Belzutifan Improves Key Outcomes of LITESPARK-005 in Adults With Advanced RCC


According to Eric Jonasch, MD, promising findings from LITESPARK-005 may help with a goal of getting belzutifan FDA approval for patients with refractory renal cell carcinoma.

Eric Jonasch, MD

Eric Jonasch, MD

Treatment with belzutifan (Welireg) led to a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared with everolimus (Afinitor) in adult patients with advanced renal cell carcinoma (RCC) whose disease progressed following PD-1/PD-L1 and VEGF tyrosine kinase inhibitor (TKI) treatments, according to a press release.1

The primary end point of the phase 3 LITESPARK-005 study (NCT04195750) was met with this result, and the study also met a key secondary end point with belzutifan demonstrating significant improvement in overall response rate (ORR) compared with everolimus. Although not statistically significant, belzutifan also showed a trend toward improvement in overall survival (OS) vs everolimus.

Results come from the prespecified interim analysis of LITESPARK-005. The safety portion of the analysis showed that belzutifan’s profile was consistent with that shown in prior studies. Full results will be presented at an upcoming medical meeting and shared with regulatory bodies.

“Based on the data in patients with von Hippel-Lindau [VHL] disease, and on the phase 1b/2 study we conducted in patients with previously treated advanced RCC, it became clear belzutifan is an active drug,” Eric Jonasch, MD, professor in the department of genitourinary medical oncology, division of cancer medicine, at The University of Texas MD Anderson Cancer Center in Houston, TX, told Targeted Oncology™. “This registrational study, where patients with treatment-refractory clear cell RCC were randomized between belzutifan and everolimus, was conducted with the goal of obtaining approval for belzutifan in the refractory disease setting.”

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The data rationalizing the exploration of belzutifan in previously treated advanced RCC were from LITESPARK-004 (NCT03401788). According to findings presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting, belzutifan achieved anti-tumor activity and consistent safety in patients with VHL-related neoplasms. Of the 61 patients in the study, 83% had hemangioblastoma, and 33% had pancreatic neuroendocrine tumors (pNETs).2

The ORR in the hemangioblastoma cohort was 59% with a complete response (CR) rate of 3% and a partial response (PR) rate of 56%. The median duration of response (DOR) observed with belzutifan in the VHL population was not reached (range, 8.3+ to 27.6+ months). For the pNETs cohort, the ORR was 90%, with CRs in 3 patients and PRs in 15. The median DOR was not reached (range, 11.0+ to 31.0+ months).

Sixteen percent of patients in the LITESPARK-004 study experienced grade 3 treatment-related adverse events (TRAEs). The most common TRAE was anemia, which occurred in 10% of patients. There were no grade 4 or 5 TRAEs during the study. Two patients discontinued treatment due to a TRAE.

LITESPARK-005 is an open-label, randomized, phase 3 study in which patients are randomly assigned to receive oral belzutifan at 120 mg once daily or oral everolimus at 10 mg once daily. In addition to PFS, the study explores a coprimary end point of OS, and secondary end points other than ORR include DOR, the number of patients with adverse events, treatment discontinuation rate, and quality of life (QOL). QOL will be determined by several measure including time to deterioration (TTD) in health-related QOL, TTD in physical functioning, TTD in disease symptoms, change from baseline in health-related QOL, change from baseline in physical functioning, and change from baseline in European Quality of Life 5 Dimensions.3

The trial aims to enroll 746 patients with previously treated advanced RCC who meet the criteria. For inclusion, patients must have evidence of unresectable, locally advanced, metastatic disease, must have had disease progression on or after systemic therapy with a PD-1/PD-L1 inhibitor, must have received 3 prior systemic regimens for locally advanced or metastatic RCC, and have adequate organ function. All patients are required to use contraception once on the study, and female patients cannot be pregnant prior to starting therapy.

“Patients with advanced RCC face low survival rates, and for those whose cancer progresses following PD-1/L1 and VEGF-TKI therapies, there is a need for new treatment options that can reduce their risk of disease progression or death,” said Marjorie Green, MD, senior vice president and head of late-stage oncology, global clinical development at Merck Research Laboratories, in a press release.1 “This is the first phase 3 trial to show positive results in advanced RCC following these therapies and the first new mechanism to demonstrate potential in advanced RCC in recent years. We look forward to discussing these results with health authorities.”

“If these data lead to the approval of belzutifan for the treatment of refractory RCC, it provides patients and practitioners with an active, well-tolerated treatment option when patients progress on prior lines of therapy. The [AE] profile, with anemia, fatigue and hypoxemia being most common AEs, is easily manageable, making it an attractive choice,” said Jonasch.


1. 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 August 18, 2023.

2. Jonasch E, Iliopolous O, Rathmell WK, et al. LITESPARK-004 (MK-6482-004) phase 2 study of belzutifan, an oral hypoxia-inducible factor 2α inhibitor (HIF-2α), for von Hippel-Lindau (VHL) disease: Update with more than two years of follow-up data. J Clin Oncol. 2022;40(suppl 16):4546. doi:10.1200/JCO.2022.40.16_suppl.4546

3. A study of belzutifan (MK-6482) versus everolimus in participants with advanced renal cell carcinoma (MK-6482-005). Updated August 1, 2022. Accessed August 18, 2023.

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