Frontline Treatment for Intermediate/Poor-Risk mRCC


Considerations for evolving from using single-agent therapy to combination approaches to treat intermediate or poor-risk metastatic renal cell carcinoma based on more recent data demonstrated in clinical trials.

Sumanta Kumar Pal, MD: We probably should have done favorable-risk [patients] last. It’s probably the most contentious element of anything we’ll talk about today, but it is a good way to get the juices flowing and the dialogue going. We’re going to move on to a topic that is much less controversial: how to treat intermediate- and poor-risk disease. We’ll probably be able to get through this a little more quickly. Bob, I gave you the last word on the favorable-risk population. Why don’t you tell us what you’re doing [at the John Theurer Cancer Center] for patients who have intermediate- and poor-risk disease?

Robert S. Alter, MD: The data are now evolving much better. We’ve all moved away from single-agent TKIs [tyrosine kinase inhibitors]. We’re loving the combination of I/O [immuno-oncology]–TKIs in this patient population. Since ASCO [American Society of Clinical Oncology Annual Meeting] 3 years ago, the data have been pouring out. We have many options, and the data just get better. We were quite excited when KEYNOTE-426 came out 3 years ago. Then the update just came out and were presented last year. In the interim, CheckMate 9ER came out, and now we have the CLEAR study. We’re seeing a lot more than just responses. We’re seeing CRs [complete responses]. When we have the opportunity of giving tolerable therapy, as Dave said before, you’re shooting for the stars. We’re still given the opportunity to give our patients quality, durable therapy with a very good chance of having the patients not allow their disease to become more quiescent. The patients can thrive with better quality.

The CLEAR study was just presented 3 weeks ago; it’s not FDA approved. We would have issues in getting that. With the CheckMate 9ER, the fallback over the last few years has been an excitement of using I/O–TKIs. I have to reflect back to what we spoke about a few minutes ago. Using ipilimumab-nivolumab as a first-line therapy is still quite effective in these patients. We have seen these patients thrive. We have the expected tolerability and toxicities. The chronic toxicity of I/O–TKIs can be detrimental to patients’ dose adjustments and quality-of-life adjustments. We definitely know about the related quality-of-life the studies have shown. I still wouldn’t go back to the high-dose IL-2 approaches with how we take care of these patients. I/O–I/O is quite effective, even though we’ve been lured into their whole response rate data. The 48-month data from CheckMate 214 are quite encouraging. We see a lot of patients can actually be observed off-therapy and maintain their CRs or PRs [partial responses]. I/O–I/O is still my first-line therapy when it comes to the patients, although we have to define the poor-risk patient on the risk of evolving to the symptoms. At times, we have to reach back and throw a TKI in the first line.

Sumanta Kumar Pal, MD: I’m just looking for 1 answer. Is it ipilimumab-nivolumab for you for intermediate- and poor-risk disease? Is that what you’re going with?

Robert S. Alter, MD: Yes.

Sumanta Kumar Pal, MD: Tian, let me ask you about your approach. I realize we’re going to have some redundancy with the first topic. Say we’re basing it on that individualized conversation with the patient. What are you typically reaching into your pocket for after that conversation with a patient with intermediate- and poor-risk disease?

Tian Zhang, MD: I think quite highly of the nivolumab-ipilimumab data, as Bob nicely summarized for us, and that about a third of patients don’t even progress at 4 years. That durable response is really great for patients. In the very poor-risk patient who was never a study candidate, they would never have gone on to any of these trials when they don’t necessarily have a chance at a second-line treatment without rapid disease control. I firmly believe those patients need a very active TKI–I/O strategy in the up-front setting. In those cases, if they have bone metastases, I would favor a cabozantinib-nivolumab approach. Lenvatinib-pembrolizumab has excellent data in that setting as well. I would favor a treatment option that gives them rapid disease control and a good chance at controlling disease so that they can actually get to a second-line approach. But in general, for the 1 or 2 IMDC [International Metastatic Renal Cell Carcinoma Database Consortium] criteria, where they may be a little anemic or they’re just missing that 1-year cutoff from the nephrectomy to time of systemic treatment, I favor giving those patients a chance at ipilimumab-nivolumab first.


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