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While several combination treatments have demonstrated clinical benefit in the treatment of metastatic renal cell carcinoma (mRCC), mechanistically, these treatment strategies draw from two therapeutic classes: immune checkpoint inhibitors and antiangiogenic agents. In December 2023, belzutifan received FDA approval for patients with mRCC who have received prior treatment with a PD-1/PD-L1 inhibitor and a VEGF-TKI.

Belzutifan is a , with the latter being upstream in the VHL-HIF-VEGF pathway and central to the pathogenesis of RCC. The recent approval is based on the a phase III open-label study that compared belzutifan versus everolimus in patients with clear-cell mRCC with prior exposure to 1-3 lines of therapy including a PD-1/PD-L1 inhibitor and a VEGF-TKI.

The results, presented at the European Society for Medical Oncology 2023 congress, suggested improvement in median progression-free survival (HR 0.74, 95% CI 0.63-0.88) and objective response rate (22.7% vs 3.5%) with belzutifan compared with everolimus. The overall survival (OS) data are not yet mature. In terms of adverse events, 38.7% vs 39.4% of patients experienced grade 3-5 toxicities in either arm of the study.

More recently, were presented at ASCO's Genitourinary Cancers Symposium by Powles et al. Patients were administered the FKSI-DRS and EORTC QLQ-C30 questionnaires at baseline, and then periodically as specified in the protocol up until 30 days after the last treatment dose. The authors reported a completion rate of 90% at baseline and 55% at the 4-month timepoint in each arm. The time to deterioration, and the least square mean change from baseline, measured as secondary end points were both superior with belzutifan, indicative of better quality of life in the experimental arm.

When evaluating subsequent treatment strategies for patients with mRCC, belzutifan is a novel and attractive option given its demonstrated efficacy in a heavily pretreated population and distinct mechanism of action.

The data presented in the meeting abstract further solidify belzutifan's clinical utility, by providing a valuable end point in the era of shared decision-making and person-centric care. Taken together, the data for safety, tolerability, and quality of life with belzutifan further support the ongoing investigation of combination strategies for metastatic disease, with several trials that are currently ongoing.

Furthermore, with the improvement in OS seen with adjuvant use of pembrolizumab in , it will be interesting to evaluate the impact of belzutifan in combination with adjuvant immunotherapy in the curative setting (clinicaltrials.gov, ).

, is a GU medical oncologist at the University of Massachusetts in Worcester.

Read the study here and an interview about it here.