ASCO Guidelines

Dr. Antonio Wolff and Dr. Kim Allison discuss the latest ASCO-CAP guideline update on HER2 testing in breast cancer. This guideline update affirms previous recommendations, and provides commentary based on data from the DESTINY-Breast04 trial. Dr. Wolff and Dr. Allison review the questions from the oncology and pathology community raised by these results, and provide commentary on patients with HER2 IHC 1+ and 2+ and ISH-negative metastatic breast cancer. Read the guideline update, "Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: ASCO-CAP Guideline Update" at www.asco.org/breast-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/breast-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.22.02864 Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I am interviewing Dr. Antonio Wolff from Johns Hopkins Sidney Kimmel Comprehensive Cancer Center and Dr. Kim Allison from Stanford University School of Medicine, co-chairs on 'Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: ASCO-CAP Guideline Update'. Thank you for being here, Dr. Wolff and Dr. Allison. Dr. Antonio Wolff: Thank you. Dr. Kim Allison: Thanks for having us. Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in developing its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the full guideline panel, including our guests on this episode today, are available online with the publication of the guideline and the Journal of Clinical Oncology, linked in the show notes. So now jumping into the content, to start us off, Dr. Wolff, what prompted the update expert panel to revisit the 2018 ASCO-CAP recommendations on HER2 testing and breast cancer, and what is the scope of this update? Dr. Antonio Wolff: Thank you, Brittany. We appreciate the opportunity of being with you today, and it's great to be here with my colleague, Dr. Kim Allison, as well. What triggered this informatory update was the release from data in trial DESTINY-Breast04, which tested the antibody-drug conjugate trastuzumab deruxtecan in patients who in the past would have been considered to have HER2-negative disease. This ADC, trastuzumab deruxtecan, has a topoisomerase inhibitor payload that is linked to the antibody trastuzumab. And in the past, from all the previous data we had, trastuzumab alone, or in combination with chemotherapy, or as part of another antibody-drug conjugate T-DM1 was essentially active in patients with HER2-positive disease, which is traditionally defined as having overexpression of the HER2 protein, which almost by default is a result of gene amplification of the HER2 gene. And what data from initial studies appear to suggest is that patients who would not be traditionally considered HER2-overexpressed or HER2-amplified were potentially benefiting or having evidence of clinical activity against this disease in the study of metastatic disease. And this was a randomized clinical trial for patients with metastatic breast cancer whose tumors were centrally determined to have IHC 1+ or IHC 2+ expression and would not have been called HER2-positive, would not have been called HER2-overexpressed. And for the tumors that were HER2 2+, they also had to have absence of gene amplification by an in-situ hybridization assay. And what was very interesting is that there was a meaningful, clinically significant improvement in survival for that patient population. And that has some clinicians to begin asking whether there is a different subset of patients who would have in the past been called as having HER2-negative disease that now could potentially be a candidate for this drug. And is there a difference between these patients and patients who, in the past, would have been called as HER2-negative on the basis of IHC 0? And so what complicated things for us a little bit is that patients with IHC 0 were not eligible for this trial. And what is left unanswered by this clinical trial is whether all patients who don't have HER2 protein overexpression or HER2 gene amplification would potentially have benefited from this drug. Kim? Dr. Kim Allison: Yeah, agree. I think the main impetus for the update was the exciting results from the DESTINY-Breast04 trial and the questions then that the pathology community and the oncology community had about whether this should change HER2 testing guidelines. Brittany Harvey: I appreciate that background on what prompted the panel to revisit this guideline. So then, Dr. Allison, how did the panel come to the conclusion that the previous recommendations are current and valid? Dr. Kim Allison: Right. So, as Antonio mentioned, the whole reason HER2 testing was first initiated was HER2-targeted therapies that showed response in the overexpressed or amplified tested population. And so guidelines have really been fine-tuned and crafted around distinguishing the HER2-positive for over-expression and amplification from negative. And this trial really questioned that in that maybe we can target lower levels of the HER2 protein, but this assay really wasn't designed for that. So we looked at the data from the trial and some of the limited other data that's out there and really came to the conclusion that, look, everyone in DESTINY-Breast04 benefited. The whole population benefited, whether you were 1+ or 2+. And because 0s were excluded from the trial, we don't know if they benefited. So we thought it was premature to create a new category, a new result category, and change our current reporting to a HER2-low category, mainly because we don't know that there's a new predictive threshold for response to treatment. So essentially, what we've got is a trial that showed great benefit but didn't create a new biomarker that is predictive or prognostic. Instead, it repurposed this older test as a trial entry criteria. And so now we're kind of stuck with 1+ or 2+ ISH negative as their trial entry criteria that gives you eligibility for trastuzumab deruxtecan. So essentially, we reaffirmed our prior recommendations with acknowledgment that what these categories: positive, equivocal, and negative, refer to is for protein overexpression or gene amplification and that we should continue to use the same scoring criteria, 1+, 2+, 0, and interpretation as were used in DESTINY-Breast04 for their clinical trial criteria. But awareness is important. Dr. Antonio Wolff: Yeah, the other thing that I would add, Brittany, I think we need to go back to what was the purpose of HER2 testing back in 1998 when we identified the survival benefit from trastuzumab in metastatic disease. And then, in 2005, when we had evidence of adjuvant benefit in improving disease-free and then overall survival for patients with early-stage disease. And the immunochemistry assays at that time were developed to differentiate between patients who had HER2 overexpressing disease or HER2 gene amplified disease versus not. At that moment, it was clearly identified that patients were considered as having HER2-positive disease that defined a biological entity, a tumor subtype, a group of patients who had worse prognoses in the absence of therapy. But then when they were treated with, for instance, chemotherapy with anthracyclines at that time, but then with HER2 targeted therapies with antibodies, these patients that otherwise would have a poor prognosis now were having an improved outcome. HER2 was a marker of poor prognosis but also a marker of a good chance of deriving clinical benefit, so there was a predictive benefit. And everything else, IHC 0, 1 or 2+, ISH-negative, there has been no evidence that targeting the HER2 pathway was clinically important. Or even more meaningful, there was no evidence that these patients have– within the subset of patients that don't have HER2 positive or overexpressing disease - there has been no evidence that those patients have a different outcome based on low levels of expression of HER2. A couple of years ago, in terms of trastuzumab, the NSABP reported findings in the data from NSABP B-47 where the antibody trastuzumab was added to chemotherapy to patients who were considered to have low levels of IHC expression, and in that case, was IHC 1+ or IHC 2+ gene non-amplified. And that settled the issue for sure, that there was absolutely no benefit in the adjuvant setting from the addition of trastuzumab. So we know that there's something different going on here. We know that if you now combine trastuzumab with a specific payload, in this case, the drug deruxtecan, which is a topoisomerase inhibitor, we are potentially targeting the HER2 protein. But these are tumors that are not considered HER2 addicted. These are not tumors whose biology is dependent on the HER2 pathway, so this is simply a better drug delivery. And in this sense, data and evidence from Michael Press, a pathologist at USC that has done some seminal work with HER2 and HER2 testing, he once proposed that the vast majority of breast cancers have some level of HER2 present. And a lot of what is considered IHC 0 is an artifact related to suppression of the detection of the HER2 protein. So there's a chance that the tumors that are truly HER2 negative or HER2 0 are going to be a very small proportion. And IHC assays were never optimized to measure very low levels of HER2. They just don't have the dynamic range for that. And then, from a clinical standpoint, there is no evidence that different levels of HER2 when, in the absence of overexpression, identify groups of patients that have disease that have a different biologic behavior. And I think, as Dr. Allison just mentioned, we don't have any evidence from the DESTINY-Breast04 trial that there is a differential benefit between IHC 1+ versus IHC 2+, ISH-negative. Those patients appear to equally benefit from therapy. Brittany Harvey: Understood. That context is helpful in understanding this updated guideline. So then you've both mentioned the category of patients who are HER2 IHC 1+ and 2+, and ISH-negative. So, Dr. Allison, this article includes a special commentary on those patients, those with HER2 IHC 1+ or 2+, and ISH-negative metastatic breast cancer. What are the essential points of this commentary? Dr. Kim Allison: Yeah. So some of them we've brought up already that this test for HER2 IHC wasn't really designed to detect the low levels of protein expression that may be present in some breast cancers, including the all-important issue that the IHC 0s may not be truly null for HER2, that we may just not be sensitive enough to detect it, or there may be fixation and ischemia, time issues that are very subtle and create a false negative result, essentially by IHC that, and that in addition to not being necessarily predictive or prognostic, the 0 versus 1+ threshold, which really is a threshold that hasn't been tested yet. But since eligibility for trastuzumab deruxtecan essentially now hinges around that 0 versus 1+ threshold, since these were clinical trial entry criteria, what can pathologists do to make best practice efforts to distinguish 0 from 1+? Because we felt like we should make some helpful recommendations, at least since this does appear to be a current status point that pathologists are going to be struggling with in practice. So the points we come up with in that commentary are to follow best practices, like making sure you're using the standardized ASCO-CAP Guidelines criteria. Making sure you pay attention to pre-analytic conditions of the tissue sample and that you're using controls with a range of protein expression, including 1+, to help ensure you've got an assay that's really looking at the right limit of detection since that has shifted somewhat in this instance. And then for interpretation side, for pathologists to be sure to look on high power, so discriminating at 40x when you're trying to score a 0 versus 1+ stain since that's now relevant, you're going to need to go on high power and really distinguish from those two. And then, consider a second pathologist review in borderline or challenging cases or perhaps using additional tools. There's some additional tools online. There are learning sets that are out there to help with that distinction. Dr. Antonio Wolff: What I would add to that is that I think, and Kim, I'm thinking of the pathologist now getting phone calls from oncologists saying, "Hey, Doctor Pathologist, you report this cancer as being IHC 0, and are you sure that this is truly IHC 0?" And I think we need to be careful not to put pathologists in an unfair situation. And I think we also need to be careful based on our behavior as oncologists that we could almost cause the extinction of the diagnosis of IHC 0 if pathologists feel somehow compelled to "try to help the oncologists" and potentially call a tumor that they would otherwise have called IHC 0, that they call that tumor IHC 1+. And I think the reason for being cautious, as Kim mentioned, is these assays were not optimized for the ability to truly distinguish between IHC 0 and 1+. And we do not know if tumors that are IHC 0 clinically behave differently from tumors IHC 1+. Right now, that does not appear to be the case. And I think to a degree, we are being forced, based on the decision by the study sponsors to launch a study that excluded patients of IHC 0. We are left, I often say, twisting ourselves into pretzels, trying to come up with a way to discriminate between IHC 0 and 1+ simply because of the eligibility of the clinical trial and now the resulting FDA label for the study. Because it is plausible that what if patients who had tumors that were IHC 0 had been included in this clinical trial? And what if we had determined that those patients also benefited from this new exciting antibody-drug conjugate? In that case, we would not be talking about creating new categories of HER2 low versus HER2 "ultra-low" and HER2 0, HER2 null. Because essentially, we would have identified a new clinical use for this exciting antibody-drug conjugate for patients who have tumors that are HER2 not overexpressed and HER2 not amplified. So, in fact, it is entirely plausible that the population of patients that could benefit from this antibody may go well above the original intent of DESTINY-Breast04. We just don't have the evidence at this point to say that those patients who would be called IHC 0 don't benefit. It's just that they were not included in the clinical trial. Brittany Harvey: Well, your points there from both of you lead nicely into my next question, in that you've talked a little bit about how this impacts both oncologists and pathologists. So, Dr. Wolff, what does this guideline and commentary mean for both clinicians and patients with breast cancer? Dr. Antonio Wolff: So I think what I would try to reassure oncologists, pathologists, and also patients and their caregivers and loved ones, over the last 20 years, I think we have seen a meaningful improvement in the quality of HER2 testing. And I think pathologists and oncologists recognize that breast cancer biomarkers, in general, in the past, were used purely for prognostic reasons or to complement anatomic pathology from a diagnostic standpoint. But now, many of these assays, especially ER and HER2, are used as the sole determinant of therapy selection in a binary fashion. If you are positive for ER, you can be a candidate for ER-targeted therapy. If you're positive for HER2, you may be a candidate for HER2-targeted therapy. And I think even though the current generation of IHCs were not equipped to make a differentiation between very low levels of HER2 expression from potentially no levels of HER2 expression, with all the limitations we just said, I think pathologists are today doing a very good job. They understand the importance of the work they do in helping us clinicians take care of patients in the clinic. As I often joke, pathologists are wearing the stethoscope with us. So I think we need to be kind to pathologists and not put them under the microscope, if you will, pun intended, or putting a lot of pressure on them. And I think I tend to trust the quality of the work they do. I think there are two things that I would like to see happening. Number one, I would love to see the study sponsor allowing investigators to use a new generation of assays that are more quantitative to be able to back on DESTINY-Breast04 and test specimens of the patients that were triggered on the trial and see if there is a differential benefit in the observed outcomes of patients treated with trastuzumab deruxtecan according to levels of HER2, but that can be measured using a truly quantitative assay. And there are a lot of new assays out there. And I think the sponsors, they do have an obligation to all the patients who are participating in the trial to allow those things to happen. And the second piece is obviously to develop assays that are more quantitative than a traditional IHC. And Kim, along these lines, a question that often comes up is what to do with patients who may have had a previous test that was IHC 0. And what should we, I guess, recommend to clinicians that they do with this situation? Dr. Kim Allison: Yeah, I think this is a common question, and because of the unreliability of a 0 versus 1+ result, and we do see them change when you look at metastatic, or core versus primary surgical excision, 0 versus 1+ results shift around much more so than you'd expect if this was a true biologic difference. So I would look at a spectrum of samples across the metastatic progression. So if any of them are not 0, I think that's a result worth looking at. And considering that either there's heterogeneity there potentially or the 0s were false negatives and not consistent over time, so I would test the metastatic sample again. If you have a new sample, if that's 0, I would still consider treating based on a prior 1+ result or a different sample that's metastatic. Dr. Antonio Wolff: Yeah, the one thing that I haven't done yet is actually for patients who have had– Let's say, that I have a primary term that was IHC 0, and then, they had, unfortunately, metastatic disease, and the diagnostic tissue that confirmed that they had metastatic disease also tested IHC 0. And now they are– unfortunately, disease has progressed after first or second-line therapy, be it anti-estrogen if they had ER-positive disease or chemotherapy if they had ER-negative disease. What I have not done is to request a new biopsy exclusively for the purpose of doing another HER2 test because in case the tumor had changed expression from 0 to 1+. Because what we don't know because of the variability, etc., Dr. Allison was just describing whether that change is real or not. Again, it's really unfortunate that patients who were IHC 0 were not allowed for this study. There are other studies taking place right now looking at tumors that are more than IHC 0 and less than IHC 1+; that's DESTINY-Breast06. And those patients are being called by the study sponsor as "ultra-low". Although I am not a pathologist, but I have no idea how a pathologist can truly try using immunohistochemistry today; really reliably differentiate between it's not 0, it's not 1+, it's in between. I am just concerned that I think we may be asking or putting pathologists in a hard spot, asking them to do something with an assay that was not designed to perform that way. Dr. Kim Allison: Even if we could get the interpretation perfect, to have digital tools to help us with interpretation, I think at that low level, IHC is just really sensitive to pre-analytics and analytic factors that are subtle. Even having a slide that's been sitting unstained for a week or so might change a 1+ to a 0 result. So it really is sensitive, maybe too sensitive, to those kinds of factors. Brittany Harvey: Absolutely. Well, thank you both for those insights on what's facing clinicians and patients and the commonly asked questions today. So then we've spent a lot of time talking about what's happened recently in this field. But, Dr. Allison, what are the ongoing developments and outstanding questions you're all facing regarding HER2 testing and breast cancer? Dr. Kim Allison: Yeah. I mean, I think we've covered some of those. Is IHC 0 truly 0? Would it be responsive to T-DXd or other antibody-drug conjugates targeting HER2? And so if that is relevant, then there's a lot of work looking at maybe more sensitive or quantitative assays that are really designed to detect those lower levels of expression, unlike the current assays. And then digital image analysis to standardize interpretation if they are leading to differences. And then new standards to help us calibrate. Brittany Harvey: Great. Well, I want to thank you both so much for all of your work to review and update this guideline on HER2 testing in breast cancer. And thank you for your time today, Dr. Wolff and Dr. Allison. Dr. Kim Allison: Thanks for having us. Dr. Antonio Wolff: Our pleasure. It's fun. Thank you. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline update, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe, so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Angie DeMichele and Dr. Lynn Henry present the latest rapid recommendation impacting two ASCO guidelines. This update focuses on testing for ESR1 mutations in patients with hormone receptor-positive, HER2-negative metastatic breast cancer, and presents treatment recommendations for patients with a detectable ESR1 mutation. Dr. DeMichele and Dr. Henry review the recent data from the EMERALD trial, discuss it's implications for practice, and ongoing developments they're monitoring for more effective therapeutic options. Read the latest update, "Testing for ESR1 Mutations to Guide Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: ASCO Guideline Rapid Recommendation Update at www.asco.org/breast-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/breast-cancer-guidelines. Read the full text of the update and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.2300638 Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Angie DeMichele from University of Pennsylvania, and Dr. Lynn Henry from the University of Michigan, authors on 'Testing for ESR1 Mutations to Guide Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer: ASCO Guideline Rapid Recommendation Update'. Thank you for being here, Dr. DeMichele and Dr. Henry. Dr. Angie DeMichele: It's a pleasure. Dr. Lynn Henry: Thank you. Brittany Harvey: Then, before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including our guests on this podcast episode today, are available online with a publication of the rapid recommendation update in the Journal of Clinical Oncology, which is linked in the show notes. So then, getting into the content of this rapid recommendation first, Dr. Henry, what prompted this rapid update, which provides updated recommendations for two ASCO guidelines? First, the 'Biomarkers for Systemic Therapy and Metastatic Breast Cancer Guideline', last published in 2022, and the 'Endocrine Treatment and Targeted Therapy for Hormone Receptor-Positive, HER2-Negative Metastatic Breast Cancer Guideline', which was last updated in 2021. Dr. Lynn Henry: Thank you, Brittany. There's been a lot of exciting news for the treatment of metastatic breast cancer in the last few years. This particular update reflects the results of the phase III EMERALD trial. This trial compared the new oral selective estrogen receptor degrader, elacestrant, to standard-of-care endocrine therapy with either fulvestrant or an aromatase inhibitor in patients with hormone receptor-positive, HER2-negative metastatic breast cancer that had previously progressed during treatment with a CDK4/6 inhibitor in combination with endocrine therapy. Compared to standard-of-care, in this trial, they showed improved progression-free survival in both the overall study population as well as specifically in the patients who had a detectable ESR1 mutation in their circulating tumor DNA. These findings were published in the Journal of Clinical Oncology in 2022, and the drug was subsequently approved by the US Food and Drug Administration in January 2023. Therefore, we felt that it was important to update the guidelines to reflect the results of this trial and the new drug approval. Brittany Harvey: Excellent. Thank you for describing the results of that trial and the new approval. So then, based on this data, Dr. DeMichele, what is the updated recommendation from the guideline expert panel for testing for ESR1 mutations? Dr. Angie DeMichele: So, the guideline panel has now recommended that ESR1 mutation testing occur for any patient who develops a recurrence or progression on endocrine therapy. And this is specifically in reference to the development of ESR1 mutations that can occur after a patient has been exposed to aromatase inhibitors. The guideline itself recommends that this testing be done on either tumor or blood, but blood is preferable because there is increased sensitivity using ctDNA testing over tumor testing. So this was an important component of the change in the recommendation because it's linked to the approval of elacestrant as a therapy. Patients are only eligible to receive elacestrant if they harbor an ESR1 mutation. Brittany Harvey: Understood. I appreciate that explanation. So then, Dr. Henry, following that recommendation for testing, what is the new recommendation for treatment for patients with a detectable ESR1 mutation? Dr. Lynn Henry: Yes. So patients who have a detectable ESR1 mutation and who have previously received treatment with endocrine therapy in combination with the CDK4/6 inhibitor for advanced breast cancer now have multiple treatment options. The newest option is this new drug, elacestrant, which is given 345 milligrams orally daily. There are still the other options that we already knew about, which include a different endocrine therapy alone, such as fulvestrant or an aromatase inhibitor, or possibly an endocrine therapy in combination with a targeted agent, such as alpelisib or everolimus. And those decisions really need to be based on what other mutations are present in the patient's cancer. Importantly, at this time, there are no safety or efficacy data to support using elacestrant in combination with targeted agents. Therefore, to date, it has only been approved to be used as monotherapy. But really, this is an exciting new potential option for treatment for patients whose tumors have a detectable ESR1 mutation. Brittany Harvey: Yes, this is an exciting option, and I appreciate you describing how this fits in with the existing treatment paradigm for these patients. So then, Dr. DeMichele, as these new recommendations are implemented, what should clinicians know? Dr. Angie DeMichele: I think this is a really important new step in breast cancer in testing for ESR1 mutations. We've not previously had a medication that required the existence of an ESR1 mutation for patients to be eligible for therapy. So obtaining ESR1 mutation testing may be new for some clinicians. As I stated earlier, this can be done either on a tumor biopsy or on blood testing using the Guardant360 ctDNA test, which is the test that was used in the clinical trial. And it was stated that the ctDNA test is more sensitive than the tumor test. But what's really important here is that the testing occur at the time that the clinician is considering switching therapies, because it's important to find that ESR1 mutation prior to starting the next therapy. ESR1 mutations don't typically exist in a tumor at the time it's diagnosed. They only emerge over time after patients have been exposed to different endocrine therapies, particularly aromatase inhibitors. It's also possible that at the time of a recurrence after aromatase inhibitor therapy or progression on an aromatase inhibitor, there will not be any detectable ESR1 mutation. However, with subsequent therapy, an ESR1 mutation can occur. So a patient may need serial testing over time to determine whether an ESR1 mutation has developed. Brittany Harvey: Understood. Those are important clinical implications. So then, Dr. Henry, Dr. DeMichele just described some of the testing implications for patients. But in your view, how does this rapid update impact patients with hormone receptor-positive, HER2-negative metastatic breast cancer? Dr. Lynn Henry: So as Dr. DeMichele mentioned, this update specifically highlights approval of a new drug, oral SERD elacestrant. This is an exciting new option for treatment of patients whose tumors have an ESR1 mutation. So previous data have demonstrated that cancers with ESR1 mutations do not respond as well to previously available standard-of-care treatments such as aromatase inhibitors. It's nice to have a drug that may be a better option than some of the previously existing treatments for hormone receptor-positive, HER2-negative metastatic breast cancer. Brittany Harvey: Definitely. That's great to hear. So then, finally, Dr. DeMichele, are there ongoing research developments that the panel is monitoring for future updates to these guidelines? Dr. Angie DeMichele: We certainly are monitoring additional research developments, Brittany. Specifically, there are numerous other selective estrogen receptor degraders that are being tested, and these also may ultimately require ESR1 mutation testing and detection for therapies. So we'll be monitoring the results of those clinical trials. We'll also be watching for additional trials that help us understand how to best utilize elacestrant and whether it can be combined with other therapies. And then, finally, I think we have to think about how to place this in the context of other types of molecular changes that we may detect in metastatic breast cancer, such as PIK3CA mutations and others. And as we move forward, I anticipate that we will have additional therapies that are specifically targeted to molecular changes in the tumor. And I think this is a really exciting development because this is a major step forward toward precision medicine, where we're really tailoring the therapy to the specific biology of the patient's tumor and actually responding to the ways in which the tumor is evolving over time and in response to treatment. So as tumors become increasingly resistant to therapies, we can actually take advantage of those resistance mechanisms to develop therapies that will be more effective. Brittany Harvey: Yes, we'll look forward to those new therapies and research developments and then updated guidelines in the future. So I want to thank you both so much for your work on this rapid recommendation update and for your time today, Dr. DeMichele and Dr. Henry. Dr. Angie DeMichele: Thank you. Dr. Lynn Henry: Thank you very much. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guidelines, go to www.asco.org/breast-cancer-guidelines. You can also find many of our guidelines and interactive resources in the newly redesigned ASCO Guidelines app, available for free in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this Podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Nigel Key and Dr. Anna Falanga join us for a conversation on the updated ASCO VTE prophylaxis and treatment in patients with cancer guideline. They discuss recent evidence assessing apixaban for VTE treatment in patients with cancer and evaluating direct factor Xa inhibitors for extended postoperative prophylaxis. Based on this new evidence, they present updated evidence-based recommendations from the guideline expert panel. Dr. Key and Dr. Falanga also discuss outstanding questions regarding VTE prophylaxis and treatment in patients with cancer. Read the full guideline update, "Venous Thromboembolism Prophylaxis and Treatment in Patients with Cancer: ASCO Guideline Update" at www.asco.org/supportive-care-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/supportive-care-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.00294. Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at ASCO.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Nigel Key from University of North Carolina, and Dr. Anna Falanga from University of Milan Bicocca, co-chairs on 'Venous Thromboembolism Prophylaxis and Treatment in Patients with Cancer: ASCO Guideline Update'. Thank you for being here, Dr. Key, and Dr. Falanga. Dr. Nigel Key: Thank you. Dr. Falanga: Thank you. Brittany Harvey: Then, before we discuss this guideline, I'd just like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including our guests on this episode, are available online with the publication of the guideline in the Journal of Clinical Oncology, linked in the show notes. So then, jumping into this guideline update, Dr. Key, what prompted an update to the 'ASCO VTE Guideline', which was last updated in 2019? Dr. Nigel Key: Okay, well, thank you, Brittany, for that question. Well, first of all, ASCO has been providing this guideline since 2007 with iterations and full reviews of the data, the last complete one being in 2019. This update was really triggered by ASCO's signals approach, which relies on experts in the field suggesting an update to the guidelines based on recent publications that may be practice-changing. So, in this case, the signals were really a randomized control trial assessing apixaban for VTE treatment, venous thromboembolism treatment, in patients with cancer called the CARAVAGGIO trial, and we'll discuss that a little bit later. There were also a couple of randomized control trials which evaluated direct factor Xa inhibitors for extended postoperative prophylaxis, and these were new areas subsequent to the 2019 guidelines. So, a systematic review was carried out in the relevant topics for randomized control trials published between November 1, 2018, and June 6, 2022. And what you'll hear today is the result of that process. Brittany Harvey: Great. And then you just described that guideline recommendations were updated both for prophylaxis and for treatment. So then, Dr. Falanga, what is the updated recommendation for perioperative VTE prophylaxis? Dr. Falanga: Thank you for this question. For this update, actually, there were two randomized trials addressing the extended thromboprophylaxis in cancer patients. This is an important question, and direct oral anticoagulants had never been included in the previous guidelines. So this new data indicating safety and in some way efficacy of these drugs were important to be in some way included. Actually, the two trials, one tested laparoscopic surgery in patients with colorectal cancer, so major surgery in colorectal cancer and tested the drug rivaroxaban against the placebo after one week of low molecular weight heparin. And the other trial tested in a different type of cancer, gynecological cancer surgery, apixaban versus a placebo after a short course with low molecular weight heparin. So the two trials are very different, and the recommendation, after all, is weak. But the panel felt it was important to split the previous recommendation 3.5 into three recommendations. The 3.6 specifies which are the cancer patients that really need extended prophylaxis, or the recommendation addresses this population in particular at high risk, which means patients with laparoscopic or laparotomic abdominal pelvic surgery for cancer who have high risk characteristics, including restricted mobility, obesity, previous history of thrombosis, and other additional risk factors. So the recommendation is limited to this population. As I said, there is a weak recommendation because the two trials differ in the type of surgery, the type of the number of patients, the timing of prophylaxis, and one tested rivaroxaban and one tested apixaban. But in any case, the recommendation now reads that prophylaxis with these two direct oral anticoagulants may be offered in addition to the previous recommendation with the low molecular weight heparin for this indication, although the low molecular weight heparin indication remains a strong recommendation where these other two drugs are added. But still other research is needed to strengthen this recommendation. Brittany Harvey: Understood. Thank you for describing where there is evidence and where future research is needed to strengthen those recommendations and the qualifying statements for who is appropriate to receive this VTE prophylaxis. So then, Dr. Key, what did the expert panel update regarding treatment of patients with cancer with established VTE to prevent recurrence? Dr. Nigel Key: Yes. First of all, I want to make it very clear that this particular recommendation deals, as you say, with patients with established venous thromboembolism. This is quite distinct from recommendations regarding primary prophylaxis in ambulatory patients, which is dealt with in a separate recommendation. That's number two in the 2019 guideline, and those have not been updated. But in terms of treatment of established venous thrombosis, there were three randomized control trials considered. They essentially all addressed the possible role of apixaban, which had not been included in the 2019 guideline. In this revised recommendation, the data looked at both the initial treatment of patients presenting with venous thrombosis as well as extended treatment, which what we know at present, really extends out to six months in terms of using non-vitamin K antagonists, preferably for extended prophylaxis. So, in 4.1, the CARAVAGGIO trial that I mentioned earlier was a very large trial involving almost 1200 patients with cancer who had symptomatic or incidental acute proximal DVT or pulmonary embolism. And these patients were randomized to six months of treatment with either apixaban or dalteparin. And, in a nutshell, apixaban was non-inferior to dalteparin for the primary outcome of a recurrent VTE during the six month trial period. There was also a similar rate of major bleeding, 3.8 versus 4% in the two arms. So this was strong evidence that initial treatment could include apixaban in addition to what was already in the recommendations. And for those choosing to treat with heparin for initial five to ten days, as before, the recommendation is for low molecular heparin over unfractionated heparin. So, the second part of this took into account the CARAVAGGIO trial, which I've already mentioned the result of, as well as two smaller trials. They had a VTE trial which had almost 300 patients, and again compared apixaban to dalteparin. And then there was a third smaller study comparing apixaban to lovenox in about 100 patients. But, essentially, the net outcome of the systematic review was that the recommendations 4.1 and 4.2 for, respectively, initial and extended treatment of established VTE, gave high quality evidence with a strong recommendation to include apixaban both for initial treatment and for extended treatment. Brittany Harvey: Understood. So then you've both discussed this a bit by describing the randomized trials supporting these recommendations. But Dr. Falanga, what should clinicians know as they implement these updated recommendations? Dr. Anna Falanga: Well, clinicians should know that there are more options to offer to their patients for long-term treatment of VTE, as Dr. Key said, up to six months. This is an important expansion of the spectrum of choices for a more personalized treatment on the basis of the patient's characteristics and the drug characteristics. So this is very important to know. Also, for the postoperative prophylaxis, this update is relevant because of the recommendation. Although we are open to the perspective of using new drugs based on oral intake as an alternative to low molecular weight heparin, and knowing this drug appears to be safe in the specific setting where they were tested in the trial is important. Brittany Harvey: Definitely, it's great to have more options for patients. So then in your view, Dr. Key, how will these guideline recommendations impact patients with cancer? Dr. Nigel Key: Well, I think that with more information that Dr. Falanga just presented, essentially we're looking at two different situations here, both the extended thrombosis prophylaxis after surgery and the choice of agent does need to be individualized with a discussion with a physician. There are still remaining concerns about increased bleeding with direct Xa inhibitors in patients with GI and GU malignancy, for example. So this needs to be taken into account, patients' creatinine values and so on, and what other drugs there are in terms of interactions with direct Xa inhibitors. So I think what you're looking at though is the ability to be confident for that patient that oral agents are, for the most part, as safe and effective as low molecular weight heparins. And hopefully, this will be something that is seen as a positive and maybe somewhat liberating effect for patients. Brittany Harvey: That's great to hear. So then finally, Dr. Falanga, you've already mentioned a few areas in which more research would be helpful to strengthen the recommendations. But are there other outstanding questions regarding VTE prophylaxis and treatment in patients with cancer? Dr. Anna Falanga: Yes, there is a lot of work to be done ahead for prophylaxis. As we already mentioned, it's important to improve the evidence for direct oral anticoagulant safety and efficacy for extended, postoperative prophylaxis. In the medical setting, we have open questions about how to improve the management of patients with VTE beyond six months; we don't know for the treatment of VTE beyond six months, and identify better what are the best drugs and the best strategies to be utilized in this interval. Then I think that we need to understand, in collaboration with cardiologists and neurologists, whether arterial thrombosis associated with the cancer may need a different treatment compared to subjects without cancer, and understand how to manage anticoagulant together with antiplatelet drugs in these patients who are often thrombocytopenic. Finally, it is, of course, important to test new drugs for VTE treatment with potentially reduced bleeding risk, such as the new inhibitors of factor XI and factor XII. I think these are the major points that we need to address in the near future possibly. Brittany Harvey: Absolutely. Well, we'll look forward to future updates of this ASCO guideline to discuss that research as it comes along. So I want to thank you both so much for your work to update this guideline and thank you for your time today, Dr. Falanga and Dr. Key. Dr. Anna Falanga: Thanks a lot. Bye bye. Dr. Nigel Key: Thank you. You're very welcome. Bye bye. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/supportive-care-guidelines. You can also find many of our guidelines and interactive resources in the newly redesigned ASCO Guidelines app, available for free in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

Dr. Barbara Andersen delves into the newly updated guideline for management of anxiety and depression in adult survivors of cancer in this ASCO Guidelines podcast episode. This guideline affirms prior guidance regarding screening and assessment of anxiety and depression, and updates evidence-based recommendations for management of both anxiety and depression. Dr. Andersen reviews the principles of the recommended stepped-care model, along with recommended treatments, including options such as cognitive behavior therapy, cognitive therapy, behavioral activation, structured physical activity and exercise, and mindfulness-based stress reduction. Challenges regarding managing anxiety and depression in adult survivors of cancer are also discussed. Read the full guideline update, "Management of Anxiety and Depression in Adult Survivors of Cancer: ASCO Guideline Update" at www.asco.org/survivorship-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/survivorship-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.00293. Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Barbara Andersen from the Ohio State University, lead author on "Management of Anxiety and Depression in Adult Survivors of Cancer: ASCO Guideline Update." Thank you for being here, Dr. Andersen. Dr. Barbara Andersen: Thank you. Thank you for the invitation. Brittany Harvey: And then, just before we discuss this guideline, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Andersen on this episode, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes. So then, to jump into the content of this guideline, Dr. Andersen, what prompted an update to this guideline, and what is the scope of this updated version of the guideline? Dr. Barbara Andersen: Well, as your listeners probably know, guidelines are routinely updated, primarily due to new accumulated evidence that suggests a change in diagnostic or treatment procedures. The first guideline from ASCO was in 2014. They made this important first step, which alone made that an important advance. The prior scope was on assessment, that is, which measures at what time points were important for assessing patients' depressive or anxiety symptoms. We then provided treatment pathways thereafter, noting currently available evidence for treatment. But a systematic review of the literature wasn't done at that time. So what this guide does is first affirm the prior recommendations regarding the measures to use for assessment, the PHQ-9 and the GAD-7. But the departure for these guidelines is based on a systematic review of the intervention and treatment literature, and from that review, we recommend particular treatments. Brittany Harvey: Understood. So, focusing on that intervention and treatment aspect of this updated guideline, I'd like to review the key recommendations starting with, what are the key general management principles for people with cancer and anxiety and/or depression? Dr. Barbara Andersen: Well, one key principle is that of education. Your listeners probably are familiar with the fact that many hospitals or centers provide patient-tailored cancer treatment-related information, treatment information on surgery, chemotherapy, immunotherapy, and other topics. But we recommend that general first-level materials on coping with stress, anxiety about treatment, and depression be routinely provided as well. What that does is for individuals with elevated symptoms, it validates what they're experiencing and normalizes the patient experience. So we hope that all patients with cancer and any patient-identified caregiver, family member should be offered the information. We have so many ways we can give information to patients these days. Verbally, material, whatever mode is easy for you and the patient, but please choose one to give information to patients. Another characteristic of the guideline is our recommendation that treatment follow the principle of stepped care. So what this means is you match the assessment of the severity, level of depression or anxiety, and you match that data to the selection of treatment contexts. This is most clearly seen in the recommendation that group treatment formats be used for those with moderate severity of symptoms versus individual or face-to-face therapy for those with severe symptoms. And this is the case for both anxiety and depressive disorders. This is a principle that's cost-effective and tailors the treatment recommendations. Another principle that we offer is when making a referral of a patient for further evaluation or psychological care; we plead with you to make every effort to reduce the barriers and facilitate patient follow-through. We say it's essential because low motivation, for example, is a symptom of depression. And that low motivation and low mood can conspire to reduce the likelihood that patients will pursue treatment. So just keep that in mind when referring patients. Brittany Harvey: Absolutely. Those are key points for general management across anxiety and depression symptoms. So, moving beyond those principles, what are the recommendations from the expert panel for treatment and care options for patients with depressive symptoms? Dr. Barbara Andersen: For depressive symptoms, we recommend cognitive behavior therapy or cognitive therapy, behavioral activation, psychosocial interventions using empirically supported components, and moderate structured physical activity and exercise. All of those are efficacious, empirically supported treatments for moderate depressive symptoms. And it might be easiest to offer group therapy for individuals with these problems. Brittany Harvey: Great. Thank you for reviewing those recommendations for patients with depressive symptoms. So, in addition, what does the expert panel recommend for treatment and care options for patients with anxiety symptoms? Dr. Barbara Andersen: Many of the same treatments are used. Cognitive therapy, cognitive behavior therapy are the most efficacious treatments out there for cancer patients or individuals without cancer coping with anxiety symptoms or depressive symptoms. Again, behavioral activation would be useful. Mindfulness-based stress reduction has garnered significant support in the recent years, as well as interpersonal therapy. Brittany Harvey: Understood. So thank you so much for going through each of those recommendations. But in your view, Dr. Andersen, what is the importance of this guideline, and how will it impact both clinicians and patients with cancer and symptoms of anxiety and/or depression? Dr. Barbara Andersen: An important element to this guideline is it names the specific empirically supported standard therapies for treatment of anxiety and depression. There's a departure, though, from our prior guideline, and in this one, pharmacotherapy is not recommended as a first-line treatment, neither alone nor in combination. It's simply not supported by the evidence. However, clinicians might consider pharmacotherapy when there's low or no availability of mental health resources. Perhaps a patient might have responded well to pharmacotherapy in the past, and patients with severe neurovegetative, or agitated symptoms of depression, those patients, as well as patients with psychotic or catatonic features, would be ones for which pharmacotherapy might be appropriate. Brittany Harvey: Understood. And then you've just mentioned that sometimes there is no or low availability of mental health resources, so that leads to my next question. But what are the both outstanding research questions and challenges regarding managing anxiety and depression in adult survivors of cancer? Dr. Barbara Andersen: The largest challenge is that we're in the midst of a mental healthcare crisis, and COVID has made that abundantly clear. There are problems with access to psychological care due in part to workforce problems, maybe organizational ones, but there is a shortage of mental health professionals, and that, in turn, limits referral networks from managing depression and anxiety. So that's one significant issue that is in place right now. Since the 2014 guideline, screening is a care aim that has been disseminated, but the principles and procedures remain to be fully implemented. I was just looking at a 2022 article in the Journal of Oncology Practice. It was a study examining screening for lung and ovarian cancer patients, two very important groups because the frequency of depressive and anxiety symptoms is perhaps highest of any other groups. So they looked at more than 20 CoC-accredited facilities that studied the electronic records to see if there was screening for the patients. And the troubling finding, from my perspective, was that there was no screening for 45% of the patients in this study. So we know that there are disparities in the use of screening and its management. Those disparities exist across race, ethnicity, cancer type, stage, and facilities. And so, that remains a challenge for many sites, including CoC hospitals, to achieve a rigorous screening program. Having said that, I want to say what some might disagree with, but from my standpoint, it's a myth that screening takes a long time. The measures that we recommend probably would take a patient maybe five, maybe ten minutes to complete. But what's time-consuming or what's troublesome in many places is the infrastructure is not in place to do the screening and interpret it in an efficient manner. The other perspective on screening is that it is the effort thereafter, which is, in fact, time and resource intense - that is, finding referral sources, making referrals. But that's the most important step because when that's not done, when patients continue with symptoms, it really incurs the greatest cost for the patients. Brittany Harvey: Absolutely. Screening and then further management of anxiety and depressive symptoms is key for maintaining quality of life. So I want to thank you so much, Dr. Andersen, for coming on today and sharing your insights and also for all your work you did to update this guideline. Dr. Barbara Andersen: Thank you so much. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/survivorship-guidelines. You can also find many of our guidelines and interactive resources in the newly redesigned ASCO Guidelines app, available for free in the Apple App Store or the Google Play Store. If you've 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. Dwight Owen is back on the ASCO Guidelines podcast, discussing the latest updates to the ASCO living guidelines for stage IV NSCLC. In Part 2, Dr. Owen presents the update for stage IV NSCLC with driver alterations. He reviews new evidence from KRYSTAL-1, and reviews a new recommended option for patients with stage IV NSCLC with a KRAS G12C mutation, adagrasib. Read the update, "Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.1" and view all recommendations at www.asco.org/living-guidelines. Listen to Part 1 for recommendations for patients with stage IV NSCLC without driver alterations. TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/living-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.00281 Brittany Harvey: Hello, and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey, and in our last episode, we addressed the living guideline updates for therapy for stage IV non-small-cell lung cancer without driver alterations. Dr. Dwight Owen from Ohio State University in Columbus, Ohio, has joined us again to discuss the updates for therapy for stage IV non-small-cell lung cancer with driver alterations, as a co-chair on 'Therapy for Stage IV Non-Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2023.1'. Thank you for joining us again, Dr. Owen. Dr. Dwight Owen: Thanks for having me, Brittany. Brittany Harvey: Then, before we discuss this update, I'd just like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Owen, who's joined us on this episode, are available online with the publication of the guideline in the Journal of Clinical Oncology linked in the show notes. So then, jumping into the content here, this living clinical practice guideline for systemic therapy for stage IV non-small-cell lung cancer with driver alterations is being routinely updated. What new studies were reviewed by the panel to prompt an update to the recommendations? Dr. Dwight Owen: Yeah. Thank you, Brittany. For this update, the panel and committee felt that it was important to review the KRYSTAL-1 trial. This was a phase I/II open-label study of adagrasib in patients with KRAS G12C mutation-positive solid tumors, which included multiple expansion cohorts, including a cohort of patients with non-small cell lung cancer. Importantly, the data that was presented in this recent publication included only patients treated at the phase II dose of 600 milligrams twice daily. The study included 160 patients with a primary endpoint of a response rate, which was evaluated in 112 of those patients. The confirmed response rate was 43%, including one complete response, with the remaining being partial responses. The median progression-free survival was six and a half months, and the median overall survival for this pretreated patient population was approaching one year. One thing of note is we saw similar toxicities as we have seen with other KRAS G12C inhibitors, which included predominantly GI side effects such as diarrhea, nausea, vomiting, but also hepatic side effects including transaminitis, some renal dysfunction as well. Dose interruption was common in over 60% of patients, and dose reduction was required in over half of patients. Overall, given the efficacy seen in this cohort, again, even though it was a phase I/II trial, it was a substantial number of patients, and we felt that it met the criteria for us to be able to include this as an additional recommendation in our guidelines. Brittany Harvey: I appreciate you reviewing that data. So then, based off this data from KRYSTAL-1, you just mentioned that there's a new recommendation from the panel. So what is this new recommendation for patients with advanced non-small cell lung cancer with a KRAS G12C mutation? Dr. Dwight Owen: For patients with stage IV non-small cell lung cancer with KRAS G12C who have received prior treatment with a chemotherapy and/or immunotherapy with a PD-1 therapy, we have added that clinicians and oncologists may consider treatment with adagrasib to our current recommendations for these patients. Brittany Harvey: Great. And then you just mentioned this is an addition onto current recommendations. So what should clinicians know as they implement this updated recommendation, and how does it fit in with those previous recommendations for patients with previously treated non-small cell lung cancer with a KRAS mutation? Dr. Dwight Owen: That's a really important point, is this is now our second option for these patients, including sotorasib, which many of us have been familiar with so far. Of course, we don't have a head-to-head trial comparing these two, but looking at the efficacy and toxicity data, they do seem quite similar. We have some more data for sotorasib from the CodeBreaK 200 study, which we'll be reviewing in a future update. However, at this point, looking at the monotherapy studies that have been done, the toxicity profiles seem fairly similar, the efficacy profiles seem fairly similar, so we don't yet have a clear differentiator that we can see, again, in the absence of a head study. The other thing I would note is that the inclusion criteria for these studies, for the most part, excluded patients with active brain metastases, which, unfortunately, is something that we see quite commonly in patients with lung cancer. And although we have seen some case reports and some anecdotal data for CNS activity with these compounds, we're still waiting for defined cohorts, which there were defined cohorts in these studies that included patients with asymptomatic but untreated brain metastases. And I think that will be something that we are actively looking for and looking forward to. Because I think having a better understanding of potential CNS activity of either or both of these compounds would really alleviate a lot of concerns that we have that those patients who really are the patients that we see in clinic were just not represented in the studies that we reviewed to date. Brittany Harvey: Understood. I appreciate that additional context around these recommendations. So what does this new therapeutic option mean for patients with stage IV non-small cell lung cancer with a KRAS G12C mutation? Dr. Dwight Owen: The end result is that we have more treatment options for patients. Again, both of these compounds seem active. There are clearly patients who benefit and, in some cases, for a substantial period of time because of these options, which were not available as of just recently and until the very recent past, KRAS was, of course, considered an undruggable target. So it's really incredible that we have these treatment options and that they're coming to clinic so quickly. I think there are some areas that we still don't understand yet in terms of the sequencing of treatment. Right now, these treatments are only approved as a subsequent treatment. In most of the studies, the vast majority of patients had received both chemotherapy and immunotherapy. We don't really know how that sequence might affect the tolerability or efficacy of the KRAS inhibitors. We do know that toxicity is an issue, and with both agents, dose reductions are frequently utilized to try to assist with tolerability. There is a slight difference in terms of how these are administered, whether it's daily with a higher pill burden versus twice daily. And so there are some nuances that clinicians can discuss with patients. But again, absent a head-to-head study, it's really important to have a discussion with your patient about what the toxicity profiles of these agents are and what the likelihood of benefit is. And we look forward to seeing more data as these get combined with other therapies and potentially have more insight into the optimal sequence of therapies for patients with KRAS G12C non-small cell lung cancer. Brittany Harvey: Absolutely. It's great to have additional treatment options for patients, and those are key points for discussions about personalized therapeutic regimens. So then, finally, are there emerging therapies or targets that the panel is considering for future living guideline updates? Dr. Dwight Owen: As I mentioned in the last podcast, the data coming out is happening so quickly that we are working to make sure that the guidelines are as up-to-date as possible based on the most recent published literature where we can actually take time to delve into the data and be transparent about the evidence based from our recommendations. We are very interested in the subsequent studies in the KRAS G12C pathway. I mentioned the CodeBreaK 200 study that we'd be including in a future publication, as well as in some of the emerging data in KRAS non G12C non-small cell lung cancer. As of now, it's very important to keep in mind that the only inhibitors we have are dependent on the G12C on the cysteine, and therefore those are the only patients that are currently able to benefit from these treatments. But in the future, we hope that that patient cohort becomes expanded, and we continue looking for new therapies for patients with other alterations, including subsequent therapies for EGFR non-small cell lung cancer and, of course, other actionable alterations as well. Brittany Harvey: That's great to hear. We'll look forward to that future research and the review of that evidence by the panel and future guideline updates. So thank you so much for your work on these updates and thank you for your time today, Dr. Owen. Dr. Dwight Owen: Thanks very much, Brittany. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast series. To read the full guideline, go to www.asco.org/living-guidelines. There's a companion living guideline update on therapy for stage IV non-small-cell lung cancer without driver alterations available there and in the JCO. You can also find many of our guidelines and interactive resources in the newly redesigned ASCO Guidelines app, available for free in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe, so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Dwight Owen is back on the ASCO Guidelines podcast, discussing the latest updates to the ASCO living guidelines for stage IV NSCLC. In Part 1, Dr. Owen presents the update for stage IV NSCLC without driver alterations. He reviews new evidence from EMPOWER-Lung3 and POSEIDON and discusses new recommended options for patients with squamous cell carcinoma and non-squamous cell carcinoma, and PD-L1 tumor proportion score 0-49%. Read the update, "Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2023.1" and view all recommendations at www.asco.org/living-guidelines. Listen to Part 2 for recommendations for patients with stage IV NSCLC with driver alterations. TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/living-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.00282 Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and I'd like to welcome back Dr. Dwight Owen from Ohio State University in Columbus, Ohio, co-chair on 'Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline Version 2023.1'. Thank you for being here, Dr. Owen. Dr. Dwight Owen: Thanks for having me, Brittany. Brittany Harvey: Then, before we discuss this update, I'd like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO conflict of interest policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Owen on this episode, are available online, with a publication of the guideline in the Journal of Clinical Oncology linked in the show notes. So then, diving into this update, this living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer without driver alterations is being updated on a regular basis. What was the new evidence identified by the expert panel through routine literature searches to prompt an update to the recommendations? Dr. Dwight Owen: Yeah. Thanks, Brittany. I think it's really important to point out that these living guidelines are evidence-based. And so, we are constantly reviewing the literature to find new data to support recommendations for treatment options for clinicians to choose for their patients with metastatic non-small cell lung cancer. Clinicians these days, and physicians and oncologists are faced with so much information coming from abstracts to press releases to publications of new clinical trial results that it can be sometimes overwhelming to keep track of all the latest breakthroughs and nuances in the literature for non-small cell lung cancer. So for this specific update, the panel and the committee reviewed two papers, including the EMPOWER Lung-3 Study and the POSEIDON Study. The EMPOWER Lung-3 study was a double-blind, placebo-controlled phase III study investigating cemiplimab plus platinum doublet chemotherapy as the first treatment for patients with either locally advanced stage III or stage IV non-small cell lung cancer without either an EGFR, ALK, or ROS1 alteration. And this is a mode of treatment that we've seen before, which is a PD-1 plus chemotherapy or PD-L1 plus chemotherapy compared to a chemotherapy control. And indeed, we did see an improvement in median overall survival in this study with the addition of cemiplimab to chemotherapy of almost 22 months versus 13 months with the placebo. This was accompanied by a higher rate of grade 3 or higher toxicities. But overall, these data were consistent with what we have seen with other studies of checkpoint inhibitor therapy plus chemotherapy in the first-line setting, which is now the current standard of care. The second study we reviewed was the POSEIDON Study, and this was an open-label phase III study of combination checkpoint inhibitors. So this was PD-L1 plus CTLA-4, durvalumab + tremelimumab with chemotherapy versus chemotherapy alone, and these patients were metastatic non-small cell lung cancer without EGFR or ALK alterations. The interesting thing about this study is there was a cohort of patients treated with durvalumab plus chemotherapy alone. But it was really the cohort of patients treated with tremelimumab, durvalumab, and chemotherapy who had a significant improvement in median survival of 14 months versus 11.7 months with chemotherapy alone, with a hazard ratio of 0.77. In this study, the tremelimumab was only given for a total of five cycles, so it was not continued during the maintenance phase with durvalumab, which is a slight difference from other combination checkpoint inhibitor therapies, which are approved based on CheckMate 227 and CheckMate 9LA, which is nivolumab + ipilimumab. So, overall, neither of these two studies present a new paradigm of treatment. But they present new treatment options for patients as a first-line treatment for non-small cell lung cancer in the form of either PD1/L1 plus chemotherapy or combined checkpoint inhibitor with a PD-L1 plus CTLA-4 plus chemotherapy, again showing improved survival compared to chemotherapy alone. Brittany Harvey: I appreciate you reviewing the details of those two trials. So then, based off this new data from the trials that you mentioned, EMPOWER Lung-3 and POSEIDON, what are the updated recommendations from the expert panel? Dr. Dwight Owen: So we felt it was important to update our prior recommendations for patients, especially with low to intermediate PD-L1 expression from 0% to 49%, that patients may offer cemiplimab plus chemotherapy as an additional treatment option in addition to the recommendations that have already been in place, regardless of histology. And then, based on the POSEIDON data, we felt that this was also a treatment option for those similar patients, especially with PD-L1 negative or up to 49%. We do feel that the patients with PD-L1 TPS scores of 50% or higher still seem to benefit the most from checkpoint inhibitor monotherapy and multiple studies that have been done there. And so we did not make any changes to the recommendations for those patients with PD-L1 high non-small cell lung cancer. Brittany Harvey: Understood. And then you just mentioned that neither of these therapies represent a paradigm change for treatment options. So what should clinicians know as they consider these new options in addition to previously recommended therapies? Dr. Dwight Owen: Yes. So I think when clinicians are looking at these studies, things to keep in mind are the size of the study, the cohorts included, the endpoints. The comparison arm, for now, remains chemotherapy alone, which again is no longer the standard of care. So we are sort of looking backwards at a historical standard of care that we no longer really confront other than for patients who have some contraindication to immunotherapy. The other thing to keep in mind is, of course, when you add more treatments together, you expect more toxicities. And that is certainly the case when we see the dual combined checkpoint inhibitor therapies plus chemotherapy. Regardless of whether it's nivolumab + ipilimumab and chemotherapy or whether it's durvalumab + tremelimumab plus chemotherapy, we do expect a higher rate of toxicities when we do add the CTLA-4 to the PD1/L1 backbone. And so this is a conversation that's really important to have with your patients. We don't have a head-to-head trial, so we are inferring differences in terms of response and benefit using the same comparison of chemotherapy but from different studies and also different populations. So that is probably one of the more important lessons to take from all of these studies is that we know that the toxicity rate does change depending on how you add therapies for these patients. And we also know that there are patients who may not need that additional therapy. So patient selection is key. And I think one of the most unmet needs right now is for patients with PD-L1 negative tumors who don't seem to benefit from checkpoint inhibitor monotherapy or even in long term data when checkpoint inhibitor therapy is given just combined with chemotherapy, these patients seem to be the ones who don't benefit as much. And so I think that would be the patient population that really warrants that extra discussion where you may consider a more aggressive treatment depending on a patient's preference in terms of susceptibility, in terms of toxicity. Brittany Harvey: Absolutely. Considerations of the toxicity profiles of these agents is key for patient quality of life. That leads nicely into my next question, but what do these new recommended therapies mean for patients with stage IV non small cell lung cancer without driver alterations? Dr. Dwight Owen: Well, I think, of course, it is beneficial to have more treatment options, but when we have more treatment options, the decision can actually become more challenging because how do you select from any of the treatment options that we have? And in the absence of direct head-to-head trials for now, we really need to look at the toxicity data, look at the outcome data, and see how the patient in front of you fits into the studies that have been done in order to make an inference and to have that informed discussion with the patient about what to expect from a specific treatment. And I think the higher rates of immune toxicities that we see when we use combination checkpoint therapy needs to be a discussion with patients, and also the type of chemotherapy backbone and how long that chemotherapy will be continued. Whether it's two cycles like Checkmate 9LA, whether it's four cycles like POSEIDON, whether we have a non-chemotherapy option to offer patients, these are all nuances that right now lead to a really robust conversation with our patients up front. And really trying to guide patients through these discussions because the information can be so overwhelming when it's given at one time. So, really trying to have that meaningful conversation in a way that the patient can help advocate for themselves in the clinical decision-making. Brittany Harvey: Definitely, those nuances are important for those individual discussions. So then, finally, you've mentioned that the panel is reviewing literature on an ongoing basis. So, what ongoing developments is this panel monitoring for future updates? Dr. Dwight Owen: So, I think all of us are very excited about the announcements that we have been hearing, both in terms of press releases, in terms of abstracts at the upcoming ACR meeting, and of course, ASCO later this year, where we expect to have a wealth of new data for patients with non-small cell lung cancer, both in the metastatic setting but also in the early stage setting. And I think one of the challenges for us in this committee and for practicing oncologists every day is the speed at which this information is coming out and making sure that we have time to really review each study and give each study the time needed to understand how it can impact our treatment selection based on what's already an accepted practice and what maybe is something that we should reconsider. And so I think it's very rewarding work to work with the committee members and the panel and ASCO. But it is also something that we take very seriously, just because data can come out so quickly at varying levels of detail. And we really want to make sure that when we make a guideline recommendation, that we are very clear that it is evidence-based and what that evidence is. Brittany Harvey: Absolutely, we appreciate the panel's evidence-based approach to developing these recommendations. So, I want to thank you for your time working on this update and for coming on the podcast to speak with me today, Dr. Owen. Dr. Dwight Owen: Thanks very much, Brittany. Brittany Harvey: And thank you to all of our listeners for tuning into ASCO Guidelines podcast series. To read the full guideline, go to www.asco.org/living-guidelines. There's a companion living guideline update on therapy for stage IV non-small-cell lung cancer with driver alterations available there and in the JCO. You can also find many of our guidelines and interactive resources in the newly redesigned ASCO Guidelines app, available for free in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe, so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experiences, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Katherine Virgo discusses the latest evidence-based guideline recommendation updates regarding initial management of metastatic prostate cancer based on the new clinical trial results comparing triplet therapies (the addition of darolutamide, abiraterone, or enzalutamide to docetaxel plus androgen deprivation therapy) to standard of care. Dr. Virgo also discusses cost of treatment options and ongoing research questions in this field. Read the full guideline, "'Initial Management of Noncastrate Advanced, Recurrent, or Metastatic Prostate Cancer: ASCO Guideline Update" at www.asco.org/genitourinary-cancer-guidelines. TRANSCRIPT This guideline, clinical tools, and resources are available at www.asco.org/genitourinary-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest disclosures in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO.23.00155. Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I am interviewing Dr. Katherine Virgo from Emory University, lead author on the 'Initial Management of Noncastrate Advanced, Recurrent, or Metastatic Prostate Cancer: ASCO Guideline Update'. Thank you for being here, Dr. Virgo. Dr. Katherine Virgo: Thank you. Brittany Harvey: Before we discuss this guideline, I'd just like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Virgo, are available online with the publication of the guideline update in the Journal of Clinical Oncology, which is linked in the show notes. So then, getting into the content of this update first, Dr. Virgo, what prompted this update to the initial management of noncastrate advanced, recurrent or metastatic prostate cancer guideline? Dr. Katherine Virgo: The update is primarily driven by new clinical trial results comparing triplet therapies to standard of care. Triplet therapy here refers to the addition of darolutamide, abiraterone, or enzalutamide to docetaxel plus androgen deprivation therapy for patients with de novo metastatic noncastrate prostate cancer. Brittany Harvey: Great. And then, based on this, what are the new and updated recommendations from the guideline panel? Dr. Katherine Virgo: The first updated recommendation adds darolutamide to the list of treatment options as follows: docetaxel, abiraterone, enzalutamide, apalutamide or darolutamide, each when administered with androgen deprivation therapy, represent five separate standards of care for noncastrate metastatic prostate cancer, with the exception of the triplet therapies of docetaxel plus abiraterone plus ADT and docetaxel plus darolutamide plus ADT. The use of any of these agents in any other particular combination or in any particular series cannot yet be recommended. The second updated recommendation states: for patients with metastatic noncastrate prostate cancer with high volume disease as defined per CHAARTED, who are candidates for treatment with chemotherapy but are unwilling or unable to receive triplet therapy, for example, due to insurance constraints, docetaxel plus ADT should be offered. We add some practical information here. Patients should be made aware that doublet therapy, docetaxel plus ADT, has inferior overall survival compared to triplet therapy, such as abiraterone and prednisone plus docetaxel plus ADT. Then, I have a few recommendations here with respect to triplet therapy, and these are new. For patients with de novo metastatic noncastrate prostate cancer with high volume disease as defined per CHAARTED who are being offered ADT plus docetaxel chemotherapy, triplet therapy, abiraterone and prednisone plus ADT and docetaxel should be offered per the PEACE-1 trial. Abiraterone and prednisone plus ADT and docetaxel demonstrated significant overall survival and radiographic progression-free survival benefits compared to ADT and docetaxel alone for patients with high volume disease. Again, we add some practical information. Overall survival data for patients with low volume de novo metastatic noncastrate prostate cancer from the PEACE-1 trial are still too immature to justify recommending abiraterone-based triplet therapy, in other words, abiraterone and prednisone plus ADT and docetaxel, for patients with low volume de novo metastatic noncastrate disease. A second new recommendation, as opposed to a revised recommendation with respect to triplet therapy, is: for patients with de novo metastatic noncastrate prostate cancer who are being offered ADT plus docetaxel chemotherapy, triplet therapy, darolutamide plus ADT and docetaxel should be offered per the ARASENS trial. Compared to placebo plus ADT and docetaxel, darolutamide plus ADT and docetaxel demonstrated significant overall survival benefits, in addition to significantly longer times to castration-resistant prostate cancer, pain progression, first skeletal event, and initiation of subsequent systemic antineoplastic therapy. The practical information offered here is that discussion with patients should include the cost of darolutamide treatment compared with other options, such as abiraterone. There was no change to the 2021 recommendation for enzalutamide other than to report long term results from the ENZAMET and ARCHES trials that was not available in 2021. We added similar practical information here with respect to discussing costs of enzalutamide treatment. Discussion with patients should include the cost of enzalutamide treatment compared with other options, such as abiraterone. Brittany Harvey: Excellent. I appreciate you reviewing those new and updated recommendations from the expert panel along with that practical information. So then, Dr. Virgo, what should clinicians know as they implement these updated recommendations? And also, in your view, how will these guideline recommendations affect patients with noncastrate metastatic prostate cancer? Dr. Katherine Virgo: That's a good question. Clearly, cost is a factor for patients, and we felt it was important to emphasize this in the guideline update. In the data supplement to the guideline update, we included a table listing all the agents discussed in the update, as well as the associated pivotal trials, main outcomes, the control group, the cost per cycle of treatment, and the cost for the full treatment course. This should be particularly helpful to clinicians as they discuss treatment options with patients. We also thought it would be helpful to have a visual guide to treatment options that reflects the clinician's decision-making process more directly. So figure one is the result of a group effort to achieve that aim. Brittany Harvey: Excellent. And there have been a lot of changes in this field that prompted this update, but what are the outstanding questions regarding triplet therapy in the treatment of patients with metastatic noncastrate prostate cancer? Dr. Katherine Virgo: Well, the burning question is whether docetaxel is really still necessary in the treatment of patients with metastatic noncastrate prostate cancer. No phase III clinical trials have yet compared, for example, androgen deprivation therapy plus darolutamide or androgen deprivation therapy plus abiraterone versus androgen deprivation therapy plus docetaxel. Also improved overall survival for patients undergoing triplet therapy is largely confined at present to those with high volume disease. So for patients with low-volume disease, clinical trials as yet show no significant benefit of triplet therapy. Brittany Harvey: Great. Well, then I guess we'll look forward to future trials to determine if that's still appropriate and look for future updates of this guideline. So I want to thank you so much for your time developing and updating this guideline. And thank you for joining me today, Dr. Virgo. Dr. Katherine Virgo: Thank you. I appreciate it. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/genitourinary-cancer-guidelines. You can also find many of our guidelines and interactive resources in the newly redesigned ASCO Guidelines app, available for free in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe, so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Scott Tagawa and Dr. Oscar Brouwer come on the ASCO Guidelines podcast to discuss the new EAU-ASCO Collaborative Guidelines on Penile Cancer. These comprehensive guidelines cover pathological assessment of tumour specimens, diagnosis and staging, local treatment of penile carcinoma, radical inguinal lymph node dissection, prophylactic pelvic lymph node dissection, surgical management, neoadjuvant and adjuvant chemotherapy, radiotherapy, systemic and palliative therapies for advanced penile cancer, follow-up, and quality of life. They highlight key recommendations, and describe the importance of a patient-focused and multidisciplinary approach to management of penile cancer. Find more information about the guidelines at www.asco.org/genitourinary-cancer-guidelines The full text of the guideline is available at https://uroweb.org/guidelines/penile-cancer Conflict of interest disclosures: Guideline Working Group Dr. Scott Tagawa Dr. Oscar Brouwer TRANSCRIPT Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Oscar Brouwer from the Netherlands Cancer Institute in Amsterdam, and Dr. Scott Tagawa from Weill Cornell Medical College in New York, co-chairs on the 'ASCO-EAU Collaborative Guidelines on Penile Cancer'. Thank you for being here, Dr. Brouwer and Dr. Tagawa. Dr. Scott Tagawa: Thanks very much. Dr. Oscar Brouwer: Yeah, thanks for having us. Brittany Harvey: Before we discuss this guideline, I'd just like to note that the guideline was led by the European Association of Urology, and the conflict of interest disclosures of the Guideline Working Group are publicly accessible through the European Association of Urology website linked in the show notes. Additionally, Dr. Brouwer's and Dr. Tagawa's individual disclosures are provided in the show notes of this episode. So, to jump into the content of this guideline, first, Dr. Tagawa, could you give us a general overview of the purpose and the scope of this collaborative EAU-ASCO Guideline? Dr. Scott Tagawa: So, I think the key word there is collaborative. This was truly a collaborative effort, and I say that in a number of ways. So, the two key organizations, the EAU and ASCO, came together with a Memorandum of Understanding and got together from the very beginning in terms of developing the scope and then throughout the methodology for the guidelines. And then, on a practical basis, I'd say even more importantly, a collaboration between multiple physicians of different disciplines from across the world. Whether we're talking about surgeons, radiation oncologists, medical oncologists, pathologists, we had panel members from all over the world as well as patient representatives from all over the world. And patient representatives really played a key role in the development of this guideline. By way of background, penile cancer in most places is considered a rare disease. For example, in the United States, we expect around 2000 cases per year. In the genitourinary world, the next rare cancer is going to be testis cancer, which is going to be four or five times higher than that per year and nowhere near prostate cancer, for instance. So, just kind of put that into perspective. But, importantly, a disease that is a worldwide issue in a number of different ways. That includes the kind of general stigma of being diagnosed with that, the physical and emotional consequences of the diagnosis, as well as treatment. And then, because in part of its rarity, the lack of prospective randomized trials to really guide clinicians and that, I would say, that total package underscores the importance of coming together with a guideline. Brittany Harvey: Great. Thank you for providing that background and perspective. So then, next, Dr. Brouwer, I'd like to review the key recommendations of this comprehensive guideline. Starting with what are the key recommendations regarding diagnosis and staging of penile cancer? Dr. Oscar Brouwer: First of all, I guess just to underline what my colleague, Dr. Tagawa, just said, it's a worldwide guideline, international, multi-continental. I think that's quite a special thing. But it also poses a few challenges, of course, because cultural differences and treatments may differ, opinions as well, distances that patients have to travel, lots of factors there, and also economy, et cetera, et cetera. So, to find a consensus there has been one of the challenges. I think we did a good job there to really make it accessible to all patients and physicians, of course, in the world. When talking about diagnosis, I think comparing our new guidelines to old guidelines really emphasizes the new 2022 WHO classification in which distinction between HPV-positive and HPV-negative disease is highlighted. We increasingly have some knowledge on the difference between the HPV-related and the non-HPV-related penile cancers. I'd say it's about 50-50, the distinction. So, 50% is HPV-related, and 50% not HPV-related. But what we know from other cancers, for instance, that HPV-positive disease is associated with better prognosis than HPV-negative. This distinction is not so clear in penile cancer yet. And one of the reasons is just the lack of data, a lack of perspective for large studies, so to say. So, what we're really highlighting and underlining in the new guideline is the importance of doing HPV testing in all patients that have penile cancer, and that tissue is taken from. We chose to go for the cheapest and easiest but reliable methods to do so. So, immunohistochemistry of p16, to be exact. This is one of the important, I think, recommendations, or maybe even more than a recommendation; obligations we set to all physicians treating penile cancer. So, just in terms of diagnosis and in terms of staging, we all know that lymph node status is the most important factor determining survival. So, finding those lymph nodes, if they are involved with cancer, yes or no. So, if they are metastatic, yes or no, is of crucial importance. This has always been the case, but I think it cannot be emphasized enough. And in this new guideline, we again emphasize the importance of doing surgical lymph node staging in high-risk patients. And what's a little bit new is that we are more or less going to the direction of preferring central node biopsy as the best method to do so. You could also, of course, remove all the lymph nodes, what we call radical lymph node dissection. It's still possible inside our new recommendations, depending on availability of all the techniques or availability of expert centers in proximity. But I think we can all see that in terms of complication rates, central node biopsy is probably superior. So this is also one of the new things in terms of staging. Brittany Harvey: Absolutely. Thank you for those highlights of diagnosis and staging in the guideline. So, following those recommendations, Dr. Tagawa, and I know this is a large section, but what does the expert panel recommend for disease management of penile cancer? Dr. Scott Tagawa: A single-sentence summary would say a multi-disciplinary approach in an expert center when possible. Re-emphasizing one of the statements that Dr. Brouwer made about sentinel lymph nodes; it appears to be better, but clearly is not available everywhere. And if I just make this US-centric for a minute, just within this country, where there are centers that are able to do it and have that expertise, there are centers that are not so far away that may not be able to do that. So regional differences within a single country that's what happens. So, anyway, multi-disciplinary input, I think, is important for many diseases, including penile cancer. A little bit of a segue, but one part of this guideline of which most of us are proud is that, front and center really, the introductory paragraph of the guidelines, where it really states that we need to really have this disease and the management patient-focused and that includes addressing some of the emotional aspects of the disease. Those are included in the management. But to kind of go through very quickly on a very high level, in the early stages management is mostly in the hands of the urologist. But sometimes there's dermatologists and others, so when there is superficial disease, we talk about superficial therapy and I'm just going to leave it at that, many of them don't have level 1 evidence, but there is, for instance, topical chemotherapy that can be helpful. And then, as the disease becomes more invasive, so does the treatment. So there's sections on organ or penile sparing that is a reasonable option that needs to be done in a good multi-disciplinary system. That is a good and sometimes a preferred option when there is adequate staging for earlier stage disease. And then the more invasive the disease becomes is when the management needs to become more multi-disciplinary both in terms of workup as well as treatment. Where there is a consideration for, in certain situations, particularly in very locally advanced where it becomes unresectable at least in some eyes, where we say, "Okay, we're actually going to recommend starting off with chemotherapy," the intent is for surgery with an alternative of chemotherapy and radiation. And currently, there are no head-to-head trials, but those are both reasonable approaches for the most locally advanced disease setting. Taking a step back, if someone starts off with a little bit less locally advanced, so we'd say the alias, gross resectable, we would at least discuss in a multi-disciplinary setting what are the risk benefits of then post-operative therapy, whether that is radiation or chemotherapy, or both. I think all patients at least deserve the opportunity to have that discussion, and then that would be on an individual basis whether we decide to do that or not. Coming from the medical oncology-centric viewpoint where we really deal with systemic therapy, we don't really have any randomized trials to say that one approach is preferred to another, so they're kind of generic. But it does look like platinum chemotherapy, taxane chemotherapy are the most active current drugs. So when we're looking at multi-agent therapy when the setting is a goal of cure, we're generally saying platinum plus taxane combinations without being specific about doublets or triplets. Triplets when they can handle them, but not everyone can handle them. And then for metastatic disease whether it's current or at presentation metastatic disease, the old guidelines actually said 'don't even bother', but now that we have some effective drugs, we would say that for palliative purposes to come in with systemic chemotherapy, the same drugs that we talked about before. And then, there may be additional therapeutic agents. So we're now in the genomic era where there has been at least an initial look at what are the genomics of HPV related, non-HPV related, and there may be some targets, we just are a little bit too early to say that there are absolutely some targets, but there definitely are recommendations for participating in clinical trials. There are some trials that are specific to penile cancer. There are other ones that are non-specific or basket trials. Let's say any disease that has EGFR positivity, a patient with penile cancer may be able to get into that clinical trial or maybe meet a therapy-based trial, so considerations for the trials, I think, are important. Brittany Harvey: It sounds like multidisciplinary care is a key tenet of this guideline. You mentioned patient-focused care is also key in this guideline. So that leads nicely into my next question. But Dr. Brouwer, what are the key recommendations both for follow-up and quality of life? Dr. Oscar Brouwer Yeah so we have, like Dr. Tagawa already said, we have quite an elaborate section, not only in the introduction of the guideline but also a separate chapter at the end, really, to acknowledge the psychosocial, sexual impact this disease can have on patients. And again, I think it's more or less a plea for a form of centralized care for such a rare disease. We have a set of recommendations that we give in terms of follow-up and quality of life, and mainly several points that should really be discussed with patients, and support should be offered. So things like psychological sexual help, but also lymphedema therapist, physiotherapy in terms of complication management. And this mainly goes for patients that undergo lymph node surgery or treatment. And in our experience, if you don't see the disease often enough, you don't have all these things in place in your hospital to offer dedicated people that can do this. So I think that's something to consider in the future for healthcare in general when treating rare diseases such as these. But, yeah, like Dr. Tagawa said, our patient representatives have had a big role in this, and we're happy with that. So I recommend everyone to read it. Brittany Harvey: Absolutely. You've both mentioned that this is a rare disease. So, in your view, Dr. Tagawa, what is the importance of this guideline, and how will it impact clinicians? Dr. Scott Tagawa: There are certain centers that have high volume and certain countries that will have a high volume. For instance, areas in Brazil have a high volume. Whether there's a high volume or a low volume, like an average center in the United States, there haven't been any recent guidelines out there from any organization. So, the EAU has had an old guideline that was really out of date - updating that, number one. And number two, having the backing of two major organizations in the EAU and ASCO, I think is quite important to get this out there on a true international basis. Because not just in this disease, but in most diseases, when there is standardization of care, there's overall better outcomes, whether it's at the center that sees a lot or the centers that rarely see any. I think this document provides guidance, and, actually, take a step back for those that are interested, on the EAU website will be the entire very comprehensive guideline. So, someone that wants to get a lot of details, it's there, very comprehensive and honestly long, but it's, I think, an excellent reference document. And then, published in European Urology will be the summary guideline that has all the key points of the guidelines and summary in the text that will refer to the overall guideline for someone that wants to get through it on a quicker basis. That will also be published on the ASCO website just to kind of get that out there. A little bit of the side in terms of answering your question is that this is a rare tumor. We want everyone to have access to the best care possible, and if nothing else, it provides guidance in a setting where most clinicians don't have a lot of expertise. Brittany Harvey: Definitely. And thank you for highlighting both the summary and full text of the comprehensive guideline. We'll provide those links in the show notes, too, for easy access for any listeners. And then, finally, you've both mentioned the impact this has for patients. But Dr. Brouwer, in your view, how will these guideline recommendations affect patients with penile cancer? Dr. Oscar Brouwer: Well, of course, it's our hope that it will be very beneficial for patients around the world. I think it cannot be emphasized enough that this initiative, in which ASCO, in this case United States group, has collaborated with the European one to make an international multi continental guideline, is quite rare, in urological cancers is the first one. I'm not even sure if there are many others like these. I do really believe it makes sense for rare diseases to not have several guidelines. It's confusing which guideline to choose, especially if there are contradictions. So I guess this initiative is the first step towards having more comprehensive, literal guidelines for such a rare disease. And I really do hope that it will help clinicians, especially when they don't have experience treating this disease, to really look at this guideline first. And in turn, of course, I hope that will benefit patients because they'll have, hopefully, access to better quality care that way. And especially, like we already touched upon, also the importance of early access to support and to palliative care throughout the whole disease process. I really hope that is something that will be offered to patients worldwide more frequently now because it is not only about treating the disease itself but also about the consequences, of course. And I really do think that people will benefit from that in terms of quality of life. Brittany Harvey: Absolutely. I want to thank you both so much for your work on this comprehensive EAU-ASCO Guideline and for talking with me today and sharing your insights, Dr. Brouwer and Dr. Tagawa. Dr. Scott Tagawa: Thank you very much. It was a pleasure. Dr. Oscar Brouwer: You're welcome. I would just like to add also a short opportunity, maybe just to thank all the panel members because it has been a huge effort. Not only an update, it has been actually rewritten from the ground up. So a lot of panel members, not only from the United States and Europe but also Canada, South America, patient representatives, all the associates that have helped. So it has been a big effort, and I congratulate and thank everyone. And thank you, Brittany, for the interview. Brittany Harvey: Definitely, it was a large group and multidisciplinary effort. So thank you to them as well. And also, thank you to all our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/genitourinary-cancer-guidelines. I also encourage you to check out the companion episode on this guideline from EAU podcasts, which you can find on Apple Podcasts, Google Podcasts, and Spotify. You can also find additional ASCO guidelines and interactive resources in the free ASCO Guidelines app available in the Apple App Store or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe, so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

Dr. Beverly Moy is back on the ASCO Guidelines Podcast to discuss the latest guideline rapid recommendation update regarding sacituzumab govitecan for patients with hormone receptor-positive HER2-negative metastatic breast cancer based on recent evidence published in TROPiCS-02. Dr. Moy reviews how this update intersects with the previous rapid recommendation update on trastuzumab deruxtecan and future areas of research that may impact further updates to this evidence-based guideline. Read the latest update, "Chemotherapy and Targeted Therapy for Endocrine-Pretreated or Hormone Receptor–Negative Metastatic Breast Cancer: ASCO Guideline Rapid Recommendation Update" at www.asco.org/breast-cancer-guidelines. TRANSCRIPT Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey and today I'm interviewing Dr. Beverly Moy from Massachusetts General Hospital in Boston, Massachusetts, lead author on 'Chemotherapy and Targeted Therapy for Endocrine-Pretreated or Hormone Receptor–Negative Metastatic Breast Cancer: ASCO Guideline Rapid Recommendation Update'. Thank you for being here, Dr. Moy. Dr. Beverly Moy: Thank you for having me, Brittany. I'm glad to be here. Brittany Harvey: Then 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 in line 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. Brittany Harvey: It's great to have you back on the podcast. Last we spoke, we were discussing the July 2022 rapid update of this guideline regarding the use of trastuzumab deruxtecan. What prompted the second rapid update to the guideline? Dr. Beverly Moy: Thank you very much for that question, Brittany. The guidelines committee decided to issue another rapid guideline update because of the second interim analysis results of the TROPiCS-02 trial. This trial showed that sacituzumab govitecan had a significant improvement of over three months in overall survival compared to chemotherapy of physician's choice in patients with pretreated metastatic hormone receptor positive and HER2/neu-negative breast cancer. So we felt that the strength of this data compelled the ASCO guideline ommittee to issue yet another update. Brittany Harvey: Understood. So then, based off this strong data that you just mentioned from TROPiCS-02, what is the updated recommendation from the guideline expert panel? Dr. Beverly Moy: So the guidelines expert panel really wanted to get this information out because we felt compelled that clinicians should be aware that sacituzumab govitecan is another treatment option for patients with endocrine-resistant metastatic hormone receptor- positive and HER2-negative breast cancer. So we felt that clinicians may use this drug in patients who have received at least two prior treatments in a metastatic setting. Brittany Harvey: Okay, you just mentioned this is one of several treatment options. So as this new recommendation is implemented, what should clinicians know? Dr. Beverly Moy: So, I think that clinicians really need to be aware that sacituzumab govitecan, which is a newer drug, as an antibody drug conjugate, it really does have a role in patients with metastatic hormone receptor positive, HER2/neu-negative endocrine-refractory breast cancer. I think clinicians have been used to this drug in the setting of metastatic triple-negative breast cancer, but the results of theTROPiCS-02 trial would show us that it actually has a lot of efficacy and even an overall survival benefit in patients with metastatic hormone receptor-positive breast cancer. So clinicians should be made aware that this is a treatment option that does give an overall survival benefit. Brittany Harvey: Great. It's great to hear that there's an overall survival benefit with this drug. So, in addition to that, how does this rapid update impact patients with hormone receptor-positive HER2-negative metastatic breast cancer? Dr. Beverly Moy: So I think that it's important for clinicians to remember that patients with metastatic hormone receptor-positive HER2/neu-negative breast cancer, the first-line therapies are endocrine therapy and targeted therapies. But when their disease becomes endocrine refractory, we have several treatment options, and usually the standard is sequential single-agent chemotherapy. What this guideline update is telling us is that sacituzumab govitecan, when compared to other treatments of physician's choice, really does improve overall survival and progression-free survival. So it really should be considered. Brittany Harvey: Excellent. And then finally, are there ongoing research developments that the panel is keeping an eye on for any future updates to this guideline? I know this guideline was last published in 2021 and there's already been two rapid updates to it. Dr. Beverly Moy: Yes, that's a really great question, Brittany, because this is a very active field, and I think that it's important actually to take this guideline update with sacituzumab govitecan in the context of our last guideline update, which, as you said earlier, was with the other antibody drug conjugate trastuzumab deruxtecan. That was our last guideline update in patients who had what we call metastatic HER2 low disease, where trastuzumab deruxtecan had a significant overall survival advantage as well. So what these two guideline updates are really pointing out is that there's this new class of drugs, these antibody drug conjugates, that have so much promise and so much activity in metastatic breast cancer, whether it's hormone receptor-positive or hormone receptor-negative. So future research really has to help us clarify how do we sequence these drugs most appropriately now that we have these two very active treatment options that have a significant overall survival advantage. And then research also has to really guide us into the resistance mechanisms that may be in common or not in common with these two antibody drug conjugates. So I think that we're really looking at results of future trials to see how best to sequence them, if they should be used earlier in treatment in the metastatic setting, and we await the results of those trials. Brittany Harvey: Absolutely. We'll look forward to those future research developments and work with you and the panel to continuously update these guidelines. So I want to thank you so much for your work leading these guideline rapid recommendation updates, and thank you for your time today, Dr. Moy. Dr. Beverly Moy: Thank you, Brittany, for having me. Brittany Harvey: And thank you to all 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 the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy should not be construed as an ASCO endorsement.

Dr. Praveen Vikas, Dr. Tyler Johnson, and Dr. Russell Broaddus present the ASCO endorsement of the Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: Guideline From the College of American Pathologists in Collaboration With the Association for Molecular Pathology and Fight Colorectal Cancer. They discuss key evidence-based recommendations, focusing on the appropriate modality of testing (immunohistochemistry, polymerase chain reaction, or next generation sequencing) across multiple cancer types. Additionally, they cover the ASCO endorsement process, points of emphasis raised by the ASCO expert panel, and implications for clinicians and patients. Read the full guideline endorsement, Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: ASCO Endorsement of CAP Guideline at www.asco.org/molecular-testing-and-biomarkers-guidelines. TRANSCRIPT Brittany Harvey: Hello, and welcome, to the ASCO Guidelines podcast; one of ASCO's podcasts, delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at: asco.org/podcasts. My name is Brittany Harvey, and today, I'm interviewing Dr. Praveen Vikas from the University of Iowa, Dr. Tyler Johnson from Stanford University, and Dr. Russell Broaddus from the University of North Carolina; authors on, 'Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: ASCO Endorsement of CAP Guideline'. Thank you for being here, Dr. Vikas, Dr. Johnson, and Dr. Broaddus. Dr. Praveen Vikas: Sure. Dr. Tyler Johnson: Thanks for having us. Dr. Russell Broaddus: 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 product. The full conflict of interest information for this guideline endorsement panel is available online with the publication of the guideline endorsement in the Journal of Clinical Oncology. To start, Dr. Vikas, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Praveen Vikas: I don't. Brittany Harvey: And Dr. Johnson, do you have any relevant disclosures that are directly related to this guideline? Dr. Tyler Johnson: I do not. Brittany Harvey: And finally, Dr. Broaddus, do you have any relevant disclosures that are directly related to this guideline topic? Dr. Russell Broaddus: I do not. Brittany Harvey: Great. Thank you all for providing that information. So, starting us off on the content of this endorsement, Dr. Vikas, what is the scope of this guideline endorsement? Dr. Praveen Vikas: So, as you can see from the topic and headline, the guideline endorsement was focused on mismatch repair and microsatellite instability testing for immune checkpoint inhibitor therapy, and this is basically an endorsement by ASCO, of a guideline that was developed jointly by CAP, and others. Brittany Harvey: Great. And then you just mentioned that this is an endorsement of the guideline developed by CAP and other organizations. Can you provide us an overview of how this guideline endorsement process works? Dr. Praveen Vikas: ASCO definitely takes great pride in endorsing some of the guidelines that are relevant to our cancer community, and of course, mismatch repair and microsatellite instability testing has been one of those areas where there is a lack of clear guidance. So, when we were approached from CAP about endorsing this guideline, we definitely realized that there's not much published from most of our oncology community, so we were very excited about looking into this guideline and endorsing it. So, this was very much for a topic that we thought is very useful and very timely. Brittany Harvey: And that's great to hear. So then, Dr. Broaddus, as an author both on the guideline endorsement and as a member of the original guideline panel, what are the key recommendations of the CAP guideline? Dr. Russell Broaddus: So, there are six key recommendations from the College of American Pathologists guideline that ASCO recently endorsed. I like to think of the first four as being bundled together because they're interrelated - we dealt with these by cancer type for the first four. So, for colorectal cancer, there's by far the most published evidence on this type of testing, and the evidence-based guideline found that really did not matter so much whether you used immunohistochemistry, or PCR-based microsatellite instability analysis, or next-generation sequencing-based analysis to detect mismatch repair or microsatellite instability. The three different techniques are almost interchangeable in their metrics. Similarly, for gastroesophageal adenocarcinoma and small intestinal adenocarcinoma, immunohistochemistry and PCR-based MSI are very, very similar. There's not quite enough published evidence to equate next-generation sequencing. There were one or two very, very good papers with limited number of patients. The guideline committee felt like if there was maybe one or two more published papers in this space, that for gastroesophageal adenocarcinoma and small bowel adenocarcinoma, it would be similar to colorectal adenocarcinoma, whereas the three techniques were nearly interchangeable. After that, unfortunately, the published evidence really drops off in both quantity and quality for almost all other cancer types. So, endometrial cancer, there's quite a bit of literature. Most of it really points to the immunohistochemistry outperforms PCR-based MSI analysis and PCR-based next-generation sequencing analysis. Most likely, that's because these PCR-based approaches nearly always are optimized to detect mismatch repair defects in colorectal cancer, or other GI types of cancer. And there's actually very good published evidence that this detection of mismatch repair can be cancer-type specific. So, the recommendation is to use immunohistochemistry for endometrial cancer. Fourth recommendation for all other cancer types not encompassed by those first three recommendations, the committee recommends to choose a laboratory-based approach to detect mismatch repair or microsatellite instability defects, but there is no good published evidence to suggest which is the best approach. And again, like with endometrial cancer, there's evidence that the PCR-based approaches, which are usually optimized for colorectal cancer and GI-type cancers, may not be sufficient to work well with cancer types outside of the GI tract. So, almost by default, the recommendation is to choose immunohistochemistry. Fifth recommendation: Many people tend to equate microsatellite instability and high tumor mutation burden. For sure, in colorectal cancer and other GI tract cancers, these two entities, there is substantial overlap. But for cancer types outside of the GI tract, you can easily have a tumor that has a mismatch repair defect, or high levels of microsatellite instability and not have high tumor mutation burdens. So, the recommendation is to not equate those two entities. And finally, last recommendation is that for all of us to remember that these defects in DNA mismatch repair or microsatellite instability, are also hallmarks of hereditary cancer syndrome - Lynch syndrome, and that if you identify unexpectedly that a patient with an advanced cancer has one of these defects and DNA mismatch repair, to consider the possibility of Lynch syndrome, and to alert the appropriate care team, for those patients' family members can be screened as well. Brittany Harvey: Understood. Thank you for reviewing those evidence-based recommendations made by the CAP panel, and then endorsed by the ASCO panel. So, were there any additional points of discussion or emphasis raised by the ASCO endorsement panel? Dr. Russell Broaddus: Yes. And very appropriately, I believe. One-- and this is purely because of the issue of scope, and not to minimize the importance of these issues. One issue that the CAP guideline did not address was the important issue of pre-analytic variables and how they can impact diagnostic testing. A second issue, again, not considered by the CAP evidence-based guideline group, because of just tremendous scope problems, is how do these tests - immunohistochemistry, PCR-based MSI analysis, PCR-based next-generation sequencing analysis - how do we incorporate their use with PD-L1 immunohistochemistry, for example? Liquid biopsies, as a second example. Should we have a staged approach in assessing tumors with all these different testing modalities? And frankly, the answer is, we don't know right now. I think this represents an excellent area where oncologists and pathologists can actually work to provide the evidence in some specific cancer types on whether multiple modalities provide benefit compared to just one modality. Brittany Harvey: Definitely, those are key points perhaps for future research, and I appreciate you explaining what was in and out of scope of this guideline. So then following that, Dr. Johnson, in your view, what is the importance of this guideline endorsement, and how will it affect ASCO members? Dr. Tyler Johnson: I think to understand the importance of this particular endorsement, it's helpful to zoom the lens out to 30,000 feet for a minute. Pretty much, all oncologists, I think remember 10 or 12 years ago, the types of drugs that we now commonly use for immunotherapy, burst onto the scene with the treatment of melanoma. And those trials were quite remarkable because previous to that, not only did we not have a cure for metastatic melanoma, we hardly had a treatment for metastatic melanoma. We had really almost nothing to offer those patients. And then there was this, initially a small and then a larger, and then a much larger series of patients, who we now know with 10 or 12 years of follow up, that many patients who were treated with immunotherapy, who had metastatic melanoma were actually cured. Not just treated but cured. So, in the decade or so since then, there has been this understandable and appropriate stampede of trying to figure out, "Okay, how do we use similar drugs in all of the other many metastatic tumor types?" And I think to generalize a lot, and to make overly simple a very complicated picture, what has emerged from that is that unfortunately for many metastatic solid tumors, immunotherapy just doesn't do much. It's essentially inert, as best we can tell clinically. But there is a small percentage of patients, exactly what percentage depends on the tumor type and the genetic analysis as we're talking about here, but there's a small percentage, maybe 10-20% of patients, who derive this unbelievable benefit from immunotherapy in metastatic solid tumors, to the point that some of those patients, including in other solid tumors, not just melanoma, appear to be functionally cured by the administration of immunotherapy. And so, the question of course that has resulted from that, is if eight or nine patients are going to get no benefit and maybe even harm from administration of immunotherapy, but one or two patients out of 10 is going to get this really remarkable benefit, it would be so great if we could be much more specific in knowing which patients are going to derive benefit, and which patients are not going to derive any benefit and may even be harmed. And I think that that's the context within which we have to understand this guideline endorsement, is that this is getting us one step further to knowing which patients are likely to get benefit from immunotherapy in metastatic solid tumors. And the really nice thing, as Russell pointed out, is that one kind of shorthand takeaway from this is that it is almost never wrong to look at the question with immunohistochemistry. And that's a great answer, because it is also almost always the most readily available test. And so, if you have a patient who has a metastatic solid tumor and you order immunohistochemistry to look for microsatellite instability, that's almost regardless of the tumor type, it's probably going to give you a reliable answer. And if it shows that they're microsatellite unstable, then that means that that patient, regardless of the tumor type, really probably should get immunotherapy upfront or very close to upfront. And then there are more nuances sort of beyond that. But I think that's really the take home message, that this gives us one powerful tool for discerning who is likely to get benefit from these therapies. Brittany Harvey: Absolutely. That's a key thought that you just mentioned, that this is about delivering personalized medicine to individual patients. So then, you've already touched on this a bit in your last answer, but finally, to wrap us up, how will these recommendations impact patients with cancer being considered for immune checkpoint inhibitor therapy? Dr. Tyler Johnson: I think that many clinical oncologists have the experience that when you sit down to talk to a patient who has newly diagnosed metastatic cancer, what their treatment is going to be, almost all of them have heard about immunotherapy somewhere; in the newspaper, or from friends, or in a cancer support group or whatever. So, most of them want to know what part, if any, immunotherapy is going to play in the care of their cancer right upfront. And I think this gets us one step closer to being able to answer that question. Now, the one thing that-- and Russell touched on this a little bit, but I think it's just important to highlight, this gives us an important way to predict people who are going to respond, but that does not necessarily mean that people who this does not identify as likely responders are therefore not going to respond. And that gets into a much more complicated question that depending on the tumor type, you may have to look at PD-L1 expression, or other things. So, it's just to say that this is not a comprehensive, definitive answer, but it is one important part of the answer. I don't know if Russell or Praveen wants to add any more thoughts about that, but that's kind of how I would contextualize this. Dr. Russell Broaddus: I think where there's a lot of opportunity here for us to start developing the evidence on the utility or not, of such staged approaches that if-- say like, immunohistochemistry does not reveal a mismatch repair defect, should we, for some of these cancer types where we don't routinely assess PD-L1, should we next do PD-L1 immunohistochemistry? And if that doesn't show overexpression, should we next try next-generation sequencing approach? Because sometimes those don't overlap with immunohistochemistry. So, I think there's a lot of room for us to provide this evidence. Dr. Praveen Vikas: Yeah. And one point I would like to add, we had a lot of discussion among our ASCO endorsement panel, was that by recommending IHC or PCR over NGS in certain cancer, there would be scenarios where NGS will be needed, because NGS would tell us a lot more, like HER2 amplifications, and that was our point of discussion. We wanted to make sure that we send that message that even in cases where IHC and PCR is being done, that we may still have additional need for NGS testing. Dr. Tyler Johnson: Yeah. Thank you, Praveen, for that. I should qualify, just to make sure that it's clear, that when I said that IHC is a good go-to, I only meant in terms of testing for this specific thing. Part of the problem with next gen sequencing is that it often takes 4-6 weeks, and so I think the practical approach is, you should send the next-generation sequencing, but in the meantime, you can do the IHC to have an answer to that particular question, and usually in one or two days, depending on the lab, and then the next gen sequencing can come back whenever it comes back, and then you can use that for directing later lines of therapy. Brittany Harvey: Excellent. Well, I've really enjoyed this discussion today, and I want to thank you all for your work on this guideline endorsement, and thank you for your time today, Dr. Vikas, Dr. Johnson and Dr. Broaddus. Dr. Praveen Vikas: Thanks so much, Brittany. Dr. Russell Broaddus: Thank you. Dr. Tyler Johnson: Appreciate the time. Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to: www.asco.org/molecular-testing-and-biomarkers-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO guidelines app, available in the Apple App store or the Google Play store. If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe, so you never miss an episode. The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity or therapy, should not be construed as an ASCO endorsement.