Efficacy improvements in First-line Renal Cell Carcinoma (RCC)

Success in oncology remains one of the most meaningful and competitive achievements in BioPharma. Over the past decade, checkpoint inhibitors have fundamentally shifted the survival expectations for many cancers, raising the bar for what is considered meaningful clinical progress.

For marketers, the challenge is not only to recognize when a therapy is approvable, but also to define the thresholds that determine commercial success. Nowhere is this more apparent than in oncology, where adoption is driven primarily by improvements in efficacy and subsequent endorsements from clinical guideline bodies such as the NCCN.

One disease area that has seen significant innovation is first-line RCC. As shown in the graph, the approval of nivolumab + ipilimumab in April 2018 marked a turning point, establishing a new trajectory for overall survival (OS). This regimen continues to be widely used today.

What’s Next in RCC?

The question now is: how high should we set the bar for OS improvements going forward? Right now companies are focused on Triplet Therapy Approaches.

Exelixis’ COSMIC-313 trial

This trial evaluated cabozantinib + nivolumab + ipilimumab, but the February 2025 readout showed no OS benefit compared with nivolumab + ipilimumab. As a result, development of this triplet has been halted.

Merck’s LITESPARK-012 Trial

This trial is currently testing two regimens:

·         pembrolizumab + belzutifan + lenvatinib

·         pembrolizumab/quavonlimab + lenvatinib

While results are still pending, there is sound rationale for both approaches. Belzutifan has demonstrated efficacy in the second- and third-line RCC setting, making its integration into first-line therapy logical. Similarly, the addition of lenvatinib to a PD-1/CTLA-4 combination could yield incremental benefit.

Outlook for the Next 2–3 Years

Will overall survival in first-line RCC improve further? The answer is uncertain. We are unlikely to see the same step-change that nivolumab + ipilimumab delivered in 2018, but the ongoing triplet strategies could offer incremental gains. Whether these improvements will be sufficient to reset commercial and clinical benchmarks remains to be seen.