Triplet Therapy Approaches for Intermediate/Poor Risk RCC

A brief discussion on triplet therapy being investigated in patients with intermediate- and poor-risk renal cell carcinoma.


Robert J. Motzer, MD:In this intermediate- and poor-risk group, there’s an interest in looking at triplets. We participated in the COSMIC-313 trial. Dr [Maria] Carlo treated patients on that study, which looked at ipilimumab-nivolumab with cabozantinib vs placebo. The other direction being taken is our randomized trials using lenvatinib-pembrolizumab as the core. Chung, you’re the PI [principal investigator] on 1 of these trials at Memorial [Sloan Kettering Cancer Center]. Can you discuss briefly what that trial involves and where you see the field going forward in these first-line trials for the intermediate and poorest patients?

Chung-Han Lee, MD:One significant clinical challenge that we’ve seen within the intermediate- and poor-risk population is the stratification between a TKI [tyrosine kinase inhibitor–I/O [immuno-oncology] vs an I/O–I/O–based combination. When we give an I/O–I/O–based combination with a drug like ipilimumab-nivolumab, a significant portion of patients may end up passing away before they can reach second-line therapy. You can see that by the lack of separation of those PFS [progression-free survival] curves very early on, and it takes time for that to separate.

There are multiple approaches to investigating triplet therapies to see whether we can maintain the durability that may be associated with ipilimumab-nivolumab but eliminate that potential of lack of clinical response at the beginning. The COSMIC-313 trial is an excellent example of that. It’s looking at the triplet combination of cabozantinib plus ipilimumab plus nivolumab vs ipilimumab-nivolumab and trying to see whether that was a significant change within things like progression-free survival. We’re excited to see those results. Hopefully, at a subsequent meeting, those will be forthcoming.

The other we’ve participated in looks at lenvatinib plus pembrolizumab as the backbone. Certainly, as all of you know, the combination of lenvatinib plus pembrolizumab has demonstrated high objective response rates and certainly a long progression-free survival. The Merck UO3 study is looking at, in a randomized phase 2 fashion, whether the addition of a third agent could be beneficial in using lenvatinib-pembrolizumab as not only the backbone but a contemporaneous control. The third agent we’ve considered in that regimen included another anti-CTLA4 agent. It also included a LAG3 inhibitor, which is another immune checkpoint inhibitor, and the ability to add on a HIF inhibitor. It’s trying to see whether, in the first-line setting, a triplet with more intense immunotherapy or more intense VEGF-targeted therapy could be beneficial as an additional agent. That trial is earlier on but very exciting.

Robert J. Motzer, MD: That’s great a great discussion on this case. Certainly, the complete responses that we see and the favorable outcomes, the sarcomatoid features, the survival benefit, and the quality of life that we see long term is a plus for ipilimumab-nivolumab. Of course, there are other options, and we can touch on some of those in the next case and maybe get a little about the underlying biology of RCC [renal cell carcinoma] with case No. 2.

Transcript edited for clarity.

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