ASCO Guidelines

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Therapy for Stage IV NSCLC With Driver Alterations: ASCO Living Guideline Update 2023.1 Part 2 Apr 06, 2023

Show notes

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.

Therapy for Stage IV NSCLC Without Driver Alterations: ASCO Living Guideline Update 2023.1 Part 1 Apr 06, 2023

Show notes

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

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.

Initial Management of Noncastrate Advanced, Recurrent, or Metastatic Prostate Cancer Guideline Update Apr 03, 2023

Show notes

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.

Penile Cancer: EAU-ASCO Guideline Mar 10, 2023

Show notes

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 collabora…

Full show notes at the publisher

Chemotherapy and Targeted Therapy for Endocrine-Pretreated or Hormone Receptor–Negative Metastatic Breast Cancer Rapid Recommendation Update Jan 20, 2023

Show notes

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.

Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: ASCO Endorsement of CAP Guideline Jan 06, 2023

Show notes

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…

Full show notes at the publisher

Targeted Therapy and Immunotherapy for Gastroesophageal Cancer Guideline Jan 05, 2023

Show notes

Dr. Manish Shah discusses the first ASCO guideline for advanced gastroesophageal cancer. He addresses biomarker testing to help guide therapy - including HER2 testing, mismatch repair testing, and assessment of PD-L1 expression. Dr. Shah then reviews the evidence-based recommendations from the ASCO Expert Panel, including first-line therapies for esophageal, gastroesophageal junction (GEJ), and gastric adenocarcinoma, along with esophageal squamous cell carcinoma, based on these biomarker results, as well as evidence in the second-line setting – and beyond – and how to provide optimal care for these patients.

Read the full guideline, "Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline" at www.asco.org/gastrointestinal-cancer-guidelines

TRANSCRIPT

Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs covering a range of educational and scientific content, and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at: asco.org/podcasts.

My name is Brittany Harvey, and today, I'm interviewing Dr. Manish Shah, from Weill Cornell Medicine, in New York, New York, lead author on 'Immunotherapy and Targeted Therapy for Advanced Gastroesophageal Cancer: ASCO Guideline'.

Thank you for being here, Dr. Shah.

Dr. Manish Shah: Thank you for having me. It's great to be here, and I'm looking forward to our interview.

Brittany Harvey: Great. And first, I'd like to note that ASCO takes great care in the development of its guidelines, and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full Conflict of Interest information for this guideline panel is available online, with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Shah, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Manish Shah: Yeah. So, I've received research funding from Merck, as well as from Bristol Myers Squibb, as well as from Oncolys Pharma. These are all companies that have worked for immunotherapy and upper GI cancers.

Brittany Harvey: Okay, thank you for those disclosures.

Then diving into the content here, what is the scope and purpose of this first ASCO guideline for advanced gastroesophageal cancer?

Dr. Manish Shah: Thank you. As you point out in the question, this is the first guideline for advanced gastroesophageal cancer, and really it is a very timely guideline because the landscape for the management of upper GI cancers has evolved and changed dramatically in the last several years. For a long time, we were really focused on chemotherapy for esophagus and gastric cancer. We, in fact, treated squamous cell cancer of the esophagus very similar to adenocarcinoma of the esophagus. And even though we knew of the different disease subtypes for gastric cancer, they didn't really play a role in differentiating management.

About 10 years ago, trastuzumab was approved for the treatment of HER2-positive gastric cancer, but since then, we've had really a run of significant positive studies that have informed practice, and we felt that this was really a timely guideline to help us with regard to our patients with upper GI cancer, particularly, with metastatic disease who need first-line, and beyond therapy.

Brittany Harvey: Excellent. Then you've just mentioned that the management of these upper GI cancers has evolved, so I'd like to review the key recommendations of this guideline that you just gave an overview of. So, starting with first-line therapy - is immunotherapy, or targeted therapy in combination with chemotherapy, recommended as first-line treatment for advanced gastroesophageal adenocarcinoma or squamous cell carcinoma? And what are these recommendations by the subgroups of patients by HER2 status or PD-L1 protein expression?

Dr. Manish Shah: The answer to that is that, in fact, it is now recommended for most patients, but I think I might start a little bit one step behind. So, with a newly diagnosed patient with an upper GI cancer, I think the first step in the management is to test for the biomarkers that will help guide therapy. So, for esophageal adenocarcinoma gastroesophageal junction, and gastric cancer, which is almost always adenocarcinoma, we recommend that everybody undergo HER2 testing immunohistochemistry, as well as a mismatch repair testing or MSI-high; either way you get it is fine, as well as an assessment of the PD-L1 expression, which is scored according to the Combined Positive Score or CPS.

So, that panel of biomarkers will help guide the management for the adenocarcinomas. And so, if you are HER2-positive, then we've known for a long time that the standard of practice would be chemotherapy with trastuzumab; typically, it's a platinum and 5-FU-based treatment with trastuzumab. Most recently, and this is in the guideline and the second part of your question, if you're HER2-positive, and you actually now are recommended to do chemotherapy with trastuzumab and pembrolizumab, which is a PD-1 inhibitor. Then that's based on the KEYNOTE-811 study, that we have the first analysis, which is a response rate analysis, and the response rate improves significantly with the addition of the immunotherapy.

But for the majority of patients who are HER2-negative, we do look at the PD-L1 status by CPS, then here it's a little bit trickier. The FDA guidance is to recommend immunotherapy with chemotherapy for all patients in the first-line setting. However, we also recognize that the higher the PD-L1 expression, the more likely the benefit from immunotherapy. And several studies have demonstrated that, and we've shown that in the guideline as well.

And there seems to be a very reasonable cutoff of a CPS score of five or higher, and above that, there really is clear benefit of the addition of immunotherapy, specifically, nivolumab to chemotherapy for gastroesophageal cancer, that's based on CheckMate 649. And then for esophageal adenocarcinoma, the additional recommendation is the addition of chemotherapy with pembrolizumab for a CPS of 10 or higher. And I think for CPS zero, most of us really felt pretty strongly that there was really no role for the use of immunotherapy because remember, these drugs do have some side effects, that although rare, can be really debilitating.

And then, there's an intermediate category of CPS, 1-4, and here, I think you have to use a little bit of a judgment call. We didn't recommend it in general but did suggest that that would be more of an individual-use basis. And the judgment call is that if the CPS is four, if you showed the slides to another pathologist, it's very possible it could have been a five. So, that kind of heterogeneity is something that we might consider to go ahead and use the immunotherapy.

But if the CPS is lower, the context is also questionable. We talked a little bit about the side effects of immunotherapy. If someone really has bad rheumatoid arthritis, we've all actually had patients given immunotherapy, they come in debilitated. So there, we really would want to be sure that the CPS is high, so that way, the patient is deriving the benefit, and we then adjust the rheumatoid arthritis medicines accordingly.

So, I think the other theme through our guideline is that with more options, we are able to actually provide more personalized care to our patients, giving them the best opportunity to receive the care with minimizing toxicity and maximizing benefit. So, that was a long-winded answer to the question that we do recommend immunotherapy in the first-line setting, in the right context, and for HER2-positive tumors, we recommend trastuzumab plus immunotherapy in the first-line setting, in the right context.

And then, the final thing was the mismatch repair status. So, unlike colon cancer where there's level one evidence comparing immunotherapy to first-line chemotherapy, we don't have that in upper GI cancers. So, we do recommend it, but as for the guidance, it would be in the second-line setting, or later.

Brittany Harvey: Great. Those are key clinical considerations that you just reviewed, and I appreciate you talking through both the evidence, and then the discussions that the panel had on the benefits of therapy, and also the adverse effects that can affect patients.

So, then, beyond first-line therapy for later-line therapies, is immunotherapy or targeted therapy recommended as second-line or third-line treatment for advanced gastroesophageal adenocarcinoma?

Dr. Manish Shah: Yeah. This is a great question, and I think it can be a point of confusion. So, for a long time, immunotherapy, specifically pembrolizumab, was approved and indicated in the third-line setting for CPS 1 or higher patients. The FDA actually removed that approval, and so it's no longer indicated in that setting. And most patients will have gotten immunotherapy in the first-line setting, and as of now, there's no data that suggests that continuing immunotherapy or rechallenging with immunotherapy would be of any benefit.

So, in general, the answer is that we would not use immunotherapy beyond first line. I guess the one caveat is if your CPS is low and you didn't receive immunotherapy in the first-line setting, but you happen to be MSI-high, then certainly, that would be an indication to use immunotherapy in that setting. But I think that would be a pretty rare event. So, if you use immunotherapy in the first-line setting, then there's really no role for continuing or re-challenging with immunotherapy in the second or later-line settings. But that's an active area of drug development, and we think that there will be an opportunity in the next few years for combination strategies to salvage people who had immunotherapy in the first-line setting.

So, in terms of second line and beyond, the other area that we should talk about is in squamous cell cancer. So, squamous cell cancer is a little bit unique, of the esophagus. It is more sensitive to immunotherapy than adenocarcinoma, and in fact, the guidance is to use immunotherapy, either with chemotherapy or as a doublet nivolumab and ipilimumab, in the first-line setting for most patients with squamous cell cancer. If, however, immunotherapy wasn't used in the first-line setting for squamous cell cancer, it is indicated in the second-line setting as nivolumab monotherapy. So, that would be one distinction between the squamous esophageal cancer and adenocarcinoma of the upper GI tract.

Brittany Harvey: Great. I appreciate you reviewing those considerations for later-line therapies, and we'll look forward to more research in this area in the future, as you just described.

Thank you for reviewing all of those recommendations. In your view, what is the importance of this guideline, and how will it impact clinical practice?

Dr. Manish Shah: So, this is an important guideline, because as we've talked earlier, there are lots and lots of options for patients, and we think that the guideline will help frame the discussion on how to best manage our patients in the first line, second line, and beyond.

I think it also frames where there are holes in our knowledge. These knowledge gaps are opportunities for research, for us to continue to develop therapies in gastroesophageal cancers.

Brittany Harvey: So, that's excellent. And you just mentioned that there's more options for patients with advanced upper GI cancers. So, finally, Dr. Shah, how will these guideline recommendations affect patients with advanced gastroesophageal cancer?

Dr. Manish Shah: Yeah. I hope that it will give patients and their physicians a strategy for how to treat patients in the first-line and beyond setting. Gastroesophageal cancer treatment has evolved significantly. Not too long ago, there was a debate of whether or not chemotherapy had a benefit in the first-line setting, or in the second-line setting, and there are randomized studies that demonstrate that for sure. Now, we're in an era where people should get chemotherapy, and then in the right context, get additional targeted agents, like immunotherapy or HER2-targeted therapy.

And if we can treat patients along the continuum of their care, thinking about first line, second line, third line, much as we do for colon cancer, we think that more patients will be able to get access to more of the drugs that are available, and in the long run, that will ultimately help more patients, and give patients better outcomes. I hope this guideline will achieve that goal for our community.

Brittany Harvey: Absolutely. And I appreciate you providing the details and the context for this new guideline. Thank you so much, for all of your work to develop these evidence-based recommendations. And thank you for your time today, Dr. Shah.

Dr. Manish Shah: Oh, absolutely. Thanks so much for having me, and I'm happy to come back anytime.

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/gastrointestinal-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available on iTunes or the Google Play Store.

If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe, so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Therapy for Stage IV NSCLC With Driver Alterations: ASCO Living Guideline Update 2022.2 Part 2 Dec 19, 2022

Show notes

Dr. Dwight Owen presents the first update to the ASCO living guideline on stage IV NSCLC with driver alterations. He identifies the latest trials that informed this update, and the updated evidence-based options for second- or later-line therapies for patients with advanced non-small cell lung cancer and an activating HER2 mutation or a KRAS-G12C mutation. Additionally, he provides important context on the reported toxicities associated with these therapeutics.

Read the update, "Therapy for Stage IV Non–Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2022.2" 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

Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at: asco.org/podcasts.

My name is Brittany Harvey, and in our last episode, we addressed the living guideline updates for 'Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations.' Today, Dr. Dwight Owen from Ohio State University in Columbus, Ohio, is joining us again to discuss the updates for therapy for stage IV non-small cell lung cancer with driver alterations, as the lead author on, 'Therapy for Stage IV Non–Small-Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, version 2022.2.'

Thank you for being here, Dr. Owen.

Dr. Dwight Owen: Thanks for having me.

Brittany Harvey: First, I'd like to note the ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest policy is followed for each guideline. The full Conflict of Interest information for this guideline panel is available online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Owen, do you have any relevant disclosures that are directly related to this guideline topic?

Dr. Dwight Owen: Yeah, thanks for asking that really important question. My institution has received research funding for me to conduct clinical trials from Merck, BMS, Pfizer, and Genentech and Palobiofarma. I have no employment, stocks, stock options, or other disclosures to declare.

Brittany Harvey: Thank you for those disclosures. Then getting into the content of this update, this is the first update to the living clinical practice guideline for systemic therapy for patients with stage IV non-small-cell lung cancer with driver alterations. What new studies were reviewed by the panel to prompt an update to this guideline?

Dr. Dwight Owen: Thanks for that question. This is a particularly exciting update because as we were preparing for this update, reviewing two manuscripts that we think offer new options for our patients with driver alterations, there were actually updated presentations at a recent meeting that showed us even more data for these targets. So, it's really an ongoing and dynamic place. So, we really focused on two updates; one was for KRAS-G12C alterations, and then one was for HER2 alteration-positive non-small cell lung cancer.

So, I'll take them one at a time; for KRAS-G12C, we included an updated recommendation based on the CodeBreak 100 study - this was a multi-center, single group, open-label, phase II study of sotorasib, which is a KRAS-G12C inhibitor, in patients with non-small cell lung cancer positive for KRAS-G12C, who had received prior systemic therapy that could either be with chemotherapy or immune therapy, and the majority of patients had received both. 124 patients were evaluable for response, and the objective response rate was 37%, with the impressive median overall survival of over 12 months, of 12.5 months, specifically.

Now, there were some notable toxicities. There's GI toxicities such as diarrhea and nausea, as well as some elevations in LFTs. We also heard recently at ESMO about CodeBreak 200, which was a randomized study of sotorasib compared to docetaxel in previously treated patients with KRAS-G12C non-small cell lung cancer. And that study did meet its primary endpoint of improvement in PFS for sotorasib-treated patients compared to docetaxel, and we are very much looking forward to seeing that final publication.

For HER2 alteration-positive non-small cell lung cancer, we really focused our efforts on DESTINY-Lung01. Now, this was a multi-center, multinational, open-label, phase II study evaluating trastuzumab deruxtecan in patients with previously treated HER2-positive non-small cell lung cancer. In this study, 91 patients were evaluable for response, and 50, which was 55%, had a confirmed objective response, and the median survival was presented at 17.8 months.

A pretty unique toxicity was observed here. So, drug-related interstitial lung disease or pneumonitis occurred in just over a quarter of patients, and there were two deaths related to this. So, this needs to certainly be monitored for. Also at ESMO, we heard results for DESTINY-Lung02, which was a multi-center, multi cohort, randomized blinded study, which was also a dose optimization study. And this study eventually led to the accelerated approval of the 5.4 milligrams per kilogram dose that seemed to be just as effective as other doses, but perhaps with less toxicity. Again, we're currently awaiting the final publication of DESTINY-Lung02. However, these results are particularly impressive and especially leading to the FDA accelerated approval for a new treatment option for our patients with HER2 alteration positive non-small cell lung cancer.

Brittany Harvey: I appreciate you reviewing that data and the new updates for both of these drugs and targets in this population.

So then, I'd like to review the recommendations that the panel updated for our listeners. First, what is the new recommendation for patients with advanced non-small cell lung cancer and in activating HER2 mutation?

Dr. Dwight Owen: So currently, these patients should continue to receive standard first-line treatment as we do not have head-to-head trials for HER2-directed therapy in the first line. However, for patients who have previously received systemic therapy and have a HER2-activating mutation, trastuzumab deruxtecan certainly should be offered to these patients.

Brittany Harvey: Understood. And then the second category of patients that you identified, what does the expert panel recommend for patients with advanced non-small cell lung cancer and a KRAS-G12C mutation?

Dr. Dwight Owen: So, similarly, these patients should continue to receive standard first-line treatment, as we do not have head-to-head trials for KRAS-directed therapy in the first line. However, for patients who have previously received systemic therapy and have a KRAS-G12C mutation, sotorasib can be offered as a subsequent therapy. Keep in mind that this is only approved in patients with the KRAS-G12C mutation, and not other KRAS alterations.

Brittany Harvey: Thank you for reviewing those two recommendations for second or later-line therapies. What should clinicians know as they implement these updated recommendations?

Dr. Dwight Owen: So, I think what we're really excited about is that both of these agents offer new treatment options for patients who historically did not have a personalized targeted treatment option. We are awaiting publication of additional studies to help interpret these data, but for now, clinicians should discuss these treatment options with their patients, and also keep in mind the pattern of toxicities that seem to be unique to each treatment.

Brittany Harvey: Great. And then, you've just addressed some of this in your last response, but what does this change mean for patients with stage IV non-small lung cancer with a HER2 or KRAS-G12C mutation?

Dr. Dwight Owen: I think the bottom line is that our patients for whom their cancer does not respond, or where it progresses after first-line treatment, will now have additional effective and approved treatment options that are really tailored to the unique characteristics of their tumor and cancer cells.

Brittany Harvey: Absolutely. It's great to have new options for patients in this field.

So then finally, are there future research developments that the panel is considering for future living guideline updates?

Dr. Dwight Owen: So, we're particularly looking forward to the final publication of the studies that were recently presented, including the CodeBreak 200, and DESTINY-Lung02 trials. There are multiple ongoing studies for additional targets, including in the targets that we talked about; so, KRAS-G12C as well as HER2, as well as a number of other targeted options that may benefit subsets of our patients with metastatic non-small cell lung cancer.

Brittany Harvey: Great. Well, I appreciate you reviewing all this data and the updated recommendations, and thank you for your time today, Dr. Owen.

Dr. Dwight Owen: Thanks for having me.

Brittany Harvey: And thank you to all of our listeners for tuning into the ASCO Guidelines podcast series. To read the full guideline, go to: www.asco.org/thoracic-cancer-guidelines. There's a companion 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 free ASCO Guidelines app, available on iTunes, or the Google Play store.

If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Therapy for Stage IV NSCLC Without Driver Alterations: ASCO Living Guideline Update 2022.2 Part 1 Dec 19, 2022

Show notes

Dr. Dwight Owen presents the first update to the ASCO living guideline on stage IV NSCLC without driver alterations. He reviews the new evidence identified by the panel along with the updated recommendation regarding the role of bevacizumab in pemetrexed maintenance therapy. Dr. Owen also discusses exciting trials the panel is looking forward to seeing results of to drive future updates to the living guidelines.

Read the update, "Therapy for Stage IV Non–Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2022.2" 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

Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at: asco.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Dwight Owen, from Ohio State University in Columbus, Ohio, lead author on, 'Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, version 2022.2.'

Thank you for being here, Dr. Owen.

Dr. Dwight Owen: Thanks very much, Brittany, for having me.

Dr. Owen, do you have any relevant disclosures that are directly related to the guideline topic?

Dr. Dwight Owen: I have research funding to my institution to conduct clinical trials from several companies, including Merck, Pfizer, Genentech, BMS, and Palobiofarma, but no ownership, no stock, and no employment history.

Brittany Harvey: Okay, Thank you for those disclosures.

Then let's get into the content of this living guideline update. So, this is the first update to the living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer without driver alterations. What new evidence was identified by the routine literature searches to prompt an update to the guideline?

Dr. Dwight Owen: Yeah, so this is a really exciting time for patients with stage IV non-small cell lung cancer. We are anxiously awaiting the results of some ongoing immunotherapy combination studies. However, for this update, we focused on a specific paper and study that evaluated a treatment that is not our first option anymore, but maybe the first option for a subset of patients.

So, before the standard introduction of immunotherapy for patients with stage IV non-small cell lung cancer, we often offered platinum-based doublet chemotherapy, and for years, we studied ways to make that better. So, we might introduce maintenance therapy where we continue a treatment after the first line of induction chemotherapy. We did either continuation maintenance, which is where you continue a treatment that seemed to be effective, or switch maintenance, where you were introduced to new therapy.

For many folks with non-squamous non-small cell lung cancer, the standard treatment options included carboplatin or cisplatin with pemetrexed, which is an antifolate chemotherapy, or carboplatin and paclitaxel with or without a VEGF inhibitor, such as bevacizumab. One of the big questions was whether there was a benefit for continuing maintenance therapy with something besides pemetrexed, in this case, bevacizumab, and if bevacizumab was given in combination with pemetrexed, whether continuing that as a maintenance would offer benefit.

Now, it's important to point out that the current FDA approval, at least in the United States, is for bevacizumab to be given with carboplatin and paclitaxel. However, several studies looked at the combination with pemetrexed and there were several issues with those studies. So, in one study they used a different agent, so ramucirumab instead of bevacizumab, both VEGF, but slightly different. In one study, the combination that was compared of pemetrexed plus bevacizumab was only compared to bevacizumab maintenance. And so, we really had a sort of hodgepodge of different trials that never answered the question of whether bevacizumab or VEGF therapy, given as maintenance offered any benefit to our patients.

What Dr. Garon and co-authors did in a study that we evaluated was conduct a meta-analysis of four of those randomized trials, focusing on the question of comparing pemetrexed maintenance therapy alone versus in combination with bevacizumab. And what they found is that there was no significant difference in overall survival with the addition of bevacizumab compared to pemetrexed by itself, and there were higher rates of toxicity in those patients, including serious and higher-grade toxicities.

So, I felt that it was really important to point out that the addition of bevacizumab or other VEGF therapies does not seem to add to a survival benefit when given as maintenance. And even though this is a subset of patients who perhaps could not get immunotherapy as a first-line treatment, maybe because of a pre-existing autoimmune disorder, but for those patients, it doesn't seem that the addition of VEGF as maintenance offers what we were hoping for.

Brittany Harvey: Understood, and I appreciate you laying out the landscape of the data in this area. So then, based off this new data and the meta-analysis that you just described, what is the updated recommendation from the expert panel?

Dr. Dwight Owen: So, the updated recommendation is a tweak to the established recommendation, which is essentially that for patients who are not candidates for immunotherapy for any reason, that platinum doublet chemotherapy is really the mainstay, and that if maintenance is offered, that it should not include VEGF therapy in combination with pemetrexed as compared to pemetrexed by itself.

Brittany Harvey: Understood. And then, what should clinicians know as they implement this updated recommendation?

Dr. Dwight Owen: I think, again, this should be a relatively uncommon scenario. Most of our patients are candidates for immune therapy. Many patients are offered platinum pemetrexed by itself. But when thinking about continuing maintenance therapy, we would recommend that most clinicians avoid the addition of therapies that haven't seemed to offer a survival benefit and incur higher rates of toxicity.

Brittany Harvey: Great. That's helpful to know. And then you've just mentioned that this doesn't apply to a lot of patients, but what does this change mean for patients with stage IV non-small cell lung cancer without driver alterations?

Dr. Dwight Owen: I think, hopefully, for the subset of patients where we're really thinking about here that we can at least avoid additional toxicity if there isn't a trade-off in terms of benefit, in terms of survival.

Brittany Harvey: Great. Definitely, that's helpful. And then finally, what ongoing research is the panel keeping an eye on for future living guideline updates?

Dr. Dwight Owen: So, there are a lot of exciting trials that are ongoing, and hopefully, we'll be able to read out soon, that would offer us updates for really how to manage these patients in the frontline setting with stage IV non-small cell lung cancer. We have multiple options now. This discussion that we've had today really focuses on the pre-immunotherapy era, but of course, bevacizumab is utilized in a regimen along with carboplatin, paclitaxel, and atezolizumab, compared to monotherapy with checkpoint inhibitors compared to chemoimmunotherapy and dual checkpoint inhibitors.

And we don't really have any head-to-head trials yet, or strategies on how to identify which patients need more aggressive combination therapies versus which patients could potentially do without chemotherapy, or with single-agent checkpoint inhibitor by itself. So, while we wait for those studies like the ECOG and Cigna study, we're really looking forward to having those to be able to help decide and tailor our treatment options for our patients.

Brittany Harvey: Great. Well, we'll look forward to the ongoing review of the literature by the panel and any future guideline updates to recommendations in the meantime.

So, thank you so much for your work on this update and thank you for your time today, Dr. Owen.

Dr. Dwight Owen: Thanks for having me.

Brittany Harvey: And thank you to all of our listeners for tuning in to the ASCO Guidelines podcast series.

To read the full guideline, go to: www.asco.org/thoracic-cancer-guidelines. There's also 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 free ASCO Guidelines app available in iTunes, or the Google Play store.

If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Immunotherapy and Biomarker Testing in Recurrent and Metastatic Head and Neck Cancers Guideline Dec 15, 2022

Show notes

Dr. Emrullah Yilmaz reviews the latest evidence and recommendations for health care providers on biomarker testing and immunotherapy for head and neck cancers. He discusses the ASCO Expert Panel's recommendations for biomarkers for the selection of patients with head and neck squamous cell carcinoma for anti-PD-1 immune checkpoint inhibitor therapy. Additionally, he reviews recommended treatment options, including first-line treatment based on PD-L1 status, therapies for platinum-refractory disease, options for patients with nasopharyngeal cancer, the role of radiation therapy for oligometastatic head and neck cancer, and immunotherapy for rare head and neck cancers. Dr. Yilmaz also explores future areas of research for therapeutic options for patients with head and neck squamous cell carcinoma.

Read the full guideline, "Immunotherapy and Biomarker Testing in Recurrent and Metastatic Head and Neck Cancers: ASCO Guideline" at www.asco.org/head-neck-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello, and welcome to the ASCO Guidelines podcast series, brought to you by the ASCO Podcast Network; a collection of nine programs, covering a range of educational and scientific content and offering enriching insight into the world of cancer care. You can find all the shows, including this one, at: asco.org/podcasts.

My name is Brittany Harvey, and today I'm interviewing Dr. Emrullah Yilmaz, from Cleveland Clinic in Cleveland, Ohio, lead author on, 'Immunotherapy and Biomarker Testing in Recurrent and Metastatic Head and Neck Cancers: ASCO Guideline'.

Thank you for being here today, Dr. Yilmaz.

Dr. Emrullah Yilmaz: Thank you so much.

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 online with the publication of the guideline in the Journal of Clinical Oncology.

Dr. Yilmaz, do you have any relevant disclosures that are directed related to this guideline topic?

Dr. Emrullah Yilmaz: No, I don't have a relevant disclosure.

Brittany Harvey: Thank you. Then let's dive right into this guideline.

So, generally, what is the purpose and the scope of this guideline?

Dr. Emrullah Yilmaz: Immunotherapy with anti-PD-1 immune checkpoint inhibitors has become one of the most important treatment options for patients with recurrent metastatic head and neck cancers. And in the last few years, there has been new studies leading to new indications such as combinations with chemotherapy, or single-agent immunotherapy in the first-line treatment. And moreover, several studies also shown the effectiveness of immunotherapy for patients with nasopharyngeal carcinoma. All these advances in this complex disease group made it necessary to have an evidence-based guideline. So, that was the basis of building this guideline.

Brittany Harvey: Understood. And then this evidence-based guideline addresses six clinical questions. So, I'd like to review the key recommendations for each of those questions for our listeners. So, let's start with the first question. What did the expert panel recommend regarding biomarkers for selecting patients with head and neck squamous cell carcinoma for anti-PD-1 immune checkpoint inhibitor therapy?

Dr. Emrullah Yilmaz: Biomarkers are key for selection of treatment for immunotherapies, especially for the first-line treatment for head and neck cancer patients. PD-L1 is measured by immunohistochemistry and reported as Combined Positive Score, CPS, or Tumor Proportion Score, TPS. CPS is slightly different than TPS, and it includes lymphocyte and macrophage PD-L1 expression, in addition to tumor cells. Head and neck cancer studies have shown that CPS is a better marker for predicting response to immune checkpoint inhibitors, and key head and neck trials started to use CPS for reporting PD-L1 status. Therefore, we recommend CPS for recurrent metastatic head and neck cancers for PD-L1 reporting. This also makes it important for the oncologists to have a communication with the pathologists to make sure the right PD-L1 scoring is reported for head and neck cancer patients. Tissue tumor mutation burden is another emerging biomarker when CPS is not available, or for rare head and neck tumors, tumor mutation burden can be used as a biomarker as well.

Brittany Harvey: Great. And then based on that PD-L1 status that you just mentioned, what is the optimal first-line treatment regimen for patients with recurrent or metastatic head and neck squamous cell carcinoma?

Dr. Emrullah Yilmaz: If PD-L1 is positive, which is CPS more than one, there are two different options. Both pembrolizumab, single agent or pembrolizumab plus chemotherapy with platinum and 5-Fluorouracil can be offered. KEYNOTE-048 study showed an overall survival benefit with pembrolizumab alone for patients with CPS more than one, which was greater for the patients with CPS 20 or more. However, the pembrolizumab plus chemotherapy has showed benefit for the patients regardless of the PD-L1 status. So, if an early response is needed for a patient with high disease burden, pembrolizumab with chemotherapy could be an option, even if the PD-L1 is positive. For patients with negative PD-L1, which is CPS less than one, we recommend pembrolizumab and chemotherapy.

There was a recent subgroup analysis of KEYNOTE-048 for CPS-low patients. Patients with CPS less than one subgroup did not have significant survival difference with pembrolizumab plus chemotherapy when compared to cetuximab plus chemotherapy. This included a small number of patients, and this study was not powered to look at this subgroup, but cetuximab and chemotherapy can also be considered in the PD-L1 negative patient.

Brittany Harvey: Understood. It's important to recognize which patients benefit from these treatments more than others in different subgroups. So, following that, what is the effect of immunotherapy compared to other systemic treatments in platinum-refractory recurrent, or metastatic head and neck squamous cell carcinoma?

Dr. Emrullah Yilmaz: Platinum-refractory disease is defined as recurrence within six months of platinum-based chemotherapy. And effectiveness of immunotherapy was actually proven in this disease group first, several years ago. The effectiveness of immunotherapy as a single agent was proven in two similarly designed phase III trials in this setting. CheckMate 141 trial compared nivolumab to standard-of-care methotrexate, cetuximab, or docetaxel, and KEYNOTE-040 trial compared pembrolizumab to similar standard-of-care agents. And both studies showed overall survival benefit when compared to standard-of-care systemic agents, and the responses were independent from the PD-L1 expressions. So, nivolumab or pembrolizumab, are options as single-agent immunotherapy treatments for the patients with platinum-refractory head and neck squamous cell carcinoma, regardless of their PD-L1 expression.

Brittany Harvey: Understood, and thank you for getting into those options for those patients. Getting into the specifics for nasopharyngeal carcinoma, what did the panel recommend regarding the role of immunotherapy for patients with recurrent or metastatic nasopharyngeal carcinoma?

Dr. Emrullah Yilmaz: So, the combination of immunotherapy with cisplatin and gemcitabine was shown to be effective in first-line treatment of recurrent metastatic nasopharyngeal carcinoma, in several phase III studies from Asia in the last few years. JUPITER-02 study used toripalimab, CAPTAIN-1 study used camrelizumab, and RATIONALE-309 study used tislelizumab in combination with cisplatin and gemcitabine in the first-line treatment, and all these studies showed progression-free survival benefit with addition of immunotherapy to chemotherapy.

Since these agents are not available in the United States as of now, our panel members recommend that pembrolizumab or nivolumab may be offered in combination with chemotherapy for the first-line treatment of recurrent or metastatic nasopharyngeal carcinoma. But the role of immunotherapy in the platinum-refractory nasopharyngeal carcinoma without the prior immunotherapy use is not well established yet. There are phase II studies that have shown that responses to immunotherapy are comparable to chemotherapy with a better safety profile. So, single-agent immunotherapy could be considered in a platinum-refractory setting if a PD-1 inhibitor was not used before.

Brittany Harvey: Those are excellent points that you just made. So, following that, the next question that the panel considered is, what is recommended regarding the use of radiation therapy in combination with immunotherapy versus immunotherapy alone, for the treatment of locoregionally recurrent or oligometastatic head and neck squamous cell carcinoma?

Dr. Emrullah Yilmaz: This is a great question, and radiation therapy is used a lot in head and neck cancers for different purposes. And immunotherapy and SBRT combinations were not shown to increase efficacy for abscopal effect for the treatment of oligometastatic disease in head and neck cancers. So, radiation therapy should not be given to increase the effectiveness of immunotherapy in recurrent metastatic head and neck cancers. However, there are several ongoing studies to evaluate the efficacy of radiation such as SBRT with immunotherapy for locoregional recurrence. So, although radiation therapy is safe to give the patients with recurrent and metastatic cancers, with immunotherapy, it should be considered for palliation or local control until the results of these trials are available.

Brittany Harvey: Great. And yes, we'll look forward to the results of those trials to find some more definitive results for these patients. So, then, the last clinical question that the panel addressed, what is recommended for the role of immunotherapy for rare head and neck cancers?

Dr. Emrullah Yilmaz: The role of the immunotherapy for rare head and neck cancers depends on the biomarkers. KEYNOTE-158 study has shown the effectiveness of pembrolizumab in advanced cancer patients, which included different types of cancers with high tissue TMB defined as more than 10 mutations per megabase. And looking at the results from that study for the patients with advanced rare head and neck cancers with limited treatment options, such as, salivary gland cancers or sinonasal cancers, if high TMB, which is Tumor Mutational Burden, is identified, then pembrolizumab may be considered for those patients. And pembrolizumab was also shown to have activity in salivary gland cancer patients expressing more than 1% PD-L1. So, that makes it an option for these patients as well.

Brittany Harvey: It sounds like understanding the biomarker status of these patients with rare head and neck cancers is essential for determining their therapy options. I want to thank you so much for reviewing all of those recommendations.

So, in your view, Dr. Yilmaz, what is the importance of this guideline, and how will it impact clinicians and patients with head and neck squamous cell carcinoma?

Dr. Emrullah Yilmaz: This guideline was written by panel members, experts in their field, including medical oncologists, radiation oncologists, head and neck surgeons, pathologists, and radiologists. It is really important for oncologists to communicate the treatment options to their patients clearly while planning treatment of head and neck cancers. So, this guideline can help the clinicians to provide evidence-based resource when to use the immunotherapy for their head and neck cancer patients. So, that can be really helpful to the clinicians.

Brittany Harvey: Excellent. Yes, it's important to have a multidisciplinary group working on these guidelines to help clinicians in all capacities.

Finally, what outstanding questions or ongoing research are you interested in for future therapeutic options in head and neck squamous cell carcinoma?

Dr. Emrullah Yilmaz: Our guideline focuses on recurrent metastatic head and neck cancers since it is the only area where the immunotherapy is approved as of now. We've had a few studies in the curative intent setting, which has not shown the benefit of addition of immunotherapy to radiation therapy, or chemoradiation. There's still several studies ongoing to investigate the effectiveness of immunotherapy in the curative intent setting, and the neoadjuvant setting, or adjuvant setting, or different combinations with the radiation therapy, with the immunotherapy, with the different sequences. So, it will be interesting to see the results of those studies in the future. So, that might be another area that the field might be moving in the future.

There are also studies ongoing to improve effectiveness of the immunotherapy in the recurrent and metastatic disease. Chemoimmunotherapy seems to be among the strongest systemic treatment options right now that we have, but there are several other combination strategies that are being developed combined with the PD-1 inhibitors, including combinations with EGFR inhibitors, angiogenesis inhibitors, intratumoral injections, vaccine developments, and there are a lot of different novel checkpoint inhibitors being developed. So, the field is advancing in that area as well. So, those are the areas that research are ongoing at this point.

Brittany Harvey: Definitely. We'll look forward to the results of those ongoing trials to inform future updates and future guidelines in this area.

So, I want to thank you so much for all of your work that you put into developing these evidence-based guidelines and thank you for your time today, Dr. Yilmaz.

Dr. Emrullah Yilmaz: Thank you so much.

Brittany Harvey: And thank you to all of our listeners for tuning to the ASCO Guidelines podcast series. To read the full guideline, go to: www.asco.org/head-neck-cancer-guidelines.

You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, available in iTunes or the Google Play Store.

If you have enjoyed what you've heard today, please rate and review the podcast, and be sure to subscribe, so you never miss an episode.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

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