ASCO Guidelines

Dr. Patel and Dr. Leighl discuss updated guidelines for treating stage IV NSCLC without driver alterations, focusing on biomarker testing and treatment options. They explore the impact of immunotherapy over chemotherapy in first-line treatment and emphasize the importance of patient-clinician communication to improve outcomes.

Drs. Banu Arun and Sana Al Sukhun discuss the ASCO resource-stratified guideline on systematic treatment for metastatic breast cancer. They highlight the four-tier resource setting approach, key recommendations for different breast cancer subtypes, and implementation considerations. This guideline is crucial for optimizing cancer care in regions with limited resources.

Dr. Isabelle Bedrosian and Dr. Mark Robson discuss the new guideline from ASCO and SSO on germline testing in patients with breast cancer. They discuss the framework for which patients should be offered BRCA1/2 testing, and what additional moderate- and high-penetrance genes may be considered for inclusion in germline testing. They highlight key aspects of personal and family history, recommendations surrounding counseling for genetic testing, and the impact for patients and their families. They close the conversation with a discussion of gaps in the research. Read the full guideline, Germline Testing in Patients with Breast Cancer: ASCO-SSO Guideline TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/breast-cancer-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.23.02225 Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts, delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.  My name is Brittany Harvey, and today I'm interviewing Dr. Isabelle Bedrosian from the University of Texas MD Anderson and Dr. Mark Robson from Memorial Sloan Kettering Cancer Center, co-chairs on “Germline Testing in Patients with Breast Cancer: American Society of Clinical Oncology – Society of Surgical Oncology Guideline.”  Thank you for being here, Dr. Bedrosian and Dr. Robson. Dr. Mark Robson: My pleasure. Dr. Isabelle Bedrosian: Thank you, Brittany. Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Bedrosian and Dr. Robson, 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 then, to jump into the content of this particular guideline, Dr. Bedrosian, could you give us a general overview of both the scope and the purpose of this guideline? Dr. Isabelle Bedrosian: Yeah, sure. So, in the last decade or so, the whole area of clinical cancer genetics has become incredibly complicated, driven, I think, predominantly by the development of extended gene testing. And in the midst of this complexity, our goal here was to try to give providers a framework through which they can think about the application of germline testing within their patient population. And really, this framework was to help them think through how testing can best be applied to patients that were both newly diagnosed with breast cancer or had a history of breast cancer, and also to help them think through the scope of that testing as well, be it BRCA testing or testing in a more extended fashion that may help inform longer-term decisions such as risk management. Brittany Harvey: Absolutely. We appreciate your efforts to provide recommendations in this framework in this complicated space.  So then, I'd like to review the key recommendations of this guideline developed by the expert panel. So first, Dr. Robson, who should be offered BRCA1/2 testing? Dr. Mark Robson: Thank you. I think this is perhaps one of the most important things that comes out of the guideline is that we, and the group, are now recommending that anyone who is either newly diagnosed with breast cancer at or before the age of 65, or if they're over 65 and have suggestive personal or family history criteria, or alternatively, if they are eligible for PARP inhibitor therapy, that they all be offered BRCA1 or BRCA2 testing. And the same would hold for women who had a personal history of breast cancer but were not currently under active treatment if their diagnosis had been made at or before 65 or older than that, with certain criteria then they should be offered testing. This is a much simpler way to look at things than the rather complicated existing criteria, which are perhaps a bit both difficult to remember and unfortunately inadequately sensitive in a setting where there is such critical, both therapeutic and risk management implications to the identification of a BRCA mutation. Dr. Isabelle Bedrosian: Yeah, I would just also add there's one other, albeit a much smaller group of women for whom BRCA testing could be considered, and those are women who develop a second primary breast cancer. That's another group that I think we can think about offering BRCA1/2 testing to. Brittany Harvey: Understood. I appreciate you both reviewing those recommendations for BRCA1/2 testing.  So, Dr. Bedrosian, which additional genes does the panel recommend including in germline testing? Dr. Isabelle Bedrosian: Yeah. So, in this area, outside of BRCA genes, Brittany, I think the panel didn't make any definitive recommendations or any specific genes that should be tested for. I think the panel felt that the decision to test for additional high penetrance genes and also for some moderate penetrance genes should be guided by the specifics of the individual case, whether the identification of germline mutations makes sense in the context of the patient's personal history and family history. So, in other words, is there a worrisome pattern in the family that might warrant more in-depth testing beyond BRCA, and also considerations around the implications of those test results. Would it change the management for the patient themselves? Either in the treatment of the index malignancy, which, in the case of most of these non-BRCA genes, there really is not changes to the management of the breast cancer that would be offered based on the finding of non-BRCA germline mutations. But potentially, the finding of a non-BRCA germline mutation in a breast cancer patient might help better understand risks of second malignancies that would then be addressed. And certainly for families as well of the patients, identifying those that are carriers could offer opportunities for risk assessment, risk mitigation. Dr. Mark Robson: I totally agree with Dr. Bedrosian. One thing I think it's important to understand is that most commercial testing done in the United States now does involve panels of genes. And the group certainly did not intend to suggest that that practice not continue. So, I think if somebody has a history of breast cancer, I think the panel felt that it would at least be reasonable to test for breast cancer susceptibility genes. However, this issue of do you test for all of the high penetrance genes when the family history doesn't suggest it, was certainly something we left open and we did not want to imply that it was obligatory to test for a large number or large panel of genes that weren't related to the patient's personal and family history. So, in other words, didn't want to imply that it was obligatory to do an extremely large panel just as a target of opportunity, if you will. Dr. Isabelle Bedrosian: I think really a key part of these guidelines was that we wanted to afford the oncologist flexibility. It's very difficult beyond BRCA to be prescriptive. There are so many considerations about testing, and those considerations will be applied differently in every patient context. So, we really wanted to let providers know that while they have to think about these other genes, and oftentimes there'll be good reason to do these other genes as part of the overall germline testing, again, that it's not obligatory to do so. It's not a fixed set that needs to be tested for. And really, the understanding of the patient's personal history, family history, therapeutic goals, and risk assessment goals should be used to determine kind of the ultimate scope of the testing. Brittany Harvey: It sounds like these decisions will be individualized, based on patient characteristics and with working between both patients and their clinicians. So that leads into my next question. But, Dr. Robson, how should patients with breast cancer considering genetic testing be counseled? Dr. Mark Robson: With this recognition and emphasis on the therapeutic implications for patients with breast cancer, both surgical and potentially systemic using PARP inhibitors, the approach has gradually moved away from the concept of testing for personal utility, in other words, just wanting to know, and more towards the idea of this being a clinically useful test that's to some extent necessary for the appropriate management of a fair number of patients. And so the counseling is usually- the pre-test counseling is perhaps more educational than we have used in the past, rather than this extensive discussion of whether or not somebody wants to know. Obviously, it's always the patient's ultimate decision whether or not to be tested, and we have to give them the same elements of education that we would have given back in the day. But it can be delivered in a more didactic type of context rather than necessarily the back and forth that takes place with formal genetic counseling.  Now, for patients who have complicated or extensive family histories or who have histories that may suggest predispositions other than those for breast cancer, the type of thing that Dr. Bedrosian was talking about earlier, they could certainly benefit, again, from a more formal evaluation by a provider experienced in cancer genetics to help select what the scope of the testing should be, for instance, and also to help interpret those results. And certainly anybody who had a pathogenic variant or a likely pathogenic variant identified should be considered for meeting with somebody who's experienced in clinical cancer genetics both to interpret and also to help with family expansion when appropriate.  Brittany Harvey: Excellent. Thank you for reviewing those recommendations from the expert panel. So, Dr. Robson just touched on this a little bit, but Dr. Bedrosian, how will these guideline recommendations affect patients with breast cancer and their families? Dr. Isabelle Bedrosian: Yeah, so from a patient perspective, I think there are two ways that these recommendations can impact care. For those women that are identified as germline carriers, specifically with BRCA, it will open the door for receipt of PARP inhibitors, which are currently recommended for patients that are high-risk primary cancer or those with metastatic disease. The other ways that patients will be affected by a germline testing is really in this idea of second cancer risks. Some of these germline mutations are well established to carry risks of either second primary breast cancer or non-breast malignancies. And understanding those risks will allow the patients and their providers to create management strategies, be they surgical or with more intensified screening that will help them mitigate the effects of that germline-driven risk.  And I think similarly for the families of patients, the ones the proband has identified, I think that family now has a very real opportunity to better understand their cancer risks and again be able to more effectively manage those risks through either surgical or non-surgical means. And it would really underscore the family component of this. I think oftentimes oncologists are very much focused on the patient and admittedly so that is the person that has the most immediate needs. But I think there's a real opportunity to extend efforts at prevention and early detection by identifying the at-risk family members and allowing them the opportunity to access care that mitigates their cancer risks and hopefully will improve survival outcomes in so doing. So, I think the opportunities for families here to understand risks of germline testing is a really important one to underscore from these recommendations. Dr. Mark Robson: Just to expand a little bit on what Dr. Bedrosian was saying, I think this is a very important place for collaboration between the oncology community and the clinical cancer genetics providers because the oncologist is pretty occupied taking care of all of their cancer patients, and the approach to people who are unaffected is a little bit different. People who are unaffected perhaps do need a little bit more pretest counseling to understand the pros and cons of choosing to be tested for the familial mutation. And certainly that idea of family expansion is something that's well known to clinical cancer genetics providers and that's really very much something that they can help the primary oncologists do. Brittany Harvey: Absolutely, these recommendations have impacts beyond just the individual patient, but also for their families as well.  So then, finally, Dr. Robson, what are the outstanding questions regarding germline testing in breast cancer? Dr. Mark Robson: Oh, there are so many. Where should I start? I think over the years we've become, as a community, pretty comfortable managing individuals who have BRCA1 or BRCA2 mutations. There are certainly some questions left, but there's a lot of familiarity with that. I think the challenges expand into these what we call moderate penetrance genes and how to guide people with alterations in those genes. Because except for PALB2, which is relatively uncommon, many of the other genes don't really have the same implications for therapy because it's not clear that they confer PARP sensitivity. It's not at all clear that they have high risks of contralateral breast cancer. And even in the unaffected setting, we know that there's a wide distribution of risk for people who carry these alterations. And some individuals with these alterations probably are not at increased risk at all because they have protective factors. So the management of breast cancer susceptibility genes beyond BRCA1 and BRCA2 is still very much in evolution. They can't be handled exactly the same way as a woman with a BRCA carrier.   And then, of course, this issue of how much should we test and what do we do with some of the alterations that we find, if you will, out of context, what are the implications for that and what's the most appropriate management? Those still remain very much open questions. So I think there's still plenty of work to do. Dr. Isabelle Bedrosian: Yeah, I agree. I think one of the enormous challenges has been the disconnect between how rapidly our technology has advanced and can sequence alterations, and our ability to really understand the biologic and clinical implications, which really is a time-dependent issue. We need to see over time how patients do for us to understand the implications of some of these germline findings. So that disconnect is a very difficult one to bridge, particularly, I think, for surgical oncologists because they are oftentimes referred patients who don't have a cancer history, necessarily, or have a distant history, and really the concern is “I'm at risk and I would like to reduce my risk.” And it becomes very difficult to counsel patients as to the benefits of risk reduction when we don't have such a great handle on the degree to which they are actually at risk. So that really is a significant gap, I think, for surgeons in particular to have to contend with. Brittany Harvey: Definitely. We'll look forward to answering some of those questions as we learn more and get more data to address those gaps.  So I want to thank you both so much for your work to develop this framework for genetic testing in breast cancer, and thank you so much for your time today, Dr. Robson and Dr. Bedrosian. Dr. Isabelle Bedrosian: Thank you, Brittany.  Dr. Mark Robson: Thank you for having us. Brittany Harvey: 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/breast-cancer-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.

Dr. Rohan Garje reviews the latest rapid recommendation update for the ASCO guideline on systemic therapy in men with metastatic castration-resistant prostate cancer (mCRPC). He reviews what prompted the guideline update and the latest recommendation from the expert panel. Dr. Garje also discusses future updates to the guideline that are currently underway, and outstanding questions regarding systemic therapy for mCRPC. Read the latest update, “Systemic Therapy Update on 177Lutetium-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer: ASCO Guideline Rapid Recommendation Update” at www.asco.org/genitourinary-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/genitourinary-cancer-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.23.02128  Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Rohan Garje from Miami Cancer Institute Baptist Health South Florida, lead author on “Systemic Therapy Update on 177Lutetium-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer: ASCO Guideline Rapid Recommendation Update.  Thank you for being here today, Dr. Garje. Dr. Rohan Garje: Thank you so much for having me, Brittany. Brittany Harvey: And then, just before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines in 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. Garje, who has joined us on this episode today, are available online with the publication of the update in the Journal of Clinical Oncology, which is linked in the show notes.  So then, to dive into the content of this rapid update, first, Dr. Garje, what prompted this rapid update to the guideline on Systemic Therapy for Metastatic Castration Resistant Prostate Cancer? Dr. Rohan Garje: So, last year, when we did a rapid update on ASCO prostate cancer guidelines, we recommended the addition of 177Lutetium-PSMA-617, also called as PLUVICTO, as a treatment choice for patients who have PSMA-positive metastatic castrate-resistant prostate cancer. After that approval, the primary imaging modality at the time of this initial drug approval was based on gallium-68, which was used in that clinical trial, which was VISION. Since then, we have access to a couple of new radiotracers, one of them being piflufolastat, also called as PYLARIFY, and the newer one called flotuflastat F-18, which is also called as POSLUMA, as additional imaging agents to detect PSMA-positive lesions. So, our expert panel group, along with my co-chairs, we thought to add these additional choices for patient selection because this provides the treating physicians additional options because there really are nuances involved in these imaging agents. So this helps broaden the access to  177Lutetium-PSMA-617 for patients. Brittany Harvey: Excellent. I appreciate you providing that background that the panel was reviewing.   So then, based on this updated information, what is the updated recommendation from the expert panel? Dr. Rohan Garje: So, for the new recommendation, the guideline expert panel recommends use of one of these three radio tracers, that is Ga-68PSMA-11, or piflufolastat F-18, or flotufolastat F-18 as one of the radiotracer choices to screen for PSMA-positive lesions on a PSMA scan, and potentially select the patients for PSMA 177lutetium. This way, we can use one of these three agents rather than previously recommended, as per FDA approval of gallium 68. Now, the reason behind these additional agents, as I was just alluding in my initial comment, is each institution may have access to one of these agents. For example, if a patient had a testing done by piflofolastat or flotufolastat, if they are PSMA-positive, it has shown PSMA-positive lesions as per VISION criteria, we do not suggest the patients to undergo gallium-68 assisted imaging again to have selection for PSMA lutetium therapy. This is unnecessary imaging. We have evidence now, based on the studies which were done with PYLARIFY, which is the piflofolastat, or the flotufolastat, which is POSLUMA, that they are equally good in detecting PSMA-positive lesions. This way we can avoid additional imagings for patients who are being screened for lutetium therapy. Brittany Harvey: Understood. Thank you for reviewing the expansion of this recommendation to avoid additional or unnecessary screening.  So then, Dr. Garje, the article mentions complete updates to the metastatic castration-resistant prostate cancer guideline are underway. At a high level, could you review what new evidence the panel will look at to update their evidence-based recommendations? Dr. Rohan Garje: There have been a lot of developments in the last year, at least, in the treatment strategies for patients with metastatic castration-resistant prostate cancer. Earlier this year, we have seen three big updates about the first-line metastatic CRPC setting, where the combination of PARP inhibitors and androgen receptor pathway inhibitors were tested. For example, in the TALAPRO-2 study talazoparib and enzalutamide, and in the MAGNITUDE study, it was niraparib along with abiraterone. And in the PROpel study, the combination of olaparib and abiraterone was studied. Now, all these combinations have recently received FDA approval with specific nuances with regards to folks who have biomarker positive disease, specifically BRCA1 and BRCA2 mutations. So it is very important to refine this information so that it is utilized by practicing oncologists so that it is widely adapted in their day to day practice. Now, in addition, we also are focusing on addressing the need for utilizing biomarkers. The biggest thing for us to offer a biomarker driven therapy is to do biomarker testing. So we are focusing on making sure patients with advanced prostate cancer get biomarker testing so that we can identify who are the patients who get selected. So this particular guideline update is addressing those needs.  And then most recently at the recent ESMO meeting, we also noted the positive data from a study called PSMAfore, which evaluated PSMA 177lutetium prior to chemotherapy. This study showed positive data based on progression free survival benefit. So we will review additional data from that and see if a guideline update can be done based on this. So it is very exciting. Now, obviously, we are also waiting on survival data on all the studies. So we are closely monitoring all the updates on these studies so that we can provide more rational guidance based on not only progression-free survival benefit in a specific cohort and also to see if it helps with overall survival improvement. Brittany Harvey: Absolutely. We'll look forward to the panel's review of this evidence and then future updates to this full guideline.  So then, finally, Dr. Garje, you've alluded to awaiting some data. So could you expand on what are some of the outstanding questions regarding systemic therapy for metastatic castration-resistant prostate cancer? Dr. Rohan Garje: I would put that in two boxes. Number one, sequencing. So we are excited that we have a broad spectrum of options; androgen receptor pathway inhibitors, chemotherapy options, radium-223. We have lutetium based options and then biomarker selected patients with PARP inhibitor combinations and select patients with benefit for checkpoint inhibitors. Now, the biggest question we need to answer is how to sequence them, which drug or which combination strategy is ideal for one particular patient. Now, obviously, when we do not have clinical trials which have addressed sequencing, we as an expert panel would want to come up with some mechanism of consensus to identify what treatment sequence would work best for patients. So that is an important question this guideline panel wants to address where we can give some generic information as a consensus, based on the experience of the panel to give guidance for practicing physicians the best sequencing.  Now, second thing, very equally important, is biomarkers. This particular guideline update is also focusing on making sure biomarker testing is universal. There has been a lot of evidence that biomarker testing happens very late in the course of the disease, which precludes a lot of patients from these combination strategies. So this particular guideline also is focusing on what biomarkers to be tested and at what time frame, so that they can be optimally utilized for the patient treatment so that the patients will have the best cancer outcomes. Brittany Harvey: Definitely, those are important questions for personalized care for people with prostate cancer.   I want to thank you so much for your work on this rapid update and your ongoing work on the updates to the full guideline, Dr. Garje, and thank you for your time today. Dr. Rohan Garje: Sure, thank you so much. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline update, go to www.asco.org/genitourinary-cancer-guidelines.  You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.   Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.  

Dr. Greg Kalemkerian joins us on the ASCO Guideline Podcast to discuss the newest ASCO – Ontario Health (Cancer Care Ontario) Guideline on systemic therapy for small-cell lung cancer (SCLC). He reviews the evidence-based recommendations from the panel, including guidance on systemic therapy options for resected, limited-stage, extensive-stage, and relapsed SCLC, and NSCLC with an EGFR mutation that has transformed to SCLC, recommendations for older adults with poor performance status, the role of biomarkers, and the use of myeloid supportive agents. Dr. Kalemkerian also highlights future research for systemic therapy options for SCLC, and the impact of guidelines on both clinicians and patients with SCLC. Read the full guideline, “Systemic Therapy for SCLC: ASCO-OH (CCO) Guideline” at www.asco.org/thoracic-cancer-guidelines." TRANSCRIPT This guideline, clinical tools, and resources are available at http://www.asco.org/thoracic-cancer-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.23.01435  Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.   My name is Brittany Harvey, and today I'm interviewing Dr. Greg Kalemkerian from the University of Michigan, co-chair on “Systemic Therapy for SCLC: American Society of Clinical Oncology – Ontario Health Guideline.” Thank you for being here, Dr. Kalemkerian.  Dr. Greg Kalemkerian: Thank you. 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. Kalemkerian, 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 move into what we're here today to discuss, Dr. Kalemkerian, can you provide an overview of both the scope and the purpose of this guideline? Dr. Greg Kalemkerian: So, the guideline is meant to update the systemic treatment for small-cell lung cancer. There have been several changes in the last couple of years. For the first time in quite a few decades, we actually have some newer drugs that have demonstrated benefits in this disease. So we're really focusing on the systemic therapy. And ASCO does endorse the ASTRO guidelines for the radiotherapy involved in patients with small-cell lung cancer. Brittany Harvey: Great. That's great to hear that there's new systemic therapy options for patients with small-cell lung cancer.  So then I'd like to review the key recommendations of this guideline. This guideline reviews eight clinical questions in total, so we can go through the key points of the recommendations for each question. So let's start with what is recommended for adjuvant systemic therapy in patients with resected small-cell lung cancer? Dr. Greg Kalemkerian: So, to start with, only fewer than 5% of people have what would be considered resectable small-cell lung cancer, and that's stage I small-cell lung cancer. So tumors less than 5 cm in size without any lymph node involvement, either hilar or mediastinal lymph node involvement. So purely the very early stages, which are rare in small-cell. And if patients undergo surgical resection for such tumors, the recommendation afterward is to provide adjuvant chemotherapy with four cycles of either cis-or carboplatin plus etoposide in order to try and improve longer-term survival for those patients.  The other part of the recommendation is we do recommend that treatment be started within eight weeks of surgery. There is little data on timing in small-cell lung cancer, but that's derived from extrapolating from non-small cell lung cancer as well. Brittany Harvey: Understood. I appreciate you reviewing those recommendations for resectable small-cell lung cancer.  So then, moving along, what does the panel recommend for patients with limited-stage small-cell lung cancer? Dr. Greg Kalemkerian: So, the treatment with limited-stage small cell lung cancer unfortunately has not changed in quite some time. We recommend that patients receive four cycles of either cisplatinum or carboplatin and etoposide concurrently with radiotherapy. Preferably the radiotherapy should be given early and concurrently with the chemotherapy, though we do not recommend that people wait for the radiation to get started in order to start the chemotherapy. So we do recommend that the chemotherapy get started as soon as possible and then the radiation can be added in on the second cycle of chemotherapy. Brittany Harvey: Then to follow that up, what is recommended for patients with extensive stage small-cell lung cancer? Dr. Greg Kalemkerian: So, extensive stage small-cell lung cancer now is probably the most straightforward of the portions of this. Based on the data from two trials thus far, the IMpower 133 trial and the CASPIAN trial, we now recommend chemotherapy with immunotherapy. The chemotherapy should be cisplatinor carboplatin plus etoposide along with concurrently either atezolizumab or durvalumab as the immunotherapy for four cycles of the combined chemo-immunotherapy followed by maintenance with the immunotherapy drug of choice. With regard to the choice of either cisplatin or carboplatin, meta-analysis has demonstrated that there is no significant difference between the two and our belief is that carboplatin is likely the more reasonable drug in the palliative treatment situation based on its better non-hematologic toxicities. Brittany Harvey: Appreciate you sharing those recommendations and some of the rationale behind those.  So then moving along, what options are available for patients with relapsed small-cell lung cancer? Dr. Greg Kalemkerian: So relapsed small-cell lung cancer gets a little more potentially complicated. One of the main drivers of outcome in patients with relapsed small cell lung cancer is the time since they completed their initial chemotherapy. Patients who have had a longer time since chemotherapy do better and have better responses to subsequent therapy. For patients who relapse with a short interval within 90 days or three months of completion of prior chemotherapy, our recommendation is that they be treated with single-agent chemotherapy. There are two drugs that are currently FDA approved for use in relapsed small cell lung cancer, topotecan and lurbinectedin, and either one of those is the preferred agent as a single-agent treatment in this scenario. For people with a longer chemotherapy-free interval, so beyond the 90 days or three months, one could either use combination chemotherapy, so reinitiation or re-induction with the regimen such as carboplatin and etoposide, or one could use single-agent chemotherapy with the preferred agents being topotecan or lurbinectedin again. The use of combination chemotherapy has been shown to improve response rates in this situation over topotecan alone. However, we have not been able to demonstrate that there is a significant improvement in overall survival. So one has to look at the individual patient and make some judgment on whether you think that the added potential toxicity of combination chemotherapy is beneficial for that individual.  For people who have progression of disease while they are on maintenance therapy with immunotherapy for extensive stage small-cell lung cancer, we do not recommend continuation of the immunotherapy. So if people progress while they're on the immunotherapy, even if they're nine months out on that, then treatment with second-line chemotherapy, either with the combination agent or with single agents, would be what we would recommend, and not continuing the immunotherapy. If patients had previously been treated for limited-stage small-cell lung cancer where immunotherapy is not part of the initial treatment at this time, and they relapse, say, six months or nine months out from their initial chemotherapy and radiation therapy treatment, then it would be reasonable to perhaps initiate carboplatin etoposide and one of the immunotherapy agents as appropriate treatment, because that patient is immunotherapy naive.  However, the single-agent immunotherapy does not have a role in the treatment of patients with relapsed small-cell lung cancer.  Brittany Harvey: Understood. It sounds like some of the treatment options are individualized to the specific patient then.  So the next question also addresses specific groups of patients. So what did the panel recommend for older adults with small cell lung cancer or for those with poor performance status? Dr. Greg Kalemkerian: Approximately half of people who have small-cell lung cancer are over the age of 70 years old, so it is a disease of older smokers. Many of these people have comorbidities that can limit our ability to use standard treatments. Many of these individuals also have poor performance status because the disease is an aggressive disease that causes a lot of problems for people. So the issue of older individuals and people of poor performance status is something that we run into on a regular basis in treating people with small-cell lung cancer.  For patients with limited-stage small-cell lung cancer who are older and have a performance status of 0 to 2, it is very reasonable to utilize standard treatment with standard chemo and radiotherapy with curative intent. For people with limited-stage small-cell lung cancer who have a performance status of 3 or 4, and this would include people who might be in an ICU with an obstructive airway, then it is reasonable to initiate chemotherapy in order to try and shrink the cancer down and improve their situation. Small-cell lung cancer is a disease that is very sensitive to chemotherapy initial treatment, so many of these people will have shrinkage of tumor and improvement of their symptoms. If the poor performance status is due to the small-cell lung cancer, it has potential to get better. So we do recommend for people at limited-stage small-cell lung cancer and a poor performance status that is felt to be due to the disease, the cancer, then it is reasonable to initiate treatment with chemotherapy. And depending on the person’s response and recovery and improvement in their performance status, then one could add radiotherapy later on or do it sequentially with the definitive radiotherapy for the limited-stage small-cell lung cancer.  For older individuals with extensive stage small cell lung cancer who have a performance status of 0-2, it is very reasonable to utilize the standard chemotherapy and immunotherapy as we outlined previously in treating that. For individuals who have a poorer performance status, so performance status 3 or 4, one really needs to individualize the situation. If the poor performance status is due to the cancer, then again, it would be reasonable to attempt chemotherapy in an effort to try and shrink the cancer. There is no data on the use of chemo plus immunotherapy in this patient population. But the use of standard chemotherapy, obviously, in the older individuals preferring carboplatin over cisplatinum with etoposide would be a reasonable option, taking into account abnormalities in organ function that may require dose adjustments or reductions. Because small-cell lung cancer is a disease that is quite sensitive and responds well to  chemotherapy, then one can individualize in those situations for patients with poor performance status to see if they can improve their overall situation and have some period of time of optimized quality of life. Clearly, it is a very individualized decision-making whether or not to treat these patients. That requires clearly the patient’s input as well, as a primary driver of what is done.  Brittany Harvey: Absolutely. That nuance is helpful for patient-clinician shared decision-making, depending on the factors that you mentioned.  So then, switching to the next topic that the expert panel addressed, what does the panel recommend for patients with non-small cell lung cancer with an EGFR mutation that has then transformed to small-cell lung cancer?  Dr. Greg Kalemkerian: The EGFR mutant non-small cell lung cancer transformation to small-cell lung cancer is relatively rare. I think in the real world, this probably is occurring in 2%-3% of people with EGFR mutant non-small cell lung cancer, but we do see it. Now, these patients are initially being treated with EGFR inhibitor therapy for their mutant non-small cell lung cancer and then they develop a more aggressive progression of disease. It is important to note that when people progress in that situation, it is important to get a biopsy in order to see whether or not transformation has occurred and whether or not there are any other new driver mutations that might be targetable. If the patient has a small cell lung cancer transformation, then the recommendation is to treat them as we treat patients with small cell lung cancer with chemotherapy consisting of platinum and etoposide for four to six cycles, as we usually do. It does not appear that there is a role for immunotherapy in this situation, though we clearly have a paucity of data on these patients. So we do not yet have any trials that have looked at the management of this population. We do have several series that have presented these individuals and what their outcomes are with treatment. And their outcomes are very similar to people with de novo small-cell lung cancer. So not a very good situation, but we do recommend that they be treated with standard chemotherapy, platinum plus etoposide.  Another question that arises is do you continue with the targeted therapy with the EGFR inhibitor. And the honest answer is we don't know. We don't have data on that. We do know from case reports, the series, and from personal experiences, that some people, in fact, I think many people, if not most of these individuals, have a mix of both EGFR mutant adenocarcinoma and small-cell lung cancer at the time that they transform. So not every tumor in their body is transforming, so that EGFR mutant tumor is still present in their body. So even though the small-cell lung cancer component, because it's progressing, is clearly not responsive to the EGFR inhibitor any longer, the adenocarcinoma component most likely is still sensitive to the EGFR inhibitor. So it is not unreasonable to continue with the EGFR-targeted therapy along with the small cell lung cancer-directed chemotherapy. Even though we don't have any strong data supporting one way or the other. Brittany Harvey: I appreciate that guidance, even with the dearth of data in this relatively rare scenario.  So then we've talked a bit about individualized treatment, and often in that conversation, biomarkers come up. So what does the guideline say regarding the role of biomarkers for patients with small-cell lung cancer? Dr. Greg Kalemkerian: This is pretty straightforward. Thus far, in people with de novo small-cell lung cancer - so we're not talking about the transformed patients from EGFR mutant, we're talking about people who present with small-cell lung cancer - we have no evidence that molecular diagnostic testing would help guide treatment or improve patient outcomes at this time. So we do not support obtaining molecular diagnostic testing for the routine care of patients with de novo small-cell lung cancer. I would love to talk for the next half hour about what's coming down the pipeline in small-cell lung cancer with regard to identifying subsets of patients and trying to identify the vulnerabilities within those subsets of patients that may lead to better-targeted therapy based on molecular diagnostics, but in the current environment, there is no role for molecular diagnostics.  Brittany Harvey: Understood. We'll look for that in future guideline updates instead, then.  So then the last clinical question that the guideline addressed - what myeloid supportive options may be offered for patients with small cell lung cancer? Dr. Greg Kalemkerian: So this has to be couched initially with whether or not one thinks that myeloid suppressive agents are necessary in the treatment of patients with small-cell lung cancer. So in extensive-stage disease with the use of chemotherapy, say, carboplatin and etoposide, the majority of patients likely don't require myeloid supportive agents. However, if one believes that the patient, because of their own individual characteristics, or in a patient who has already developed myelosuppressive problems, then one could either utilize trilaciclib, which was FDA-approved a couple of years ago and was shown to improve the blood counts in people with small cell lung cancer treatment, or one could utilize G-CSF. So either trilaciclib or G-CSF could be utilized to support the patient's bone marrow. In patients who have limited-stage disease, for many years, we have recommended against using G-CSF in combination with chemotherapy and radiotherapy due to concerns for increasing toxicities, including thrombocytopenia. Recent data suggests that this may not necessarily be a hard and fast rule and that if one feels that the patient requires or would benefit from some myeloid support, then G-CSF may be offered to patients undergoing chemotherapy and radiotherapy. I do not think that the standard patient that we see who is starting on treatment requires such support, but some subsets of patients or patients who have already proven that they're getting into trouble with their counts, G-CSF could be utilized in this situation.  So with regard to this recommendation, overall, it's that for patients with extensive stage disease, trilaciclib or G-CSF could be used if one feels they're necessary. And for limited-stage small cell lung cancer, G-CSF could be utilized if you feel it's necessary.  Brittany Harvey: Thank you for reviewing those options and all of these recommendations. The panel was certainly hard at work reviewing the evidence and developing these recommendations.  In your view, Dr. Kalemkerian, what is the importance of this guideline for both clinicians and for patients with small-cell lung cancer? Dr. Greg Kalemkerian: Well, I think it's not just small-cell lung cancer, but when you look at guidelines overall, I think they are very important to have evidence-based guidelines as well as expert consensus-based guidelines because, quite honestly, the field is moving very quickly, the field of oncology. Now, small-cell lung cancer hasn't moved as quickly as we would like compared to other aspects of oncology, but it's very hard for the clinician who is trying to care for patients with lots of different tumor types to keep up with all of the flood of literature, the flood of new FDA approvals that are coming out every week. So I do think that utilizing the guidelines is important in order to see what the standard approach might be.  Now, I also have to couch that with saying that guidelines are never enough. We have to look at the individual sitting across the exam table from us. We have to personalize the treatment to that individual. I will say that in my own practice, there are very few people who walk in the door who are the optimal patient, who are the person who has outstanding physical function. And in lung cancer, that's even more true because patients tend to be older smokers, and they have a lot of comorbidities and other things that you have to personalize therapy towards in them. So the guidelines are a very good starting point in order to know what the optimal treatment might be and then to adjust that accordingly to the person sitting in the room with you.  Brittany Harvey: Definitely, we hope guidelines are a place that clinicians can turn to for evidence-based recommendations and succinct recommendations, but individualized patient and clinician decision-making is paramount to each of our guidelines.   So then, Dr. Kalemkerian, we've already talked about this a little bit when you mentioned molecular testing advances down the road. So maybe I'll ask what are the most pressing, unanswered questions about systemic therapy for small-cell lung cancer? Dr. Greg Kalemkerian: Yeah, so one of them I'll come back to limited-stage small-cell lung cancer. So, obviously, in the extensive stage, we've now incorporated immunotherapy. And yet I didn't talk about immunotherapy in the limited-stage setting, and neither do the guidelines because thus far we don't have any data on the use of immunotherapy in limited-stage small-cell lung cancer. We are expecting data to be coming down the line within the next year hopefully, definitely, within the next two years, because a number of trials that are either ongoing or have recently been completed looking at incorporating immune checkpoint inhibitors into the treatment of limited-stage small-cell either concurrently with chemoradiation or as consolidation after chemoradiotherapy. So that data is anxiously anticipated. And we're hoping that that might move the needle a little bit further in limited-stage small-cell lung cancer and hopefully improve that long-term survival or cure rate that we see in that disease.  Other avenues coming down the line – many of us have made a career of doing negative trials in small-cell lung cancer, myself included, and a lot of that has had to do with trying to target therapies to specific molecular abnormalities, and none of those have really panned out thus far. But coming down the line, as we start to molecularly subtype lung cancers, and the best molecular subtyping that we have thus far is not based on mutational analysis, but more based on expression, gene expression analysis, expression of particular transcriptional factors within different subsets of small cell lung cancer, we're now starting to see some vulnerabilities. So one of these subsets in the small cell lung cancer array has a high expression of DLL3, which is part of the Notch pathway, and we can target that. We haven't figured out how to target it as far as its activity goes, but we can target it as a homing device in order to get either drugs delivered by use of antibody-drug conjugates, or to use a BiTE—a T-cell engaging type molecule—that targets both DLL3and T cells in order to try and amplify that immune response in small cell lung cancers. So recently a compound called tarlatamab had data presented at ASCO and also published in JCO that shows some response, about 20-25% response, in people with relapse small cell lung cancer. These were heavily pretreated patients. So that's moving the needle a bit in favor of a specific targeted therapy. And we're hoping that will lead to further avenues to look at the vulnerabilities of different subsets and be able to develop newer targeted treatments for these diseases, trying to amplify that immunotherapy response as well.  Small cell lung cancer is a little bit of an outlier in that it does not respond well to immunotherapy compared to other tumors. Not what we expected based on the high tumor mutational burden and the aggressiveness of the disease. But we know that it does not express a lot of PD-L1. We know that it doesn't have MHC class I molecules. So there are a number of reasons why it doesn't respond, and there is work going on to try and amplify that immune response as well. So I think those three things: the use of immunotherapy in limited-stage, the development of targeted therapies based on subsets, and trying to amplify that immune response are the things that I look forward to in the next few years. Brittany Harvey: That's great to hear. We'll await the data to provide answers to those outstanding questions.  So I want to thank you so much for your work to develop these evidence-based guidelines, and thank you for sharing your perspective with me today, Dr. Kalemkerian.  Dr. Greg Kalemkerian: Thank you, Brittany. And thanks to ASCO for getting these guidelines together and getting the outstanding group of people we had to work on it and getting them out in a timely manner so they can help our patients. Brittany Harvey: And also, 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/thoracic-cancer-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.    

Dr. Eric Singer highlights the recent rapid recommendation update from ASCO on the management of metastatic renal cell cancer (ccRCC), based on the review of evidence from the phase III COSMIC 313 trial. Dr. Singer reviews the discussion from the Expert Panel and emphasizes clinicians should continue to follow the previously issued recommendations for the management of metastatic ccRCC. He also mentions future directions, ongoing clinical trials, and outstanding questions for these evidence-based guidelines. Read the latest update, “Management of Metastatic Renal Clear Cell Cancer: ASCO Guideline Rapid Recommendation Update” at www.asco.org/genitourinary-cancer-guidelines. TRANSCRIPT Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Eric Singer from the Ohio State University Comprehensive Cancer Center, lead author on the “Management of Metastatic Renal Clear Cell Cancer: ASCO Guideline Rapid Recommendation Update.”  Thank you for being here, Dr. Singer. Dr. Eric Singer: Brittany, great to be with you. Thank you for the invite.  Brittany Harvey: Great. Then, before we discuss this guideline, I'd just 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. Singer, 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, Dr. Singer, to dive into this rapid update, can you tell me a little bit about what prompted this rapid update to the Management of Metastatic Renal Clear Cell Cancer Guideline, which was previously published in 2022? Dr. Eric Singer: Sure. One of the big motivators for this was the fantastic work done by Toni Choueiri and colleagues in publishing the COSMIC-313 trial, which looked at triplet therapy for the management of metastatic kidney cancer: a combination of ipilimumab, nivolumab, and cabozantinib versus patients with placebo plus ipi and nivo. And this was a much-awaited trial, and these results came out. And certainly, there was a lot of interest amongst providers as well as patients to help understand the results of this important study and whether or not we should be changing our practice. So, the guideline group who wrote the initial guideline in 2022 felt that this was a significant enough study to warrant a rapid update. Brittany Harvey: Understood. So then, based on this new data from COSMIC-313, what is the updated recommendation from the Guideline Expert Panel? Dr. Eric Singer: So, the recommendations largely do not change. Unfortunately, while there was some fantastic information gleaned from COSMIC-313, the survival outcomes that were seen at this point, in context with the toxicity signals that were seen at this point, led the Guideline Committee to recommend against adopting triplet therapy as a standard option. However, the Guideline Committee did encourage patients and providers to continue to refer to and accrue to clinical trials that will be again asking similar questions about the combinations that we should be using to treat metastatic kidney cancer going forward. So essentially, we felt that the survival benefit was not adequate to recommend first-line treatment adoption of this triplet regimen in context with the toxicities that were seen in the triplet regimen.  Brittany Harvey: Understood. That's helpful to know.  So then, what should clinicians know as they implement this guidance into practice?  Dr. Eric Singer: I would recommend that we continue to follow the original guideline as published. There are multiple doublet agents or doublet therapeutic combinations that are available, which we found to have strong survival outcomes and more manageable toxicity profiles than the triplet regimen studied in COSMIC-313. Brittany Harvey: Great. Additionally, what does this update mean for patients with metastatic renal clear cell cancer? Dr. Eric Singer: Yeah, as we all think about how best to manage patients with metastatic kidney cancer, a lot of the things that we're thinking about are, will this treatment make people live longer, and will this treatment make patients live better, balancing both efficacy and also looking at toxicity. And I think in this case, there wasn't the survival endpoints or the survival benefit we were hoping for, again, sort of a surprisingly low number of complete responses seen in this study compared to prior pivotal trials, and quite a bit of toxicity because we're combining three different drugs. And when we do combine medications, we're always hoping for synergy in terms of the efficacy so the combination working better than what we'd expect just by adding those outcomes together. But unfortunately, we also got quite a bit of additive toxicity in the combination as well. So, I think that we still have many excellent options to choose from and that, unfortunately, at this time, there didn't seem to be the survival benefits in light of the toxicity to warrant a change. Brittany Harvey: Absolutely. That balance of benefit and harms is crucial.  So then, finally, you mentioned that this guideline encourages enrollment in clinical trials, but I want to also ask you, what are the outstanding questions that we're looking forward to regarding the management of metastatic renal cell cancer? Dr. Eric Singer: Brittany, I think there's a lot of important questions for us to work on answering. Like we were sort of alluding to in a study like this, we want to know not only which patients are likely to benefit from a combination of therapies, but we also want to begin to learn more about which patients are at an especially high risk of toxicity from combined treatments. So, not only can I counsel a patient about what we think this will do for disease control, but also to identify potential risk factors for adverse events because that can help us choose between the multiple different options we have available. We also have a lot of options at our disposal now in terms of combining different types of therapy: How should we integrate surgery, radiation, systemic therapy? What order should we do them in? What is the best combination to use at each of these steps, so that we can continue to help patients live longer and live better on their kidney cancer journey?   Brittany Harvey: Absolutely. Well, I want to thank you so much for your work to update this guideline very rapidly, and thank you for sharing your insights with me today, Dr. Singer. Dr. Eric Singer: Brittany, my pleasure. And again, I really appreciate the work of everyone who's been on the metastatic kidney cancer panel, such fantastic professionals in terms of their clinical expertise, and then also the fantastic ASCO staff, where we really wouldn't be able to do this work without the amazing dedication and hard work of our ASCO team members. Brittany Harvey: Definitely a big thank you to the entire expert panel.  And also 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/genitourinary-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.  Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.      

Dr. Jaydira Del Rivero and Dr. Kimberly Perez discuss ASCO guidelines on systemic therapy for well-differentiated metastatic GEP-NETs. They cover treatment options, differentiation of GI and pancreatic neuroendocrine tumors, and the need for evidence-based recommendations on sequencing therapy.

Dr. Michael Atkins and Dr. Vernon Sondak discuss the updated systemic therapy for melanoma recommendations, including neoadjuvant and adjuvant therapy for resected cutaneous melanoma, options for unresectable/metastatic melanoma, and therapies for non-cutaneous melanoma. They highlight the importance of the guideline and address pressing questions for better treatment strategies.

Dr. Julia Rowland discusses evidence-based recommendations for integrative therapies for managing anxiety and depression symptoms in adults with cancer. The podcast explores options such as acupuncture, aromatherapy, hypnosis, mindfulness, music therapy, relaxation, reflexology, Tai Chi and/or Qigong, and yoga. The podcast also discusses therapies with insufficient evidence to support a recommendation. It highlights how this guideline complements the recent ASCO guideline on conventional therapies for managing anxiety and depression, and the impact for patients and clinicians.

Dr. Navneet Singh joins us again, this time to discuss the rapid recommendation update for stage III non-small cell lung cancer, incorporating updated data presented at the 2023 ASCO Annual Meeting. He discusses the new trials that prompted the guideline update and updated recommendations on adjuvant osimertinib for patients with EGFR exon 19 deletion or exon 21 L858R mutation, and the option of neoadjuvant chemoimmunotherapy for patients with stage III NSCLC. Read the update, "Management of Stage III Non-Small Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update" at www.asco.org/thoracic-cancer-guidelines TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/thoracic-cancer-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.23.01261 Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.  My name is Brittany Harvey, and today I'm interviewing Dr. Navneet Singh from the Postgraduate Institute of Medical Education and Research in Chandigarh, India, Co-chair on “Management of Stage III Non-Small Cell Lung Cancer: ASCO Guideline Rapid Recommendation Update.”  Thank you for being here, Dr. Singh. Dr. Navneet Singh: Thank you for having me. Brittany Harvey: Then, before we discuss this guideline, I'd just 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 is joining us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.  So then, to dive into the content of this guideline, first, Dr. Singh, what prompted this rapid update to the ASCO management of stage III non-small cell lung cancer, which was initially published in 2021? Dr. Navneet Singh: There have been a number of studies that have involved patients with stage III non-small cell lung cancer since the publication of the stage III NSCLC management guidelines. Of note, three trials deserve special recognition and have actually formed the basis for this rapid update. These include the ADAURA trial for use of osimertinib as adjuvant treatment for completely resected stages Ib to IIIa NSCLC and harboring a sensitizing EGFR mutation. The other two trials have explored the use of PD-1 immune checkpoint inhibitor therapy in combination with chemotherapy as neoadjuvant treatment of potentially resectable stages I to III NSCLC. And these are the CheckMate 816 trial with nivolumab and the KEYNOTE-671 trial with pembrolizumab. Brittany Harvey: Great, thank you for that background. So then, based off these three new trials that you just mentioned, what are the updated recommendations issued in this rapid recommendation update? Dr. Navneet Singh: The first updated recommendation is based on the overall survival benefit observed in the ADAURA trial. And this recommendation is that patients with dissected stage III NSCLC and harboring an EGFR exon 19 deletion or an exon 21 L858R mutation should be offered adjuvant osimertinib after platinum-based chemotherapy. The second important update is that in the absence of contraindications, patients with stage III non-small cell lung cancer who are planned for surgical resection should receive a neoadjuvant combination of a platinum doublet chemotherapy, and immunotherapy. Now, both of these are based on high-quality evidence and have a strong strength of recommendation. Brittany Harvey: Understood. I appreciate you reviewing both the level of evidence and the strength of the recommendation for those as well. So then, what should clinicians know as these new recommendations are implemented? Dr. Navneet Singh: Now, it's very important for clinicians involved in the management of lung cancer to realize the importance of biomarker testing, something that was initially believed to have relevance only for metastatic disease. But now, with the availability of data indicating the benefit of immunotherapy and targeted therapy not just in metastatic disease but also in early-stage as well as locally advanced disease, clinicians need to ensure that biomarker testing, especially EGFR mutation and PD-L1 expression by approved and validated methods is performed in all patients with stages I to  III non-small cell lung cancer. This is important to decide and select patients for the appropriate biological therapy, which is either targeted therapy or immunotherapy that can be used in conjunction with or following chemotherapy. I need to clarify here that the spectrum of biomarker testing that is recommended for metastatic disease is much larger than what is currently being advocated for early or locally advanced NSCLC. Brittany Harvey: Great, and I appreciate that clarification. So then you've just described what this guideline means for clinicians, but how does this rapid update impact patients diagnosed with stage III non-small cell lung cancer? Dr. Navneet Singh: Well, for patients with stage III non-small cell lung cancer, all the three trials that form the basis for this rapid update indicate very encouraging developments. The neoadjuvant chemo-immunotherapy approach is now the standard of care for potentially resectable stage III disease, as this combination has been shown to be superior to chemotherapy alone in terms of higher probability of achieving a complete or major pathological tumor response, as well as improving recurrence or event-free survival following surgical resection. Similarly, adjuvant osimertinib for resected stage III NSCLC patients having a sensitizing EGFR mutation has been shown to significantly improve overall survival compared to placebo. It is important to highlight here that osimertinib treatment in stage III NSCLC should be initiated following the completion of adjuvant chemotherapy. Brittany Harvey: Understood. So then this panel works to rapidly update this guideline, turning it around after the ASCO Annual Meeting. But what are the ongoing research developments that the panel is monitoring for future guideline updates? Dr. Navneet Singh: Well, the expert panel is eagerly awaiting overall survival data from the neoadjuvant chemo-immunotherapy trials. We have several unanswered questions which ongoing research will attempt to answer. And some of these questions include number one, whether adjuvant immunotherapy is beneficial for patients who have already received neoadjuvant chemo-immunotherapy, and if so, what is the optimal duration for the same? Second, is the three-year adjuvant osimertinib duration appropriate? Can lesser duration of treatment suffice for a subgroup of patients? And if so, it would lead to a reduction in both treatment costs as well as a reduction in potential treatment-related adverse effects. On the other hand, other patients in whom stopping at three years may not be warranted, and should patients with exon 19 deletion be treated differently from those with exon 21 L858R mutation? Third, does a similar adjuvant targeted therapy approach be warranted for ALK-rearranged NSCLC that has been surgically resected? And fourth, are there specific subgroups of patients undergoing neoadjuvant treatment in whom immunotherapy as a neoadjuvant treatment may not be effective? Examples are those with EGFR mutations or ALK rearrangements, or even those with no PD-L1 expression. Brittany Harvey: Absolutely. We'll look forward to finding the answer to those questions for future guideline updates. So I want to thank you so much for your work to rapidly update this guideline and thank you for your time today, Dr. Singh. Dr. Navneet Singh: Pleasure. 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/thoracic-cancer-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.