Findings support 120 mg daily as preferred belzutifan dose for advanced clear cell RCC
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NASHVILLE, Tenn. — Belzutifan exhibited efficacy at two doses for patients with advanced clear cell renal cell carcinoma, according to randomized phase 2 study results presented at International Kidney Cancer Symposium: North America.
However, 120 mg daily is the optimal dose moving forward, researchers concluded.
"The main take-home message is that the 120 mg dose of belzutifan had similar efficacy as the 200 mg dose, with [a] slightly better side effect profile, and should be the dose used in future clinical trials and clinical practice," researcher Pooja Ghatalia, MD, assistant professor in the department of hematology/oncology at Fox Chase Cancer Center, told Healio.
Belzutifan (Welireg, Merck) is an oral hypoxia-inducible factor-2 alpha inhibitor. It is approved in the U.S. for treatment of adults with von Hippel-Lindau disease who require therapy for associated renal cell carcinoma, central nervous system hemangioblastomas or pancreatic neuroendocrine tumors that do not require immediate surgery.
Belzutifan also has shown antitumor activity among patients with previously treated advanced clear cell carcinoma.
In the phase 1 LITESPARK-001 study, researchers evaluated belzutifan doses from 20 mg once daily to 240 mg once daily without reaching the maximum-tolerated dose. They established 120 mg once daily as the recommended phase 2 dose based on the totality of safety, pharmacokinetic and pharmacodynamic data.
Ghatalia and colleagues conducted the LITESPARK-013 study to compare the 120 mg dose with a 200 mg dose, aiming to determine whether a higher belzutifan dose could improve efficacy while maintaining an acceptable safety profile.
The study included 154 patients with advanced clear cell renal cell carcinoma, all of whom had measurable disease.
Study participants had received up to three prior systemic regimens for advanced disease and experienced disease progression during or after anti-PD-1/anti-PD-L1 therapy.
Researchers randomly assigned patients 76 patients to oral belzutifan 120 mg once daily. The other 78 patients received the agent dosed at 200 mg once daily.
Investigators stratified by International Metastatic RCC Database Consortium risk (0 vs. 1 to 2 vs. 3 to 6), as well as by number of prior tyrosine kinase inhibitor therapies (0 vs. 1 vs. 2 or 3).
Objective response rate per blinded independent central review served as the primary endpoint. Secondary endpoints included duration of response and PFS per blinded independent central review, as well as OS, safety and pharmacokinetics.
Median follow-up was 20.1 months (range, 14.8-28.4).
Researchers reported comparable efficacy outcomes between the 200 mg and 120 mg groups, including similar ORRs (23.1% vs. 23.7%), disease control rates (78.2% vs. 75%) and percentage of patients who experienced reduction in target lesions (65% vs. 68%).
Median duration of response was 16.1 months (95% CI, 2.1+ to 23.5+) in the 200 mg group and had not been reached (95% CI, 2.6+ to 16.1+) in the 120 mg group.
Results showed no statistically significant difference in PFS (median, 9.1 months vs. 7.3 months; HR = 0.94; 95% CI, 0.63-1.4) or OS (median not reached in either group; HR = 1.11; 95% CI, 0.65-1.9) between the 200 mg and 120 mg groups
A comparable percentage of patients assigned the 120 mg dose and 200 mg dose experienced treatment-related adverse events (92.1% vs. 92.3%), treatment-related anemia (81.6% vs. 83.3%) and hypoxia (23.7% vs. 26.9%).
A higher percentage of patients assigned the 200 mg dose experienced any adverse events that led to dose modifications (57.7% vs. 46.1%), any event that led to treatment discontinuation (14.1% vs. 5.3%) and any treatment-related adverse event that led to treatment discontinuation (9% vs. 2.6%).
The results of this trial, together with those of the phase 3 LITESPARK-005 study, support 120 mg once daily as the appropriate belzutifan dose for patients with clear cell renal cell carcinoma, Ghatalia said.
"Merck has several clinical trials planned with this agent in first-line metastatic renal cell carcinoma, as well as in the adjuvant setting," Ghatalia told Healio. "Belzutifan is an active drug that will probably be combined with other agents and will be moved to earlier lines of therapy."
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Ghatalia P, et al. Abstract 4. Presented at: IKCS: North America; Nov. 9-11, 2023; Nashville, Tenn.
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