Standard Belzutifan Dose Equally Effective as Higher Dose in ccRCC

Jaime Merchan, MD

For patients with previously treated clear cell renal cell carcinoma (RCC), belzutifan (Welireg) demonstrated comparable efficacy at both the standard dose of 120 mg and a higher 200 mg dose, according to findings from the LITESPARK-013 trial (NCT04489771).¹ The safety profile at both dose levels was also consistent with prior data, confirming the tolerability of the agent.

Belzutifan is a hypoxia-inducible factor (HIF)–2α inhibitor being evaluated as a treatment for patients with advanced clear cell RCC. The study sought to evaluate the efficacy and safety of 2 doses of belzutifan in this patient population, which consisted of those with measurable disease per RECIST v1.1, those who received no more than 3 prior systemic regimens for locally advanced/metastatic RCC, and those treated with only 1 prior anti–PD-1/L1 therapy for locally advanced/metastatic RCC. Further, patients were required to have recovered from all adverse events (AEs) from previous therapies to at least grade 1 or baseline and have a Karnofsky performance status score of at least 70%.

The study randomly assigned patients in a 1:1 ratio to receive belzutifan at a dose of 120 or 200 mg once daily.² The primary end point evaluated in the study was objective response rate (ORR) per RECIST v1.1, and secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.

A total of 154 patients were enrolled, including 76 treated with the 120 mg dose and 78 given the 200 mg dose. At a median follow-up of 20.1 months (range, 14.8-28.4), the ORR in the 120 mg arm was 23.7% vs 23.1% in the 200 mg arm, respectively (P =.5312; 95% CI, -14.0% to 12.9%). In the 120 mg arm, the median DOR was not reached vs 16.1 months in the 200 mg arm, and there were no differences in PFS or OS observed between groups.

For safety, treatment-related AEs deemed grade 3 or 4 were seen in 35 patients (46.1%) treated at the 120 mg dose and 36 patients (46.2%) treated at the 200 mg dose. Overall, these findings strengthen the case for 120 mg once daily as the optimal dose for belzutifan, as similar therapeutic benefits were seen to the 200 mg dose while minimizing potential exposure-related risks.

In an interview with Targeted Oncology^TM, Jaime Merchan, MD, professor, co-leader of the Translational and Clinical Oncology Research Program and director of the phase 1 clinical trials program at the Sylvester Comprehensive Cancer Center at the University of Miami, delved into data from the LITESPARK-013 trial evaluating belzutifan for advanced clear cell RCC treatment.

3D render of human kidney on science background: © Rasi - stock.adobe.com

Targeted Oncology: Can you provide an overview of the phase 2 LITESPARK-013 trial?

Merchan: LITESPARK-013 was a randomized, phase 2 trial comparing 2 different dose levels of belzutifan, a novel HIF–2α blocker, in patients with clear cell renal cell carcinoma. The objectives of the study were to try to determine the differences in the efficacy between the 2 doses, the standard dose of 120 mg per day vs the high dose of 200 mg per day.

What previous findings from the trial can you highlight?

The results of the study presented last year at [the 2023 European Society of Medical Oncology Annual Meeting] showed that both the low and the high doses of belzutifan were associated with similar efficacy with similar response rates and also no significant differences in median progression-free survival, suggesting that both doses were effective and probably that the lower dose of 120 [mg], which is the standard dose, is enough to induce clinical benefit.

What can you discuss about this post hoc efficacy analysis of the trial?

The current study [was] presented at [the American Society of Clinical Oncology] 2024 [Annual Meeting], [and] is a post hoc efficacy analysis conducted on a pooled population. The analysis included both low- and high-dose treated patients to explore potential correlations between efficacy and various clinical factors. These factors included differences in IMBC scores, differentiation status, the number of prior lines of therapy (one or more), and the type of first-line therapy administered, such as [tyrosine kinase inhibitors] or checkpoint inhibitors.

What were the main takeaways from this analysis?

In this pooled analysis, there were no correlations, or no clear correlation, between efficacy on any specific subgroup, which suggests that belzutifan produces a long-lasting benefit and responses, regardless of the subgroups analyzed in RCC.

What are the next steps for evaluating belzutifan in RCC treatment?

Future studies that are currently going on are combination studies of belzutifan with TKIs [tyrosine kinase inhibitors] or checkpoint inhibitors in not only in the second-line, but also in the first-line setting. And moreover, there are upcoming studies using belzutifan in the adjuvant setting in combination with pembrolizumab [Keytruda]. This is actually a phase 3, randomized study that is almost completed, and we are awaiting the results.

REFERENCE:

1. Ghatalia P, Agarwal N, Brugarol J, et al. LITESPARK-013: Randomized phase 2 study of two doses of belzutifan in patients with advanced clear cell renal cell carcinoma (ccRCC). Presented at: 2023 International Kidney Cancer Symposium; November 9-11, 2023. Accessed November 10, 2023. Abstract 33.

2. Agarwal N, Brugarolas J, Ghatalia P, et al. Randomized phase II dose comparison LITESPARK-013 study of belzutifan in patients with advanced clear cell renal cell carcinoma. Ann Oncol. 2024;35(12):1148-1156. doi:10.1016/j.annonc.2024.08.2338