RCC Treatment Sequencing and Combination Approaches: JAVELIN Renal 101 and COSMIC-313

A roundtable discussion, moderated by Katy Beckermann, MD, PhD, discussed the treatment sequencing, management, and future directions of advanced or metastatic kidney cancer, as well as relevant clinical trial data from the 2024 American Society of Clinical Oncology Annual Meeting. Dr. Beckermann was joined by Yousef Zakharia, MD; Pavlos Msaouel, MD, PhD; Benjamin Maughan, MD, PharmD; and David McDermott, MD.

In the first segment of the roundtable series, the panel focuses on the implications of the final overall survival (OS) analysis from the JAVELIN Renal 101 trial and the challenges of combining PD-1/PD-L1 inhibitors with TKIs for optimal patient outcomes.

View the next segment on CheckMate 67T: Do Recent Updates Make This Practice-Changing.

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Dr. Beckermann: We are excited to discuss the updates in kidney cancer this year, including some exciting research and clinical advancements, with this wonderful group.

I know there are many interesting aspects we have each noticed at this meeting. Some clinical updates include final analysis from the JAVELIN Renal 101 trial. Do any of you have thoughts on this study? The final OS is being reported this year, which is exciting to see.

As a reminder, this trial involves avelumab and axitinib. We’ve been waiting for this data for some time. The primary endpoints are an ORR of 51% and a PFS of about 14 months. The final OS shows a hazard ratio of 0.88, with a median OS of about 47 months for the combination arm and 39 months for the Sunitinib arm. Does this trial change your practice, and how does it affect your thoughts on IOTKI regimens?

Dr. Zakharia: Yes, combining avelumab plus axitinib was one of the first IO/TKI trials to report initially. However, compared to other PD-1 and TKI combinations, this regimen seemed less favorable. Many of us were concerned about the lack of an OS signal with this combination. I am glad the data has matured, and it is the longest follow-up data we have on an IO/TKI regimen. However, the OS signal is still lacking, so this update does not change my practice.

Dr. Beckermann: Does this inform us more about metastatic renal cell carcinoma (RCC)? We have had several trials and discussions about PD-1 versus PD-L1 agents. Does this raise questions about the efficacy of PD-L1 in metastatic or earlier settings for kidney cancer?

Dr. Maughan: It certainly raises that possibility. This is a provocative question, especially since we have multiple phase 3 trials running in parallel, both using the same TKI. The main difference is PD-1 versus PD-L1. Comparing this trial with the axitinib and pembrolizumab trial, the final OS readout shows no significant difference between the experimental arm and the TKI plus PD-L1 inhibitor, while the other trial shows an OS signal. This readout is practice-informing or reaffirming, solidifying the least favored status of this combination.

Additionally, the long-term follow-up addresses whether current TKIs result in a synergistic immunological effect with PD-1 or PD-L1, a purported rationale for these combinations. So far, we have not seen this clinically as we have in laboratory models.

Dr. Beckermann: Thinking about future IO/TKI combinations or building on an IO/IO backbone, how do you aim to achieve the best survival for your patients? How do you consider frontline treatment with recent IO/TKI updates and the 8-year survival data from the CheckMate 214 study?

Dr. McDermott: It is challenging to build on a IO/TKI backbones for several reasons. Dr. Maughan mentioned the preclinical evidence suggesting these combinations enhance the immune response, but we have not seen much clinical evidence. The exception is a higher CR rate with these combinations than with either alone. However, continuing the TKI indefinitely for responders makes it hard to see ongoing immune responses off drug, which is what we want.

Another issue is toxicity, as seen in COSMIC-313. Adding a third drug to a PD-1 and TKI combination often results in dose-limiting or dose-reducing toxicity, which lowers the chances of a durable long-term effect. This was evident in COSMIC-313.