FDA Approves Belzutifan for Adult Patients With Advanced RCC


Belzutifan is now an FDA-approved treatment for adult patients with advanced renal cell carcinoma.

  • This approval of belzutifan (Welireg) for the treatment of advanced renal cell carcinoma (RCC) is supported by findings from the phase 3 LITESPARK-005 study (NCT04195750).
  • Statistically significant and clinically meaningful improvements in progression-free survival (PFS) were observed with belzutifan.
  • This approval provides adult patients with RCC who progressed on immune checkpoint and anti-angiogenic agents with a new mechanism of action.

The FDA approved belzutifan for the treatment of adult patients with advanced RCC whose disease progressed following PD-1/PD-L1 and VEGF tyrosine kinase inhibitor (TKI) treatment.1

This regulatory decision is supported by data from the phase 3 LITESPARK-005 study in which the co-primary end point of PFS was met. Treatment with belzutifan reached a statistically significant and clinical meaningful improvement in PFS at the landmark 18 months analysis, as 22.5% of patients remained progression-free vs 9% with everolimus (Afinitor; HR, 0.74; 95% CI, 0.63-0.88). Belzutifan demonstrated a statistically significant improvement in PFS compared with everolimus (HR 0.75, 95% CI 0.63-0.90, one-sided P =.0008). Kaplan-Meier analysis indicated non-proportional hazards, with similar median PFS estimates of 5.6 months (95% CI 3.9-7.0) for belzutifan and 5.6 months (95% CI 4.8-5.8) for everolimus.

A statistically significant improvement in the key secondary end point of overall response rate (ORR) was also observed with belzutifan vs everolimus. In the belzutifan arm, the observed ORR was 22.7% of belzutifan vs 3.5% in the everolimus arm.

LITESPARK-005 is an open-label, randomized, phase 3 study that randomized 746 patients with advanced RCC who progressed after treatment with anti-PD-1/PD-L1 and VEGF-targeted therapies to receive either belzutifan 120 mg orally once daily or everolimus 10 mg orally once daily.2,3

Investigators evaluated the coprimary end points of PFS and overall survival (OS).4 Secondary end points of the trial included ORR, duration of response, the number of patients who experience 1 or more adverse events (AEs), the number of patients who discontinued study treatment as a result of AEs, time to deterioration (TTD) of health-related quality of life (HRQOL), TTD in physical functioning, TTD in disease symptoms, change from baseline in HRQOL per the EORTC Core Quality of Life questionnaire C30 (EORTC QLQ-C30) items 29 and 30 score, change from baseline in physical functioning based on the EORTC QLQ-C30 items 1-5 score, change from baseline in disease symptoms according to the functional Assessment of Cancer Therapy Kidney Cancer Symptom Index-Disease Related Symptoms items 1-9 score, and change from baseline in European Quality of Life 5 Dimensions per the 5-level Questionnaire Health Utility score.3

Enrollment was open to patients with unresectable, locally advanced, or metastatic disease who had received no more than 3 prior systemic agents for locally advanced or metastatic RCC and had adequate organ function.

To date, there have been no statistically significant OS benefits seen with belzutifan compared with everolimus, though there is a signal for OS benefit (HR, 0.88; 95% CI, 0.73-1.07; P =0.099). At 18 months, the OS rates are 55.2% and 50.6% for belzutifan and everolimus, respectively.

A complete response was observed in 3.5% of those treated with belzutifan vs none with everolimus. Both arms showed a similar median time to response at 3.7 months and 3.8 months, but the median duration of response was longer with belzutifan at 19.5 vs 13.7 months with everolimus.

For safety, both arms had similar grade 3 or worse AEs, but those that led to treatment discontinuation were seen in 6% of patients given belzutifan vs 15% of those given everolimus. The most commonly reported AEs included anemia and fatigue. Approximately 30% of patients in the belzutifan arm had grade 3 or worse anemia.

  1. FDA approves belzutifan for advanced renal cell carcinoma. News release. U.S. Food & Drug Administration. December 14, 2023. Acccessed December 14, 2023. http://tinyurl.com/54xcm7f6
  2. Jonasch E, Donskov F, Iliopoulos O, et al. Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease. N Engl J Med. 2021;385(22):2036-2046. doi:10.1056/NEJMoa2103425
  3. Merck announces Welireg® (belzutifan) phase 3 LITESPARK-005 trial met primary endpoint of progression-free survival in certain previously treated patients with advanced renal cell carcinoma. News release. Merck. August 18, 2023. Accessed December 1, 2023. https://tinyurl.com/5duv497t
  4. A study of belzutifan (MK-6482) versus everolimus in participants with advanced renal cell carcinoma (MK-6482-005). ClinicalTrials.gov. Updated August 1, 2022. Accessed December 1, 2023. https://tinyurl.com/3ejtc595

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