ASCO Guidelines

An interview with Dr. Beverly Moy from Massachusetts General Hospital in Boston, MA, lead author on "Chemotherapy and Targeted Therapy for HER2-Negative Metastatic Breast Cancer That is Either Endocrine-Pretreated or Hormone Receptor-Negative: ASCO Guideline Rapid Recommendation Update." Dr. Moy reviews data from the recently published DESTINY-Breast04 study, and the ASCO Expert Panel's updated recommendation on the use of trastuzumab deruxtecan. For more information, visit www.asco.org/breast-cancer-guidelines. TRANSCRIPT Brittany Harvey: Hello, and welcome to the ASCO Guideline podcast series brought to you by the ASCO podcast network, a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Beverly Moy from Massachusetts General Hospital in Boston, Massachusetts, lead author on 'Chemotherapy and Targeted Therapy for HER2-Negative Metastatic Breast Cancer That is Either Endocrine-Pretreated or Hormone Receptor-Negative: ASCO Guideline Rapid Recommendation Update'. Thank you for being here, Dr. Moy. Dr. Beverly Moy: It's my pleasure. Thank you for having me. Brittany Harvey: Great. First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Moy, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Beverly Moy: I do not have any relevant disclosures that are directly relevant to this guideline topic. Brittany Harvey: Thank you. Then let's talk about this rapid update. So first, what prompted a rapid update to this guideline on chemotherapy and targeted therapy for patients with HER2-negative metastatic breast cancer that is either endocrine-pretreated or hormone receptor-negative, which was last updated in 2021? Dr. Beverly Moy: First, I would state that ASCO issues rapid guideline recommendation updates when really important advances in the treatment and management of cancer have been presented. This mechanism really allows clinicians to keep up with the rapid advances in cancer management. The fact that a rapid update had to be issued just one year after the full updated guideline that was published in 2021, as you just mentioned, is really a testament to the advances in cancer research and clinical trials that have been made recently. But I will state that the reason why this rapid update was done was because the result of the DESTINY-Breast04 study were so strong and compelling and showed such a large degree of benefit to a large group of metastatic breast cancer patients that we felt as the guideline panel that this rapid update had to be out there. We really wanted to make sure that the oncology community was aware of these results. That's based on the strength of the trial. The DESTINY-Breast04 trial was a very large randomized study that showed that trastuzumab deruxtecan significantly improved progression-free survival and overall survival compared to treatment of physician's choice in patients with metastatic, "HER2-low" breast cancer. Brittany Harvey: So then based off this new data from the DESTINY-Breast04 trial that you just mentioned, what is the updated recommendation from the guideline expert panel? Dr. Beverly Moy: So the updated recommendation is that patients with HER2-low, or to be specific, HER2 IHC1+ or 2+ and ISH negative metastatic breast cancer who have received at least one prior chemotherapy for metastatic disease, if they're hormone receptor-positive, are refractory to endocrine therapy, those patients should be offered treatment with trastuzumab deruxtecan. Brittany Harvey: And then what should clinicians know as they implement this new recommendation for trastuzumab deruxtecan? Dr. Beverly Moy: I think that there are a few things that clinicians really need to be aware of. One is that it significantly improved progression-free survival and overall survival, and that's pretty important. The paper was published in the New England Journal of Medicine, and folks can refer to that study specifically. But to be specific, it improved progression-free survival at a median follow-up of about 18 months from 9.9 months with trastuzumab deruxtecan compared to 5.1 months with treatment of physician choice in the entire study population. Median overall survival was 23.4 months with trastuzumab deruxtecan and 16.8 months with treatment of physician's choice. So that's really a marked improvement in both of those outcomes. It is also important to note that trastuzumab deruxtecan has a very important side effect, and that's the potential of developing drug-related interstitial lung disease or pneumonitis. And that could be very serious. This side effect was confirmed in about 12% of the patients who received trastuzumab deruxtecan, and about 1.3% of patients actually had severe symptoms requiring oxygen, and three patients in the study, so less than 1% actually died of this side effect. So that's something that needs to be monitored for very carefully, and clinicians need to be very cognizant of this potential side effect when using this drug. Brittany Harvey: Thank you for reviewing both the impact on survival and then the adverse event of interstitial lung disease. So how does this guideline update impact patients with breast cancer? Dr. Beverly Moy: So metastatic breast cancer is incredibly common. And this HER2-low, and I say, "HER2-low" because this is a definition that has never been made before. The patients with HER2 IHC1+ or 2+ and ISH negative disease, that's a very large group of patients. That's a lot of patients. So it's really important that this guideline is going to impact a very large group of patients. Again, it's those who've had at least one prior line of chemotherapy in the metastatic setting. And if they had hormone receptor-positive disease, it has to be refractory to endocrine therapy. But that's a lot of patients. And the results of this randomized study do show that trastuzumab deruxtecan is superior to other treatment of physician's choices that were available before this study came out in terms of its efficacy. So this guideline is very significant for clinicians and metastatic breast cancer patients across the world. Brittany Harvey: Definitely. It's great to have a new option and one that has such a great clinical impact for patients. So then finally, Dr. Moy, what are the outstanding questions regarding chemotherapy and targeted therapy for HER2-negative metastatic breast cancer? Dr. Beverly Moy: I think like any good study, this raises a lot of other important questions. Again, this HER2-low definition that I described is an interesting one. It's a very large bucket of patients. One obvious question is, would this drug be as effective in patients who are truly HER2-negative, so HER2 IHC of 0? Kind of, overnight, the results of this study has changed the paradigm for many oncologists because we used to just say HER2-positive or HER2-negative. And now we're looking back at patients' charts to see what their immunohistochemistry results were. Does it really matter if it's IHC 0 or 1+ or 2+? So that would be very interesting. Another outstanding question is: what about the use of trastuzumab deruxtecan earlier in the treatment? I said that it should be offered for patients who've received at least one prior line of chemotherapy? What about first line chemotherapy in the metastatic setting? And there are multiple studies studying this drug in actually early stage breast cancer as well. So lots of unanswered questions about this compound that's pretty remarkable. Brittany Harvey: Great. Well, I want to thank you so much for your time today, Dr. Moy, for discussing the results of the DESTINY-Breast04 trial with me, and for your work to rapidly update this guideline. Thank you so much. Dr. Beverly Moy: Thank you, Brittany. It was a pleasure. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

An interview with Dr. Ishmael Jaiyesimi from Beaumont Health Royal Oak and Oakland University William Beaumont School of Medicine in Royal Oak, MI, and Dr. Andrew Robinson from Kingston General Hospital, Queen's University in Ontario, Canada, authors on "Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline." Dr. Jaiyesimi and Dr. Robinson review the latest recommendation updates for first-, second-, and third-line therapy in patients with stage IV NSCLC without driver alterations. Read the full guideline at www.asco.org/thoracic-cancer-guidelines. TRANSCRIPT Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Ishmael Jaiyesimi from Beaumont Health Royal Oak and Oakland University William Beaumont School of Medicine in Royal Oak, Michigan, and Dr. Andrew Robinson from Kingston General Hospital, Queen's University in Ontario, Canada, authors on 'Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Guideline Update'. Thank you for being here, Dr. Jaiyesimi and Dr. Robinson. Dr. Ishmael Jaiyesimi: Thank you for inviting me. Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Jaiyesimi, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Ishmael Jaiyesimi: I do not have any financial disclosures. Thank you. Brittany Harvey: Thank you. And Dr. Robinson, do you have any relevant disclosures that are directly related to this guideline topic? Dr: Andrew Robinson: Yes, I do. I have had funding of less than $5,000 from BMS, Merck, and AstraZeneca in the past two years. Brittany Harvey: Okay. Thank you for those disclosures. So, then let's talk about the content of this guideline update. So, Dr. Jaiyesimi, what prompted this guideline update, and what is the scope of the update? Dr. Ishmael Jaiyesimi: The purpose of this guideline update is to update the ASCO and Ontario Health guidelines on the systemic treatment of patients with non-driver alteration stage IV non-small cell lung cancer last published in January of 2020. The update is the result of potentially practice-changing evidence published since the last update. ASCO published the last full clinical practice guideline updates on systemic therapy for patients with stage IV non-small cell lung cancer that included those whose cancer did not have driver alterations in January of 2020. The scope of evidence for the update guideline is made of ongoing or completed randomized controlled trials for non-driver alterations from 2018 to 2021. These updated algorithms provide recommendations from the ASCO expert panel and emphasized rapid changes in the management of patients with advanced non-small cell lung cancer and the importance of clinical research. Brittany Harvey: Thank you for that overview, Dr. Jaiyesimi. So, then talking about those changes you just mentioned, I'd like to review the new or changed recommendations for this guideline. So, let's start with for patients with stage IV non-small cell lung cancer without driver alterations, and with high PD-L1 expression and non-squamous cell carcinoma, what are the updated recommendations for first-line therapy? Dr. Ishmael Jaiyesimi: In addition to 2020 options for patients with high PD-L1, 50% or more expression, non-squamous cell carcinoma, and performance status of zero to one, and absence of targetable oncogenic driver alterations, clinicians may offer a single agent atezolizumab alone, or single agent cemiplimab alone, or a combination of nivolumab and ipilimumab without chemotherapy, or a combination of nivolumab and ipilimumab with two cycles of platinum-based chemotherapy. The number of acceptable options has increased. And each of the recommendations carries a strength of recommendation and quality of evidence with it. Brittany Harvey: I appreciate you reviewing those options. So, then Dr. Robinson, moving on to the next category of patients addressed in this guideline, for patients with stage IV non-small cell lung cancer without driver alterations and with negative or low positive PD-L1 expression and non-squamous cell carcinoma, what are the updated recommendations for first-line therapy? Dr. Andrew Robinson: Thank you for that question. So, in addition to the 2020 options for patients with negative, 0%, and low positive PD-L1 expression, with a TPS score of 1 to 49% and I'd add, unknown PD-L1, non-squamous, non-small cell lung cancer and a good performance status, clinicians may offer combination nivolumab and ipilimumab or combination nivolumab and ipilimumab with two cycles of platinum-based chemotherapy. These are the additional recommendations and this gives an increased number of acceptable options, particularly for patients who cannot or choose not to take cytotoxic chemotherapy. Brittany Harvey: Understood. Thank you for reviewing those options. So. then the next category of patients this guideline addresses, for patients with stage IV non-small cell lung cancer without driver alterations and with high PD-L1 expression and squamous cell carcinoma, what are those updated recommendations for first-line therapy? Dr. Andrew Robinson: So, similar to the patients with non-squamous cell carcinoma for patients with stage IV non-small cell lung cancer that is squamous cell and a good performance status of zero to one, clinicians may also offer single agent atezolizumab alone or single agent cemiplimab or combination nivolumab and ipilimumab or combination nivolumab and ipilimumab with two cycles of platinum-based chemotherapy followed by ongoing nivolumab and ipilimumab. So, these are additional recommendations in this group as acceptable options for treatment. Brittany Harvey: Great thank you for reviewing those options. So, then Dr. Jaiyesimi, what is recommended for patients with stage four non-small cell lung cancer without driver alterations and with negative or low positive PD-L1 expression and squamous cell carcinoma for first-line therapy? Dr. Ishmael Jaiyesimi: In addition to 2020 recommendations, for patients with negative, TPS 0%, and low positive, with TPS 1% to 49%, PD-L1 expression, squamous cell carcinoma, and performance status of zero to one, clinicians may offer a combination of nivolumab and ipilimumab alone or a combination nivolumab and ipilimumab with two cycles of platinum-based chemotherapy. Brittany Harvey: Great! So, then we've just reviewed the updates and changes to the first-line therapy recommendations. So, Dr. Jaiyesimi, were there any updates to second- or third-line therapy recommendations for patients with stage IV NSCLC without driver alterations? Dr. Ishmael Jaiyesimi: For patients with non-squamous cell carcinoma who receive an immune checkpoint inhibitor and chemotherapy as first-line therapy, the clinician may offer paclitaxel plus bevacizumab in the second-line setting. For the majority of patients with non-squamous cell carcinoma who received chemotherapy with or without bevacizumab and immune checkpoint inhibitor therapy, in either sequence, clinicians should offer the option of single-agent pemetrexed (non squamous cell carcinoma, non-small cell lung cancer), or docetaxel (all histologic types), or weekly paclitaxel plus bevacizumab, (non-squamous cell carcinoma, non-small cell lung cancer) in the third-line setting. For patients in whom the initial treatment was not a chemoimmunotherapy combination should receive the treatment not given earlier that is platinum doublet chemotherapy (if the initial treatment was monotherapy with an immune checkpoint inhibitor, or dual immune checkpoint inhibitor therapy) and immunotherapy with an approved PD-1 or PD-L1 inhibitor in the second line setting (if the initial treatment was platinum doublet chemotherapy). Brittany Harvey: Okay, thank you for reviewing those recommendations as well. So, then Dr. Robinson, what is the importance of these recommendation updates for practicing clinicians? Dr. Andrew Robinson: These updates give an increasing menu of choices for patients and physicians, particularly in the first-line setting. The increased list of acceptable first-line options may help us physicians may run into situations where their preferred first-line option isn't available, or for other reasons shouldn't be given. Now we recognize that given the increasing variety of options in the first line, it would be really nice if we could have guidelines, that say in this certain patient treatment with nivolumab and ipilimumab is recommended and in that certain patient chemotherapy plus pembrolizumab is recommended, and divide things up that way so that the right patient gets the right treatment. However, the guideline committee did not feel that this was appropriate at that time as the only comparative data with these different strategies is insufficient, either population-based data or cross trial and network comparisons, that, however well done, do not have a defense against confounders and bias that a randomized study has. So, the advances in drug development and research in non-small cell lung cancer in the past decade have made available multiple treatment options, particularly for first-line therapy for patients, and to some extent, this has also made the process of decision making in this context challenging for practicing clinicians, especially in the community and for patients and caregivers. Clinicians need to understand patients' comorbidities as well as other variables that can potentially influence treatment decisions prior to making final therapeutic recommendations for any given patient, and also become comfortable handling a few of these regimens. Each of these are somewhat complex regimens with sometimes subtle and sometimes not-so-subtle differences that require expertise and appropriate treatment and monitoring. So, with so many options available, it's important that clinicians get familiar with a few of them at least given that all of these regimens are now considered as appropriate standard of care regimens suitable for first-line therapy, it may also help justify physicians, researchers and ethics boards who are participating, designing and overseeing simple clinical trials that pragmatically ask the questions as to what should be used when. So, physicians should simultaneously become familiar with these guidelines, familiar with different therapies, have expertise in a few of these therapies, and continue to stress cancer clinical trials that may improve outcomes, and also may help us determine which treatment for which patient at which time. Brittany Harvey: Definitely, that makes sense. Thanks for reviewing these recommendations and also the limitations of the evidence around them. So, finally, Dr. Robinson, how will these guideline recommendations affect patients with stage 4 non-small cell lung cancer without driver alterations? Dr. Andrew Robinson: Well, there are more options available which should be good but we wish what we meant when we say there are more options for patients, what we meant is that if one option doesn't work that other options are then available. However, in this case, we mean that there are more options for patients for their initial therapy, particularly including more non-chemotherapy or reduced chemotherapy options. It's difficult to imagine that many patients and clinicians will now discuss, say 8 options with patients with high PD-L1 lung cancer. Pembrolizumab, cemiplimab, atezolizumab, pembrolizumab with platinum doublet, nivolumab, ipilimumab, nivolumab and ipilimumab chemotherapy, and the majority of patients with high PD-L1 will likely continue to have single-agent PD-1 or PD-L1 inhibitors. For patients with low PD-L1 lung cancer, the inclusion of nivolumab and ipilimumab without chemotherapy as a potential option may allow some patients to avoid chemotherapy toxicity and trade for other toxicities and choose a different therapy. Patients who enroll on clinical trials where the comparator arm is any one of these therapies should be comfortable knowing that they are considered acceptable standards. The advancement in non-small cell lung cancer diagnosis and treatment would allow patients with stage IV non-small cell lung cancer without driver mutations who are eligible for immunotherapies with or without chemotherapy, a chance of living longer and the opportunity to participate in ongoing research to further move the ball down the field. Brittany Harvey: Definitely. And, thank you for reviewing that as well. So, I want to thank you both for all of your work to review the rapid changes in evidence in this field and provide these guideline updates. I want to thank you again for your time today, Dr. Robinson and Dr. Jaiyesimi. Dr. Ishmael Jaiyesimi: Thank you for having me. Dr. Andrew Robinson: Thank you. It was a pleasure to be here. Brittany Harvey: And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines. There's a companion guideline update on therapy for stage IV non-small cell lung cancer with driver alterations available there and on the JCO. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

An interview with Dr. Ishmael Jaiyesimi from Beaumont Health Royal Oak and Oakland University William Beaumont School of Medicine in Royal Oak, MI, and Dr. Andrew Robinson from Kingston General Hospital, Queen's University in Ontario, Canada, authors on "Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline." Dr. Jaiyesimi and Dr. Robinson review the latest recommendation updates for therapeutic options for patients with stage IV NSCLC with ALK rearrangement or RET rearrangement. They also discuss new agents on the horizon. Read the full guideline at www.asco.org/thoracic-cancer-guidelines. TRANSCRIPT Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs, covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Ishmael Jaiyesimi from Beaumont Health Royal Oak and Oakland University William Beaumont School of Medicine in Royal Oak, Michigan, and Dr. Andrew Robinson from Kingston General Hospital at Queen's University in Ontario, Canada, authors on 'Therapy for Stage IV Non-small Cell Lung Cancer with Driver Alterations: ASCO Guideline Update'. Thank you for being here, Dr. Jaiyesimi and Dr. Robinson. Dr. Ishmael Jaiyesimi: Thank you. Dr. Andrew Robinson: It's a pleasure to be here. Brittany Harvey: Great! First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Jaiyesimi, do you have any relevant disclosures that are directly related to this guideline? Dr. Ishmael Jaiyesimi: None. Brittany Harvey: Thank you. And, Dr. Robinson, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Andrew Robinson: Yes, I have received funding less than $5,000 from AstraZeneca, Merck, and BMS over the past two years. Brittany Harvey: I appreciate those disclosures. So, then Dr. Jaiyesimi, let's talk about the purpose of this guideline. So, what is the purpose of this guideline update, and what clinical scenarios does this guideline address? Dr. Ishmael Jaiyesimi: The purpose of therapy for stage IV non-small cell lung cancer with driver alterations, is to rapidly update the ASCO and Ontario Health guideline on the systemic treatment of patients with stage IV non-small cell lung cancer, last published in February of 2021. The update is a result of potentially practice-changing evidence published since the last publication in February 2021. The update is based on two clinical trials from 2020 to 2021. The clinical scenario this guideline covers are stage IV non-small cell lung cancer with driver alteration with an ALK gene rearrangement and RET gene rearrangements. Brittany Harvey: Great. So, then let's review those two clinical scenarios that you just mentioned. So, there are a few new recommendations regarding ALK rearrangement. So, what are the recommended first-line options for patients with stage 4 non-small cell lung cancer in an ALK rearrangement? Dr. Ishmael Jaiyesimi: In the previous guideline alectinib or brigatinib were recommended as first-line therapy with a strong recommendation and level of evidence in patients with ALK gene rearrangement, and a performance status of zero to two. In the current update, lorlatinib was cited as the first-line ALK inhibitor that may be offered as an alternative first-line therapy. If alectinib, brigatinib, or lorlatinib are not available, ceritinib or crizotinib should be offered. This is based on the CROWN study that showed alectinib was superior to crizotinib in the first-line setting. Unfortunately, we don't have head-to-head comparative data with alectinib or brigatinib, so we cannot conclude that any one treatment is more effective than the other, and decisions should be made on experience, toxicity, and on. Brittany Harvey: Okay, thank you for describing how a clinician should select between those treatments as well. So, then the second clinical scenario that Dr. Jaiyesimi just mentioned, Dr. Robinson, what is recommended for both first-line and second-line treatment for patients with stage IV non-small cell lung cancer and a RET rearrangement. Dr. Andrew Robinson: Thank you. So, for patients with a RET rearrangement and a good performance status of zero to two and previously untreated non-small cell lung cancer, clinicians may offer selpercatinib or pralsetinib as first-line therapy. Selpercatinib was recommended in the 2020 guidelines and pralsetinib has been added to that. As with other driver mutation recommendations for scenarios where randomized studies against standard non-driver mutation treatments have not been done or completed, these recommendations are with a lower level of evidence and somewhat weaker recommendations, an alternative approach of first-line standard non-driver mutation treatment may also be offered. As a guideline group, we listed this approach of non-driver treatment behind the targeted therapies, because there's a belief that the targeted approach may be superior upfront. But we should also continue to, of course, encourage participation in ongoing trials comparing selpercatinib or pralsetinib to standard first-line non-driver mutation treatment to determine whether our assumptions are correct. For patients with a RET rearrangement who've had previous RET targeted therapy, clinicians may offer treatment as per the non-driver mutation guidelines. And for patients with a RET rearrangement who have had previous chemotherapy, chemoimmunotherapy, clinicians may offer selpercatinib or pralsetinib for them. Brittany Harvey: Okay. And then you've just mentioned some ongoing trials as well. So, that leads to my next question of what ongoing trials and new agents is the panel monitoring for the next guideline iteration? Dr. Andrew Robinson: It's really an exciting time with new agents on trials and I think we can divide it into more driver mutations, more lines of therapy, and more certainty with what we're doing. In terms of driver mutations, there are several phase II and III trials with agents such as sotorasib and adagrasib in KRAS-G12C mutated non-small cell lung cancer, trastuzumab deruxtecan in the DESTINY trials in HER-2 mutated lung cancer, mobicertinib and amivantamab in EGFR, exon 20 insertion lung cancer or HER-2 exon 20 insertion lung cancer, etc. So, looking at more driver mutations is all of those agents plus a number of others that will be coming out over the next couple of years at ASCO. We're also interested in more lines of therapy. So, for patients who progress after standard first-line, say osimertinib with EGFR or after progression on ALK therapies such as lorlatinib. So, we're looking forward to studies such as the CHRYSALIS studies of amivantamab and lazertinib in EGFR mutation-positive patients who have progressed after osimertinib, and other studies that are looking at the increasing treatment options for second-line treatment and third-line treatment. And then we're looking at interest to phase three studies that are comparing targeted agents to docetaxel in the second-line setting such as the sotorasib studies in KRAS-G12C patients and capmatinib and MET exon 14 patients, particularly as many of these patients may do well with non-driver mutated guided first-line treatment. There are phase three trials comparing RET inhibitors to standard first-line chemoimmunotherapy which will also be keenly awaited to see if our, and when I say our, I mean, the ASCO guideline panel and also the thoracic oncology community writ large, our assumption that targeted therapy will be superior to first-line therapy is actually borne out with clinical trial evidence. So, there's plenty of evidence that we're excited to keep our eye on and update as soon as possible, which is more driver mutations, more lines of therapy for patients who have established driver mutations, and more certainty, hopefully, regarding the timing of these various interventions. Brittany Harvey: Definitely, there's a lot going on in this space. So, we'll look forward to the results from these ongoing trials and the panel's review of that evidence, and eventually updated recommendations. So, then Dr. Jaiyesimi, in your view, why is this guideline update important and how will it impact practice? Dr. Ishmael Jaiyesimi: This guideline is important because it emphasizes rapid development in the research and treatment in advanced non-small cell lung cancer and that non-small cell lung cancer are heterogeneous. Clinicians need to identify biomarkers of the molecular pathways, including targetable driver mutations, example: epidermal growth factor receptors, the BRAF, the MET, the KRAS, and etcetera, and fusion rearrangement, example: anaplastic lymphoma kinase, c-ROS oncogene 1, RET, and on that drive malignancy in patients with non-small cell lung cancer, especially in those patients with adenocarcinoma histology and a little or never smoking history regardless of histology. Because of the availability of effective targeted agent for many of these cancers, at minimum, determination of epidermal growth factor receptor mutation status and anaplastic lymphoma kinase rearrangement status before initiating therapy because rapid and sensitive tests are available. An initiation of immunotherapy could increase the toxicity of tyrosine kinase inhibitors later in the patient's course. All this, in my opinion, will impact clinical practice. Furthermore, an opportunity for patients with driver mutation to enrolled in ongoing clinical trials targeting the driver mutations. Brittany Harvey: Yes. You've just mentioned that this is not a one size fits all approach for patients. And so, in your view, Dr. Jaiyesimi, how do these guideline recommendations affect patients living with stage IV non-small cell lung cancer with driver alterations? Dr. Ishmael Jaeysimi: I believe along with my associates the improvement in the treatment of stage IV non-small cell lung cancer brings hope to the patient with driver alteration for a possibility to use targeted therapy and no chemotherapy or immunotherapy upfront to some patients and this may enhance their lives, increase longevity with some tolerable side effects, and better quality of life, and a truly wide range of opportunities for patients to participate in clinical trials. Brittany Harvey: Great! Yes, it seems like the data has come fast, and a lot of new results of recent trials have driven these updated recommendations and we're also looking forward to many of the results from upcoming clinical trials that you both mentioned. So, I want to thank you so much for your work on these guideline updates, and thank you for taking the time to speak with me today, Dr. Jaiyesimi and Dr. Robinson. Dr. Ishmael Jaiyesimi: Thank you, Brittany. Dr. Andrew Robsinson: It was a pleasure to be here and I hope that this was educational. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline go to www.asco.org/thoracic-cancer-guidelines. There's a companion guideline update on therapy for stage IV non-small cell lung cancer without driver alterations available there and on the JCO. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO the mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

An interview with Dr. Lynn Henry from the University of Michigan in Ann Arbor, MI, lead author on "Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline Update." Dr. Henry reviews new biomarkers for the purposes of making treatment decisions for triple-negative breast cancer, and hormone receptor-positive, HER2-negative breast cancer, as well as tumor agnostic tumor biomarkers. Specific biomarkers addressed in this conversation include PIK3CA, ESR1, BRCA 1/2, PALB2, HRD, PD-L1, dMMR/MSI-H, TMB, NTRK, ctDNA, and CTCs. Read the full guideline at www.asco.org/breast-cancer-guidelines. TRANSCRIPT Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs, covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Lynn Henry from the University of Michigan in Ann Arbor, Michigan, lead author on 'Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline Update'. Thank you for being here, Dr. Henry. Dr. Lynn Henry: Thank you very much for inviting me to participate. Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Henry, do you have any relevant disclosures that are related to this guideline topic? Dr. Lynn Henry: No, I do not. Brittany Harvey: Great! Thank you. Then let's talk about the scope of this guideline. So, what prompted this update to the guideline on the use of biomarkers to guide decisions on systemic therapy for patients with metastatic breast cancer, which was last updated in 2015? And what is the scope of this guideline update? Dr. Lynn Henry: Yes, so a lot has happened in the past six or seven years that influence how we treat metastatic breast cancer. And there are many new drugs that have been approved by the FDA during that time. When we reviewed the prior guideline and the new treatment landscape, we realized that while much of what was included in the old guideline was still relevant, there were quite a number of new biomarkers related to new drugs that needed to be included. The newly recommended biomarkers are primarily applicable to making decisions about treatment of estrogen receptor, progesterone receptor, and HER2-negative breast cancer, also called triple-negative breast cancer, as well as for treatment of hormone receptor-positive HER2-negative breast cancer. And finally, there are now some tumor biomarkers that can be tested for that are tumor agnostic, and these were included as well. Brittany Harvey: Great! So, then let's discuss the updated guideline recommendations based off these new biomarkers for our listeners. The guideline reviews testing for several different biomarkers. So, I would like to review each of the biomarkers that the panel assessed. Let's start with what is the role of PIK3CA mutation testing? Dr. Lynn Henry: Yeah! So, PIK3CA activating mutations are commonly found in tumors that are hormone receptor-positive and HER2-negative. Based on the results of the SOLAR-1 trial, patients whose tumors have an activating PIK3CA mutation had improved progression-free survival when treated with the PI3 kinase inhibitor alpelisib plus fulvestrant compared to fulvestrant alone. This improvement was not seen in patients whose cancers didn't have a mutation. So, therefore, this provided the evidence for the clinical utility of evaluating tumors for the somatic PIK3CA mutations. Testing of either a tumor specimen or plasma to look for PIK3CA mutations can be performed. However, it's important that if the plasma is tested, and no PIK3CA mutations are identified in the circulating tumor DNA, then our tumor specimen should really be tested if possible, because of the possibility of a false negative finding in the plasma. Also, since these mutations can be acquired over time, a more recent specimen should be tested if possible, as opposed to testing the primary tumor. Finally, in the SOLAR-1 trial, a patient's tumor had to have one of the 11 pre-specified PIK3CA mutations in exon 7, 9, or 20. And therefore, when mutations are identified using next-generation sequencing, it is important to confirm that the identified mutation is one of those 11 activating mutations and not a different one that may not convey benefit from treatment with a PI3 kinase inhibitor. Brittany Harvey: Great! I appreciate you're reviewing that recommendation, as well as the clinical utility of it and the evidence behind it. So, then following those recommendations, what is the role of testing for ESR1 mutations? Dr. Lynn Henry: At this time, there are insufficient data to support routine testing of metastatic hormone receptor-positive HER2-negative tumors for ESR1 mutations. However, the panel did note that there's a retrospective analysis of two different phases three trials that demonstrated that fulvestrant improved progression-free survival compared to the aromatase inhibitor exemestane in patients who had previously progressed on a non-steroidal AI and whose tumors had an ESR1 mutation. Importantly, there are ongoing clinical trials addressing this issue, including the PADA-1 trial, which is evaluating the effect of the switch of fulvestrant from aromatase inhibitor therapy, versus remaining on that therapy when ESR1 mutations are detected in the blood. However, although preliminary findings were presented at a recent large breast cancer meeting, and were suggestive of a possible progression-free survival benefit from switching therapy, data have not yet been published, and therefore they were not included in this guideline. Brittany Harvey: Great! So, we'll look forward to those updated data to potentially review that recommendation in the future. So, following those recommendations, what is the role of testing for germline BRCA 1 or 2 and PALB2 pathogenic mutations? Dr. Lynn Henry: So, the answer for germline BRCA1 and BRCA2 mutations is relatively straightforward. Patients with metastatic HER2-negative breast cancer can be either hormone receptor-positive or negative, and who are candidates for treatment with a PARP inhibitor should undergo testing for germline BRCA1 and BRCA2 pathogenic or likely pathogenic mutations to determine whether they should receive treatment with a PARP inhibitor. This recommendation is based on the results of two large randomized clinical trials comparing PARP inhibitor therapy to physician's choice chemotherapy, although notably, the chemotherapy options did not include taxanes, anthracyclines, or platinums. In contrast, there remains insufficient evidence to support a recommendation either for or against testing for germline PALB2 pathogenic variant for the purpose of determining eligibility for treatment with a PARP inhibitor. The panel did note, however, that there are small single-arm studies that show that there is high response rate to PARP inhibitors in patients with metastatic breast cancer and coding DNA repair defects, such as either germline PALB2 pathogenic variants or somatic BRCA1 or 2 mutations. It was also noted that it is likely that patients who harbored mutations in these genes will actually be identified through routine testing with panel testing for germline variants. Brittany Harvey: Okay, understood. So, then following those recommendations, what is the role of testing tumors for homologous recombination deficiency? Dr. Lynn Henry: So, although there are emerging data from other solid tumors to support the use of homologous recombination deficiency, or HRD testing to guide therapy, current data do not support the assessment of HRD in the management of metastatic breast cancer. Therefore, we did not recommend routine testing of tumors for HRD at this time. Brittany Harvey: It's important to note where we both have evidence and where we don't have evidence. So, then what is the role of testing for expression of PD-L1 in metastatic breast cancer? Dr. Lynn Henry: So, the panel recommends that patients who are candidates for treatment with immunotherapy, with either a PD1 or PD-L1 inhibitor, should undergo testing for expression of PD-L1 in the tumor and immune cells with an FDA-approved test. At present in the United States, pembrolizumab is the only approved immunotherapy for the treatment of metastatic breast cancer, and it is given in combination with chemotherapy. The FDA-approved test for this drug is the 22C3 assay which evaluates PD-L1 staining in the tumor and surrounding stroma to calculate a combined positive score or CPS, with positive considered to be a score of 10 or greater. Of note, in other countries, there are different anti PD1 and PD-L1 antibodies that are approved for treatment, and each has been approved with its own companion diagnostic. So, it is important to make sure that you're using the right biomarker test, depending on which drug you are planning to use. Brittany Harvey: Great! I appreciate you reviewing the test in addition to the role of the biomarker. So, then, following those recommendations, what is the role of testing for deficient mismatch repair microsatellite instability-high? Dr. Lynn Henry: Similar to PD-L1 testing, it is recommended that patients with metastatic breast cancer who are candidates for a treatment regimen that includes an immune checkpoint inhibitor should undergo testing for deficient mismatch repair or microsatellite instability-high to determine eligibility for treatment with one of the drugs that is currently FDA approved, either dostarlimab or pembrolizumab. In contrast to the PD-L1 data, however, there are no randomized studies that have been conducted specifically in patients with breast cancer addressing this question. The testing recommendation was therefore included in these guidelines because of the tumor agnostic FDA approval of these drugs. In terms of which biomarker methodology to use, it was noted that, while the original studies assessed the deficient mismatch repair and MSI high using immunochemistry, and PCR respectively. The FDA has subsequently approved the next-generation sequencing platform to use in selecting candidates for these treatments. And so, therefore, there are a number of different tests that can be used. Brittany Harvey: Thank you for reviewing those recommendations as well. So, then following, what is the role of testing for tumor mutational burden? Dr. Henry Lynn: So, tumor mutational burden describes the quantity of somatic mutations in the tumor. Similar to the biomarkers we were previously discussing, there are minimal data specifically in metastatic breast cancer to support the assessment of tumor mutational burden for making treatment decisions. However, the testing recommendation was again included in the guidelines because of the tumor agnostic FDA approval of the drug pembrolizumab in the setting of high TMB. And also there is one single arm phase two trial that looked at this specifically. Importantly, the panel noted that there are a variety of factors that influence assessment of TMB. These include sample type, pre-analytical factors so how the sample was handled, the size of the panel and mutations that are tested, depths of the sequencing, type of the mutations that are included on the panel, and cut point variables. So, in particular, assessment of TMB in cell-free DNA assays such as circulating tumor DNA is an area of evolving evidence. There are therefore very important caveats to be aware of when selecting a TMB assay and assessing the results, many of which are outlined in the guideline manuscript itself, and different assays can yield different results for the same tissue specimen. It is therefore very important to use the approved companion assay and the approved cut point when making decisions regarding a specific treatment. Brittany Harvey: Absolutely. I appreciate your reviewing those details. So, then what is the role of testing for neurotrophic tyrosine receptor kinase? Dr. Lynn Henry: So, I'm going to abbreviate that to NTRK. So, NTRK fusions are rare in metastatic breast cancer. One study said 0.39% of all breast cancers have NTRK fusions. So, as with the above biomarkers, the NTRK testing recommendation is based on the results of phase 1 and phase 2 studies that were identified by the panel evaluating the efficacy and safety of these inhibitors for the treatment of advanced solid tumors with NTRK gene fusions, noting that there are only minimal data available that are specific to metastatic breast cancer. Brittany Harvey: Understood. Some of these are very rare in metastatic breast cancer. So, then, following that recommendation, what is the role of using circulating tumor DNA? Dr. Lynn Henry: So, for circulating tumor DNA, although the ctDNA technology holds promise in metastatic disease, for its ability to potentially identify tumor-specific mutations that are shed into the blood and that may be targetable, to date, neither the measurement of changes in ctDNA as a marker of treatment responsiveness nor identification of specific mutations in the blood to direct therapy has actually been prospectively shown to improve patient outcomes compared to standard imaging-based detection of tumor progression. Therefore, at present, the guideline does not recommend routine assessment of ctDNA for monitoring response to therapy among patients with metastatic breast cancer, although many studies are underway evaluating this question. Brittany Harvey: Understood. Then the last biomarker that the panel assessed in this guideline update, what is the role of using circulating tumor cells? Dr. Lynn Henry: Similar to circulating tumor DNA, there are insufficient data to recommend routine use of circulating tumor cells to monitor response to therapy among patients with metastatic breast cancer. To date, studies that have examined the clinical utility of this marker to determine the optimal time for treatment change have not led to improvements in outcomes in metastatic breast cancer. Brittany Harvey: Great! Well, thank you for reviewing all of these recommendations. The panel certainly took on a lot of biomarkers and performed a critical review of all the evidence to make recommendations in this setting. So, in your view, Dr. Henry, what is the importance of this guideline update and what should clinicians know as they implement these updated recommendations? Dr. Lynn Henry: Yeah, that's an excellent question. So, this guideline addresses the key questions that we face, as we're making decisions about how best to treat patients with metastatic breast cancer. Importantly, the guideline highlights the current state of the science, with a focus on the available published data from randomized clinical trials. It also discusses the limitations of our current knowledge, as well as key considerations for different biomarkers. Of course, we recognize that there are new data emerging on a regular basis. And the panel therefore also highlighted where data are anticipated but not yet available, as well as key questions which we hope will be able to be addressed in the more distant future. Brittany Harvey: And then finally, how will these guideline recommendations affect patients with metastatic breast cancer? Dr. Lynn Henry: Yeah, so really, that is the bottom line, isn't it? So, ideally, this guideline will enable the dissemination of best practices in terms of biomarker selection and analysis to guide clinicians as they are making treatment decisions in conjunction with patients. Treatment of metastatic breast cancer has become more complex, with regimen selection affected by both inherited germline genetics and somatic changes in the cancer that can evolve over time. The assessment of relevant biomarkers should allow patients to receive the optimal therapies that are most likely to be effective based on the individual characteristics of their cancers. Brittany Harvey: Well, I want to thank you so much for reviewing this guideline with me today, and all of the recommendations and our gaps in evidence, for our listeners. Thank you for your work on this guideline update and thank you for your time today, Dr. Henry. Dr. Lynn Henry: Thank you so much! Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

Dr. Tian Zhang, an expert in kidney cancer from UT Southwestern Medical Center, discusses the latest guidelines for managing metastatic clear cell renal cell carcinoma. He highlights the importance of accurate diagnostics and the benefits of cytoreductive nephrectomy. The podcast delves into advances in treatment, emphasizing personalized strategies and the role of combination therapies. Zhang also addresses tailored approaches for special patient subsets, ensuring effective management of complex cases to improve patient outcomes.

An interview with Dr. Pauline Funchain from Cleveland Clinic in Cleveland, OH, author on "Systemic Therapy for Melanoma: ASCO Guideline Rapid Recommendation Update." Dr. Funchain reviews recent evidence and updated recommendations from the ASCO Expert Panel for the use of tebentafusp in patients with metastatic uveal melanoma. For more information, visit www.asco.org/melanoma-guidelines. TRANSCRIPT Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I am interviewing Dr. Pauline Funchain from Cleveland Clinic in Cleveland, Ohio, author on Systemic Therapy for Melanoma: ASCO Guideline Rapid Recommendation Update. Thank you for being here, Dr. Funchain. Dr. Pauline Funchain: It's great to be here with you, Brittany. Thank you! Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Funchain, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Pauline Funchain: I do not have relevant disclosures that relate to this guideline topic. Brittany Harvey: Great, thank you. Then getting into the rapid update, what prompted this rapid update to the Systemic Therapy for Melanoma: ASCO Guideline published in 2020? Dr. Pauline: So, earlier this year, on January 25th, the FDA approved tebentafusp for metastatic uveal melanoma. So, this is the first FDA approval for metastatic uveal melanoma. We felt it was really important to put out a rapid update to let both clinicians know about the therapy and also so that more patients can get access to it as quickly as possible. Brittany Harvey: Understood. So, then based on this new FDA approval, what are the updated recommendations for patients with uveal melanoma? Dr. Pauline Funchain: So, any patients who have a previously untreated metastatic uveal melanoma, and also who are HLA-A*02:01 positive, this group of patients should be offered tebentafusp as systemic therapy. This is the only systemic therapy that has been shown to prolong overall survival in patients with metastatic uveal melanoma. And if you look at the kind of benefit that was seen, patients who were on tebentafusp had a median overall survival of 21.7 months versus 16 months in comparison to investigator's choice. In this case, that was either single agent pembrolizumab, ipilimumab, or dacarbazine. So, it is a pretty significant overall survival benefit. Brittany Harvey: Great! Thank you for reviewing those updated recommendations and the data behind them. So, what should clinicians know as they implement this updated recommendation? Dr. Pauline Funchain: So, they should know that there was a great overall survival benefit seen, but it doesn't correlate with the objective response rate that was seen in the trial. So, for patients who were treated with tebentafusp, the objective response rate was 9%. And for those patients who were treated with the investigator's choice, again, that was single agent pembrolizumab, ipilimumab, or dacarbazine, the response rate was 5%. So, that margin was not very different in terms of objective response rate when looking at RECIST-based criteria, so radiologic criteria for response, but the survival was clearly seen. And interestingly, even in those patients that had radiologic progression, there was an improved survival for those patients who were on tebentafusp versus investigator's choice. So, there is some kind of survival benefit that may not correlate with what is seen on imaging. So, clinicians should know that they may not see a dramatic response in terms of tumor size on imaging, but patients may still benefit from the therapy. Brittany Harvey: Understood. So, then you've just talked a little bit about responses in patients. So, how does this guideline update affect patients with melanoma? Dr. Pauline Funchain: So, despite a difference in response rate, long story short, there is an overall survival difference. So, really, this is the first overall survival difference that we have seen in metastatic uveal melanoma. It is really exciting. It is finally an approved drug for metastatic uveal melanoma, which did not have any approved or standard of care, systemic drugs. So, this is a really big win for a rare disease. I think, in terms of the general melanoma field and also the cancer field in general, this is really an exciting first-in-class drug on two different fronts. It is the first approved T-cell receptor therapy. It is also the first bispecific protein and it works differently than other immunotherapies we have seen. So, hopefully, this is something we see more of in other cancers. Brittany Harvey: Definitely, it's good to see that these patients finally have an option and we'll look forward to research in other cancers as well. So, then finally, Dr. Funchain, what are the outstanding questions regarding systemic therapy for melanoma? Dr. Pauline Funchain: Well, there are multiple questions that are outstanding. I think, for metastatic uveal melanoma, I think there are a lot of questions about the dissociation between the radiologic response and survival. I think there are questions about knowing when to stop tebentafusp if it's not working because we don't really have a good sense of what we should be using to know if this is not the right therapy for that patient. I think we would love to know what the biomarkers of response are, and we may need different ways of looking for how to judge if a patient is benefiting from tebentafusp and other systemic therapies. And I think that there's still a big question in uveal melanoma about whether we start with systemic therapy or local therapy. I don't think that's been answered. Now, in terms of the entire guideline, I think for melanoma in general, there are new data that are emerging and have been recently published and we will be looking forward to the next ASCO guideline in systemic therapy for melanoma because I think that there are a lot of emerging data that need to be addressed. Brittany Harvey: Definitely. We'll look forward to that new research in uveal melanoma and to reviewing the updated data with the guideline panel for the next edition of the systemic therapy for melanoma guideline. So, I want to thank you so much for your work to rapidly updating this guideline, and thank you for your time today, Dr. Funchain. Dr. Pauline Funchain: Thank you for having me. It is really meaningful to us to be able to offer education and get the word out about therapies that can help our patients. Brittany Harvey: Agreed. And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast series. To read the full rapid recommendation update, go to www.asco.org/melanoma-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available on iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

An interview with Dr. Sharon Giordano from the University of Texas MD Anderson Cancer Center in Houston, TX, and Dr. Nancy Davidson from Fred Hutchinson Cancer Research Center and the University of Washington in Seattle, WA, co-chairs on "Systemic Therapy for Advanced HER2-Positive Breast Cancer: ASCO Guideline Update." This guideline updates recommendations on systemic therapies for advanced HER2-positive breast cancer, focusing on second-line, third-line, and greater treatment. Read the full guideline. TRANSCRIPT Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Sharon Giordano from the University of Texas MD Anderson Cancer Center in Houston, Texas, and Dr. Nancy Davidson from Fred Hutchinson Cancer Research Center and the University of Washington in Seattle, Washington, co-chairs on 'Systemic Therapy for Advanced Human Epidermal Growth Factor Receptor 2 Positive Breast Cancer: ASCO Guideline Update'. Thank you for being here. Dr. Giordano and Dr. Davidson. Dr. Sharon Giordano: Thank you. Dr. Nancy Davidson: Thank you for having us. Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Giordano, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Sharon Giordano: No, I do not. Brittany Harvey: Thank you. And Dr. Davidson, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Nancy Davidson: No, I do not. Brittany Harvey: Thank you. Let's talk about the content of this guideline update. So first, Dr. Giordano, what prompted an update to this guideline on the systemic therapy for advanced HER2-positive breast cancer, and what is the focus of this update? Dr. Sharon Giordano: So, we were prompted to update the guidelines for HER2-positive metastatic breast cancer because several new studies have been presented and published, which are really changing our standard of care approaches. We have new therapies and new combinations that have resulted in improvements in progression-free survival and in overall survival for this patient population. Given the clinical importance of these new studies, we felt that an update of the treatment guidelines was clearly needed. Overall, the focus of our update is really in the title, so, it's systemic therapies for advanced HER2-positive breast cancer. And specifically, what we're focusing on is updating the recommendation for second-line therapy, and then adding multiple new options for systemic therapies for third-line and greater treatment. Brittany Harvey: Great. Thank you for that overview. So, then I'd like to review the updated recommendations of this guideline for our listeners. Starting with, Dr. Davidson, what is recommended for first-line therapy for patients with advanced HER2-positive breast cancer? Dr. Nancy Davidson: So, that was the part of this guideline that really did not change. In the previous iteration and in the current iteration, we felt that the evidence suggested that a combination of trastuzumab and a taxane should be the first-line treatment for individuals with metastatic HER2-positive breast cancer unless they have some sort of contraindication to the taxanes. Now, the evidence supporting that is very strong. The trial that supported this continues to be updated and continues to show benefit. So, that's a very high level of evidence and our recommendation on this was extremely strong. Brittany Harvey: Great. And then following those first-line recommendations, Dr. Giordano, what is recommended for second-line treatment for these patients? Dr. Sharon Giordano: So, we did change our recommendation for second-line treatment for HER2-positive patients. The current new recommendation is, and I quote from our guideline, "If a patient's HER2-positive, advanced breast cancer has progressed during or after first-line HER2 targeted therapy, and the patient has not received trastuzumab deruxtecan, clinicians should recommend trastuzumab deruxtecan as a second-line treatment." So, as I said before, this recommendation is a change from our prior second-line recommendation. Previously, we had recommended T-DM1. So, this change was really, I think, one of the most important changes to the guidelines with this update. We made the recommendation based on the initial presentation of the results of the Destiny-Breast03 trial, really given the magnitude of the benefit that was seen in the study. And the manuscript I would note was published this month in the New England Journal of Medicine. Overall, the study showed statistically significant and highly clinically meaningful reduction in progression-free survival. So, just to give you some of these numbers, to kind of give you a sense of how big the impact was, so 76% of patients who were treated with trastuzumab deruxtecan versus 34% of patients treated with trastuzumab emtansine were alive and without disease progression at a year, with a hazard ratio of 0.28. The response rates are also quite impressive with 80% versus 34% response rates. And the overall survival data are still immature but do favor treatment with trastuzumab deruxtecan and that hazard was 0.55. So, I will note though, that toxicity was a bit higher with the new drug, with trastuzumab deruxtecan. So, any grade adverse events were 98% versus 87%. And then if you look at grade three and four drug-related adverse events, it was 45% versus 40%. I think of note, rather than just kind of the overall numbers, though, one thing that clinicians need to be aware of is the risk of interstitial lung disease with this new drug. And this occurred in about 10% of treated patients in this study, although only 1%, or I think it was two patients, who had grade three or higher pulmonary toxicity. So, this is a toxicity that is specific to this drug that clinicians do need to be aware of. Dr. Nancy Davidson: I think the other thing on that, Sharon, is that the incidence was lower in the Destiny Breast03 trial than it had been in some of the really early studies of this agent, so, that should be reassuring to us. Although, of course, it doesn't mean that the side effect doesn't happen, you have to take note of it. Dr. Sharon Giordano: That's a great point. It definitely was lower than we'd seen before. So, a little bit of a relief, but still there. Brittany Harvey: Great, thank you both for reviewing that data. I appreciate the overview. So then, following those recommendations for second-line treatment, Dr. Davidson, what are the recommended options for third-line therapy for patients with HER2-positive advanced breast cancer that has progressed on second-line or greater HER2 targeted therapy? Dr. Nancy Davidson: Well, of course, this is the area where there has been considerable change as well. And that's because of the wealth of new anti-HER2 agents that Dr. Giordano talked about earlier. So, we had a variety of recommendations for clinicians and patients to make decisions about how to proceed. I think certainly one of them, is that if the patient did not receive trastuzumab emtansine (T-DM1) in the second line, as we just talked about, our new recommendation would be that they would not, that they would receive trastuzumab deruxtecan, so you put off for T-DM1 in that [third-line] setting. And that's a new recommendation for us. And the strength of the recommendation is quite high. Another agent that's come along that's very exciting is tucatinib, one of the small molecule inhibitors. And we think that that is also an alternative, that tucatinib in combination with trastuzumab and capecitabine, again, nice activity and pretty strong recommendation based on analyzed critical trials. And then finally, if for some reason the patient didn't receive the trastuzumab deruxtecan in a second-line setting and you're now in the third-line setting, that would be a very reasonable agent for them as well. Those are all pretty strong recommendations. And I think the choice of which to proceed will depend a little bit on the decision making between the patient and the doctor about the mode of administration, your side effect profile, what seems the most appropriate, and it might be more one of the order of the recommendation. As opposed to saying, 'This one, but not that one', it might be, 'Pick this one next and know that you will be able to return to some of these in the future.' Now, there are a lot of other possibilities here. We already had available to us neratinib and capecitabine, that continues to be part of the portfolio. And we also had lapatinib and capecitabine, also part of the portfolio. Other combinations of chemotherapy, trastuzumab could be considered, a new agent called margetuximab with chemotherapy, which has also come on to the market. And of course, there's the possibility of thinking about the anti-HER2 agents in the context of endocrine therapy for those patients who have estrogen receptor-positive breast cancer as well. And new information suggesting that you might, in some cases, even think about one with CDK 4/6 inhibitors in the context of trastuzumab and fulvestrant. So, lots of possibilities here that patients and doctors can weigh, and again think about order of administration as opposed to selecting for or against the other. I do think that the leading contenders at the beginning are going to be T-DM1 or trastuzumab deruxtecan, if that hasn't been used, or tucatinib in combination, those would be my personal preferences. Brittany Harvey: Great. Thank you for reviewing those options and describing where a patient might receive these during their treatment. Dr. Nancy Davidson: I'd like to hear Dr. Giordano's thoughts on that, how would you stack those up? Dr. Sharon Giordano: Yeah, well, as you said, I think it does depend on what the patient's been treated with previously. I mean, certainly, T-DM1 or trastuzumab deruxtecan, if they haven't had those agents. Otherwise, I think the data from the tucatinib trastuzumab capecitabine regimen is pretty impressive as it did show an overall survival benefit. And as you know, I think that regimen is also really interesting, because it does seem to have some efficacy for patients with brain metastases. That actually has a very nice advantage. Then the other ones, I think it just sort of depends on what they've seen previously, what side effects they may be experiencing, and kind of other quality of life issues. I don't see that there's a clear way to sequence the other ones since most of them haven't really been directly compared head-to-head against each other. Brittany Harvey: It seems like it may be an individual discussion between clinicians and patients at that level. So, then, Dr. Giordano following that, how will this guideline impact clinicians and what should they know as they implement these updated recommendations? Dr. Sharon Giordano: I think the bottom line is really the clinicians are now going to have more options for the treatment of HER2-positive advanced breast cancer which is fantastic news to have all these different choices and options for our patients. To me, I think probably the most important changes and recommendations, again, are the addition of trastuzumab deruxtecan in the second-line setting just given the very impressive clinical benefit that's seen with that drug, or, as Nancy mentioned in the third-line setting if patients, for some reason haven't received it previously. And then I also think, as we talked about, the tucatinib combination is really an exciting new combination that does seem to have significant clinical benefit. I think the clinicians will need to be aware that that might be an option for patients with CNS metastases that are progressing. And also, just to be aware, as we mentioned before, about the risk of the interstitial lung disease with trastuzumab deruxtecan but it's really encouraging to me to have such a long list of drugs and combinations that we can use to treat our patients. Brittany Harvey: Excellent. Those are great points. So, then finally, to wrap us up, Dr. Davidson, in your view, how will these guideline recommendations impact patients with advanced HER2-positive breast cancer? Dr. Nancy Davidson: Well, Brittany, I think one thing we hope, of course, is that those patients will cumulatively have a longer survival, and a better survival as a consequence of all of these new insights that we've been able to make. I can imagine it would be maybe a little confusing to patients that there are so many things that they might potentially be able to choose from, but this is one where I think that the larger the panel of agents that you have available to you, the happier it is. So, I hope that patients are going to look at this as an opportunity for partnership with their oncologists to try to figure out of all these possibilities, what's the best one for me now, and they're going to have the comfort of knowing that there'll be other things that they can fall back on in the future, and that, hopefully, these things will improve outcomes. And again, without excessive toxicity. This last thing I'm going to hope that clinicians and physicians will remember is that we've made a lot of headway here, but that our results are not perfect. And so, right now, we're able to change guidelines, these guidelines today because of clinical trials that have been put together in the last several years and successfully implemented. And I hope that we're going to continue to do that because until we get to a point where survival from HER2-positive breast cancer is 100%, we've got work to do. So, they're going to be other new clinical research strategies, and I hope that doctors and patients will take advantage of those whenever possible. Brittany Harvey: Absolutely, both hoping for longer survival and better quality of life and looking forward to more clinical trials to give clearer answers. I want to thank you both so much for your time today and for all of your work on updating these guideline recommendations, Dr. Davidson and Dr. Giordano. Dr. Nancy Davidson: Thanks, Brittany. Dr. Sharon Giordano: Thank you so much. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guideline Podcast Series. To read the full guideline go to www.asco.org/breast-cancer-guidelines. There's a companion guideline update on the management of advanced HER2-positive breast cancer and brain metastases also just published in the Journal of Clinical Oncology and on asco.org. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines App available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast expressed 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.

An interview with Dr. Naren Ramakrishna from Orlando Health Cancer Institute in Orlando, FL, and Dr. Carey Anders from Duke University in Durham, NC, co-chairs on "Management of Advanced Human Epidermal Growth Factor Receptor 2 Positive Breast Cancer and Brain Metastases: ASCO Guideline Update." This guideline reviews evidence in both the local therapy management and systemic therapy management for patients with HER2-positive breast cancer and brain metastasis, and provides updated recommendations for these patients. Read the full guideline at www.asco.org/breast-cancer-guidelines. TRANSCRIPT Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Naren Ramakrishna from Orlando Health Cancer Institute in Orlando, Florida. And Dr. Carey Anders from Duke University in Durham, North Carolina, co-chairs on 'Management of Advanced Human Epidermal Growth Factor Receptor 2 Positive Breast Cancer and Brain Metastases: ASCO Guideline Update'. Thank you for being here. Dr. Ramakrishna and Dr. Anders. Dr. Carey Anders: Thank you. Dr. Naren Ramakrishna: Thank you. Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Ramakrishna, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Naren Ramakrishna: No. Brittany Harvey: And Dr. Anders, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Carey Anders: I do. I would just like to disclose that I receive research funding, compensated consulting roles, and royalties from several of our industry partners who are developing brain permeable compounds. Brittany Harvey: Thank you. Let's talk about the content of this guideline. So, Dr. Anders, what prompted an update to this guideline? And what is the scope of this guideline update? Dr. Carey Anders: Thank you for that question, Brittany. Our previous guideline in the management of HER2-positive breast cancer brain metastasis was published in 2018. And since that time, we've seen significant progress in both the local therapy management and systemic therapy management for our patients with HER2-positive breast cancer and brain metastasis. I think collectively, this body of work really prompted the panel to think through the changes that we could make to improve the care of our patients taking these updates into account. I'd love to hear Dr. Ramakrishna's take on the rationale for the update as he was also involved in the 2018 guideline. Dr. Naren Ramakrishna: Thank you, Carey. Well, it's really an exciting time right now for breast cancer brain metastasis treatment. And the recent data that Dr. Anders referred to has really opened up a whole new era in terms of therapeutic possibilities for breast cancer brain metastasis patients. In the past, we've relied on traditional methods of treatment like whole-brain radiotherapy, surgery, and stereotactic radiosurgery as mainstays of treatment. But this exciting data that Dr. Anders referred to, has resulted in the possibility of avoiding certain of the local therapy options in select patients, which has the potential to increase patient survival and quality of life, and is a major advancement. Brittany Harvey: Excellent. It's great to hear about those advancements. So, then next, I'd like to start by reviewing the guideline recommendations for our listeners. Dr. Ramakrishna, what are the key recommendations for local therapy for patients with HER2-positive breast cancer and brain metastases? Dr. Naren Ramakrishna: Since the 2018 updated guidelines, we've continued with our stratification of patients by prognosis by the number of metastases, size of metastases, and also whether they are symptomatic or asymptomatic. Overall, the changes include the offering of systemic therapy for patients after multidisciplinary review for asymptomatic metastases, particularly those less than two centimeters in size. In select cases, one might also offer it for patients with metastases larger than that. The other major change that we see in this update is an increasing reliance on stereotactic radiosurgery rather than whole-brain treatment as a local therapy option, both in the post-operative setting and for single or multiple metastases, for which surgery is not recommended. Finally, we see a significant change in the application of whole brain radiation, where whole-brain radiation is recommended typically for extensive disease, either with multiple, very large metastases, or many, many small metastases. We recommend whole brain treatment to always be administered with a neuroprotectant, and where possible, with what's called hippocampal sparing, which is thought to reduce the neurocognitive negative effects of whole-brain radiation treatment. Brittany Harvey: Understood, I appreciate those recommendations for local therapy and that overview that you provided. So then Dr. Anders, in addition to those recommendations, what are the key recommendations for systemic therapy for these patients? Dr. Carey Andres: Sure, Brittany, happy to review. I think some of the general principles from the 2018 guidelines remain in place. So, for instance, our patients who have progressive disease in the brain, are eligible for local therapy and have controlled extracranial disease, we still recommend continuing the current HER2-directed therapy along with the same algorithm for the treatment of patients with HER2-positive metastatic breast cancer. There are some interesting and exciting changes to the guidelines with the advent of several of the promising systemic therapies that Dr. Ramakrishna outlines such that we do have the option of leading with systemic therapy for our patients with small asymptomatic lesions in the brain predominantly based on the HER2CLIMB clinical trial which established tucatinib, capecitabine and trastuzumab in this setting. So, in concert with our local therapist, we have the consideration for moving to the HER2CLIMB regimen in the setting of active asymptomatic brain metastasis in concert with our local therapist. So, that's one key change from the 2018 guidelines. Another is the introduction of the compound trastuzumab deruxtecan, an antibody-drug conjugate, which has been shown in second line in the setting of metastatic HER2-positive breast cancer to be superior to our traditional T-DM1 therapy in this setting. In the study, the Destiny-Breast03 study that illustrated the superiority of trastuzumab deruxtecan patients with stable brain metastasis were included and illustrated in this compound, illustrated significant benefit for patients with stable brain metastasis. So, in addition to the HER2CLIMB regimen in the setting of stable brain metastasis, we also have the option of trastuzumab deruxtecan in this setting. And that was an update in our 2022 guidelines. So, we essentially have more systemic therapy tools in our toolkit to consider in concert with local therapy. And I just want to emphasize the importance of communication between the systemic therapy team and the local therapy teams, particularly when we're making the decision to move forward with the systemic therapy in the setting of progressive or stable brain metastasis. Brittany Harvey: Thank you. Yes, that multidisciplinary care is key, and I appreciate your reviewing those updates. So then, in addition to those what is recommended regarding screening for the development of brain metastases for patients with HER2-positive breast cancer? Dr. Carey Andres: So, this is a very active conversation. And in fact, I had this very conversation with two patients in the clinic just yesterday. So, should we be screening our patients with advanced HER2-positive breast cancer with brain MRIs in the absence of symptoms? I think the bottom line is we just don't have the data yet. I think we will have the data and in fact, there are ongoing prospective studies trying to determine whether or not screening brain MRIs in the absence of symptoms in this setting will improve our patient survival, and also improve our patients' quality of life. Until we have that data because we do have these new tools in the toolkit for systemic therapy treatment, the panel loosens the guidelines a bit to say that it's not that we no longer recommend screening in the asymptomatic state, but there's not enough data for or against. And I think this really will help the physician and patients as they're making decisions about their screening and restaging studies in a personalized manner. In addition to the lack of data, we also strongly recommend that clinicians and patients have a very low threshold to obtain a brain MRI in the presence of symptoms and this is really important with regards to communication about symptoms as subtle as they may be. I'd love to hear Dr. Ramakrishna's take on this challenging space where we clearly need more data. Dr. Naren Ramakrishna: Yes, Carey, I completely agree that it's quite challenging and the practice patterns are quite diverse throughout the country. It's also a source of a great deal of apprehension and anxiety for patients who automatically typically would assume that more frequent screening is better, especially when they do develop brain metastasis if that's to occur. So, we do look forward to better data for guidance. And it certainly is an area that should undergo multidisciplinary reviewing recommendations for any particular patient. Brittany Harvey: Understood, thank you both for reviewing the evidence as it states now and we'll look forward to that emerging data for perhaps a future guideline update. So then, Dr. Ramakrishna, what in your view is the importance of this guideline update and what does it mean for clinicians? Dr. Naren Ramakrishna: Well, this is a practice-changing update. I mean, I don't think that's an overstatement. Because for the first time, upfront therapy is going to include the possibility of systemic therapy. And this also means that there has to be multidisciplinary and multimodality discussions regarding local versus systemic therapy for a large proportion of HER2-positive breast cancer brain metastasis patients. So, practice patterns are going to shift as a result of the incorporation of systemic therapy into the treatment paradigm. And finally, the other very important, practice-changing local therapy change is that the use of whole-brain treatment will be reduced relative to stereotactic radiosurgery, but in some cases, also as a result of the use of systemic therapy, and when it is employed, it must be utilized with a neuroprotectant and/or hippocampal sparing. Brittany Harvey: Great and then finally, how will these guideline recommendations affect patients with HER2-positive metastatic breast cancer and brain metastases? Dr. Carey Andres: So, I would just echo Dr. Ramakrishna's comments about the advances that we've seen and the importance of multidisciplinary care. I think from a systemic therapy perspective, we have the wonderful problem of having multiple agents to consider in this space. And as we've seen, really an explosion of HER2-directed therapies that are now approved and available to patients. One of our challenges has been how to sequence these therapies. And so, we were hopeful that these guidelines will help clinicians and patients determine when to pick individual regimens that best fit the patient's scenario, whether or not their brain metastases are stable at that decision tree, or whether or not they're progressive at that decision tree. I would also point the listeners to the updated guidelines in the management of patients with HER2-positive metastatic breast cancer, as these guidelines will certainly complement the decision-making and systemic therapy, incorporating the presence or absence of brain metastasis. Brittany Harvey: Great, and yes, thank you for highlighting that companion guideline. Both are available at asco.org/breast-cancer-guidelines and in the Journal of Clinical Oncology. So, I want to thank you both so much for your work on these guidelines and for taking the time to speak with me today, Dr. Anders and Dr. Ramakrishna. Dr. Naren Ramakrishna: Thank you very much, Brittany. Dr. Carey Andres: Thank you! Thanks for the opportunity. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast series. To read the full guideline go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines App available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

An interview with Dr. Jennifer Ligibel from Dana Farber Cancer Institute in Boston, MA and Dr. Catherine Alfano from Northwell Health Cancer Institute and Feinstein Institutes for Medical Research in New York, NY, co-chairs on "Exercise, Diet and Weight Management During Cancer Treatment: ASCO Guideline." This guideline addresses recommendations for exercise, diet, and weight management for adult patients undergoing active cancer treatment, highlighting where there is evidence to recommend interventions, and where future research is needed. Read the full guideline at www.asco.org/supportive-care-guidelines. TRANSCRIPT Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast series brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Jennifer Ligibel from Dana Farber Cancer Institute in Boston, Massachusetts, and Dr. Catherine Alfano from Northwell Health Cancer Institute, and Feinstein Institutes for Medical Research in New York, New York, co-chairs on 'Exercise, Diet and Weight Management During Cancer Treatment: ASCO Guideline'. Thank you for being here, Dr. Ligibel and Dr. Alfano. Dr. Jennifer Ligibel: Thanks for having us. Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The full conflict of interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology. Dr. Ligibel, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Jennifer Ligibel: I have no personal conflicts with this guideline. Brittany Harvey: Thank you. Dr. Alfano, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Catherine Alfano: I have no conflicts. Brittany Harvey: Thank you. Then, getting into the content of this guideline. Dr. Ligibel, can you start us off with an overview of the scope of this guideline? Dr. Jennifer Ligibel: Sure. So, this guideline was developed to provide recommendations around exercise, diet, and weight management for patients undergoing active cancer treatment. We defined active cancer treatment as either the perioperative period or the period of time in which patients were receiving chemotherapy and/or radiation. This guideline specifically focuses on adult cancer patients and largely focuses on individuals undergoing treatment for curative intent. There were a number of reasons why we thought it was important to develop a guideline specifically for patients who were undergoing cancer treatment. There are a number of other guidelines that talk about the role of these types of lifestyle factors in preventing cancer, and also information widely available about the potential benefits of exercising more, consuming certain types of diets, or losing weight after cancer treatment is finished. But there's much less information about the feasibility and potential benefits and safety of increasing your exercise, changing your diet, or losing weight during cancer treatment. This is the time when oncology providers are primarily working with patients in a time when patients have a lot of questions about what they should be eating and what they should be doing. So, this guideline was developed to specifically try to provide guidance during treatment. Brittany Harvey: Yes, definitely an area in which guidance is very much needed. So, then Dr. Alfano, I'd like to next review the key recommendations of this guideline, starting with what are the recommendations regarding exercise during cancer treatment? Dr. Catherine Alfano: For exercise, the expert panel felt that the evidence was very strong. And so, oncology providers should recommend aerobic and resistance exercise during active treatment with curative intent because it can mitigate the side effects of cancer treatments. So, exercise has been shown during active cancer treatment to reduce fatigue, to either improve or preserve a patient's cardiorespiratory fitness, their physical functioning, their strength outcomes, and in some kinds of patients exercise has been shown to improve quality of life and reduce anxiety and depression. The evidence is not sufficient to recommend exercise specifically for improving cancer control outcomes yet. This is a source of ongoing study, but we felt that the evidence was strong enough that oncology providers should recommend aerobic and resistance exercise, and it should become the standard of care for all cancer patients. The second recommendation regarding exercise is that oncology providers may recommend pre-operative exercise for patients specifically undergoing surgery for lung cancer. So, this can be called prehab or pre-habilitation exercise. And this exercise has been shown to reduce outcomes like the length of hospital stay and postoperative complications. Brittany Harvey: Excellent. Thank you for reviewing those recommendations and the level of evidence behind them. So, then, Dr. Ligibel, what did the panel recommend regarding particular dietary patterns or foods for patients during cancer treatment? Dr. Jennifer Ligibel: One of the things that we recognized as a panel as we reviewed the evidence that shaped these guidelines was that there was much less evidence for both dietary factors and whether that was specific dietary patterns or some specific foods, as well as weight management, how those types of changes during treatment, affected outcomes, or even the feasibility of changing your diet or losing weight during cancer treatment. We, for this guideline, really relied on randomized trials to help shape our guidance, and we realized very quickly that there were few randomized trials testing dietary change or weight management during cancer treatment. So, as a panel, we debated for a long time about what we should say in this setting. We did find that there were a few randomized trials that specifically looked at neutropenic diets. We defined that as diets that omitted fresh fruits and vegetables for patients who had undergone treatment for hematologic malignancies, and in particular bone marrow transplants. Those studies were designed to look at whether those types of diets reduce the risk of infection. We did not see evidence that omitting fruits and vegetables during cancer treatment for those malignancies, reduced infection, and so the group provided a recommendation that neutropenic diets not be recommended for patients during cancer treatment, but we were unable to provide specific guidance regarding other dietary factors or the incorporation of specific foods during cancer treatment. As a group, we recognize the importance of a healthy diet for general health. But given that we were really looking at randomized trials of the effects of changing someone's diet during treatment, we ultimately did not make a recommendation for a particular diet during cancer treatment, but really called for more research with well-designed clinical trials to test the impact of things like plant-based diets, intermittent fasting, other types of diets for which there may be interesting preclinical evidence, but very little information in people about the benefits or even the safety of these types of diets during cancer treatment. Brittany Harvey: Understood, I appreciate you outlining the nuance of that recommendation, and also the areas for future research, which we can get into a little bit more in a little bit. So then, in the last category of recommendations, Dr. Alfano, what does the guideline state regarding interventions to promote intentional weight loss or avoidance of weight gain during cancer treatment? Dr. Catherine Alfano: So, when our panel reviewed the evidence for weight loss or the avoidance of weight gain during cancer treatment, unfortunately, we decided that ultimately, there's insufficient evidence right now to recommend either for or against intentional weight loss or the prevention of weight gain during active treatment to improve outcomes related to the quality of life or things like treatment toxicities, or ultimately cancer control outcomes. Brittany Harvey: Thank you, Dr. Alfano, for that recommendation, as well. So, Dr. Ligibel, in your view, what is the importance of this guideline? And how will it impact both clinicians and patients? Dr. Jennifer Ligibel: This guideline is really the first large-scale effort to pull together all of the data from randomized trials about the effects of changing your lifestyle, exercising more, in particular, changing your diet, changing your weight during cancer treatment. I think that as a panel, we found very clear and consistent evidence as Dr. Alfano outlined, that exercise has concrete benefits for patients during cancer treatment. I think that this is really an important call to action, both for providers in speaking about these topics to their patients, but also for payers. And as we think about our healthcare system, about how we're going to support patients in becoming more active in a safe way during their cancer treatment. I think that it's very important that we recognize that encouraging physical activity is not just telling people that they should go out and do it. We really need to think about how we support patients in making these types of lifestyle changes in a sustained way. So, I think that this guideline really provides clear evidence that exercise is important. It also provides clear evidence that we need more research in other areas. Patients are asking their oncology providers every day, what they should be eating, whether they should be thinking about losing weight, and we really don't have clear evidence to guide these conversations at this point. I do think it's important to recognize that as a panel, we all felt very strongly that this guideline should not be interpreted as saying that a healthy diet or maintaining a healthy weight during treatment wasn't important. But we were really struck by the dearth of high-level evidence to be able to help our patients make informed choices and I think that's something that, from this guideline, we really need to come up with a plan be better able to ask the question that comes up in the clinic every day of, 'Doctor, what should I eat?' Brittany Harvey: Those are excellent points. I appreciate the panel looking critically at the evidence that's actually out there to try and determine recommendations. So then, Dr. Ligibel just mentioned a few areas in which more research is needed. So, Dr. Alfano, what are the outstanding questions regarding optimal diet, weight management, and exercise during active cancer treatment? Dr. Catherine Alfano: Being treated for cancer makes many patients feel like they have no control over their health and that causes them enormous anxiety. Patients are really looking for things that they can do to take the reins of control back over their health to improve their long-term health and well-being during treatment. I want to underscore the importance of the oncology team in helping patients improve their exercise. Research has shown that 50% of patients undergoing cancer treatment are not getting enough exercise. Patients want to receive guidance about exercise from their oncology team. And importantly, patients whose oncology clinicians discuss exercise with them are more likely to make these healthy behavior changes. So, it really underscores the importance of the oncology team in helping patients to access these important components of their health that they're asking for. The appropriate referral for exercise in patients undergoing treatment for cancer can really depend on several factors such as comorbidities, treatment toxicities, and the patient's pre-existing physical activity level. For example, many patients can safely perform unsupervised exercise, but others may need supervised cancer-specific exercise because they've got problems that they need to deal with clinically supervised exercise or to participate in a formal cancer rehabilitation program prior to undertaking exercise on their own. I want to highlight for everyone that there are national efforts that are focusing on building referral algorithms and clinical decision support tools to help point to the most safe, feasible, and effective intervention for a given patient. Brittany Harvey: Excellent. Well, thank you both so much for outlining the recommendations here and describing the nuance that the expert panel went through. It was certainly a large effort that you've helped lead. And so, I want to thank you so much for your work on these guidelines, and for your time today, Dr. Ligibel and Dr. Alfano. Dr. Jennifer Ligibel: Thanks for having us. Dr. Catherine Alfano: Thank you. Brittany Harvey: Thank you to all of our listeners for tuning in to the ASCO guidelines podcast series. To read the full guideline go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

An interview with Dr. David Schiff from the University of Virginia Medical Center in Charlottesville, VA, Dr. Michael Vogelbaum from Moffitt Cancer Center in Tampa, FL, and Dr. Vinai Gondi from Northwestern Medicine Cancer Center Warrenville and Proton Center in Warrenville, IL, authors on "Radiation Therapy for Brain Metastases: American Society of Clinical Oncology Guideline Endorsement of the American Society for Radiation Oncology Guideline." An ASCO endorsement panel endorsed the "Radiation Therapy for Brain Metastases: an ASTRO Clinical Practice Guideline," and the authors review the endorsement process and key points in this episode. Read the full guideline endorsement at www.asco.org/neurooncology-guidelines. TRANSCRIPT Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network, a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows including this one at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. David Schiff, from the University of Virginia Medical Center in Charlottesville, Virginia, Dr. Michael Vogelbaum from Moffitt Cancer Center in Tampa, Florida, and Dr. Vinai Gondi from Northwestern Medicine Cancer Center Warrenville and Proton Center in Warrenville, Illinois, authors on 'Radiation Therapy for Brain Metastases: American Society of Clinical Oncology Guideline Endorsement of the American Society for Radiation Oncology Guideline'. Thank you for being here, Dr. Schiff, Dr. Vogelbaum, and Dr. Gondi. Drs. Schiff, Vogelbaum, and Gondi: Our pleasure. Brittany Harvey: First, I'd like to note that ASCO takes great care in the development of its guideline products and ensures that the ASCO conflict of interest policy is followed for each guideline product. The full conflict of interest information for this guideline endorsement panel is available online with the publication in the Journal of Clinical Oncology. Dr. Schiff, do you have any relevant disclosures that are directly related to this topic? Dr. David Schiff: No relevant disclosures, Brittany. Brittany Harvey: Thank you. And Dr. Vogelbaum, do you have any relevant disclosures that are related to this topic? Dr. Michael Vogelbaum: I have no relevant disclosures. Brittany Harvey: Thank you. And Dr. Gondi, do you have any relevant disclosures that are related to this topic? Dr. Vinai Gondi: Brittany, my only relevant disclosure is that I served as vice-chair of the guidelines that we're discussing today, but otherwise, no relevant disclosures. Brittany Harvey: Excellent! Thank you all. So, then starting us off, Dr. Schiff, what is the scope of this guideline endorsement? And how does it intersect with the recently published 'Treatment for Brain Metastases: ASCO-SNO-ASTRO Guideline'? Dr. David Schiff: Sure. A little bit of background, from the start of the joint ASCO and SNO guideline effort, we had the participation of radiation oncologists, in addition to neurosurgeons, medical oncologists, and neuro-oncologists. As we were getting underway, ASTRO reached out asking to participate formally as well. They had been planning to update their brain metastasis guidelines but were a year or two away from getting started. And they recognized it would be redundant for them to create comprehensive guidelines that covered chemotherapy, immunotherapy, and surgery as our guidelines were poised to do. By participating with ASCO and SNO, they were able to have their task force focus specifically on key questions related to radiation oncology practices. In particular, the ASTRO project went into considerable depth on issues of radiation and radiosurgery dose, fractionation schemes, and the risk of radiation complications. These were areas that our guidelines didn't address. Several members of the ASTRO task force including their chair, Paul Brown, and co-chair Dr. Gondi were members of our committee, and we added Dr. Brown as a co-chair to our committee when ASTRO came on board. The overlap between our two groups helped ensure that our recommendations were in harmony. Brittany Harvey: So, then, Dr. Vogelbaum, can you provide us with an overview of how the ASCO guideline endorsement process works? Dr. Michael Vogelbaum: Sure, Brittany. So, as Dr. Schiff mentioned, ASCO had convened a guidelines panel to develop the new 'Treatment for Brain Metastasis: ASCO-SNO-ASTRO Guideline'. And this was a multidisciplinary panel that he and I co-chaired and was anchored by a guideline specialist from ASCO, Hans Messersmith, and the process was that we had evaluated recent literature pertaining to the treatment of the brain metastases, and so, we had a very good understanding of what was supported by high-quality evidence and what was not there yet, as a group. So, when ASTRO came to ASCO and asked whether or not we would be interested in endorsing their guidelines, we were already prepared with all the evidence. And so, the same panel got together again, to evaluate the ASTRO guidelines. And we did this, again, in a very structured manner. We reviewed the guideline questions and recommendations, compared them to the evidence, and went through the same type of review and polling process that we had when we had developed our own original guidelines. In the end, we had a conversation with the ASTRO guidelines leadership about some of the points that we raised questions about, and we were able to reach an accommodation that allowed us to fully endorse the ASTRO guidelines. Brittany Harvey: Thank you, Dr. Vogelbaum for that overview of the endorsement process. So, then, Dr. Gondi, what are the key recommendations of the ASTRO guideline? Dr. Vinai Gondi: Thank you, Brittany. As Dr. Schiff and Dr. Vogelbaum outlined, ASTRO commissioned a list of key questions that they sought to address specifically to inform the radiotherapeutic management of brain metastases. And to address these questions, ASTRO not only convened a panel of expert radiation oncologists across the country but also engaged with the Agency for Healthcare Research and Quality (AHRQ) to create a comparative effectiveness evidence review, in addition to our own high-level evidence review to address these questions. The four key questions that were addressed in the ASTRO guidelines are: Number one: What are the indications for stereotactic radiosurgery alone for patients with intact brain metastases? Number two: What are the indications for observation, preoperative radiosurgery or post-operative radiosurgery, or whole-brain radiotherapy in patients with resected brain metastases? Number three: What are the indications for whole-brain radiotherapy for patients with intact brain metastases? Number four: What are the risks of symptomatic radionecrosis with whole-brain radiotherapy and/or stereotactic radiosurgery for patients with brain metastases? The recommendations that were made are based on a high-level review of a considerable amount of literature over the past several years that addressed these specific questions. I would encourage the listeners to this podcast to read through the guidelines to understand the specific nuances of each of those recommendations. Brittany Harvey: Excellent! Thank you for that overview. Then, in addition to what Dr. Gondi just said, Dr. Vogelbaum, were there any additional points of discussion raised by the ASCO endorsement panel? Dr. Michael Vogelbaum: Brittany, yes, there was an area of discussion where we needed to interact with the ASTRO guidelines leadership, as I mentioned earlier, and it really related to that key question one that Dr. Gondi described, which is what are the indications for SRS alone for patients with intact brain metastasis. The approach that had been strongly endorsed by ASCO was that there would be a multidisciplinary approach to decision making. And really the benefit of that, the value of that radiosurgery really comes in the form of the interaction between the radiation oncologist and the neurosurgeon. The way that the original proposal had been formulated, there was a size cut-off that was higher than we thought was appropriate for really endorsing that kind of conversation between the radiation oncologist and the neurosurgeon. And so really, we proposed that we bring that cut-off down further, there actually was another subpart to the guideline that had looked at a lower cut-off, but did not specifically call out that interaction between the neurosurgeon and the radiation oncologist. And we felt it would be more appropriate to insert that at that cut-off rather than the larger lesion cut-off. And after a conversation, there was agreement, that was really the only guideline or subpart of the guidelines where there was any real debate or discussion. For the rest of it, the comments that came up from the panel were easily addressed and it really just came down to this one modification. And fortunately, ASTRO agreed, and we were able to go ahead and complete the endorsement. Brittany Harvey: Great! It's great that this was able to be a complete endorsement of that guideline. So, then, Dr. Gondi, in your view, what is the importance of this guideline endorsement? And how will it affect ASCO members? Dr. Vinai Gondi: Thank you, Brittany. A number of responses to that. Number one is, as Dr. Vogelbaum, outlined the purpose of these guidelines was meant to be patient-centric and patient-focused, that we had patient champions who had navigated, who are part of the guideline development team, but also to be multidisciplinary. And so, the type of input and feedback we received from the ASCO team was super valued and valuable, as we were formulating these guidelines and Dr. Vogelbaum outlined a good example. Number two, it had been almost a decade since the last guidelines had come out from ASTRO related to brain metastases management. And much has happened in our field over the past several years that has been practice-changing. We have several novel and innovative radiotherapy technologies and techniques, such as the emergence of radiosurgery, the use of novel radioprotectants, such as hippocampal avoidance, and memantine, but also the emergence of innovative and novel neurosurgical interventions and CNS active systemic therapies. So, the modern management of brain metastases has really undergone quite a revolution over just the past few years, and it is important that these guidelines be updated to reflect those changes, but also to inform radiation oncologists on the contemporary management of brain metastases and in evidence-based care. So, we believe that these guidelines will significantly impact ASCO members. Certainly, those who are radiation oncologists, as brain metastases are some of the most common patients that radiation oncologists manage in the community and in academic centers, but also for other members of ASCO medical oncologists, surgeons to understand sort of the nuances of radiotherapy management that is evidence-based, so they can have a patient-centered, patient-focused, multidisciplinary discussion with their radiation oncologist as well. Brittany Harvey: Those are excellent points for clinicians on the management for brain metastases. So, then finally, Dr. Schiff, Dr. Gondi just mentioned how these guidelines are patient-centric. So, how will these guideline recommendations impact patients with brain metastases? Dr. David Schiff: Yeah, well, I think what I'm about to say is really going to echo what Dr. Gondi just said. You know, 20 years ago, patients diagnosed with brain metastases were typically immediately referred to a radiation oncologist, they almost always got whole-brain radiation therapy, the median survival was about four months, and many, if not most patients, died from their brain metastases. The situation has really changed recently. With the rapid advances in management from new therapies, and well-designed clinical trials in recent years, outcomes have markedly improved, it's probably less than a quarter of patients now who succumb to their intracranial disease. But at the same time, decision-making for patients has become much more complicated. Nowadays, medical oncologists may reach out initially to neurosurgeons for consideration of radiosurgery or surgical resection, or in some circumstances utilize systemic therapy as a first step. Conversely, a patient might see a neurosurgeon first, who may or may not be aware that there's appropriate immunotherapy or targeted agent that might make sense prior to going on to radiosurgery. It's obviously a challenge for sub-specialists to keep up with all the emerging clinical trial data and new drugs. Our two sets of guidelines provide a roadmap for physicians of different expertise to help determine what types of therapies or referral should be considered when brain metastases are found. The end result of all this is improved control of intracranial disease and improved quality of life for the patients. Brittany Harvey: Absolutely. Those are key points. It's excellent to see these guidelines, and the overarching 'Treatment for Brain Metastases: ASCO-ASTRO-SNO Guideline' be published. So, I want to thank you all for your time today, Dr. Schiff, Dr. Vogelbaum, and Dr. Gondi. Thank you for all of your work on these guidelines. Dr. Michael Vogelbaum: My pleasure. Dr. Vinai Gondi: Thank you for having us. Dr. David Schiff: Thank you, Brittany. It was great to participate in this important project. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series. To read the full guideline endorsement go to www.asco.org/neurooncology-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in iTunes or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. 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.