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Opinion|Videos|September 29, 2025

Future of Clear Cell Renal Cell Carcinoma

Author(s)Brian I. Rini, MD
Arpita Desai, MD
Sundhar Ramalingam, MD

Panelists discuss how the future of renal cell carcinoma (RCC) treatment lies in developing better biomarkers for patient selection, novel immune therapies including chimeric antigen receptor (CAR) T cells and T-cell engagers, HIF-alpha inhibitors, radioligand therapies, and moving beyond the current immunotherapy-based doublet paradigm that has dominated for 7 years.

Video content above is prompted by the following:

The future of clear cell RCC treatment focuses on overcoming the current plateau in first-line therapy improvements since 2018's immune-based doublet establishment.Desai highlights several promising directions, including HIF-alpha inhibitors showing activity in refractory settings and potential frontline applications. Biomarker development remains critical for personalizing treatment selection among multiple effective options, with adaptive trial designs offering more efficient drug development pathways.

Novel cellular therapies represent the most exciting advancement opportunities, including CAR T-cell therapy adaptations for solid tumors and bispecific T-cell engagers leveraging successful hematologic malignancy approaches. Prostate-specific membrane antigen–targeted radioligand therapy, successfully deployed in prostate cancer, shows promise for RCC applications. Carbonic anhydrase IX (CA9)-directed imaging and therapy capitalize on this near-universal clear cell RCC target for both diagnostic and therapeutic applications.

The expert panel emphasizes the critical need for nonangiogenic, non-PD1/CTLA4-based therapeutic approaches to break the current treatment paradigm limitation. While metabolic pathway inhibitors have shown limited success, continued exploration of novel drug classes remains essential. Combination strategies beyond current immune-TKI approaches may unlock superior efficacy without proportional toxicity increases. Treatment sequencing optimization, duration studies, and treatment-free survival strategies represent near-term opportunities for improving patient outcomes within existing therapeutic frameworks. The field anticipates breakthrough innovations similar to the immune therapy revolution that transformed RCC treatment over the past decade.

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