Belzutifan Demonstrates Superior PFS, ORR vs Everolimus in Advanced RCC

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Treatment with belzutifan (Welireg) led to a significant benefit in progression-free survival (PFS) and objective response rate (ORR) vs everolimus in patients with advanced clear cell renal cell carcinoma (RCC) previously treated with immune checkpoint and antiangiogenic therapies, according to findings from the phase 3 LITESPARK-005 study (NCT04195750).¹

The study included 746 patients, including 374 in the belzutifan arm and 372 in the everolimus arm. At the first interim analysis with a median follow-up of 18.4 months, the median PFS was 5.6 months in both groups; at 18 months, 24.0% of the participants in the belzutifan group and 8.3% in the everolimus group were alive and free of progression (2-sided P =.002), meeting the prespecified significance criterion.

With belzutifan, the confirmed ORR was 21.9% (95% CI, 17.8%-26.5%) and with everolimus, it was 3.5% (95% CI, 1.9%-5.9%; P <.001). This also met the prespecified significance criterion.

“I think we have been waiting for this data for years…The progression-free survival is 5.5 months on both regimens, everolimus and belzutifan. The hazard ratio here, which I do think is important to focus on, is .75, so certainly, there is some benefit there,” explained Sumanta Kumar Pal, MD, professor, Department of Medical Oncology and Therapeutics Research and co-director, Kidney Cancer Program at the City of Hope Comprehensive Cancer Center in an interview with Targeted Oncology^TM.

At the second interim analysis and at a median follow-up of 25.7 months, the median overall survival (OS) with belzutifan was 21.4 months vs 18.1 months with everolimus. At 18 months, 55.2% and 50.6% of the patients in the belzutifan and everolimus arms, respectively, were alive (HR, 0.88; 95% CI, 0.73-1.07; 2-sided P =.20). This finding did not meet the prespecified significance criterion.

Safety findings showed that belzutifan did not demonstrate any new safety signals. Grade 3 or higher adverse events (AEs) were seen in 61.8% of the belzutifan group and 62.5% in the everolimus group. Grade 5 AEs were seen in 3.5% and 5.3% of patients across arms. Further, 5.9% of patients in the belzutifan arm and 14.7% of patients in the everolimus arm discontinued treatment as a result of their AEs.

“I am happy to have more therapies available that have the ability to stabilize disease and have a better [adverse] effect profile,” explained Thomas E. Hutson, DO, PharmD, director of the urologic oncology program for Texas Oncology Baylor University Medical Center, in an interview with Targeted Oncology^TM. “I am most excited about a novel mechanism of action and a [AE] profile as it is, with some degree of efficacy and its ability to be combined with something else.”

About the LITESPARK-005 Trial of Belzutifan

Belzutifan is a hypoxia-inducible factor 2α inhibitor. In early-phase studies, the agent has shown clinical activity in clear cell RCC. In December 2023, the FDA approved belzutifan for the treatment of patients with advanced RCC whose disease progressed following PD-1/PD-L1 and VEGF tyrosine kinase inhibitor treatment, as supported by findings from the phase 3 LITESPARK-005 study.²

LITESPARK-005 is a phase 3, multicenter, open-label, active-controlled trial evaluating treatment with belzutifan vs everolimus in patients with advanced clear cell RCC. Those enrolled were required to have previously received immune checkpoint and antiangiogenic therapies.³

Patients were randomly assigned in a 1:1 ratio to receive 120 mg of belzutifan or 10 mg of everolimus given orally once a day. Treatment continued until disease progression or unacceptable AEs occurred.

PFS and OS served as the dual primary end points of the study. ORR was the key secondary end point, measured as a confirmed complete or partial response. Additional secondary end points included duration of response, the number of patients who experience 1 or more 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), change from baseline in physical functioning based on the EORTC QLQ-C30, change from baseline in disease symptoms according to the functional Assessment of Cancer Therapy Kidney Cancer Symptom Index-Disease Related Symptoms, and change from baseline in European Quality of Life 5 Dimensions per the 5-level Questionnaire Health Utility score.

REFERENCES:

1. Choueiri TK, Powles T, Peltola K, et al. Belzutifan versus everolimus for advanced renal-cell carcinoma. N Engl J Med. 2024;391(8):710-721. doi:10.1056/NEJMoa2313906

2. FDA approves belzutifan for advanced renal cell carcinoma. News release. FDA. December 14, 2023. Accessed August 23, 2024. http://tinyurl.com/54xcm7f6

3. A study of belzutifan (MK-6482) versus everolimus in participants with advanced renal cell carcinoma (MK-6482-005). ClinicalTrials.gov. Updated June 28, 2024. Accessed August 23, 2024. https://tinyurl.com/3ejtc595