Balancing Efficacy and Toxicity in Metastatic Renal Cell Cancer Management

Dr. Eric Singer highlights the recent rapid recommendation update from ASCO on the management of metastatic renal cell cancer (ccRCC), based on the review of evidence from the phase III COSMIC 313 trial. Dr. Singer reviews the discussion from the Expert Panel and emphasizes clinicians should continue to follow the previously issued recommendations for the management of metastatic ccRCC. He also mentions future directions, ongoing clinical trials, and outstanding questions for these evidence-based guidelines. Read the latest update, "Management of Metastatic Renal Clear Cell Cancer: ASCO Guideline Rapid Recommendation Update" at www.asco.org/genitourinary-cancer-guidelines.

TRANSCRIPT

Brittany Harvey: Hello and welcome to the ASCO Guidelines Podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one at asco.org/podcasts. My name is Brittany Harvey, and today I'm interviewing Dr. Eric Singer from the Ohio State University Comprehensive Cancer Center, lead author on the "Management of Metastatic Renal Clear Cell Cancer: ASCO Guideline Rapid Recommendation Update."

Thank you for being here, Dr. Singer.

Dr. Eric Singer: Brittany, great to be with you. Thank you for the invite.

Brittany Harvey: Great. Then, before we discuss this guideline, I'd just like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Singer, who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

So then, Dr. Singer, to dive into this rapid update, can you tell me a little bit about what prompted this rapid update to the Management of Metastatic Renal Clear Cell Cancer Guideline, which was previously published in 2022?

Dr. Eric Singer: Sure. One of the big motivators for this was the fantastic work done by Toni Choueiri and colleagues in publishing the COSMIC-313 trial, which looked at triplet therapy for the management of metastatic kidney cancer: a combination of ipilimumab, nivolumab, and cabozantinib versus patients with placebo plus ipi and nivo. And this was a much-awaited trial, and these results came out. And certainly, there was a lot of interest amongst providers as well as patients to help understand the results of this important study and whether or not we should be changing our practice. So, the guideline group who wrote the initial guideline in 2022 felt that this was a significant enough study to warrant a rapid update.

Brittany Harvey: Understood. So then, based on this new data from COSMIC-313, what is the updated recommendation from the Guideline Expert Panel?

Dr. Eric Singer: So, the recommendations largely do not change. Unfortunately, while there was some fantastic information gleaned from COSMIC-313, the survival outcomes that were seen at this point, in context with the toxicity signals that were seen at this point, led the Guideline Committee to recommend against adopting triplet therapy as a standard option. However, the Guideline Committee did encourage patients and providers to continue to refer to and accrue to clinical trials that will be again asking similar questions about the combinations that we should be using to treat metastatic kidney cancer going forward. So essentially, we felt that the survival benefit was not adequate to recommend first-line treatment adoption of this triplet regimen in context with the toxicities that were seen in the triplet regimen.

Brittany Harvey: Understood. That's helpful to know.

So then, what should clinicians know as they implement this guidance into practice?

Dr. Eric Singer: I would recommend that we continue to follow the original guideline as published. There are multiple doublet agents or doublet therapeutic combinations that are available, which we found to have strong survival outcomes and more manageable toxicity profiles than the triplet regimen studied in COSMIC-313.

Brittany Harvey: Great. Additionally, what does this update mean for patients with metastatic renal clear cell cancer?

Dr. Eric Singer: Yeah, as we all think about how best to manage patients with metastatic kidney cancer, a lot of the things that we're thinking about are, will this treatment make people live longer, and will this treatment make patients live better, balancing both efficacy and also looking at toxicity. And I think in this case, there wasn't the survival endpoints or the survival benefit we were hoping for, again, sort of a surprisingly low number of complete responses seen in this study compared to prior pivotal trials, and quite a bit of toxicity because we're combining three different drugs. And when we do combine medications, we're always hoping for synergy in terms of the efficacy so the combination working better than what we'd expect just by adding those outcomes together. But unfortunately, we also got quite a bit of additive toxicity in the combination as well. So, I think that we still have many excellent options to choose from and that, unfortunately, at this time, there didn't seem to be the survival benefits in light of the toxicity to warrant a change.

Brittany Harvey: Absolutely. That balance of benefit and harms is crucial.

So then, finally, you mentioned that this guideline encourages enrollment in clinical trials, but I want to also ask you, what are the outstanding questions that we're looking forward to regarding the management of metastatic renal cell cancer?

Dr. Eric Singer: Brittany, I think there's a lot of important questions for us to work on answering. Like we were sort of alluding to in a study like this, we want to know not only which patients are likely to benefit from a combination of therapies, but we also want to begin to learn more about which patients are at an especially high risk of toxicity from combined treatments. So, not only can I counsel a patient about what we think this will do for disease control, but also to identify potential risk factors for adverse events because that can help us choose between the multiple different options we have available. We also have a lot of options at our disposal now in terms of combining different types of therapy: How should we integrate surgery, radiation, systemic therapy? What order should we do them in? What is the best combination to use at each of these steps, so that we can continue to help patients live longer and live better on their kidney cancer journey?

Brittany Harvey: Absolutely. Well, I want to thank you so much for your work to update this guideline very rapidly, and thank you for sharing your insights with me today, Dr. Singer.

Dr. Eric Singer: Brittany, my pleasure. And again, I really appreciate the work of everyone who's been on the metastatic kidney cancer panel, such fantastic professionals in terms of their clinical expertise, and then also the fantastic ASCO staff, where we really wouldn't be able to do this work without the amazing dedication and hard work of our ASCO team members.

Brittany Harvey: Definitely a big thank you to the entire expert panel.

And also thank you to all of our listeners for tuning in to the ASCO Guidelines Podcast. To read the full guideline, go to www.asco.org/genitourinary-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines app, which is available in the Apple App Store or the Google Play Store. If you have enjoyed what you've heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

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