Evolution of Combination Therapy in nccRCC, Papillary Subtype

A roundtable discussion, moderated by Laurence Albiges, MD, PhD, discussed the risk stratification and management of metastatic non-clear cell renal cell carcinoma (nccRCC), along with recent advancements in targeted therapies and immuno-agents, treatment sequencing and combination approaches, and adjuvant therapy options. Dr. Albiges was joined by Renée Maria Saliby, MD, MSc; Tian Zhang, MD; and Shahla Bari, MD.

In the third segment of the roundtable series, the panel highlights recent advancements in combination therapies for nccRCC, highlighting improved response rates and progression-free survival, particularly in papillary RCC, with a focus on trials such as KEYNOTE-B61 and a cabo-nivo investigation.

View the next segment on Management Round-Up: Translocation, Chromophobe, RMC, and Other Subtypes.

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Dr. Albiges: What has been the evolution of combination therapy most recently?

Dr. Saliby: Building on single-agent therapies, which had promising but not super successful results, several trials have grouped non-clear cell subtypes together to evaluate combination treatments. One of the biggest trials, which I believe you led, is KEYNOTE-B61, evaluating pembrolizumab and lenvatinib in nccRCC. The patients were treatment-naïve, and we saw a significant jump in the objective response rate, from around 20% to approximately 49%, with a median progression-free survival (PFS) of more than 1 year, about 18 months. This trial also showed successes in individual subtypes of nccRCC, which we will discuss further.

Another immune checkpoint-based therapy is cabo-nivo, which is being investigated in a trial led at Memorial Sloan Kettering Cancer enter. Here, we saw an objective response rate of around 48% to 49%, with PFS reaching double digits, and a median overall survival of about 28 months.

Dr. Albiges: We are changing the game because, for the first time, we are seeing response rates around 50%. So, every other patient will achieve significant tumor shrinkage, with PFS being above 1 year, even reaching 1.5 years. This is very different from the single-agent TKIs we have seen for a long time. Maybe we are selecting these patients well, as you stressed, these are phase 2 and non-randomized phase 2 trials. The contribution of each component is something we may want to challenge, but we have 2 consistent trials. In the lenvatinib-pembrolizumab study, KEYNOTE-B61, we had enough patients to look into the different subtypes.

Dr. Saliby: Exactly.

Dr. Albiges: Let us dig into the different subtypes. Dr. Zhang, papillary RCC is the most frequent subtype within this entity. In the KEYNOTE-B61 trial, it had the largest patient group, almost 100, and it was also the largest group in the pembrolizumab single-agent study. How do you treat papillary RCC today?

Dr. Zhang: There is a lot of good data from single-cohort phase 2 trials, especially for combination treatments. As a community, we are still considering whether we can test the contribution of individual components. When someone with papillary kidney cancer comes in, I discuss the single-agent data with cabozantinib, the combination data with lenvatinib and pembrolizumab, and cabozantinib with nivolumab in smaller cohorts. I also mention the ongoing NCTN trial, PAPMET2, which compares cabozantinib versus cabozantinib with atezolizumab. We then make a shared decision.

It is encouraging to see PFS over 1 year and more than 50% of patients responding to treatment. The lenvatinib-pembrolizumab study also reported that 10% of patients had complete responses. Aiming for complete responses and tumor shrinkage is essential, as patients are more encouraged when they see their tumors shrink.