What Does the Future Hold for Triplet Combinations in RCC?

A roundtable discussion, moderated by Brian Rini, MD, of the Vanderbilt University Medical Center, focused on the spectrum of therapy for frontline renal cell carcinoma (RCC), including a comparison of monotherapy and doublet and triplet treatment options. Dr. Rini was joined by a panel that included Monty Pal, MD; Moshe Ornstein, MD; and Shuchi Gulati, MD, MSc.

In the next segment of the roundtable series, the panel discusses triplet combinations in development for RCC and how new trials can be more thoughtfully designed.

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Dr. Rini: What about triplets? Moshe, start with you. Merck has a big triplet study ongoing. There are some others being planned. Are they all going to follow the same path of they’re really hard to get a marginal benefit or not?

Dr. Ornstein: Some of the question revolves around can you give the triplets safely from a toxicity perspective and whether cabozantinib/ipilimumab/nivolumab was the right triplet.

For Merck’s trial where you’re doing lenvatinib and pembrolizumab and their anti-CTLA-4, is there something different about that triplet where you can have the appropriate drug delivery to really see the benefit upfront and the potential for survival benefit?

I wouldn’t close the door on the triplets yet. I think this triplet combination of cabozantinib/ipilimumab/nivolumab wasn’t the right one because of the toxicity. So far, everything we’ve seen in kidney cancer is more is better upfront up until COSMIC-313 for the most part. The doublets were superior to the single agents. If you’re taking 2 different mechanisms that have at least potential synergy, I think we should try it and see if we can get it right from a safety perspective.

Dr. Rini: Shuchi, what do you think?

Dr. Gulati: When we start designing these triplet trials, we probably need to start thinking about biomarkers. I know we are really behind in the biomarker space, but is there a biological rationale to combine these? Or are you just adding toxicity by combining everything together? It’s time for us as a group to start thinking about biological rationales behind combining these drugs, not just throwing everything together.

Dr. Rini: I totally agree with you. It’s just not how drug development tends to proceed.

Dr. Gulati: That’s a dream, as a junior investigator.

Dr. Rini: I’m 100% supportive.

Dr. Gulati: For that reason, the OPTIC trial is really good, even though we still don’t know what to do with some groups in that categorization. But maybe some data from trials like OPTIC will add to our understanding of this is the group that needs the triplet and this one will not benefit. I think we need to start working toward that. I know we all are.

Dr. Rini: I agree. We haven’t even talked about biomarkers because we don’t have any clinically actionable biomarkers. PD-1 is unreliable. There are things being investigated, and we certainly all agree that some sort of risk-adapted approach based on biomarkers. There are patients who can get, as we said, nivolumab or pembrolizumab monotherapy and do really well. We have no way to identify them. There are probably others that need a triplet of whatever different mechanisms.

Dr. Gulati: We don’t know who those patients are. It’s certainly not the poor-risk patients, based on COSMIC-313.

Dr. Rini: They probably need other mechanisms, not the ones we have. We don’t have those biomarkers, so in the meantime we’ll just keep cramming drugs together. I agree with Moshe. The Merck trial is different and also has belzutifan in it. We can maybe touch on belzutifan in a second. It has some different mechanisms, but I think we learned that just to cram everything together, that’s not going to work. We’re going to have to be more thoughtful, whether it’s patient selection or staggered approach or dosing. I’m sure there’s other strategies, different mechanisms. But I think we will get to a place where triplets are standard. I’d be shocked if all these trials are negative, and we’re sitting here in 10 years with doublets. Maybe it’s drugs that haven’t entered the arena yet in terms of that third drug.

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Continue on to watch the next roundtable segment.