Clinical Implications and Future Directions

Clinical Implications and Future Directions

The apparent broad activity of pembrolizumab plus lenvatinib across diverse non–clear cell RCC histologies can be attributed to the combination's dual mechanism of action, which overcomes the inherent heterogeneity challenges that have historically plagued this disease category. The multi-kinase inhibitory activity of lenvatinib combined with the immunomodulatory effects of pembrolizumab create a synergistic approach that demonstrates effectiveness across papillary, chromophobe, translocation, and unclassified subtypes. This combination has established a new treatment benchmark and is now recognized as a preferred option in national guidelines, including NCCN, for patients with advanced non–clear cell RCC, representing more than 90% to 95% of non–clear cell cases encountered in clinical practice.

However, certain distinct histologic subtypes still require specialized treatment approaches outside the pembrolizumab plus lenvatinib paradigm. Specific variants such as succinate dehydrogenase-deficient RCC have established treatment combinations such as bevacizumab plus erlotinib that remain the preferred approach for those particular histologies. These exceptions represent a small minority of non–clear cell RCC cases and highlight the importance of precise histologic classification in treatment planning, even within the broader context of improved outcomes with immunotherapy plus tyrosine kinase inhibitor combinations.

The 3-year follow-up data from KEYNOTE-B61 definitively establishes pembrolizumab plus lenvatinib as the current standard of care for first-line treatment of advanced non–clear cell RCC. With impressive response rates, excellent disease control, prolonged progression-free survival of 17.9 months, and remarkable median overall survival of 41.5 months, this combination has transformed treatment expectations for this historically challenging patient population. While future research directions may explore histology-specific studies, genomic-based treatment selection, and novel therapeutic agents, the current evidence strongly supports relying on pembrolizumab plus lenvatinib as the backbone of treatment for the vast majority of patients with advanced non–clear cell RCC across its common histologic variants.