have had previous treatment in the perioperative setting. So either neoadjuvant or adjuvant therapies. And in a subgroup of patients, they observed that even in the patients that had received adjuvant anti-PD-1 who went on to then progress later, they got actually a similar overall response rate at approximately 60% even in that group. And so I think that that seems like an exciting number as well. One would on first principles think that if patients got an adjuvant anti-PD-1, then a PD-1 LAG-3 combo could be less active. When and how the patients progressed or did not on that adjuvant therapy, however, I think makes a big difference. And given the relatively small sample size of patients that were included in this report, which is on the order of 20-ish patients who were in the previous PD-1 treated adjuvant cohort, I don't know that we can make super broad analyses trying to compare across the development programs.  What I would take from this abstract, however, is that it does appear that this other PD-1 LAG-3 combination cemiplamab plus fianlimab is also very active and certainly deserves to be investigated in similar clinical trial contexts as the nivolumab plus relatlimab combination that we previously discussed. And while it's not specifically stated here, that is happening, there is a frontline phase 3 trial for this combination of fianlimab and cemiplamab as well as adjuvant considerations, also ongoing. Dr. Diwakar Davar: So, thank you. We've seen a lot of LAG-3 data this last 2 months, the phase 2/3a RELATIVITY-020 trial has just been published in the JCO, I encourage people to read that. And so that was the evaluation of nivolumab and relatlimabin the post-PD-1 patient population that Jason alluded to, where the response rate that was observed was 12%. So we've seen a lot of interesting data, a lot of interesting survival data, and now a new potential combination with LAG-3 with fianlimab and cemiplamab from Regeneron. So it'll be a very interesting next couple of years as we see whether or not this new combination, how it shakes up against the established nivu-rela combination, again, albeit with the limitations of cross-trial comparisons and also how it performs against cemiplamab in this ongoing, as you alluded to, ongoing global phase 3 trial.  So, pivoting away from melanoma, now addressing the context of another cutaneous malignancy, a very high-risk one, Merkel cell carcinoma. So, Merkel cell carcinoma for those who are not necessarily treating a lot of this is a very rare and very aggressive cutaneous tumor. It's a neuroendocrine tumor of the skin. It's a cancer that's typically associated more than about 60% of the time with a cancer-causing virus, an oncogenic virus known as a Merkel Cell Polyomavirus.   And in this setting, checkpoint inhibitor therapy has been approved for the last couple of years, initially with a PDL-1 inhibitor, avelumab, and then more recently with a PD-1 inhibitor, pembrolizumab. And, at this point in time, there are three FDA-approved agents that are checkpoint inhibitors that are available for the treatment of this disease.   And CheckMate-358 was essentially a trial of nivolumab plus/minus ipilimumab in the setting of this Merkel cell carcinoma. So, Jason, what are your thoughts on how the addition of ipi did in this setting [in Abstract 9506]?  Dr. Jason Luke: Yeah, so I think this is a really interesting abstract because there's a slightly more context even than what you alluded to there. This study is an open-label, multi-cohort, but single-arm investigation where one cohort of patients received nivolumab alone and the other cohort received ipilimumab. It needs to be buttressed by a previous publication in The Lancet last year by the group at the Moffitt Cancer Center who also did a prospective study looking at nivolumab and ipilimumab. In that previous study that the Moffit group did, they got a response rate of 100%. All patients responded to the combination of nivolumab and ipilimumab in their study and that was quite provocative, suggesting that while anti-PD-1 alone has about a 50% response rate, adding ipi in that scenario then took it to 100. So these data were very much of interest because this could be a confirmatory data set to suggest for this rare tumor that perhaps a combination regimen should be preferred. Of course, one has to remember that adding ipilimumab to anti-PD-1 substantially enhances the toxicity profile. And these patients tend to be elderly that develop this kind of cancer, Merkel cell carcinoma. So that's a rather important caveat.   Just to get to the crux of what happened in this trial. As opposed to the previous Moffit trial, there actually did not appear to be a major increase in the benefit of adding ipilimumab, at least in this trial. Because again, in parallel cohorts, the NIVO monotherapy arm had a 60% response rate, which is roughly a little bit higher, but roughly in line with what we've seen previously. And the response rate to nivolumab plus ipilimumab was 58%. So, I mean basically the same. So, how can it be then, that we have this previous very high-profile publication that says 100% response? Now, we have a second publication that says adding ipi doesn't do anything - that's confusing, and I think it'll be really important to try to look at what were the differences between these two cohorts of patients. Did one of them have higher risk features, greater disease burden, et cetera? We don't really know that just yet, but trying to tease that out will be important.  This data also emphasized, though, the complexity around the dosing of ipilimumab. And in melanoma, we never really figured out what the best dose of ipilimumab was to give either alone or even in combination with a PD-1. And we don't really have time to get into all of it right away here, but there are multiple studies in melanoma that would suggest that giving ipi on an every 3-week dosing schedule is superior to giving it on a 6-week dosing schedule. In this study, they did use the 6-week dosing schedule. So, whether or not that could have made a difference, I guess, is unknown. But I would notice that in the previous Moffitt trial, they also used that six-week dosing schedule. This one's a head-scratcher for why did these data not confirm a previous data set? But for the time being, I think this emphasizes that PD-1 monotherapy really is the standard approach that should be considered for patients with metastatic Merkel cell carcinoma.  Dr. Diwakar Davar: That's great, Jason. And so, again, it's a very tough patient population. These are very rare patients. The Moffitt trial that Jason alluded to essentially was a trial that had in each arm, there were approximately 25 patients, of which 13, or between 11 to 13 patients were actually checkpoint inhibitor naive, wherein the dramatic 100% response rate was seen. And this is a trial where at least in this update, we've got about 25 patients in nivo monotherapy, I mean in 43 patients. And so, in a disease that is thought to be extraordinarily sensitive to checkpoint inhibitor immunotherapy because of the role of the virus and the high TMB that it's associated with, it is very interesting that the addition of an additional checkpoint inhibitor did not appear to improve outcomes. But as you alluded to multiple reasons, but we don't know how it's going to shake out. Next, Abstract 9507 and this is a very interesting trial known as the MATISSE trial. So, in the context of cutaneous squamous cell carcinoma, cutaneous squamous cell carcinoma is a relatively not uncommon cancer, primarily seen in older cancer patients, particularly a little bit more common in men. And in this setting, we've got checkpoint inhibitor therapy that is FDA-approved, at least two of which are FDA-approved right now, pembrolizumab and cemiplamab both were approved in the advanced cancer setting. And we do know that because of the extraordinarily high tumor mutation burden associated with cutaneous squamous cell carcinoma, checkpoint inhibitor therapy has got a very dramatic effect. Response rates are between 35% to 42% with pembrolizumab and 40% to 50% with cemiplamab, depending on whether or not one looks at the relapsed metastatic or the locally advanced patient populations.  And interestingly, much like we've seen with melanoma, we have migrated the use of this therapy early in the lines of patients, particularly in the setting of perioperative therapy. So, Jason, how would you contextualize the results of the MATISSE trial in relation to the existing and known data from several of our colleagues regarding the role of what checkpoint inhibitor therapy is doing in terms of organ preservation?  Dr. Jason Luke: Yeah, and I think this is an area of tremendous excitement. And as you were alluding to, the activity of anti-PD-1 really was transformative in this disease, which really can be a disfiguring and locally destructive disease. And with that activity for unresectable disease, last year, near the end of the year, there was a first report of a large neo-adjuvant clinical trial in cutaneous squamous which showed really outstanding results in terms of improving surgery and pathologic complete response using anti-PD-1 in that setting. And for this trial, this was a trial done in Europe; they took a similar tact of trying to think about giving anti-PD-1 or anti-PD-1 with anti-CTLA-4 with ipilimumab in that neoadjuvant period to see whether or not they could reduce the use of extensive surgery and/or radiation therapy.  The short version is they were able to do that. And so they described 40% of patients with single-agent anti-PD-1 and 53% of patients who received a combination having major pathologic response to treatment. And this was so much so that 10 of the patients who had pathologic responses actually withdrew their consent to go on to have surgery because they decided that they had had such a good effect of the immunotherapy, they weren't willing to put themselves through what was going to be a very difficult surgery. And I think that speaks to the upside potential of these checkpoint immunotherapy approaches in certain settings, specifically here in cutaneous squamous cell carcinoma. Moreover, they describe clinical response in neoadjuvant setting as 50% for PD-1 monotherapy and 61% for the combination and I really think that this is really ready for prime time.  With the study published in the New England Journal last year and these data now, I really think the field needs to start moving towards the use of perioperative anti-PD-1 with or without ipilimumab as a standard approach. And I think it's the case that even the NCCN and ASCO and various guideline societies are going to start acknowledging that this ought to be considered for most patients who are facing difficult surgical operations for continuous squamous cell carcinoma. Dr. Diwakar Davar: So, Jason, you bring up a fascinating point, which is the appearance of this in guidelines. So this is undoubtedly extraordinarily good data. It's confirmatory, the pathologic response rates in many ways paradoxically low. You'd expect something about 50% or so. But the reason it's low is because 10% of patients who actually benefited didn't undergo surgery. So really the degree of benefit is tremendous. It's about 50% to 60%. So the fascinating thing in the setting that we'd have is if one is going to try to get the drug FDA-approved, what we now have is the conventional setting in which one needs a definitive endpoint. And at least we know that pathological response rate is not a definitive endpoint in the context of melanoma or, for that matter, cutaneous squamous cell carcinoma. The only setting in which it is a regulatory endpoint is a non-small cell lung cancer or triple-negative breast cancer. But recently there's been some very exciting data from another PD-1 inhibitor called dostarlimab in a trial done by your former colleague Dr. Luis Diaz when he demonstrated a dramatic result of dostarlimab in the context of perioperative rectal cancer where it is micro-satellite high wherein the standard of care is typically very disfiguring abdominal perineal resection.    So in the context of some of our listeners who might be thinking a little bit about how this pertains to regulatory approval, what are your thoughts about the paradigm of avoiding highly disfiguring surgery relating to what was seen in the rectal cancer discussion to what we're now seeing with perioperative therapy in the context of cutaneous squamous cell carcinoma?  Dr. Jason Luke: I think it's a very important question. And the easy out for diseases that have a pattern of progression that is metastasis is to use event-free survival which can include both the pre-surgical and the post-surgical period in terms of looking for whether or not the cancer comes back. And that works for diseases potentially like lung cancer, like you said, maybe melanoma. In cutaneous squamous cell carcinoma, however, that's not probably going to work because this tends to be a locally invasive and less of a metastatic disease. So here then, we really need to have sort of organization across patient advocacy, dermatology, medical oncology to come up with what the most appropriate considerations are going to be for evaluating that long-term benefit because I think we need a tangible result that we can show the FDA. Everyone is really impressed by these results, and I think that next step is to craft this into a way that we have a measurable output that we can then go to them with and say bless this so that all of our patients can get this kind of treatment. Dr. Diwakar Davar: Really great discussion, Jason. And I think this is going to be an area of particular interest going forward, given both the number of trials that have been conducted in this space and also the role of the very interesting regulatory paradigm that has now been set initially at least with the rectal cancer that is microsatellite high and now potentially we will see with cutaneous squamous cell carcinoma.   And so the final abstract that we have selected for you is Abstract 9511. And this is a trial that was conducted by a mutual colleague, Dr. Ryan Sullivan, and his colleagues. And it's essentially a trial of looking at targeted therapy with or without navitoclax in BRAF mutant melanoma patients. And part of the reason to highlight this, it's very interesting preclinical data supporting the addition of navitoclax, b but also a great example of an early trial that came through the CTEP portfolio. And so Jason, can you tell us about why this is exciting and how we might contextualize the addition of navitoclax to the targeted therapy backbone?   Dr. Jason Luke: Sure. So listeners will be quite aware of targeting mutant BRAF as a therapeutic strategy across oncology that was really initially pioneered in melanoma with the development of vemurafenib as the first selective BRAF inhibitor. But the field, of course, moved eventually to BRAF and MEK combinations across essentially all settings. We know that dabrafenib and trametinib are now approved pan-cancer for anywhere we find a BRAF V600e mutation. In the context of melanoma, looking at mechanisms of resistance, we observed that they were quite heterogeneous with reactivation of elements of the mitogen-activated protein kinase pathway, the MAPK pathway. But also there were metabolic changes in the cancer cells themselves which could drive resistance and were downstream of some of those reactivation signaling points. So one of those is the induction of anti-apoptotic machinery in the cell. So activation of BCL-2 or Bcl-xL to try to save those melanoma cells when they were under stress by blockade with BRAF and MEK inhibitors. And that observation was made now about a decade ago or more. And that raised the possibility that repurposing a drug that was being used actually in the chemo malignancy space might be useful in augmenting targeted therapy. And that's where we come in with the navitoclax as a BH3-mimetic that can actually knock down those antiapoptotic proteins, BCL-2 Bcl-xL. And so that was the context for this initially phase I clinical trial of combining navitoclax with the dabrafenib and trametinib.  And those data supported the safety of doing that and moved to this study, which was a randomized phase 2 study of that triplet regiment versus the dabrafenib and trametinib alone. And so this study started quite a long time ago, before the sort of initiation or widespread use of anti-PD-1 antibodies. And so it had to kind of undergo some various iterations throughout its course but eventually has now read out. And it had two primary endpoints, with one being focused on improving the complete response rate for targeted therapy because that's been associated with long-term outcomes as well as to look at the maximum tumor shrinkage of patients within this trial and of course to look at other endpoints like response rate, progression-free survival, et cetera.  About half the patients who participated in the trial had prior immune checkpoint blockade and they were actually distributed evenly across the two arms. So we think that probably won't impact on the outcomes. And what was observed in the clinical trial was that in fact, the triplet did improve the complete response rate for targeted therapy. So navitoclax plus dabrafenib and trametinib had a complete response rate of 20% versus dabrafenib and trametinib alone being at 15%. Both of them had an overall response rate in the 80% range, with slightly higher for the triplet at 84% versus 80% for the double-edged standard therapy. There was also a suggestion that there may be a disproportionate benefit for the triplet actually in patients with smaller baseline tumors. And we know that the efficacy of targeted therapy is more pronounced in the lower-volume disease state.   And so overall, when we look at this without really adding much toxicity, I think this is an intriguing place to look at further drug development. BRAF and MEK inhibition has been a backbone therapy in Melanoma for a long time, but we really haven't been able to move past it or augment it in any real way because of the heterogeneity of treatment resistance. And here, by going after metabolic changes, we perhaps might have the opportunity to enhance our targeted therapy somewhat further. And so we'll look forward to further results investigating this regimen in subsequent clinical trials. Dr. Diwakar Davar: Fantastic discussion, Jason. So these are all great insights. As you've heard, we've now discussed a couple of key abstracts covering major topics that will be presented, major themes of the malignancy space at ASCO 2023, including the addition of a lactate inhibitor to checkpoint in both a randomized large phase 3 trial and a smaller phase 2 trial, the context of targeted-therapy in melanoma making another forerun in the post-3c setting. And two very interesting studies I have looked at, checkpoint inhibitor therapy in the context of cutaneous squamous cell carcinoma and Merkel cell carcinoma, addressing themes that are of huge importance going forward, including the role of perioperative therapy in squam and the addition of a CTLA-4 inhibitor in Merkel. These oral abstracts are all going to be presented at the 2023 ASCO Annual Meeting. We look forward to seeing you there.  So, thank you Jason for taking the time to join us and for highlighting these important advances in immunotherapy. And thank you to our listeners for your time today. You will find links to the abstracts discussed today in the transcript of this episode. And finally, if you value the insights that you hear on the ASCO Daily News Podcast, please take a moment to rate, review, and subscribe wherever you get your podcast. Thank you for your attention. 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. Diwakar Davar @diwakardavar Dr. Jason Luke @jasonlukemd   Follow ASCO on social media: @ASCO on Twitter ASCO on Facebook ASCO on LinkedIn   Disclosures:  Dr. Diwakar Davar:  Honoraria: Merck, Tesaro, Array BioPharma, Immunocore, Instil Bio, Vedanta Biosciences Consulting or Advisory Role: Instil Bio, Vedanta Biosciences Consulting or Advisory Role (Immediate family member): Shionogi Research Funding: Merck, Checkmate Pharmaceuticals, CellSight Technologies, GSK, Merck, Arvus Biosciences, Arcus Biosciences Research Funding (Inst.): Zucero Therapeutics Patents, Royalties, Other Intellectual Property: Application No.: 63/124,231 Title: COMPOSITIONS AND METHODS FOR TREATING CANCER Applicant: University of Pittsburgh–Of the Commonwealth System of Higher Education Inventors: Diwakar Davar Filing Date: December 11, 2020 Country: United States MCC Reference: 10504-059PV1 Your Reference: 05545; and Application No.: 63/208,719 Enteric Microbiotype Signatures of Immune-related Adverse Events and Response in Relation to Anti-PD-1 Immunotherapy  Dr. Jason Luke:  Stock and Other Ownership Interests: Actym Therapeutics, Mavu Pharmaceutical , Pyxis, Alphamab Oncology, Tempest Therapeutics, Kanaph Therapeutics, Onc.AI, Arch Oncology, Stipe, NeoTX Consulting or Advisory Role: Bristol-Myers Squibb, Merck, EMD Serono, Novartis, 7 Hills Pharma, Janssen, Reflexion Medical, Tempest Therapeutics, Alphamab Oncology, Spring Bank, Abbvie, Astellas Pharma, Bayer, Incyte, Mersana, Partner Therapeutics, Synlogic, Eisai, Werewolf, Ribon Therapeutics, Checkmate Pharmaceuticals, CStone Pharmaceuticals, Nektar, Regeneron, Rubius, Tesaro, Xilio, Xencor, Alnylam, Crown Bioscience, Flame Biosciences, Genentech, Kadmon, KSQ Therapeutics, Immunocore, Inzen, Pfizer, Silicon Therapeutics, TRex Bio, Bright Peak, Onc.AI, STipe, Codiak Biosciences, Day One Therapeutics, Endeavor, Gilead Sciences, Hotspot Therapeutics, SERVIER, STINGthera, Synthekine Research Funding (Inst.): Merck , Bristol-Myers Squibb, Incyte, Corvus Pharmaceuticals, Abbvie, Macrogenics, Xencor, Array BioPharma, Agios, Astellas Pharma , EMD Serono, Immatics, Kadmon, Moderna Therapeutics, Nektar, Spring bank, Trishula, KAHR Medical, Fstar, Genmab, Ikena Oncology, Numab, Replimmune, Rubius Therapeutics, Synlogic, Takeda, Tizona Therapeutics, Inc., BioNTech AG, Scholar Rock, Next Cure Patents, Royalties, Other Intellectual Property: Serial #15/612,657 (Cancer Immunotherapy), and Serial #PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof) Travel, Accommodations, Expenses: Bristol-Myers Squibb, Array BioPharma, EMD Serono, Janssen, Merck, Novartis, Reflexion Medical, Mersana, Pyxis, Xilio

Listen to a soundcast of the March 16, 2023, FDA approval of Tafinlar (dabrafenib) for pediatric patients with low-grade glioma with a BRAF V600E mutation

Featuring perspectives from Dr Richard Finn, Dr Lipika Goyal and Prof Arndt Vogel, moderated by Dr Katie Kelley, including the following topics: •      First-Line Treatment for Advanced Hepatocellular Carcinoma (HCC) — Dr Finn  o   Introduction (0:00) o   Case: A man in his early 70s with newly diagnosed metastatic HCC receives atezolizumab/bevacizumab — Warren S Brenner, MD (2:27)) o   Case: A woman in her late 50s with a history of hepatitis C and chronic kidney disease on dialysis with localized HCC after surgical resection; patient developed metastatic disease 10 months later — Liudmila N Schafer, MD (6:48) o   Faculty presentation: Dr Finn (11:47) •      Selection and Sequencing of Therapies for Relapsed/Refractory HCC — Dr Kelley  o   Case: A man in his mid 60s with metastatic HCC and a medical history of hepatitis C develops interstitial lung disease on atezolizumab/bevacizumab — Priya Rudolph, MD (21:48) o   Cases: A man in his late 60s with post-transplant recurrence develops metastatic HCC and receives lenvatinib followed by cabozantinib followed by regorafenib and a man in his late 70s with metastatic HCC after treatment with atezolizumab/bevacizumab, lenvatinib and currently cabozantinib — Lionel A Kankeu Fonkoua, MD and Susmitha Apuri, MD (26:58) o   Faculty presentation: Dr Kelley (35:56) •      Current and Future Role of Immunotherapy in the Treatment of Advanced Biliary Tract Cancers (BTCs) — Prof Vogel  o   Case: A woman in her mid 70s with metastatic cholangiocarcinoma who received first-line gemcitabine/cisplatin with durvalumab — Dr Brenner (45:40) o   Case: A man in his early 70s with localized cholangiocarcinoma deemed potentially resectable with tumor response — Jeremy Lorber, MD (50:23) o   Faculty presentation: Dr Vogel (55:10) •      Integration of Targeted Therapy into the Management of Advanced BTCs — Dr Goyal  o   Cases: A woman in her late 70s with intrahepatic cholangiocarcinoma considered unresectable — an FGFR2-KIAA1598 fusion was detected on NGS and a man in his early 60s with metastatic cholangiocarcinoma with severe muscle pain on pemigatinib — Dr Fonkoua and Joseph Martins, MD (1:06:18) o   Cases: A man in his early 50s with recurrent metastatic cholangiocarcinoma with a BRAF V600E mutation treated with dabrafenib/trametinib and a woman in her mid 60s with cholangiocarcinoma with an IDH1 mutation receives ivosidenib — Farshid Dayyani, MD, PhD and Niyati A Nathwani, MD (1:12:26) o   Faculty presentation: Dr Goyal (1:19:08) CME information and select publications

Featuring perspectives from Dr Christopher Lieu, including the following topics: •       Early-Onset Colorectal Cancer o   Introduction (00:00) •       Localized Disease o   Case: A woman in her mid 30s with left-sided T3N0 Grade II obstructing adenocarcinoma of the colon — William R Mitchell, MD (16:31) o   Case: A woman in her early 50s with Stage II mismatch repair-proficient sigmoid colon cancer with focal intramural lymphovascular invasion after 6 cycles of adjuvant capecitabine — Priya Rudolph, MD, PhD (19:51) •       Metastatic Disease o   Case: A woman in her mid 80s with pan-RAS wild-type (WT) metastatic rectal cancer with poor tolerance to chemotherapy, now receiving regorafenib with slowly progressive disease — Eric H Lee, MD, PhD (32:09) o   Case: A man in his early 60s with recurrent, microsatellite stable, HER2-negative, RAS WT rectal cancer, currently receiving TAS-102/bevacizumab — Swati Vishwanathan, MD (35:16) •       HER2-Positive Disease o   Case: A woman in her mid 50s with RAS WT, HER2-amplified metastatic colon adenocarcinoma — Gigi Chen, MD (44:38) o   Case: A woman in her mid 60s with multiregimen-relapsed RAS WT, HER2-positive metastatic rectal cancer, now receiving trastuzumab/tucatinib — Sunil Gandhi, MD (50:47) •       Microsatellite Instability-High Disease; BRAF-Mutant Disease o   Case: A woman in her late 70s with HER2-negative, BRAF V600E-mutant, microsatellite stable metastatic colon cancer after mFOLFOX/bevacizumab followed by maintenance 5-FU/bevacizumab — Victoria Giffi, MD (58:14) CME information and select publications

In this week's episode, we'll discuss the findings from a phase 3 trial of PI3Kδ inhibitor leniolisib in activated PI3Kd syndrome, learn more about the efficacy and safety of dabrafenib plus trametinib in relapsed/refractory BRAF V600E mutation-positive hairy cell leukemia, and review the findings from a study conducted in an international cohort of patients with Tγδ LGL leukemia.

Featuring perspectives from Drs Tanios Bekaii-Saab, Scott Kopetz, and John Strickler and Prof Eric Van Cutsem, moderated by Dr Kristen Ciombor, including the following topics: •      Integration of Therapies Targeting BRAF and HER2 in Metastatic Colorectal Cancer (mCRC) — Dr Strickler o   Introduction (0:00) o   Case: A man in his early 40s presenting with microsatellite-stable (MSS) rectal cancer and liver metastases — Victoria Giffi, MD (2:04) o   Cases: A man in his late 70s with HER2-amplified colon cancer and extensive liver metastases and a man in his late 50s with KRAS G12S-mutant HER2-amplified colon cancer and lung metastases — Ranju Gupta, MD and Shaachi Gupta, MD, MPH (9:12) o   Faculty presentation (16:39) •      Optimizing the Use of Immune Checkpoint Inhibitors in the Management of mCRC — Dr Ciombor o   Case: A man in his mid 50s with BRAF V600E-mutant, KRAS/NRAS wild-type metastatic colon cancer with disease progression on FOLFOXIRI/bevacizumab — Lai (Amber) Xu, MD, PhD (26:13) o   Case: A man in his late 60s with localized unresectable microsatellite instability-high carcinoma of the cecum — Farshid Dayyani, MD, PhD (32:02) o   Faculty presentation (41:11) •      Evidence-Based Selection and Sequencing of Therapy for Patients with mCRC — Prof Van Cutsem o   Case: A man in his late 70s with metastatic rectal cancer and newly diagnosed PMS2-positive Lynch syndrome — Liudmila N Schafer, MD (51:39) o   Case: A man in his mid 50s with pan-RAS wild-type metastatic rectal cancer treated with FOLFOX/cetuximab — Warren S Brenner, MD (56:55) o   Faculty presentation (1:03:36) •      Promising Agents and Strategies for Patients with mCRC — Dr Bekaii-Saab o   Case: A woman in her early 50s with KRAS and BRAF wild-type, HER2-negative T3N1 rectal cancer with liver and lung oligometastases who underwent multiple ablations and stereotactic body radiation therapy and is currently receiving FOLFIRI/panitumumab – MSS, mismatch repair-proficient, PD-L1 0% — Jennifer L Dallas, MD (1:13:13) o   Case: A woman in her early 60s with metastatic KRAS G12C-mutant cancer of the sigmoid colon — Philip L Brooks, MD (1:18:43) o   Faculty presentation (1:22:32) •      The Changing Management Paradigm for Localized CRC — Dr Kopetz o   Case: A man in his early 70s with 2 synchronous T3N0 cancers of the splenic flexure and cecum who is found to have circulating tumor DNA after resection — Dr Brenner (1:35:56) o   Case: A man in his early 80s with a Stage II obstructing cancer of the right colon — Namrata I Peswani, MD (1:46:12) o   Faculty presentation (1:47:58) CME information and select publications

An interview with Dr. Van Morris from The University of Texas MD Anderson Cancer Center in Houston, TX and Dr. Cathy Eng from Vanderbilt-Ingram Cancer Center in Nashville, TN, co-chairs on "Treatment of Metastatic Colorectal Cancer: ASCO Guideline." Dr. Morris and Dr. Eng review the evidence-based recommendations from the guideline, focusing on areas of uncertainty in the treatment of metastatic colorectal cancer, and highlighting the importance of multidisciplinary collaboration and shared decision-making between patients and clinicians. Read the full guideline at www.asco.org/gastrointestinal-cancer-guidelines.   TRANSCRIPT Brittany Harvey: Hello, and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at: asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Van Morris, from The University of Texas MD Anderson Cancer Center in Houston, Texas, and Dr. Cathy Eng from Vanderbilt-Ingram Cancer Center in Nashville, Tennessee - co-chairs on, 'Treatment of Metastatic Colorectal Cancer, ASCO Guideline.' Thank you for being here, Dr. Morris, and Dr. Eng. Dr. Cathy Eng: Thank you. Dr. Van Morris: Thank you. 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. Morris, do you have any relevant disclosures that are directly related to the guideline topic? Dr. Van Morris: Not personally, but I do have research support to my institution from Pfizer and Bristol Myers Squibb who have products that I'll be discussing on this podcast. Brittany Harvey: Thank you, Dr. Morris. And Dr. Eng, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Cathy Eng: Also, not personally associated with any honorarium specific to this topic. Brittany Harvey: Great. Thank you both. So then, let's talk about the content of this guideline. So first, Dr. Morris, can you provide an overview of the scope of this guideline? Dr. Van Morris: Sure. So colorectal cancer is the second-leading cause of cancer-related death in the United States. And especially in the time of the recent COVID-19 pandemic with people less likely to go for screening colonoscopies, there's great concern that more and more patients will be presenting at the time of their initial diagnosis with later-stage, more advanced colorectal cancer. So with that said, research is moving very quickly for the benefit of patients with colorectal cancer, and we were interested in assembling a multidisciplinary team that consisted of medical oncologists, surgical oncologists, radiation oncologists, pathologists, and radiologists as well, to help us make guidelines that really summarize the most relevant up-to-date practices, based on rigorous literature review for treatment recommendations for advanced metastatic colorectal cancer. Brittany Harvey: Great. And then as you just mentioned, this guideline provides recommendations, and a lot of those focus on areas of uncertainty in the treatment of metastatic colorectal cancer. And I'd like to review those key recommendations that you mentioned for our listeners. So, Dr. Eng, starting with - for patients with previously untreated, initially unresectable metastatic colorectal cancer, who are candidates for chemotherapy plus bevacizumab, is doublet or triplet cytotoxic chemotherapy recommended? Dr. Cathy Eng: For treatment-naive patients, bevacizumab has been approved, and we do agree that it's a very reasonable treatment option with doublet or triplet therapy for our patient population. Obviously, these are guidelines, and it's extremely important to keep in mind that as a provider, you need to discuss the potential side effects with the patient. With bevacizumab, you know, standard concerns must be discussed with the patient, especially in regards to wound healing, if they've had recent surgery or any potential risk factors for a recent cardiac event from a recent thrombosis. So, those things obviously, would preclude the patient from initiating treatment with bevacizumab. But currently, doublet therapy or triplet therapy could be a potential option for patients. Brittany Harvey: Great. And yes, as you mentioned, shared decision-making is paramount to these decisions. So then following that recommendation, Dr. Morris, which patients should be offered pembrolizumab in the first-line setting? Dr. Van Morris: Yeah. So, I think that this represents really one of the exciting advances in the treatment of metastatic colorectal cancer over the past several years. We have great data now that suggests for patients with microsatellite instability-high metastatic colorectal cancer, especially who have not had any prior treatment, we would recommend use of immune checkpoint blockade therapies, really coming from the seminal KEYNOTE-177 trial. This was a phase III international trial that looked at patients with advanced unresectable or metastatic colorectal cancer. And patients were either randomized to pembrolizumab monotherapy, or cytotoxic chemotherapy with FOLFOX, with or without bevacizumab. And this trial did meet its primary endpoint and showed an improvement in progression-free survival, with use of pembrolizumab as a single agent relative to cytotoxic chemotherapy. And based on this trial and the clear benefit that we see in patients with pembrolizumab, the FDA has approved this as an option for patients with MSI-high untreated metastatic colorectal cancer. There are other trials which have looked at use of immunotherapy; the CheckMate 142 trial looked at combination PD-1 CTLA-4 therapy as a single-arm study. And, you know, there's another trial, the CheckMate 8HW, which is looking at one versus two immunotherapy agents in this setting as well. But really, as it stands for now, patients with MSI-high untreated metastatic colorectal cancer are the ones who benefit from the use of immunotherapy. One of the questions that we often get in talking with other clinical oncologists is the FDA approval for pembrolizumab in any cancer type for a TMB, tumor mutation burden, greater than 10. And, we talked about this with our panel in this context, and we don't see that patients with microsatellite-stable metastatic colorectal cancer, who have a tumor mutation burden over 10 benefit from use of immunotherapy. There is one exception to this for patients who harbor pathogenic POLE or POLD1 mutations, these patients oftentimes do experience sustained clinical benefit with immunotherapy. But in general, patients with microsatellite-stable metastatic colorectal cancer, who don't have POLE/POLD1 mutations, we don't favor use of immunotherapy in that context at this point in time. Brittany Harvey: Great. Thank you for reviewing that recommendation and the data behind who benefits and who doesn't benefit from immunotherapy in this setting. So then following that, the next question that this guideline addressed is for treatment-naive RAS-wild type metastatic colorectal cancer. So, for these patients, Dr. Eng, is anti-EGFR therapy recommended for patients with right or left sided primary tumors? Dr. Cathy Eng: That is such an important question, and thank you for asking this. We know based upon pivotal data from CALGB/SWOG 80405, that right-sided tumors treatment-naive, even if they're RAS-wild type, these patients should not receive anti-EGFR therapy. But also, we've learned from 80405, FIRE-3, and PEAK, which was a phase two study, that there appeared to be some benefit versus anti-VEGF therapy for left-sided tumors based upon studies that have been conducted. So, at this year's ASCO, actually, the PARADIGM trial was specifically a phase III trial, more focused on left-sided tumors. It was amended twice before it decided to focus on the left-sided patient population. And it was a phase III study where patients were randomized to FOLFOX plus panitumumab versus FOLFOX and bevacizumab. And the primary endpoint was overall survival. And we added this data to our guidelines. This data just came out, hot off the presses in June, at this year's ASCO. And the primary endpoint was fulfilled. And basically, it prospectively demonstrated that the data from the other three trials, based upon a pooled analysis, suggested left-sided tumors fare better with anti-EGFR therapy. And in fact, the PARADIGM trial basically validated those findings. Obviously, the PARADIGM trial just recently presented, we have not seen the final publication, we do not know much about the maintenance setting, but specifically, when thinking about anti-EGFR therapy, it is very reasonable to consider it in a left-sided tumor, all RAS-wild type patient population. I would like to mention though, and we do highlight this also in the guidelines, which is critically important, is that there was another study, which is a phase III trial called, TRIPLETE, that was presented as well, looking at FOLFOXIRI plus panitumumab versus basically, standard treatment. And what it noted is that there is no additional benefit for FOLFOXIRI plus panitumumab in left-sided tumors in regards to response or progression-free survival, there was no additional benefit. So, FOLFOX plus panitumumab seems very reasonable, FOLFOXIRI plus panitumumab is not necessarily needed in left-sided tumors. Brittany Harvey: Great. Thank you for that explanation, and also for the work of the panel to rapidly include this new information recently presented at ASCO. So then following those recommendations, Dr. Morris, what recommendation did the panel make for patients with previously-treated metastatic colorectal cancer with a BRAF V600E mutation? Dr. Van Morris: Yeah. So, this recommendation was made essentially based on one randomized phase III clinical trial, which reported out about three years ago now, the BEACON trial. This is looking at patients with BRAF V600E mutated metastatic colorectal cancer, which we know accounts for probably eight to 10% of all patients with advanced colorectal cancer, and when found, really harbors a poor prognosis relative to BRAF-wild type counterparts. So, the BEACON trial was a trial that looked at patients with previously-treated metastatic colorectal cancer, who have BRAF mutations, either kind of standard of care cytotoxic chemotherapy, or a BRAF/EGFR combination with encorafenib and cetuximab or alternatively, a BRAF/EGFR/MEK combination. That trial showed that improvement in survival outcomes with a BRAF/EGFR-targeted approach, as well as the BRAF/MEK/EGFR. However, because there was no difference in survival with the addition of the MEK inhibitor, the FDA subsequently approved encorafenib and cetuximab as the recommended treatment for patients with BRAF V600E previously-treated metastatic colorectal cancer. Because the MEK combination with binimetinib was not recommended by the FDA, you know, we did not include that analysis in our guidelines for ASCO. But as it stands right now, we do strongly encourage all clinicians to check for their BRAF V600E mutation status in their patients with metastatic colorectal cancer, with the goal of getting them to a targeted therapy approach over their treatment course. Brittany Harvey: Great. Thank you for providing that information. So, following that, Dr. Eng, what are the recommendations for patients with colorectal peritoneal metastases? Dr. Cathy Eng: The current recommendations for colorectal cancer with peritoneal disease, really, there's no strong evidence to support the role of heated intraperitoneal chemotherapy. We now know based upon the literature from one of the largest studies to date, the PRODIGE data, demonstrating that there may be some potential benefit from cytoreductive surgery for the patients in regards to overall survival. But these patients are at high risk for bowel obstruction, potentially for perforation, and obviously, quality of life is an issue. So, these patients should always be discussed in a multidisciplinary tumor board whenever possible, and hopefully, to meet with a surgeon that is more experienced, specifically, in treating peritoneal disease, because these patients do require a lot of multidisciplinary care and discussion. So currently, based upon the existing data, we don't recommend heated intraperitoneal chemotherapy, but there may be a role for cytoreductive surgery. Brittany Harvey: Thank you, Dr. Eng for going over those recommendations. So then following that, Dr. Morris, for patients with unresectable liver-limited metastatic colorectal cancer, which liver-directed therapies are recommended? Dr. Van Morris: So, this is I think a really good question and one that just like the prior question with regards to peritoneal surgery, is one that we felt was a challenging one, but a common one that we wanted to address. And specifically, I think this is an example of where level of evidence comes into the strength of recommendation. So, for patients with unresectable liver-limited metastatic colorectal cancer, we looked at the questions of, "What is the role of SBRT - stereotactic body radiotherapy, and what is the role of SIRT, which is selective internal radiotherapy?" And for both of these, we felt that the level of evidence was weak, and I think that it's very important to make note of that in assessing the recommendations. But to start with, for SBRT, we looked at one meta-analysis for patients with oligometastatic colorectal cancer, and also analyzed 18 non-randomized control trials in this setting. Most of the patients in these studies had one to five liver metastases, with the majority having one or two liver metastases. From the meta-analysis, we saw kind of a one-year local control rate of around 67%, a two-year control rate of 59%. So, based on those and recognizing the limitations of non-randomized trials and making recommendations, the panel did feel that it was reasonable to consider use of SBRT for oligometastatic colorectal cancer. The SABR-COMET trial is one that had looked at the role of radiotherapy for treatment of oligometastatic colorectal cancer, and I just want to make the point as well, that we did not include that in our analysis or recommendations at this point in time, because this really didn't include a lot of patients with colorectal cancer that we felt warranted inclusion. Now, with regards to SIRT, we looked at kind of one meta-analysis and three randomized control trials for patients with mostly liver-limited metastatic colorectal cancer. All patients had liver disease, but there were about 40% of the patients we looked at in the meta-analysis, had extra hepatic disease as well. In the frontline setting, there really was no difference in progression-free survival or overall survival with the use of SIRT. And more recently, we've seen in a second-line trial, it was called the EPOCH trial, reported several years ago, this looked at patients with previously-treated metastatic colorectal cancer in the second-line setting. Patients were randomized to either chemotherapy with, or without transarterial radioembolization with Y90. While there was an improvement in overall response rate, there was no meaningful improvement in overall survival with the use of SIRT. But there were significant increases in grade 3 or grade 4 toxicities when SIRT was added to chemotherapy. So, kind of given this, we didn't feel at this point in time that SIRT should be recommended for patients with metastatic colorectal cancer. Although, again, I do want to highlight that really these discussions should be happening at high-volume centers, kind of with a multidisciplinary group of clinicians. Brittany Harvey: Definitely. And thank you for highlighting that multidisciplinary collaboration. And the last section of recommendations, Dr. Eng, what is recommended for patients with metastatic colorectal cancer, and potentially-curable oligometastatic liver metastases? Dr. Cathy Eng: So, another controversial topic. And once again, this is why we decided to include this as part of the guidelines, because this is a common scenario where patients are potentially curable, following liver resection for oligometastatic disease. We cannot highlight enough the importance of multidisciplinary discussion. Prior data has not been strong regarding specific guidelines following liver resection. We do recommend that based upon the existing data, there is no level one evidence to say, you should go one way or another following metastatic resection, and whether or not adjuvant therapy is warranted in that setting. But we do recommend multidisciplinary management and engagement and discussion. So, although it's not definitive, it basically suggests that there is a role for resection. It does provide improved five year survival relative to systemic chemotherapy, if the patient is potentially resectable, but does require multidisciplinary discussion. And it is a shared decision-making process. Brittany Harvey: Great. Thank you. And I appreciate you highlighting the importance of shared decision-making throughout this guideline. So then, Dr. Morris, what is the importance of this guideline in your opinion, and how will it impact clinical practice? Dr. Van Morris: Yeah. So, I think that we understand that management of metastatic colorectal cancer is extremely complex given the various molecular annotations and the multimodality therapies which are possible for our patients. So, we tried to limit the guidelines here to include what we feel are the most recent updates, but also kind of the most clinically-relevant multidisciplinary questions that get asked for treatment of metastatic colorectal cancer. We also recognize that things are changing quickly. And for example, we didn't decide to include at this point in time, management of HER2 neu amplified metastatic colorectal cancer, although we are seeing more and more data coming out, suggesting targeted therapies. So, I think it's important for clinicians to realize that these are guidelines which are ever-changing, given the updates with new therapies available for our patients. And the other thing I think that's very good about these guidelines is that, even though we may be making recommendations about controversial topics in the management of metastatic colorectal cancer - specifically, I think the use of HIPEC with cytoreductive surgery, locally-directed therapies to the liver, and the role of perioperative chemotherapy and metastasectomy - I think it's important for oncologists to realize that these recommendations come with varying strengths of level of evidence and that we as oncologists should be considering the level of evidence that's out there when making recommendations that affect our patients as well. So, we really wanted to support these guidelines and recommendations and empower clinicians to know and understand the quality of evidence that exists in the management of patients with metastatic colorectal cancer. Brittany Harvey: Excellent. And yes, those are key points on the level of evidence and the strength of recommendations throughout the guideline. And then finally, Dr. Eng, you've talked a bit about shared decision-making and the importance of this guideline for patients. So, how will these guideline recommendations affect patients with metastatic colorectal cancer? Dr. Cathy Eng: The reason that we created these guidelines is to help patients, their caregivers, and providers, learn of the most recent developments in colorectal cancer, and the best approach based upon the information that we have personally reviewed with our multidisciplinary team of faculty members that participated in this exercise. We really just want to make sure that patients do get optimal care. And we hope that these guidelines also will help provide a foundation for some of the clinical trials that may be under development, or for other clinical trials that are being considered. So, we really just want to provide the most up-to-date information to all individuals that are interested in colorectal cancer so we can help guide their care better. Brittany Harvey: So, I want to thank you both so much for your work on these guidelines, and all of the time it's spent developing these recommendations, and thank you for your time today, Dr. Morris, and Dr. Eng. Dr. Van Morris: Thank you. Brittany Harvey: And thank you to all of our listeners for tuning into the ASCO Guidelines Podcast series. To read the full guideline, go to: www.asco.org/gastrointestinal-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.   The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy, should not be construed as an ASCO endorsement.  

Featuring perspectives from Dr Robert Haddad, including the following topics: ESMO 2022 (0:00) Case: A man in his early 50s presents with metastatic anaplastic thyroid cancer — Ezra Cohen, MD (18:39) Case: A man in his late 60s who has undergone immunotherapy for melanoma is diagnosed with Stage I (cN2 N1) p16-positive squamous cell carcinoma (SCC) of the left tonsil — Erik Rupard, MD (26:21) Case: An Asian woman in her early 40s who has received cisplatin/radiation therapy and gemcitabine/cisplatin for locoregionally advanced nasopharyngeal cancer develops metastatic disease (PD-L1 CPS 10) — Dr Cohen (31:21) Case: A man in his early 70s presents with recurrent and rapidly progressing HPV-negative metastatic head and neck cancer — Neil Morganstein, MD (38:55) Case: A man in his late 50s who has undergone definitive radiation therapy and surgery for locally recurrent SCC of the head and neck presents with worsening shortness of breath — Mamta Choksi, MD (41:42) Case: A man in his early 70s with a longstanding history of T-cell large granular lymphocytic leukemia presents with metastatic HPV-positive SCC of the left nostril (PD-L1-negative) — Spencer H Bachow, MD (44:50) Case: A man in his late 50s presents with HPV-positive Stage III cancer of the base of the tongue — Dr Cohen (49:03) Case: A man in his early 70s presents with metastatic anaplastic thyroid cancer (PD-L1-positive, mutations in TERT promoter, PT53 and MEN1) — Dr Rupard (52:00) Case: A man in his early 60s presents with metastatic papillary thyroid cancer with a BRAF V600E mutation — Dr Cohen (56:16) CME information and select publications

The evolution of biomarkers informing therapy decisions began in 2004, when the FDA approved a medicine to treat EGFR mutated non-small cell lung cancer (NSCLC). Since then, researchers have identified more than 20 distinct mutations in driver genes that are specific to lung cancer, nine of which are treatable through FDA-approved therapy drugs: epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS1, BRAF V600E, NTRK, MET, RET, and histological expression of programmed death ligand 1 (PD-L1).Confirming a patient's biomarker status can open the door to precision medicine. The molecular characterization of lung cancer has considerably changed the classification and treatment of these tumors, becoming an essential component of pathologic diagnosis and oncologic therapy decisions. The success of targeted anticancer therapies and new immunotherapy approaches has created a new paradigm of personalized therapy and has also led to accelerated development of new drugs for lung cancer treatment. Additional research is needed to identify and help treat the approximately one-third of lung cancer patients for whom biomarkers have yet to be identified.This podcast focuses on clinically relevant cancer biomarkers as targets for therapy, as well as potential new targets for drug development. We spoke in our first episode with Dr. David M. Waterhouse, who just moved to the Dana Farber Cancer Institute at Harvard Medical School, and until last month was the former Director of Clinical Research at Oncology-Hematology Care, in Cincinnati. We also talk about how these biomarkers are used in academic versus community hospitals. In this second episode, we talk with Dr. Sinchita Roy Chowdhuri, a molecular pathologist from University of Texas MD Anderson Cancer Center, about what you didn't know about actionable biomarkers for NSCLC.

ASCO: You're listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the voice of the world's oncology professionals. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guests' statements on this podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so data described here may change as research progresses. In the Research Round Up series, ASCO experts and members of the Cancer.Net Editorial Board discuss the most exciting and practice-changing research in their field and explain what it means for people with cancer. In today's episode, our guests will discuss new research in head and neck cancer, brain tumors, and health equity that was presented at the 2022 ASCO Annual Meeting, held June 3-7 in Chicago, Illinois. First, Dr. Cristina Rodriguez will discuss 2 studies on new treatment options for locally advanced head and neck cancer. Dr. Rodriguez is a medical oncologist at Seattle Cancer Care Alliance, an Associate Professor in the Division of Medical Oncology at the University of Washington, and an Associate Member for solid tumor clinical research at the Fred Hutchinson Cancer Research Center. She is also the Cancer.Net Associate Editor for Head and Neck Cancers. You can view Dr. Rodriguez's disclosures at Cancer.Net. Dr. Rodriguez: Hello. My name is Christina Rodriguez. I'm a medical oncologist with a clinical and research focus on head and neck cancer. And today I'm going to discuss research on head and neck cancer that was presented at the most recent 2022 ASCO Annual Meeting. I don't have any relationship to disclose that pertains to the research that I will talk about today. I'd like to discuss 2 abstracts that I thought were practice changing or practice affirming that really addresses some of the key questions that patients and doctors like me have about the treatment of patients with head and neck cancer. So, as you know, most patients with head and neck cancer present with typically locally advanced disease, and most head and neck cancer patients are treated with the intent of curing them most of the time with the use of radiation either as the main treatment or after surgery. And many clinical trials have shown that when we add a chemotherapy called cisplatin to radiation, we improve curative outcomes for patients. But the first abstract that I will talk about, abstract 6003, asks the question "What do we do for patients who are not candidates for cisplatin chemotherapy?" And we know that a significant proportion of our patients will have other medical problems that could make it difficult for us to give chemotherapy and often will result in complications or more toxicity or in side effects for patients. This clinical trial was carried out in India, and it compared radiation alone for patients with head and neck cancer versus radiation given with a non-cisplatin chemotherapy called docetaxel. What's unique about this clinical trial is that it's specifically focused on patients who were not candidates for cisplatin chemotherapy, something that really hasn't been done for this population. Interestingly enough, they found that when we give docetaxel with radiation in these patients, we find that they do better, they live longer, and they feel better based on quality-of-life questionnaires. So I will say that this study, abstract 6003, tells us that even in patients who are not candidates for cisplatin to be given with radiation, there is an alternative treatment that we can use, such as docetaxel given with radiation, that might still improve patient's cure rates for their head and neck cancer. The second study that I think was another interesting study was a clinical trial that asked the question, "Can we give cisplatin in an alternative manner for patients who are undergoing definitive radiation treatment as their main treatment for head and neck cancer?" Like I mentioned, the clinical trials that led to the use of chemoradiation as a standard use cisplatin given in larger doses every 3 weeks, but there's been concern about how well that approach is tolerated by patients. So this particular clinical trial compared patients receiving radiation as curative intense therapy for head and neck cancer with either the cisplatin given every  3 weeks or the cisplatin given at a lower dose once a week. It's important to know that this trial was done in India, where the population is pretty different from what we see in the United States. These are mostly patients who have HPV-negative cancers, mostly cancers acquired through exposures like tobacco and alcohol. And what they found was that these 2 groups of patients had very similar outcomes. In other words, there didn't seem to be a reduction in the rates of cure when we give chemotherapy every week versus every 3 weeks. And interestingly enough, it looked like from a toxicity or side effect standpoint, the every week seems to be a little bit better tolerated. Patients who got the treatment every 3 weeks also had less need for hospitalization or IV fluids and less utilization of health care resources. I think this is a very interesting finding because it really provides us with what we call high-level data that the weekly administration can work. I think it's important to recognize that the population that it studied for this particular clinical trial really was more an HPV-negative population. That's important to know because the standards for HPV-positive head and neck cancer are generated from larger trials that use cisplatin every 3 weeks. But we are continuing to study this question, and there's actually a large NRG study, HN009, that is asking that question both for the HPV- positive and HPV- negative population. So we are, I think, making strides in terms of asking the questions that allow our patients not only to receive treatment that is highly efficacious but also that limits side effects and toxicity. I will also mention that these trials were completed during the COVID-19 pandemic, which tells you that the dedication of these researchers to complete something like this in such a challenging time is to be commended. That's all I have to say, and thank you for listening to this brief summary of new research in head and neck cancer from the ASCO 2022 Annual Meeting. ASCO: Thank you, Dr. Rodriguez. Next, Dr. Glenn Lesser will discuss 3 studies that looked at new treatments for different types of brain tumors. Dr. Lesser is the inaugural Louise McMichael Miracle Professor and Associate Chief in the section on Hematology and Oncology in the Department of Internal Medicine at Wake Forest Health. He is also the Cancer.Net Associate Editor for Central Nervous System Tumors. You can view Dr. Lesser's disclosures at Cancer.Net.   Dr. Lesser: Hello. My name is Glenn Lesser, and I'm a professor of medical oncology and the director of medical neuro-oncology at the Wake Forest Baptist Comprehensive Cancer Center in Winston-Salem, North Carolina. I'm also the editor of the brain tumor section for ASCO's Cancer.Net. And today, I would like to briefly discuss several clinically relevant research studies involving patients with brain tumors that were presented at this year's ASCO Scientific Program. Of note, I have no disclosures or relationships relevant to the abstracts I'll be discussing today. The first presentation to talk about is a late-breaking abstract presented by Dr. Eric Bouffet, who described the results of a phase II trial of 2 targeted anticancer agents, dabrafenib and trametinib, in pediatric patients with a kind of brain tumor called a low-grade glioma, which harbored something called a BRAF V600E mutation in their tumor DNA. By way of background, gliomas account for about 45% of all pediatric brain tumors, and the majority of these gliomas are low-grade, which include World Health Organization grade 1 and 2 tumors. Common types of pediatric low-grade gliomas include pilocytic astrocytomas, gangliogliomas, and low-grade gliomas that are not otherwise specified. Now, mutations in the BRAF gene are common in certain kinds of cancers, particularly melanoma, and novel oral targeted therapies have been developed to effectively treat these tumors by targeting this mutant BRAF gene. A particular mutation in this gene called a V600E mutation occurs in about 15% to 20% of pediatric low-grade gliomas. The presence of this mutation is thought to lead to an increased risk of progression to a higher grade or a more malignant glioma in these patients, and these mutations in their tumors also predict a less favorable response to chemotherapy. In adults, recent studies in patients with malignant gliomas, papillary craniopharyngiomas, and melanomas containing V600E mutations have shown excellent results, with 1one of several similar 2-drug combinations that target both the V600E mutation and a second pathway that cells use to escape from this BRAF blockade. Now, early pediatric data suggested that one of these pairs of drugs, the combination of dabrafenib and trametinib, was safe and tolerable and had the ability to effectively treat patients whose tumors had the V600E mutation. So with that as background, this study was started and enrolled patients from 12 months to 18 years of age who had a low-grade glioma that contained a BRAF V600E mutation. And it randomized them to receive either the combination of dabrafenib and trametinib, or an older, standard cytotoxic chemotherapy regimen consisting of carboplatin and vincristine. Importantly, these patients were newly diagnosed, and this was the first systemic treatment they got, following their surgery or biopsy. 110 patients were enrolled, with 73 given the new targeted therapy combination and 37 receiving the standard combination. The most common types of tumors that the patients enrolled on this study had included pilocytic astrocytoma, ganglioglioma, and low-grade glioma. The results of this trial were that the patients who received the newer combination, targeted treatment of dabrafenib and trametinib, did substantially better than those who received standard, older cytotoxic chemotherapy. Their overall response rate - that's defined as a complete or partial disappearance of the tumor on MRI scan - was 47% versus 11% in the control arm. When patients who had stable disease by MRI were included, 86% of those on the new combination versus 46% of those patients treated with the older chemotherapy had the so-called best clinical response. Now, a large number of patients responding to dabrafenib and trametinib, remain on treatment and are receiving these drugs with an ongoing imaging and clinical response at the time of this report. Patients receiving the new combination had a median or average progression-free survival of 20 months versus about 7.4 months with the older, standard chemotherapy. The investigators conducting this study also had patients fill out a variety of questionnaires to assess their quality of life while on treatment. Once again, the patients who received dabrafenib and trametinib, on average, experienced an improved quality of life in contrast to those on standard chemo who, on average, had a worse quality of life. The new treatment was also well-tolerated with fewer serious adverse events or side effects when compared with standard chemotherapy. And these side effects were no different than what has been seen in patients without brain tumors who have been treated with this combination, including fevers, headaches, fatigue, skin changes, and lower blood counts. The authors appropriately suggested that these findings demonstrate the importance of molecular testing of these pediatric low-grade glioma tumors at the time of diagnosis and that this combination of dabrafenib and trametinib is a new potential standard of care in those patients who have the BRAF V600E mutant, low-grade tumors. Of note, liquid formulations of these drugs have been developed for those pediatric patients who are unable to swallow capsules or tablets. The second presentation at ASCO highlighted the continued importance of prospective randomized clinical trials in patients with malignant brain tumors. Dr. Jann Sarkaria from the Mayo Clinic presented the long-awaited results of the Alliance for Clinical Trials in Oncology cooperative group phase II/III study of a PARP inhibitor or placebo added to standard temozolomide and radiation in adult patients with newly- diagnosed glioblastoma, and in addition, glioblastomas that had specific molecular finding called MGMT promoter methylation. This change to the DNA of the tumors prevents the MGMT DNA repair enzyme from being made in the tumors and leads to a better outcome with temozolomide treatment. Some very elegant laboratory science had suggested that adding a type of drug called a PARP inhibitor, which also causes defects in DNA repair, could lead to improved killing of glioblastoma tumor cells. So patients with newly- diagnosed glioblastomas, which had MGMT promoter methylation on genomic analysis, were enrolled on this study between December of 2014 and October of 2018. The study was conducted in 2 phases separated by a pre-planned pause after the first group of patients were enrolled, which was the phase II part of the study. This was done in order to allow a preliminary analysis of the outcomes of the treatment arms to make sure that there was a signal of activity that justified moving on to test this treatment in a larger number of patients, the so-called phase III part of the trial. This trial design hopes to minimize the number of patients treated with an inactive drug and save years of drug development time by avoiding large trials that go on for a long time with what turns out to be ineffective drugs. For this trial, 447 patients were eventually treated on this trial. Despite the convincing laboratory evidence and early, promising clinical results that led to the trial moving to the second or phase III portion, the final results showed no statistically significant difference in progression-free or overall survival between the 2 arms, that is, those treated with a PARP inhibitor, and those treated with placebo. I personally was very excited about this study and had hoped that the long wait to hear the results indicated that something good was happening. In addition, several of my patients who were treated on the study did exceedingly well, so I, incorrectly, it turns out, expected positive results from the trial. These negative results are a stark reminder of why we spend lots of time and money and energy performing well-designed clinical trials to determine appropriate treatment strategies for our patients, rather than relying on expert opinion or 1 institution's published experience. This approach turns out to be the best way to fairly test treatment strategies and establish new therapeutic approaches which are truly effective. A final, interesting abstract that was presented at a poster discussion session at ASCO was from the group with the University of Pennsylvania in Philadelphia, and it dealt with the risk of bleeding in patients with brain tumors who had blood clots and were then treated with a newer class of blood thinners or anticoagulants called direct oral anticoagulants, or DOACs for short. It's been known for over 100 years that a variety of types of cancer cause patients to be hypercoagulable, that is, to be predisposed to developing blood clots throughout the venous system. Patients with malignant brain tumors have the highest incidence of all tumors of developing blood clots, which typically occur in the legs, called deep venous thrombosis or DVTs, or in the lungs, called pulmonary emboli or PEs. These clots can lead to a variety of severe and debilitating symptoms, including leg pain, swelling, shortness of breath, heart strain, and even death. For the past 2 to 3 decades, affected patients have typically been treated with a class of medications called low-molecular-weight heparins, which need to be injected under the skin once or twice daily. Over the past decade, a new class of oral anticoagulants called DOACs have generally replaced low-molecular-weight heparins as the primary method of treatment for patients with and without cancer who develop venous blood clots because of their safety, ease of administration, and a lack of requirement for regular blood tests or monitoring. However, little, if any, data has been available to determine the safety of these agents in patients with brain tumors and blood clots, a situation where bleeding into the brain or the brain tumor as a side effect of the anticoagulant could be catastrophic. In fact, this potential risk led to the exclusion of patients with brain tumors from several of the large trials which established the safety of the DOACs. Despite the absence of evidence, the DOACs are now pretty broadly used in brain tumor patients for the reasons described above. So this abstract described a cohort of patients with glioblastoma who developed venous blood clots between 2014 and 2021 while under treatment at Penn. The authors reviewed the medical record to determine the relative efficacy or effectiveness and the toxicity or side effects experienced by patients treated with the low-molecular-weight heparins and with the DOACs, including the rates of bleeding into the brain or the brain tumor. 121 patients were identified who fit these criteria, and the cumulative incidence of clinically significant intracranial hemorrhage, that is, bleeding into the brain or the brain tumor, by 30 days after starting the drugs, was minimal and similar in the 2 groups. When measured at 6 months, 24% of the patients in the low-molecular-weight heparin group had developed intracranial bleeding, and 4 of those patients had died from this bleeding, while none of the 32 patients in the DOAC group experienced this complication. Thus, these investigators felt that their data suggested that there was a lower incidence of clinically important intracranial hemorrhage or bleeding in patients with glioblastoma and venous blood clots who were treated with DOACs as compared to low-molecular-weight heparin. They went on to suggest that the use of DOACs was a safe alternative in patients with glioblastoma. Now clearly, either a prospective trial, a larger trial, or additional retrospective evaluations with a larger number of patients are needed to prove the safety of this approach. But this data is pretty comforting, as the use of these agents is now widespread in patients with high-grade gliomas. The ease of administration of a pill once or twice a day, as compared with potentially lifelong injections once or twice a day, is a major quality of life advantage for our patients. Thank you for listening to this brief summary of new research in neuro-oncology from the 2022 ASCO Annual Meeting. ASCO: Thank you, Dr. Lesser. Finally, Dr. Manali Patel discusses new research focused on reducing disparities in cancer care. Dr. Patel is a medical oncologist and Assistant Professor of Medicine at Stanford University. She is also the Cancer.Net Associate Editor for Health Equity. You can view Dr. Patel's disclosures at Cancer.Net. Dr. Patel: Today I have the privilege of discussing several really exciting research abstracts that were presented at the 2022 ASCO Annual Meeting. My name is Manali Patel. I'm a thoracic oncologist, meaning I take care of patients and try to provide good care delivery for patients with lung cancer. And I also am a researcher focused on health equity. I have no relevant disclosures for any of the studies that I will be presenting today with the exception of one that I was leading. And there were several wonderful abstracts that were presented on describing disparities and the ongoing state of disparities continuing within cancer care delivery. What I was particularly struck by were many of the abstracts that I'm presenting this morning and this podcast that really focus on what we can do as a nation and what we can do individually in our clinics to try to move towards action to overcoming these inequities. The first abstract I want to present was looking at how the Affordable Care Act and changes in the Affordable Care Act led to differences in mortality or deaths by race and ethnicity following the enactment in California. And this particular study looked at greater than 150,000 people who were diagnosed with breast cancer, colorectal cancer, and cervical cancer. And they evaluated death rates from these cancers both before and after the implementation of the Affordable Care Act. And what they found was that the cancer death rates for everyone was much lower after the Affordable Care Act was passed, but specifically for individuals who had self-identified as Hispanic ethnicity, who also identified as Black and who identified as White. And so what this abstract showed me was that at a larger level and a macro level, our policies that are enforced at the national level really do play a role in terms of how we can overcome disparities in cancer. Our group, as I mentioned before, has worked on really trying to integrate community health workers into care. So this abstract paired with local union organizations in Chicago and in Atlantic City to try to help individuals who self-identified as having been from families that were from low-income households and racial and ethnic minorities to communicate their goals and their preferences for care and to also better their relationships with their clinicians as well as to describe their symptoms. And what we found in this randomized trial was that for individuals who received this community health advocate who helped them to better engage with their clinician and who also helped them to describe the symptoms that they were experiencing as well as receive community resources such as food boxes if they were food insecure or be connected to household agencies if they were having difficulties with housing, we found a significant improvement in quality of life, but we also found reductions in the use of the hospital unnecessarily. We also found that this translated into reductions in total cost of care, thereby reducing the amount of out-of-pocket costs these individuals were spending on their cancer care. One of the other abstracts that I thought really was reflective of the many different ways that we can move towards action was an abstract which looked at during the pandemic, trying to reduce the number of times people need to come in for mammograms, their biopsies, and then any further testing that they needed after their biopsy. And this particular study evaluated what was called a same-day biopsy service, which layered on a same-day mammogram reading program. So at this particular institution, they had already implemented when you came in to get your mammogram as a woman or a man, you would have a read on the same day. So you did not have to wait to find out what your results were. And what they did further to push better care was that they layered on on that same day you could get your biopsy. So almost a one-stop shop. And what they found was that for everyone, regardless of race and ethnicity, the time to biopsies decreased by almost half. And the median days, for example, from an abnormal mammogram to obtaining a biopsy, meaning a sample of that tissue, that it decreased from 10 days median to 5 days. And particular patient populations did much better. And so they were able to show that when you do interventions that move the care to provide better care for everyone, everyone benefits, but particularly our patient populations who identify as racial and ethnic minorities who were more likely to experience delays in care, they also received some benefit from this intervention. The last study I want to highlight is work which looked at how to improve specialized services for people who would otherwise not receive those. And this particular study looked at stem cell transplantation for people with blood cancers. And what they found was that these services are often only offered in very tertiary centers, so places that may not be as accessible, large institutions that a lot of people may not have access to receiving care. So what they did was they partnered with this large academic institution so that they could build a pathway for individuals who would otherwise not get stem cell transplantation so that they could have access to those services. And it was really a multipronged approach where they not only educated the clinicians in the community practice about the effort, but they also educated the institution-level clinicians about the effort. They also provided shared medical records, which oftentimes in practice, we don't share our medical records with other clinics. And what they were able to do was to convince these clinics and the institution, let's share the medical records so that then you can have access to seeing what's happening for patients that are diagnosed in the community. And then that way we can both document, we can both have access in the community as well as in the institution where they're receiving the specialized service so that there's better communication. They also provided a navigator for each patient that would help each patient to identify any sort of barriers that they may experience to receiving stem cell transplantation. And then they offered telemedicine, which allowed for individuals to receive specialized services in the comforts of their own home without having to travel after the stem cell transplantation had occurred. And what they found was that usually in the institution, most individuals were more affluent. So they had higher levels of socioeconomic status. But after the intervention, individuals that were referred from this community clinic made it such that the affluence really decreased so that it was showing that people who wouldn't otherwise have access, who had identified as having low income, were now able to receive those services and had been receiving transplantation. I think that these studies really do move us towards a new paradigm of taking action on the many disparities that we know continue to happen. I really appreciate you all for listening to this brief summary of the new research on health equity from the 2022 ASCO Annual Meeting, and I hope to see you next year. ASCO: Thank you, Dr. Patel. You can find more research from recent scientific meetings at www.cancer.net. Cancer.Net Podcasts feature trusted, timely, and compassionate information for people with cancer, survivors, and their families and loved ones. Subscribe wherever you listen to podcasts for expert information and tips on coping with cancer, recaps of the latest research advances, and thoughtful discussions on cancer care. And check out other ASCO Podcasts to hear the latest interviews and insights from thought leaders, innovators, experts, and pioneers in oncology. Cancer.Net is supported by Conquer Cancer, the ASCO Foundation, which funds lifesaving research for every type of cancer, helping people with cancer everywhere. To help fund Cancer.Net and programs like it, donate at CONQUER.ORG/Donate.

The evolution of biomarkers informing therapy decisions began in 2004, when the FDA approved a medicine to treat EGFR mutated non-small cell lung cancer (NSCLC). Since then, researchers have identified more than 20 distinct mutations in driver genes that are specific to lung cancer, nine of which are treatable through FDA-approved therapy drugs: epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS1, BRAF V600E, NTRK, MET, RET, and histological expression of programmed death ligand 1 (PD-L1).Confirming a patient's biomarker status can open the door to precision medicine. The molecular characterization of lung cancer has considerably changed the classification and treatment of these tumors, becoming an essential component of pathologic diagnosis and oncologic therapy decisions. The success of targeted anticancer therapies and new immunotherapy approaches has created a new paradigm of personalized therapy and has also led to accelerated development of new drugs for lung cancer treatment. Additional research is needed to identify and help treat the approximately one-third of lung cancer patients for whom biomarkers have yet to be identified.This podcast focuses on clinically relevant cancer biomarkers as targets for therapy, as well as potential new targets for drug development. We speak in our first episode with Dr. David M. Waterhouse, who just moved to the Dana Farber Cancer Institute at Harvard Medical School, and until last month was the former Director of Clinical Research at Oncology-Hematology Care, in Cincinnati. We also talk about how these biomarkers are used in academic versus community hospitals. In our second episode, we will talk with Dr. Sinchita Roy Chowdhuri, a molecular pathologist from University of Texas MD Anderson Cancer Center in Houston, about what you didn't know about actionable biomarkers for NSCLC.

Listen to a soundcast of the June 22nd 2022 FDA approval of Tafinlar (dabrafenib) for in combination w/trametinib (brand name Mekinist) for unresectable or metastatic solid tumors with BRAF V600E mutation.

Dr Subbiah highlights the significance of the FDA approval of dabrafenib and trametinib in adult and pediatric patients at least 6 years of age with BRAF V600E–mutant metastatic or unresectable solid tumors and contextualizes the pivotal data for rare tumor types.

Featuring perspectives from Dr Melissa Johnson, including the following topics: Introduction: KRAS in Lung Cancer (0:00) Case: A woman in her early 60s with adenocarcinoma of the lung and a ROS1 fusion, with bone, brain and leptomeningeal metastases — Gigi Chen, MD (15:52) Case: A man in his late 50s with Stage IVa lung cancer and malignant pleural effusion and a BRAF V600E mutation (PD-L1 60%) — Jiaxin (Jason) Niu, MD, PhD (22:28) Case: A woman in her mid 60s with adenocarcinoma of the lung, a solitary brain metastasis and an ALK fusion — Neil Morganstein, MD (29:33) Case: A woman in her early 50s with metastatic adenocarcinoma of the lung and a RET mutation (PD-L1 TPS 40%) — Rao Mushtaq, MD (36:42) Case: A woman in her early 70s with Stage IV lung adenocarcinoma and malignant pleural effusion and NRG1 fusion — Dr Niu (41:45) Case: A man in his late 60s with metastatic squamous cell carcinoma of the lung with an IDH1 mutation — Sulfi Ibrahim, MD (51:08) MET Exon 14 and HER2 Mutations (54:07) CME information and select publications

In this episode, Lipika Goyal, MD, leads an engaging discussion with Christine Chio, PharmD, BCOP, and Caroline Kuhlman, NP, on current treatment of patients with cholangiocarcinoma. Topics include:Initial diagnosisBiomarker testing to guide treatment with immunotherapies and targeted agentsAdverse event managementStrategies for counseling patientsPresenters:Christine Chio, PharmD, BCOPClinical Ambulatory GI Oncology PharmacistDepartment of PharmacyMassachusetts General HospitalBoston, MassachusettsLipika Goyal, MDAssistant Professor of MedicineDivision of Hematology/OncologyDepartment of MedicineHarvard Medical SchoolAttending PhysicianMassachusetts General Hospital Cancer CenterBoston, MassachusettsCaroline Kuhlman, NPDepartment of Gastrointestinal OncologyMassachusetts General Hospital Cancer CenterBoston, MassachusettsLink to the full program on the CCO website: https://bit.ly/3JGDBCk 

CME credits: 0.25 Valid until: 01-05-2023 Claim your CME credit at https://reachmd.com/programs/cme/clarifying-the-value-of-anti-egfr-therapy-in-metastatic-colorectal-cancer/13269/ Even with the recent advances in therapeutic options for patients with BRAF V600E-mutated metastatic colorectal cancer (mCRC), they still have an uphill climb ahead of them. How will the new standard of care in the second-line setting address global challenges and unmet needs regarding molecular profiling and treatment sequencing options? Join us as 3 experts, Dr. Scott Kopetz, Dr. Elizabeth Smyth, and Dr. Elena Elez, untangle these new advances in treatment and offer their insights on how diagnostic testing can improve patient outcomes.

CME credits: 0.25 Valid until: 28-02-2023 Claim your CME credit at https://reachmd.com/programs/cme/clarifying-the-value-of-anti-egfr-therapy-in-metastatic-colorectal-cancer/13269/ Even with the recent advances in therapeutic options for patients with BRAF V600E-mutated metastatic colorectal cancer (mCRC), they still have an uphill climb ahead of them. How will the new standard of care in the second-line setting address global challenges and unmet needs regarding molecular profiling and treatment sequencing options? Join us as 3 experts, Dr. Scott Kopetz, Dr. Elizabeth Smyth, and Dr. Elena Elez, untangle these new advances in treatment and offer their insights on how diagnostic testing can improve patient outcomes.

Molecular Testing PearlsIn Part 4 of our Heme Path series, we thoroughly examine the details of molecular testing and how it relates to hematologic and oncologic malignancies I. Molecular Testing BasicsA. Provides a means of assessing patient's genotypes, specifically at smaller changes in the genetic information B. How is it performed?1. Polymerase chain reaction (PCR)-based testing, which involves using a specific primer that is complementary to the area of interest on the patient's DNA2. PCR can allow for both amplification and quantification of gene of interest C. Can look for either single gene mutations (faster) or a panel of mutations (slower but more information) also known as NGSII. Clinical Utility of Molecular TestingA. Very useful in risk stratification based on the mutations noted (some mutations are unfavorable and some are favorable)B. Certain genetic mutations have drugs that are effective against them, therefore provides information about targeted therapeutic options C. In hematologic malignancies, can be used to also assess response to treatment1. You can determine minimal residual disease or MRD2. Can look for a gene mutation that was present in the original cancer clone and see if there is any amount of residual cancer left over on the order of 1 in a million cellsD. In solid cancers, used to determine presence of genetic changes that have prognostic and targeted treatment implications1. BRAF V600E mutation in melanoma → BRAF inhibitor pill treatment2. EGFR mutation in lung cancer → EGFR inhibitor pill treatmentIII. How is molecular testing different than FISH?A. Both require choosing probes and understanding what you are looking for before running the testB. FISH (discussed in part 3!) reports out of 200 cells and provides information about only larger kilobase sized genetic changes (translocations, inversions, deletions)C. Molecular testing analyzes a much larger number of cells and can detect changes at the single base pair level. Much more detailed and microscopic evaluation of genetic changesIV. Single Gene Molecular TestingA. Look for a specific gene mutation (i.e. EGFR for lung cancer, BRAF for melanoma, FLT3-ITD for AML)B. Pros: 1. Faster turnaround time 2. Has a higher resolution and effective for detecting MRDB. Cons:1. Only looks for one genetic mutation as opposed to a panel like in NGS2. Some diseases ideally require understanding of multiple mutations not just one for prognostication and treatment planningV. Next Generation Sequencing (NGS)A. Allows to sift through a larger part of the genome to identify a panel of mutations B. Panel of mutations chosen is based on the clinical context1. For example: NGS for acute myeloid leukemia is much different than NGS testing for lung cancer as each cancer has a much different genetic mutation profileC. Overview of technical aspects of running NGS1. Massively parallel sequencing meaning that many tiny primers are used and the areas that primers encode may be overlapping2. A computer takes all of the smaller pieces and puts them together to determine the correct sequenceD. Pros:1. Gives us an understanding of many different mutations present based on the panel chosen2. Again, this has both prognostic and predictive treatment implicationsE. Cons:1. May find mutations of undetermined significance meaning we currently do not understand how these mutations will affect prognosis and treatment decisions2. Very time consuming (~2-4 week turnaround time)3. CostlyReferences:1. https://jamanetwork.com/journals/jamaoncology/fullarticle/2734828 - Quick overview of NGS2. https://ashpublications.org/blood/article/125/26/3996/34323/Minimal-residual-disease-diagnostics-in-acute - Look at table 1 to see the difference in sensitivity for MRD testing3. https://www.oncotarget.com/article/27602/text/ - Emphasizes prognostic relevance of EGFR mutations in NSCLC4. https://www.nejm.org/doi/full/10.1056/NEJMoa1612674 - Phase 3 trial showed that targeted treatment for EGFR mutation in NSCLC was superior to chemotherapy5. https://www.nejm.org/doi/full/10.1056/nejmoa1614359 - Phase 3 trial showed that targeted treatment of FLT3 mutation in AML improved outcomesPlease visit our website (TheFellowOnCall.com) for more information Twitter: @TheFellowOnCallInstagram: @TheFellowOnCallListen in on: Apple Podcast, Spotify, and Google Podcast

Featuring perspectives from Dr Jason Luke, including the following topics:  Introduction (0:00) DREAMseq Phase III Study (3:03) Case: A woman in her mid-50s with metastatic melanoma and a BRAF V600K mutation — Evan J Lipson, MD (18:08) Case: A man in his mid-60s with metastatic melanoma and a BRAF V600E mutation — Raji Shameem, MD (22:23) Case: A man in his late 60s with metastatic melanoma and a BRAF V600K mutation — Syed F Zafar, MD (33:04) Case: A man in his late 70s with melanoma and a history of transient ischemic attacks — Elizabeth Guancial, MD (37:39) Case: A man in his late 40s with resectable melanoma — Dr Lipson (42:38) Case: A man in his mid-50s with metastatic melanoma and a BRAF mutation — Allan Freedman, MD (46:08) Journal Club with Dr Luke (49:49) Beyond the Guidelines (52:39) CME information and select publications

Featuring perspectives from Prof Georgina Long, including the following topics: Introduction (0:00) Making Progress Against Melanoma — A Historical Perspective (4:03) Management of BRAF Inhibitor-Related Pyrexia (17:26) Case: A man in his late 70s with melanoma and a history of transient ischemic attacks — Elizabeth Guancial, MD (28:23) Case: A woman in her late 50s with metastatic melanoma and asymptomatic brain metastases — Evan J Lipson, MD (42:56) Case: A woman in her mid-80s with metastatic melanoma — Mamta Choksi, MD (51:27) Case: A man in his late 50s with metastatic melanoma with a BRAF V600E mutation — Allan Freedman, MD (59:40) CME information and select publications

An interview with Dr. David Schiff from the University of Virginia Medical Center in Charlottesville, VA, and Dr. Michael Vogelbaum from Moffitt Cancer Center in Tampa, FL, co-chairs on “Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline.” This guideline comprehensively addresses the treatment of brain metastases from non-hematologic solid tumors, including surgery, systemic therapy, radiation therapy, and timing of therapy. Read the full guideline at www.asco.org/neurooncology-guidelines.   TRANSCRIPT [MUSIC PLAYING] SPEAKER 1: 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 asco.org/podcasts. My name is Brittany Harvey, and today I am interviewing Dr. Michael Vogelbaum from Moffitt Cancer Center in Tampa, Florida, and Dr. David Schiff from the University of Virginia Medical Center in Charlottesville, Virginia, Co-chairs on Treatment for Brain Metastases, American Society of Clinical Oncology, Society for Neuro-Oncology, and American Society for Radiation Oncology Guideline. Thank you for being here, Dr. Vogelbaum and Dr. Schiff. MICHAEL VOGELBAUM: My pleasure. BRITTANY HARVEY: Before we begin, 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. Vogelbaum, do you have any relevant disclosures that are directly related to this guideline topic? MICHAEL VOGELBAUM: I have no disclosures relevant to this guideline. BRITTANY HARVEY: Thank you. Then, Dr. Schiff, do you have any relevant disclosures that are directly related to this guideline topic. DAVID SCHIFF: Hi, Brittany. No, I do not. BRITTANY HARVEY: Great. Then first, Dr. Schiff, can you give us an overview of the scope and the purpose of this guideline? DAVID SCHIFF: Sure. Our overall purpose was to provide guidance on the appropriate treatment of adult patients with parenchymal brain metastases from solid tumors, encompassing surgery, radiation, and systemic therapy, as well. Previous guidelines in this area were for the most part produced by neurosurgeons and radiation oncologists for their respective professional organizations, although they did incorporate multidisciplinary input. But over the last decade, treatment options for certain types of brain metastases have undergone a substantial change. The expanding armamentarium for medical oncologists in treating both extra-CNS disease as well as brain metastases highlighted the need for a new set of guidelines to evaluate the role of systemic approaches, such as targeted agents and immunotherapy, for the primary treatment of brain metastases in the context of more established treatments like surgical resection, radiosurgery, and fractionated radiotherapy. Additionally, recent studies have clarified the role of radiation techniques like whole brain radiation with hippocampal avoidance and radiosurgery to surgical resection cavities. By assembling a multidisciplinary group of experts from surgical neuro-oncologists, medical oncologists, neuro-oncologists, and radiation oncologists, we sought to provide as comprehensive and up to date a set of therapeutic guidelines as possible. In order to accomplish this, the panel performed a systematic review of randomized as well as nonrandomized evidence from 2008 through April, 2020. We focused on the roles of surgery, systemic therapy, and radiation therapy, as well as the timing and interactions among these modalities. And we included all randomized clinical trials, as well as large single arm phase II studies and institutional case series, and we also reviewed case control and cohort studies. BRITTANY HARVEY: OK, great. That's helpful background. And then you mentioned a couple focus areas, as well, of the systematic review. And so I'd like to review the key recommendations that were based off that evidence. So, starting with surgery, Dr. Vogelbaum, what are the key recommendations for surgery in adult patients with brain metastases? MICHAEL VOGELBAUM: So, the role of surgery, I think, was well established via randomized trials to some degree, and then via some of the larger single arm studies. Patients with suspected brain metastases without a primary cancer diagnosis were felt to benefit from surgery to obtain a diagnosis and undergo removal of the tumor. But more to the point, patients with larger tumors with mass effect-related symptoms are the ones most likely to benefit from surgery. What we also noted was that patients who have multiple brain metastases with extensive and uncontrolled systemic disease are unlikely to benefit from surgery unless the remaining disease is controlled via other measures, typically medical measures. We also contemplated the type of resection performed, the technique being used. There was some developing literature looking at the techniques of either an en bloc resection or a piecemeal resection. And when we critically evaluated the literature, we felt that no recommendation could be made regarding the method of resection, as there was not sufficient evidence to support one approach over another. Another technique that is being used more recently is the use of laser interstitial thermal therapy, which is a minimally invasive technique to treat tumors in general. But again, there was insufficient evidence to really be able to make a recommendation for or against the use of LITT, as it's called. BRITTANY HARVEY: OK, thank you for reviewing both those techniques and those recommendations and highlighting where there wasn't enough evidence to actually make a recommendation. So, then, following that, Dr. Schiff, what does the guideline recommend for patients with brain metastases regarding systemic therapy, including chemotherapy, immunotherapy, and targeted agents? DAVID SCHIFF: Brittany, there is a role for systemic therapy as the initial or primary modality in some cases, but I think it's really important to emphasize this only pertains to patients whose brain metastases are asymptomatic and those with particular histologies or molecular profiles. So, there are really-- there are three primary sites for which targeted or immunotherapy can be considered. The first is non-small cell lung cancer, for which osimertinib, or if you're in China, where there's access to another drug called icotinib, specifically for EGFR-mutated disease, alectinib, brigatinib, and ceritinib are appropriate approaches in ALK-rearranged asymptomatic brain metastases. And finally, pembrolizumab in combination with pemetrexed and a platinum agent in immunotherapy naive patients whose tumors express PD-L1. The second primary tumor is melanoma. And for melanoma patients who have asymptomatic BRAF V600E mutant brain metastases, dabrafenib with trametinib is an appropriate option to consider. For all melanoma patients with asymptomatic brain metastases, ipilimumab with nivolumab is also an option. And finally, for breast cancer, the combination of tucatinib, trastuzumab, and capecitabine for HER2 positive asymptomatic brain metastases in patients who have progressed on previous anti-HER2 antibody therapy. When patients treated with systemic therapy progress intracranially, local therapies such as surgery, radiation, and radiosurgery should not be deferred. BRITTANY HARVEY: OK, those are helpful notes for clinicians, and particularly around the primary tumor sites. So, then, Dr. Vogelbaum, what are the key recommendations for radiation therapy in patients with brain metastases? MICHAEL VOGELBAUM: So, Brittany, the panel started by noting which patients would not benefit from radiation therapy, in particular, those with asymptomatic brain metastases and a poor performance status, with a Karnofsky Performance Score, or KPS, of less than or equal to 50, or performance status of less than 70 and no systemic therapy options. In those cases, radiation therapy is unlikely to be of real benefit. But then when speaking to the different modalities of radiation to be used, a lot of the review focused on the two most commonly used modalities, which is Stereotactic Radiosurgery, or SRS, versus Whole Brain Radiotherapy, or WBRT. And the first recommendation was that SRS alone as opposed to either whole brain radiotherapy alone or a combination of the two should be offered to patients with one to four unresected brain metastases, except for the situation of small cell carcinoma, which has a different approach that's used often with prophylactic cranial irradiation. So, that's a separate group. But for others, SRS is the modality that should be offered. And then for patients who underwent surgical resection of their brain metastases, we know that there needs to be some form of radiation treatment to the surgical cavity. And the recommendation was that SRS alone should be offered to those patients if the surgical cavity can be safely treated, and considering the extent of remaining intracranial disease. Obviously, for patients who have a lot of disease but otherwise have a treatable systemic disease, then whole brain radiotherapy may make more sense. But for the ones that are more limited after surgery, it should be SRS. And then when the panel considered a situation where you have patients with more than four unresected metastases and the options included radiosurgery, whole brain radiotherapy, or radiosurgery plus whole brain radiotherapy-- and in general, these are reasonable options. But it was felt that SRS may be preferred for patients with better prognosis or where systemic therapy that is known to be active in the central nervous system is available. Additional recommendations revolved around both protective, radioprotective, and radiosensitizing agents. So, in terms of trying to protect memory, there are two approaches that are used. One is to give memantine during whole brain radiotherapy, or to do whole brain radiotherapy using a hippocampal avoidance technique. And it was felt that either one of those or both should be offered to patients who will receive whole brain radiotherapy and have no tumors in the hippocampus, and they're expected to live more than four months. And then finally, that radiation sensitizing agents should not be offered to patients, because they've not been shown to be effective. BRITTANY HARVEY: Understood. And it's helpful to know both what those recommendations are for specific approaches, and as you said, critical to know who will and who will not benefit from radiation therapy. So, then we've just reviewed the key surgery, systemic therapy, and radiation therapy recommendations. Dr. Schiff, did the panel recommend anything regarding the timing of surgery, radiation therapy, and systemic therapy? MICHAEL VOGELBAUM: The panel had just a couple of points in this regard. Although there are some recent data suggesting a decreased incidence of leptomeningeal metastases in patients who undergo radiosurgery before craniotomy, as compared to the reverse sequence, the panel concluded no recommendation on this point regarding the specific sequence of therapy could be made. And to reiterate, for those circumstances in which systemic therapy may be of use for brain metastases, that therapy should proceed, local therapy like surgery or radiation, only if the brain metastases are asymptomatic. BRITTANY HARVEY: Great. Thank you both for reviewing these recommendations. In your view, Dr. Vogelbaum, what is the importance of this guideline, and how will it impact clinicians? MICHAEL VOGELBAUM: I think one of the important points that David raised that at the beginning was that this really is the most comprehensive look at the evidence revolving around the treatment of patients with brain metastases and leptomeningeal disease. And in particular, this may be new information for an audience that has not been involved in that treatment for many decades, the medical oncology community. So, I think some of the impact on clinicians may be that the guidelines will help them understand the durability of surgery and radiosurgery, and those had been the only treatments available for a long time. And so now we have these new medical therapies that are showing activity in the brain, but one needs to balance that against what is known about the effective treatments in the past. Some of the new targeted immunotherapies may not provide as consistent or durable of a benefit as has been shown previously with surgery and radiotherapy. Hopefully, understanding this challenge with respect to consistency and durability will serve to support the development of phase 0 or window of opportunity clinical trials to better understand the determinants the biological determinants of response or resistance to systemic therapies we want to improve on that, for sure, and those clinical trials are going to be essential for us to be able to do that. And then ultimately, also, identify opportunities to synergistically combine radiation and medical therapies and better understand the timing of these combinations. This is a great area for clinical trial development in the future. BRITTANY HARVEY: Definitely. We'll look forward to future research in those areas. So then, finally, Dr. Schiff, to wrap us up, how will these guideline recommendations affect patients? DAVID SCHIFF: Yeah. Over the last 30 years, the management of brain metastases have involved hugely, from an area where almost everyone got whole brain radiation therapy and many patients died from their brain disease. The use of local therapies like surgical resection and radiosurgery has greatly improved local control of brain metastases. And with options like radiosurgery alone for a limited number of brain metastases, systemic therapies as the initial approach, and hippocampal avoidant whole brain radiation therapy with memantine, patients are experiencing improved long term cognitive function and quality of life, as well. So, I think the careful delineation of the role of each of these modalities that these guidelines provide will really help maximize benefit and minimize the risk for this very large number of cancer patients. BRITTANY HARVEY: Definitely, improve quality of life is always a goal. So, I want to thank you both for your work on these guidelines and thank you for taking the time to speak with me today, Dr. Vogelbaum and Dr. Schiff. DAVID SCHIFF: My pleasure. MICHAEL VOGELBAUM: Thank you, Brittany. 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/neurooncology 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. [MUSIC PLAYING]

Proceedings from a daylong symposium hosted in partnership with Florida Cancer Specialists, featuring key clinical presentations and papers in gastrointestinal cancers. Featuring perspectives from Drs Tanios Bekaii-Saab and Kristen Ciombor, including the following topics: Introduction Case: A woman in her early 70s with metastatic hepatocellular carcinoma (HCC) — Dr Peles Treatment Options for Child-Pugh B HCC — Dr Choksi First-Line Treatment for Advanced HCC with Child-Pugh B or C Cirrhosis — Dr Bekaii-Saab Second-Line Systemic Treatment for Advanced HCC After Atezolizumab/Bevacizumab — Dr Ciombor Case: A woman in her early 60s with microsatellite instability-high Stage IV colorectal cancer (CRC) and a BRAF V600E mutation — Ina J Patel, DO Case: A woman in her late 50s with microsatellite stable metastatic CRC and a KRAS G12C mutation — Dr Apuri First-Line Immunotherapy for MSI-High dMMR Metastatic CRC Chalk Talk — Dr Ciombor ctDNA in Early and Metastatic CRC Chalk Talk — Dr Bekaii-Saab Gastric, Gastroesophageal and Esophageal Cancers Chalk Talk — Dr Ciombor Case: A woman in her late 60s with metastatic pancreatic cancer — Lowell L Hart, MD Case: A woman in her early 90s with metastatic cholangiocarcinoma — Dr Choksi CME information and select publications

Featuring perspectives from Drs Ross Camidge, Alexander Drilon and Justin Gainor, including the following topics:  Selection and Sequencing of Therapy for Patients with Non-Small Cell Lung Cancer (NSCLC) with an ALK Rearrangement Introduction (0:00) Case: A woman in her mid 30s with newly diagnosed metastatic NSCLC with an ALK mutation — Nikesh Jasani, MD (5:58) Case: A woman in her early 50s with metastatic adenocarcinoma of the lung with an ALK rearrangement — Lowell L Hart, MD (10:03) Optimal Use of Recently Approved RET Inhibitors in the Care of Patients with NSCLC with RET Alterations Case: A woman in her early 60s with metastatic adenocarcinoma of the lung, PD-L1 0%, KIF5B-RET fusion — Mohamed K Mohamed, MD, PhD (15:02) Case: A man in his early 70s with metastatic adenocarcinoma of the lung, PD-L1 65%, KIF5B-RET fusion — Joshua Bauml, MD (18:08) Current and Future Directions in the Management of NSCLC with ROS1 Rearrangement Case: A man in his late 60s with metastatic adenosquamous carcinoma of the lung, PD-L1 >95%, ROS1 rearrangement — Margaret Deutsch, MD (25:24) Case: A woman in her late 50s with metastatic adenocarcinoma of the lung with a ROS1 fusion and severe rheumatoid arthritis — Gigi Chen, MD (29:49) Rational Approaches to Targeting BRAF in Patients with NSCLC Case: A man in his early 60s with metastatic adenocarcinoma of the lung with a BRAF V600E mutation, PD-L1 TPS 80% — Neil Morganstein, MD (38:04) Case: A man in his early 70s with metastatic NSCLC with a BRAF V600E mutation — KS Kumar, MD (42:59) Other Validated Targets Beyond EGFR (eg, MET, KRAS G12C) Case: A woman in her early 70s with metastatic adenocarcinoma of the lung with MET exon 14 skipping and MET amplification mutations, PD-L1 TPS 95% — Dr Mohamed (47:02) Case: A woman in her mid 40s with metastatic adenocarcinoma of the lung with a KRAS G12C mutation — Sulfi Ibrahim, MD (50:57) CME information and select publications

Host: Scott Kopetz, MD, PhD Guest: Rona Yaeger, MD Advances in the diagnosis and treatment of mCRC enable personalized care based on the molecular profile of the tumor to achieve improved outcomes. About 5% to 15% of mCRC patients have a mutation in the proto-oncogene BRAF. BRAF is part of an essential cell signaling pathway, mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK). The BRAF V600E mutation induces constitutive activation of BRAF, leading to increased cell growth and proliferation downstream. Patients with the V600E mutation have a 2-fold increased risk for mortality compared to patients with wild-type BRAF, suggesting this gene mutation may act not only as a prognostic biomarker but also as a predictive biomarker. Understanding the current research regarding the consequences of the V600E mutation and testing for it can help guide treatment decision-making in patients with BRAF V600E–mutated mCRC. This web-based, on-demand activity will feature an expert panel discussion on the latest trends and emerging research in the treatment of BRAF-mutated mCRC. Expert faculty will review and provide their interprofessional perspectives on testing patients for BRAF mutations, recent and emerging data for combination therapies, appropriate treatment selection, and side effect management.

To begin this week, we'll discuss a report that focused on the characteristics and outcomes of patients with both COVID-19 and cancer in Wuhan, China. Next, we'll turn to a paper on the efficacy of stereotactic ablative radiotherapy in men with oligometastatic prostate cancer. Lastly, we'll talk about the FDA's approval of encorafenib plus cetuximab in patients with BRAF V600E–mutated colorectal cancer.Coverage of stories discussed this week on ascopost.com:Outcomes of COVID-19 Infection in Patients With Cancer in Wuhan, ChinaStereotactic Ablative Radiation vs Observation in Oligometastatic Prostate Cancer: ORIOLE TrialFDA Approves Encorafenib/Cetuximab for BRAF V600E–Mutated Metastatic Colorectal Cancer

This week, we'll be featuring three researchers discussing findings presented at the 2020 Gastrointestinal Cancers Symposium: Dr. Scott Kopetz, of The University of Texas MD Anderson Cancer Center, discusses quality-of-life results from the BEACON CRC trial in BRAF V600E–mutated colorectal cancer; Dr. Brian Wolpin, of Dana-Farber Cancer Institute, talks about the efficacy of a blood-based screening test using cell-free DNA to identify methylation signals of hard-to-detect gastrointestinal cancers; and Dr. Zev Wainberg, of UCLA Medical Center, discusses a subset analysis of how a combined positive score in gastric and gastroesophageal junction cancers related to the efficacy of pembrolizumab in patients with PD-L1–positive disease.Coverage of stories discussed this week on ascopost.com:2020 GI Cancers Symposium: Patient-Reported Outcomes From IMbrave150, BEACON CRC2020 GI Cancers Symposium: Detecting GI Tumors Using a Cell-Free DNA Test