KEYNOTE-B61 Trial Review

The KEYNOTE-B61 study represents one of the largest prospective phase 2 trials conducted in the non–clear cell renal cell carcinoma (RCC) space, evaluating the combination of lenvatinib and pembrolizumab. This single-arm study enrolled 158 patients with various non–clear cell histologies, including papillary, chromophobe, unclassified, and translocation RCC. With a median follow-up of nearly 42 months, the trial reported an overall response rate of 50.6%, highlighting a promising efficacy signal in a population historically difficult to treat. Response rates varied by subtype, with chromophobe RCC showing a lower rate of 31%, and translocation RCC the highest at 67%. Importantly, the trial demonstrated a durable duration of response, with 35% of responders maintaining their response beyond 3 years.

This trial’s emphasis on long-term follow-up and detailed end points, such as complete response rates and duration of response, marks an important evolution in the study of non–clear cell kidney cancers. Earlier trials often lacked extended follow-up, limiting insight into the durability of responses. The presence of a 10.1% complete response rate, including significant responses in papillary RCC, is encouraging and suggests that immune-based therapies can achieve meaningful long-term benefits in this diverse group of cancers. Despite some limitations, such as the single-arm design and the challenge of isolating the contributions of each drug, the data reflect progress in treatment outcomes compared to older studies like ESPN and ASPEN.

While these results signal a shift in how non–clear cell RCC is approached, there remain nuances to consider. For example, the role of pembrolizumab versus lenvatinib alone in some subtypes is unclear, especially in chromophobe RCC where responses were modest. Clinicians are cautiously optimistic, recognizing that while the overall response rates are improving and some patients achieve durable remissions, further research is needed to clarify the biology and optimize treatment strategies across different histologic variants. Nonetheless, these findings represent a hopeful step toward more effective therapies for patients with non–clear cell RCC.