Therapies Under Investigation for Frontline mRCC

Martin H. Voss, MD: Speaking to the metaphor of hitting a home run, it’s relevant. Leaving this particular topic of favorable risk aside, it’s relevant to talk a little about what’s coming. We’ve obviously had a tremendous impact on patient outcomes across the board with the introduction of doublets. Of course, the field isn’t sitting still, and there are more novel agents being developed. We’re also seeing triplets arrive in the phase 2 and phase 3 space. I want to talk a little about that and hear your thoughts speaking a little to combinations that are in the pipeline. Let’s turn to the investigational space for your thoughts on what you think is exciting coming our way for clear cell RCC [renal cell carcinoma] in the first line. If anyone wants to take the lead and speak to any of the many combinations we have coming, kick us off.

Thomas Powles, MD, MBBS, MRCP: Can I shout out for COSMIC-313?

Martin H. Voss, MD: Speak about that a little, Tom.

Thomas Powles, MD, MBBS, MRCP: I’ll make a shout-out for that. I quite liked the trial. It’s ipilimumab-nivolumab vs ipilimumab-nivolumab-cabozantinib in patients with intermediate and poor risk. It’s a big, randomized phase 3 trial. It’s got PFS [progression-free survival] as its primary end point and OS [overall survival] as an end point as well. It will have to hit OS. It has a really good chance of hitting PFS and response because we know ipilimumab-nivolumab’s response rate is about 40%, and its PFS is between 9 and 10 months. Let’s say cabozantinib-nivolumab’s response rate is 60%, and its PFS is more like 15 to 20 months. Cabozantinib-nivolumab would beat ipilimumab-nivolumab, so I can’t see that not coming up and winning.

But a positive trial doesn’t necessarily mean a positive trial when you think, what’s the key question from my perspective? Is it early control of the disease with a VEGF-targeted therapy that allows more patients to go into a long-term durable remission and affect overall survival? One of the problems with ipilimumab-nivolumab is that if you give it to 10 patients, then some will progress straight through and some are difficult to salvage with VEGF-targeted therapy. The question is whether you get initial control, and whether that initial control with VEGF-targeted therapy settles everything down for a long enough time for the immune combination to go on and have longer beneficial effects.

It’s a really important trial. It’s going to have more toxicity, of course. The OS signal is probably going to take some time to read out, but I would expect a short-term positive result of that trial. Friends of mine like Dave McDermott and others are saying, “I’d like to see 25% CR [complete remission] rate.” If we’re going to use triplets, I’d like it to knock it out of the water. I don’t want to just see an OS trend, 0.85 hazard ratio, and a PFS that’s in line with what we would expect with cabozantinib-nivolumab. The results have to be much better because the PFS and response rates are bound to that. That’s the next big study that reads out for me. It’s very exciting.

Martin H. Voss, MD: It’s fully accrued, so we’re all excited to see the results for that. Along the theme of more activity up front, possibly at the expense of more toxicity up front, we can also speak a little about up-front data that incorporate novel cytokines. There’s a history of IL-2 in this disease that Sandy alluded to, and now we have novel cytokines coming. Sandy, do you want to speak a little to the bempegaldesleukin data, the combination trial PIVOT-10?

Sandy Srinivas, MBBS: There are so many different strategies. One is to try to improve the cure rate. One is to try to make our existing therapy a little easier. High-dose IL-2 has been around, but it’s been such a challenge that there aren’t too many people who are eligible to get high-dose IL-2. This is a strategy of trying to come up with a regimen that might have similar activity to high-dose IL-2 but not have its identical adverse effects. I don’t fully remember what the status of accrual for this trial is.

Martin H. Voss, MD: It’s fully accrued also, I believe. It’s listed as active, not accruing on ClinicalTrials.gov, so I assume it’s fully accrued. Terrific.

Robert S. Alter, MD: I can speak on PDIGREE. It’s a study that we’ve had that has since closed. It’s been important to recognize that the science is great, and how can we apply it clinically? PDIGREE offers that approach in regard to real community oncology and how we practice. It’s a study of taking patients with advanced RCC and giving the standard 4 cycles of ipilimumab-nivolumab. Then based upon the scan at that point, if you have achieved a CR, you maintain on maintenance nivolumab. If you have progression of disease, you go on cabozantinib. It’s a population where we most commonly see patients who don’t exactly have a pure progression of disease, and patients who don’t have a CR. These patients are randomized to receiving nivolumab as a single agent or having nivolumab and cabozantinib.

This is the importance about recognizing that it’s a standard practice that our CRs are treated with nivolumab single agent, and our progressions are treated with cabozantinib, so it’s a real-world experience. The question is, are we content enough that ipilimumab-nivolumab followed by nivolumab is good enough? What can we do better? Can we become more aggressive? We have CheckMate 9ER to know that we can use these therapies in combination—that being cabozantinib-nivolumab—but then we always have that impatient question: Can we do better than just maintenance of stable disease?

When it comes to our patients, it’s different from lung cancer and breast cancer, where you definitely see a significant partial response. In those patients, we’re looking at numbers. Whereas in kidney cancer, you don’t see that much, and we’re content with stable disease. But are we beyond the point where we’ve matured where stable disease is not good enough for us or our patients anymore? Should we step it up a bit? This is a real-world study about how we may feel and our patients’ desire to do better in a regimen that we’ve been very commonly using.

Martin H. Voss, MD: Excellent. Thank you for this summary. It’s great to see so many new strategies coming our way. It makes us hopeful that we can push the envelope further for our patients.

Transcript Edited for Clarity