Pembrolizumab Plus Lenvatinib for Previously Untreated Advanced Non–Clear Cell Renal Cell Carcinoma: 3-Year Follow-Up of the Phase 2 KEYNOTE-B61 Study

Panelists discuss how they will review the KEYNOTE-B61 phase 2 study examining pembrolizumab plus lenvatinib for previously untreated advanced non–clear cell renal cell carcinoma (RCC), including an overview of non–clear cell RCC and integration of the 3-year follow-up data into clinical practice.

Panelists discuss how non–clear cell renal cell carcinoma (RCC) represents a challenging, heterogeneous collection of rare tumors comprising 25% to 30% of all RCC cases, requiring careful histological review and individualized risk stratification based on tumor biology, disease tempo, and burden rather than traditional treatment algorithms used for clear cell RCC.

Panelists discuss how the KEYNOTE-B61 phase 2 single-arm study represents the largest prospective trial evaluating pembrolizumab plus lenvatinib as first-line treatment for advanced non–clear cell renal cell carcinoma (RCC), enrolling 158 patients across all major histological subtypes with an impressive median follow-up of 41.6 months and updated 3-year survival data.

Panelists discuss how the KEYNOTE-B61 study population truly represents real-world clinical practice, with papillary renal cell carcinoma (RCC) being the most common subtype followed by chromophobe, unclassified, and translocation RCC as the top 4 subtypes typically encountered in clinic, while rarer variants comprise only 2% to 3% of non–clear cell cases.

Panelists discuss how the KEYNOTE-B61 study demonstrated remarkable efficacy with a 50.6% objective response rate and 82% disease control rate across all non–clear cell renal cell carcinoma (RCC) histologies, representing a significant improvement over historical tyrosine kinase inhibitor (TKI) data that showed response rates below 30% and setting a new treatment benchmark for this patient population.

Panelists discuss how the durability of response data was particularly compelling, with a median duration of response of approximately 2 years and 35% of patients maintaining responses at 3 years, especially noting the surprising 31% response rate in chromophobe renal cell carcinoma (RCC) despite this histology's historically poor responsiveness to immunotherapy due to low tumor mutational burden.

Panelists discuss how the KEYNOTE-B61 study demonstrated impressive survival outcomes with a median progression-free survival (PFS) of 17.9 months and median overall survival (OS) of 41.5 months, effectively doubling the historical tyrosine kinase inhibitor (TKI) monotherapy benchmarks of 8 to 9 months PFS and 21 months OS in patients with non–clear cell renal cell carcinoma (RCC).

Panelists discuss how managing the safety profile of pembrolizumab plus lenvatinib requires proactive patient education and early toxicity identification, with approximately 25% of patients discontinuing therapy due to adverse events in both clinical trials and real-world practice, emphasizing the importance of distinguishing between tyrosine kinase inhibitor (TKI) and immunotherapy-related adverse events for appropriate management.

Panelists discuss how pembrolizumab plus lenvatinib has established a new benchmark and become the preferred first-line treatment option for more than 95% of patients with non–clear cell renal cell carcinoma (RCC), according to national guidelines, demonstrating activity across all major histological subtypes despite the heterogeneous nature of these diseases, while acknowledging that specific rare histologies may still require tailored approaches.