Yu-Wei Chen, MD, MS, Assistant Professor of Medicine, University of California, San Diego, La Jolla, California, reviews later-line treatment strategies for advanced renal cell carcinoma (RCC) in the immunotherapy era. Dr. Chen focuses on how limited real-world delivery of subsequent therapies makes optimal sequencing essential for patient outcomes.
He reviews historical and contemporary data supporting the use of vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (TKIs) as the backbone of post-immunotherapy treatment. Axitinib, cabozantinib, and lenvatinib plus everolimus are discussed, with cabozantinib showing consistent efficacy and low primary progression rates across multiple post-immuno-oncology (IO) studies.

Immune checkpoint inhibitor rechallenge strategies are examined using data from OMNIVORE, TITAN-RCC, HCRN, and FRACTION-RCC. These studies demonstrate low response rates and limited benefit, reinforcing that IO rechallenge is rarely effective after prior exposure.

Combination IO TKI approaches in the post-IO setting are also reviewed. Trials such as CONTACT-03 and TiNivo-02 failed to improve outcomes over TKI monotherapy and were associated with increased toxicity.

Dr. Chen highlights the emergence of belzutifan, a HIF-2α inhibitor, supported by data from LITESPARK-005 showing improved progression-free survival, response rates, and quality of life compared with everolimus. Emerging belzutifan VEGF TKI combinations show promise in reducing primary progression.

Dr. Chen also discusses sequencing after adjuvant pembrolizumab, highlighting unresolved questions and the need for future prospective trials.

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