ASCO Guidelines

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.

In this discussion, Dr. Eric Singer, lead author and expert from the Ohio State University Comprehensive Cancer Center, provides insights on the ASCO guidelines for managing metastatic renal clear cell cancer. He reviews the impactful findings from the COSMIC 313 trial, especially regarding triplet therapy, while cautioning against its potential toxicity. Emphasis is placed on balancing treatment efficacy with patient safety, advocating for established doublet therapies. The conversation also points to future clinical trials and ongoing questions that remain in the field.

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.

Dr. Supriya Mohile , Dr. William Dale, and Dr. Heidi Klepin discuss the updated guideline on the practical assessment and management of age-associated vulnerabilities in older patients undergoing systemic cancer therapy. They highlight recent evidence that prompted the guideline update, and share the updated evidence-based recommendations from the panel, focusing on geriatric assessment-guided management. Dr. Mohile also reviews what the expert panel recommends should be included within a geriatric assessment, and Dr. Dale highlights the Practical Geriatric Assessment tool, aimed at helping clinicians implement a geriatric assessment. Dr. Klepin comments on the impact for both older adults with cancer and their clinicians, and reviews outstanding questions and challenges in the field. Read the full guideline, "Practical Assessment and Management of Vulnerabilities in Older Patients Receiving Systemic Cancer Therapy: ASCO Guideline Update" at www.asco.org/supportive-care-guidelines TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/supportive-care-guidelines. Read the full text of the update and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.00933. See also the Practical Geriatric Assessment tool and associated videos (How to do a Geriatric Assessment, What to do with the Results of a Geriatric Assessment) mentioned in the podcast episode. 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. William Dale from City of Hope National Medical Center, Dr. Heidi Klepin from Wake Forest Baptist Comprehensive Cancer Center, and Dr. Supriya Mohile from University of Rochester Medical Center—co-chairs on "Practical Assessment and Management of Vulnerabilities in Older Patients Receiving Systemic Cancer Therapy: ASCO Guideline Update." Thank you for being here, Dr. Dale, Dr. Klepin, and Dr. Mohile. Dr. William Dale: Nice to see you. Thanks for having us. 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 ensures that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including our guests joining us on this podcast episode today, are available online with the publication of the guideline in the Journal of Clinical Oncology linked in the show notes. Diving into the content of this guideline first, Dr. Dale and Dr. Mohile, can you speak to what prompted an update of this ASCO guideline on the practical assessment and management of age-associated vulnerabilities in older patients undergoing systemic cancer therapy, which was previously published in 2018? Dr. William Dale: Sure. Yes. In 2018, that was the very first guideline for older adults that ASCO had created, and that was based on work that had been done up to that time, focused on chemotherapy toxicities. And to summarize what was put out at that time, the evidence was thought to be strong enough for doing geriatric assessments. And these are specialized assessments across a number of domains, including functional impairments, cognitive losses, social impairments, etc. But to do these kinds of geriatric assessments with validated tools; that a certain selection of these domains to cover everything that was relevant; to conduct non-cancer prognostication so that for decision-making purposes, if someone were to have their cancer cured, what would be their prognosis, and help make decisions about giving chemotherapy and what doses; and then to enact geriatric assessment-guided target interventions was the fourth recommendation. And so that's where we were in 2018. In 2020 at ASCO, there was an oral session that had four randomized controlled trials that enrolled older adults. And in that was kind of the signal that there was more coming. And in 2021, two big trials that are practice-changing were published. One led by Dr. Mohile in Lancet that we call the GAP70+ study, and another one was published in JAMA Oncology. And they essentially showed the same thing, which was that GA-guided interventions could change the primary outcome, which was to reduce chemotherapy toxicity up to 20%, and also to affect a number of other outcomes. That, along with a number of other trials that have since come out and are included in the upcoming guidelines, and made it a high priority to update these guidelines. So that's where we got from there to here. And I think it's worth saying a few words about these new trials, particularly the GAP and GAIN studies. So the GAIN study included patients who were 65 and older who were starting systemic chemotherapy and looked at the likelihood of having chemotherapy toxicity as described and looked at a number of other outcomes. Most importantly, it showed that chemotherapy toxicity could be reduced with these interventions based on the geriatric assessment from about 60% to about 50%. It also showed that the likelihood of completing advanced directives would go up by around 25%. And importantly, there was no impact after all of the use of the geriatric assessments on mortality. So patients were living just as long, but they were having less toxicity and they were having more goal-concordant care. And at almost the same time, the GAP study came out, which I would hand over to Dr. Mohile to describe. Dr. Supriya Mohile: Thank you, Dr. Dale. I agree that it was time for an update, and I'm glad ASCO partnered with us to do this. I'll also just mention that Dr. Dale, Dr. Klepin, and I lead the Cancer and Aging Research Group, and many of the original predictive models that showed that geriatric assessment could help us identify patients at highest risk for toxicity were designed by Cancer and Aging Research Group investigators. And that's what informed the first guideline. I'll mention Dr. Arti Hurria, who unfortunately passed away a few years ago, and she led some of the first large studies that developed these predictive models. We built on that data in both GAP and GAIN studies to show that the geriatric assessment—when you assess and provide management—can reduce chemotherapy toxicity. Like GAIN, GAP70+ implemented a geriatric assessment intervention that both assessed and provided management to older adults. There were some key differences. In GAP70+, the patients had advanced cancer, whereas, in the GAIN study, it was a more generalizable population of patients with both curative intent and advanced cancer. And in the GAP70+ study, we enrolled patients who already had geriatric assessment domain impairments, meaning that these patients were more vulnerable because of those aging-related conditions. We were trying to enroll patients who are traditionally excluded from therapeutic clinical trials. The GAP70+ study was done in oncology offices by Community Oncology practices. So this was what I think was really interesting, in that geriatricians were not involved in implementing the geriatric assessment in this study. Oncologists received the assessment information from their team, and they're the ones that implemented the recommendations. We found in GAP70+ that not only chemotherapy toxicity was reduced, that we were able to reduce the prevalence of falls and reduce the incidence of polypharmacy, which are important geriatric outcomes for older adults. We included patients who were receiving chemotherapy, but also patients who are receiving high-risk targeted agents in GAP70+, which also leads us to believe that these interventions are important for patients who are receiving treatments other than chemotherapy. So we believe these two trials, plus others, really inspired the ASCO guidelines. Brittany Harvey: Absolutely. I appreciate you both for providing that context and background and some of the new evidence that's informed this latest update. So then I'd like to move into some of the updated recommendations of the guideline. So, Dr. Mohile, what is the updated recommendation from the panel regarding the role of geriatric assessment in older adults with cancer? Dr. Supriya Mohile: So the first guideline really focused on the assessment piece, what should be assessed, and why, which we still incorporate in this new guideline. This guideline extends now because of the randomized controlled trials into management. And when we think about geriatric assessment, we think about two pillars of management. One is how geriatric assessment influences cancer decisions, that includes what treatments to provide, what dose to provide. And then the second is how geriatric assessment can influence management recommendations that are supportive care based that address some of the geriatric assessment domain impairments. I'll just give you an example of both. So when we see patients with advanced cancer who have geriatric assessment domain impairments who are presenting for treatment, often the doses of chemotherapy may be overtreatment because those doses were developed in therapeutic clinical trials in younger, more fit patients. And in our geriatrics world, we often think about going slow and starting low, and we may do a first cycle that's dose reduced a touch, to kind of see how the patient does physiologically with that first cycle. There are therapeutic clinical trials like FOCUS2 in patients with metastatic colon cancer that show the benefits of being careful with dosing in the first cycle. So, in GAP70+, the oncologists who received information from the assessment were more likely to reduce the dose of the treatment in the first cycle which led to less toxicity but did not lead to a difference in survival, so do not compromise survival. And I think this is because we don't know the right doses for patients who have significant aging-related impairments. So that's one example of decision-making. As examples for geriatric management recommendations that are supportive care, this can be done in almost like an algorithmic approach. So, if a patient has an impairment on a physical function test, then through the geriatrics literature we know of management recommendations that can improve outcomes like physical therapy, home safety evaluations, balance, training, fall prevention information. And if we implement those supportive care recommendations through that patient who's at risk for falls, we may prevent falls and we were able to show that in addition in GAP70+ as well as other trials showed benefits in some of those outcomes. And so those are the two pieces that I think are newer with this guideline than with the previous guideline. We know more about how those management recommendations can improve outcomes. Brittany Harvey: Understood. Yes. It's helpful to understand those examples of how integrating this geriatric assessment can help improve the management of care for these patients. So then you've mentioned some of the geriatric assessment domain impairments. So, Dr. Mohile, what does the guideline recommend should be included within a geriatric assessment? Dr. Supriya Mohile: This was a really great question for us to rise and think about, as part of this guideline and as a panel, we went back and forth with all of the authors to try to think about what is the most streamlined number of domains that should be assessed? What are the highest priority domains that, if you could only do a few things in a busy oncology clinic, which are the ones that oncologists should have to do because without doing them, they won't have relevant information to inform treatment decisions or to improve the outcomes of their patients? And so when we think about geriatric assessment, there has been literature to show that almost all of the domains we do are important in identifying patients who are at risk of poor outcomes. These include physical function, cognitive function, emotional health, comorbidities, polypharmacy, nutritional status, and social support. That sounds like a lot, but we do many of those assessments sort of naturally in oncology clinics. There are just a few that are not done as standard. For example, it is not standard for oncologists to assess cognition using a validated screening test for cognition. And we know that recognizing patients who may have cognitive impairment is really important in identifying vulnerabilities and providing support systems in place so patients who are receiving treatment can go through treatment safely. Other things, like just doing a formalized nutritional assessment, really bringing in the caregiver, are done not in a standard way. And so what the geriatric assessment allows is for us to assess each of those domains in a standard way. When we're communicating to our colleagues and tumor boards, we can describe vulnerabilities in a standard way. And we're moving now past the eyeball test, which is different for different clinicians, and having more objective ways of describing health status to be able to have a common language across studies and in clinical care. Brittany Harvey: That's helpful to understand moving past the less formal approach to geriatric assessment and making it more standardized. So then, Dr. Dale, this guideline offers a specific tool, the Practical Geriatric Assessment, as an option for clinicians conducting a geriatric assessment. What is this tool and where can clinicians access it? Dr. William Dale: Very good question. Just to set the context a bit, after hearing about all the evidence that we've just described. We did do some work as a task force through ASCO and through some work that Dr. Klepin and her colleague have done to understand now that the guidelines in 2018 had come out, they weren't really being used. So when we asked, about 25% of people would say they were using them very much, even though we saw in these large studies that we did, that those who were using the guidelines were changing their practice significantly in the ways that Dr. Mohile mentioned. And this was among a large group of community oncologists. So we have been breaking down the geriatric assessment into the most concise, most straightforward, and easiest-to-use version of the geriatric assessment, maintaining its validity and maintaining the number of domains. We really tried to make it simple. So the Practical Geriatric Assessment is not the only tool, but it is a tool that accomplishes this practical charge to make it accessible to community oncologists while also being valid. So those domains that Dr. Mohile mentioned physical function, functional status, nutrition, social support, psychological considerations, comorbidities are all in the Practical Geriatric Assessment. But what we've done is boil it down to here's a very specific tool that we think is valid but easily applied. Here are the very specific thresholds that tell you when a deficit has been identified and then gives recommended actions to be taken, whether it's in decision-making or in other interventions like a referral to somebody, perhaps physical therapy, or a cognitive specialist, all of which come from the GAP. So this tool is designed to be very straightforward and practical, but still cover all the relevant domains. And it will be made available through both the ASCO website and through the Cancer and Aging Research Group website so that people can access it easily. Brittany Harvey: That sounds like a real challenge that the ASCO working group took on to create a comprehensive yet practical tool for clinicians to use. We'll also provide some links for people to access this in the show notes of this podcast episode. So then I want to move on. Dr. Klepin, in your view, how will this guideline update impact both clinicians and older adults with cancer? Dr. Heidi Klepin: Yes. Thank you. As was mentioned, for clinicians, the guidelines provide an overview of new evidence and concrete recommendations to address the challenge experienced every day in practice, that of providing personalized care in the context of age-related conditions to maximize benefits and minimize the risk for older adults with cancer. The evidence summary will educate clinicians on key outcomes that can be positively impacted by use of geriatric assessment, including decreasing treatment toxicity, enhancing decision-making, and improving communication and patient-caregiver satisfaction. And this information on outcomes is really critical to informing the use of geriatric assessment in practice. We hope that the evidence-based recommendations with the provision of the practical geriatric assessment and the associated trigger table to guide management strategies will empower clinicians to incorporate geriatric assessment into their workflow by helping them overcome some of those known barriers that Dr. Dale mentioned, such as lack of time and uncertainty about which measures to use and what to do with the information once you have it. So, we anticipate that providing clear recommendations and accompanying readily available materials to support the implementation that clinicians in both community and academic practices will be able to use the geriatric assessment and incorporate it into routine care. For patients, we anticipate that the guideline recommendations would translate into increased use and access to this type of assessment as part of their routine oncology care. So, we hope that our patients will actually be able to access this regardless of whether they're receiving care at a specialized academic center versus a community oncology clinic. So, by doing this, we would extend the proven benefits of geriatric assessment, including lower rates of side effects, experiencing fewer hospitalizations, and improving satisfaction to older adults regardless of where they receive treatment. And we feel like this is critically important, since currently, most older adults receive cancer care in community oncology clinics without access, as was mentioned, to any geriatric specialty care. So, as more older adults have the opportunity to participate in this type of assessment as part of routine care in their oncology clinics, they'll be able to discuss the results of the assessment with their healthcare providers, which can help them make better-informed decisions and engage, I think, more completely in what we would consider patient-centered decision making. And ultimately, we would hope that the guidelines would provide an evidence-based and practical strategy for improving the quality of care received by older adults with cancer. Dr. Dale, would you be interested in commenting a little bit more on the patient perspective informed by our patient partners on the guideline panel? Dr. William Dale: Yeah. Thank you, Dr. Klepin. Very well said. Yeah, our guideline panel, just to fill out the picture of that, included our patient partners, along with a wide diversity of perspectives. We had experts in geriatric oncology, but we had community oncologists who take care of cancer patients. We have people from across the country. We had different backgrounds and different levels of experience. But to focus on the patients for a group that we've worked with for some time called SCOREboard, and they were some of the strongest voices on this. Whenever people said, "Well, do we really need to require this?" The patient partners were insistent that this be included as a requirement as much as possible for what happens. I think one of the most important roles they've played is as advocates for this. If I can, when the community oncologists are having some concerns about how hard this would be or how difficult it might be, the patient partners have been the first to say, we need to find a way to do it and insist that we empower the patients to ask for it. So, one of the hopes for all of these guidelines is also that it get disseminated to patients who can self-advocate as they go forward and have tools that will be made available for them to use in this self-advocacy. Brittany Harvey: Definitely, that self-advocacy is important and the geriatric assessment is critical for optimal care for older adults. So, then we've talked a lot about the new evidence regarding geriatric assessment and also making it easier for clinicians to implement the geriatric assessment, but Dr. Klepin, what are the outstanding questions and challenges regarding geriatric assessment in older adults with cancer? Dr. Heidi Klepin: Thanks. So, while there's strong evidence and clear rationale to incorporate geriatric assessment into routine clinical care, there are outstanding questions and challenges that we have to consider. First and foremost, still remains a challenge of implementation. As mentioned, we hope that the Practical Geriatric Assessment, the detailed recommendations, and the associated educational materials on what to do with the geriatric assessment information will help overcome implementation barriers for many. But we recognize that more work needs to be done to both train providers to facilitate behavior change as well as to tackle clinic and healthcare system barriers to routine use. And along these lines, we also recognize that it's important to educate patients and caregivers about the role of geriatric assessment and its value in order to optimize uptake in community clinics. We want all of our patients to be as enthused and recognize the importance of the geriatric assessment, as our colleagues on the recommendation panel did. Another consideration is the challenge of tailoring use of geriatric assessment to specific disease and treatment settings. And more research is underway testing geriatric assessment and management strategies in varied disease settings, as well as with varied treatment types and intensities. And finally, I would suggest that another challenge is the lack of routine incorporation of geriatric assessment measures into cancer clinical trials. And this will really be necessary to interpret clinical trial data for older adults optimally and to reinforce the value of routine geriatric assessment in clinical care. Brittany Harvey: Absolutely. These are key points for moving forward and looking forward to additional research in this area and maybe future guideline updates down the line. So, I want to thank you all so much for your work on updating this guideline and for your time today. Dr. Dale, Dr. Klepin, and Dr. Mohile. Dr. Heidi Klepin: Thank you for having us. Dr. William Dale: Yeah, thanks for having us here. We're delighted to be talking about this. Dr. Supriya Mohile: Thank you. 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/supportive-care-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.

Dr. Charles Loprinzi shares the latest update to the management of cancer cachexia guideline. Dr. Loprinzi discusses the evidence that prompted the rapid update to the guideline and reviews the new evidence-based recommendations, including the addition of low-dose olanzapine as a treatment option for patients with advanced cancer to improve weight gain and appetite. Dr. Loprinzi reviews the limitations of the update, and outstanding research questions in the domain of cancer-associated cachexia. Read the latest update, "Cancer Cachexia: ASCO Guideline Rapid Recommendation Update" at www.asco.org/supportive-care-guidelines TRANSCRIPTThis guideline, clinical tools, and resources are available at http://www.asco.org/supportive-care-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.23.01280 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. Charles Loprinzi from Mayo Clinic, Co-Chair on "Cancer Cachexia: ASCO Guideline Rapid Recommendation Update." Thank you for being here today, Dr. Loprinzi. Dr. Charles Loprinzi: It's a pleasure to participate. Brittany Harvey: Then, just 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. Loprinzi who has joined us here today, are available in line with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. Then, to get into the content of this rapid recommendation update, first, Dr. Loprinzi, what prompted this rapid update to the ASCO management of cancer cachexia guideline, which was previously published in 2020? Dr. Charles Loprinzi: The impetus for the updated guideline was a recent JCO publication regarding the results of a randomized controlled trial looking at olanzapine. This prompted the expert panel to revisit this topic. The trial, conducted in India, involved 124 patients with stomach, hepatopancreatobiliary, or lung cancers as they initiated chemotherapy. Weight gain greater than 5% occurred in 60% of patients in the olanzapine arm versus 9% of the patients in the placebo arm with a p-value of 0.001 or less. Substantially improved appetite was seen in 43% versus 13%, with placebo also a p-value of less than 0.001. Grade 3 or greater chemotherapy toxicity was less common with olanzapine 12% versus 37%, with placebo with a p-value of 0.002. No substantial olanzapine-associated toxicity was apparent. There was one evidence of this with olanzapine versus two for placebo. So that was the reason for going ahead with this update. Brittany Harvey: I appreciate that background information. So then, based on this updated study on olanzapine, what are the updated recommendations from the expert panel for treating cancer cachexia? Dr. Charles Loprinzi: So, let me start to address this question by reviewing what the 2020 ASCO guidelines published said regarding the management of cancer cachexia in adults with advanced cancer. It concluded that evidence was insufficient to strongly endorse any pharmacologic agent for established anorexia/cachexia. Nonetheless, the guideline recommendation supported that clinicians could offer a short-term trial of a progesterone analog such as megestrol acetate or a corticosteroid such as dexamethasone to patients experiencing weight loss and/or appetite stimulation. These drugs stimulated appetite and caused weight gain, but they did not improve quality of life, they did not improve survival, and there was toxicity associated with these agents and therefore it was not strongly recommended. The expert panel thoroughly discussed a potential role for olanzapine because of a couple of trials suggesting it was beneficial but concluded that the evidence was insufficient for a recommendation. Now, there was evidence from two randomized trials that supported olanzapine was an effective alternative for treating cancer-associated anorexia/cachexia. Thus, olanzapine was considered promising, but the data were not conclusive enough to support a guideline treatment recommendation. The new JCO publication was the impetus for making this guideline change. Brittany Harvey: Understood. So then, based off this new change to the recommendations, what is the breadth of these recommendations and what do these options mean for patients with advanced cancer? Dr. Charles Loprinzi: The updated guidelines recommended that for adults with advanced cancer, clinicians could offer low-dose olanzapine once daily to improve appetite and cause weight gain. It was noted that the majority of the evidence for this recommendation came from patients with lung or GI cancers, and the largest study enrolled patients who were receiving cytotoxic chemotherapy concurrently. Having said this, there's evidence from the other two randomized trials noted above that olanzapine is helpful in patients with a wide variety of cancers and regardless of whether patients were receiving concomitant chemotherapy. Of note, extensive data support that olanzapine leads to significant appetite stimulation and weight gain in patients without cancer who were taking olanzapine for psychiatric reasons. This was known from a long time ago in patients in that situation, who don't necessarily want to gain weight, would gain 10-20-30-40 pounds, get prediabetes, and get diabetic sort of troubles. The guideline update continues to support that clinicians may offer a short-term trial of a progesterone analog or a corticosteroid to those experiencing weight loss and/or appetite when there's a good reason for not using olanzapine. Brittany Harvey: Understood. I appreciate you reviewing those two updated recommendations from the guideline panel. So then you've talked about this a little bit already in describing the study details, but what is exciting about olanzapine in this setting and what should clinicians know as they implement these updated recommendations? Dr. Charles Loprinzi: It's exciting that olanzapine is now the best-studied established treatment available for patients suffering from cancer-associated anorexia/cachexia in different oncologic situations, for prevention and/or for treatment of cancer-associated or cancer treatment-associated nausea and/or vomiting, and for treatment of cancer-associated anorexia/cachexia. Varying daily doses of olanzapine have been used, ranging from 2.5 to 10 milligrams per day. Data support that it is quite appropriate to use the 2.5-milligram per day dose for the initial treatment of cancer-associated appetite and/or weight loss. For patients who do not appear to benefit and have no apparent olanzapine toxicity, it seems reasonable to me to try a higher dose. Another thing to note is that olanzapine is a generic drug which is relatively inexpensive. While this drug has been noted to cause sedation, such sedation is usually short-lived despite drug continuation. Brittany Harvey: So then, it's great to hear that recent data have caused an update to these guidelines. But in your perspective, Dr. Loprinzi, what are the most pressing outstanding questions regarding the management of cancer cachexia? Dr. Charles Loprinzi: My goodness, you're putting pressure on me. I've been involved with a large number of cancer anorexia/cachexia trials for the better part of four decades, which did not support as strong an ASCO guideline recommendation as we now have with olanzapine. Noting that I was involved with one of the trials that supported that olanzapine was helpful for treating cancer-associated anorexia/cachexia. This is one of the trials. It was a short trial. We were mainly looking at nausea and vomiting treatment for advanced cancer, but we saw a marked increase in appetite in over just a day or two of using olanzapine. Having said this, there's always room for improvement, and a number of drugs are under development for treatment of cancer-associated anorexia/cachexia. Recent discussions regarding the topic of olanzapine for treating cancer-associated anorexia/cachexia noted that the primary endpoint of the current trial was weight gain and that this was felt to be a more objective endpoint than appetite would be. As noted in the earlier part of the discussion, substantial improvement was seen both in weight gain and appetite, both with p-values of less than 0.001. My own opinion is that appetite improvement is as important, if not more important than is weight gain in the study population. Given that the trial was double-blinded and placebo-controlled, appropriate questionnaires regarding appetite should be able to be considered as an objective evaluation of a subjective symptom in the same way that appropriate questionnaires regarding a patient's pain can be considered an objective evaluation of a subjective symptom. For some of these subjective symptoms, you just don't have other good ways we can figure these things out by a blood test or something like this. So it's what the patient says which is most important. Brittany Harvey: Absolutely. Incorporating how the patient feels is key to achieving better outcomes for patients. So I want to thank you so much for your work to rapidly update this guideline and thank you for your time today, Dr. Loprinzi. Dr. Charles Loprinzi: You're welcome. Pleasure to participate. 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/supportive-care-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, 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.

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.