KEY TAKEAWAYS
- The LITESPARK-013 phase 2 trial investigated whether increasing the belzutifan dose could enhance efficacy while ensuring an acceptable safety profile.
- The primary endpoint was ORR. The secondary endpoints cover DOR, PFS, OS, safety, and PK.
- The result demonstrated that the two doses of belzutifan were proven to be similar in efficacy while offering a safer choice consistent with past findings.
Researchers assessed the HIF-2α inhibitor belzutifan for clear cell renal cell carcinoma (ccRCC). In the LITESPARK-001 phase 1 trial, dosages up to 240 mg daily did not reach the maximum tolerated dose (MTD). So, the recommended phase 2 dose (RP2D) was set to 120 mg QD, considering pharmacodynamics (PD), pharmacokinetics (PK), and safety parameters.
In the LITESPARK-013 phase 2 study, researchers aimed to evaluate whether the increased belzutifan dosage could enhance efficacy while still maintaining an acceptable safety profile.
Patients with advanced ccRCC, who had measurable disease per RECIST v1.1, and up to three prior systemic regimens (including an anti–PD-1/L1 agent) with disease progression during or after such treatment were randomly assigned to receive either belzutifan 120 mg or 200 mg once daily in a 1:1 ratio. Stratification was based on the IMDC risk score (0 vs. 1-2 vs. 3-6) and the number of prior TKI therapies for advanced ccRCC (0 vs. 1 vs. 2-3).
The primary endpoint was the objective response rate (ORR) per RECIST v1.1, evaluated by a blinded independent central review. The secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics (PK).
The study included 154 participants (120 mg: n=76; 200 mg: n=78), and the baseline characteristics were balanced. Median follow-up was 20.1 months (range 14.8-28.4). The ORR was 23.7% (18 PR) for 120 mg and 23.1% (4 CR; 14 PR) for 200 mg (P=0.5312; −0.5% [95% CI, −14.0 to 12.9]. PFS (median 7.3 vs 9.1 months; HR 0.94 [95% CI 0.63-1.40]) and OS (medians not reached; HR 1.11 [95% CI, 0.65-1.90]) showed no significant differences. Median DOR was not reached for the 120 mg arm (range 2.6+ to 16.1+) and was 16.1 mo (2.1+ to 23.5+) for the 200 mg arm; 64.7% and 51.3% of patients (pts) had ongoing responses ≥15 mo, respectively.
Of the 154 participants, 142 pts had treatment-related AE (TRAE) (92.1% with 120 mg; 92.3% with 200 mg). Discontinuation due to TRAE occurred in 2 (2.6%) on 120 mg and 7 (9.0%) on 200 mg. Treatment-related anemia (81.6% with 120 mg and 83.3% with 200 mg) and hypoxia (23.7% with 120 mg and 26.9% with 200 mg) were similar between arms.
The results were consistent with the prior reports of antitumor activity in ccRCC, with belzutifan showing similar efficacy between the RP2D of 120-mg dose and the 200-mg dose. This highlights the safety profile of belzutifan and reinforces the 120 mg QD dose as the preferred and recommended dosage for belzutifan.
Clinical Trial: https://clinicaltrials.gov/study/NCT04489771
Agarwal N, Brugarolas J, Ghatalia P, George S, Haanen J.B.A.G., Gurney H.P., Ravilla R, Van der Veldt AAM, Beuselinck B, Pokataev I, Suelmann BB, Tuthill M, Vaena D, Zagouri F, Wu J, Liu Y, Perini R, Merchan JR, Atkins MB. Safety and efficacy of two doses of belzutifan in patients with advanced RCC: Results of the randomized phase II LITESPARK-013 study. Ann Oncol. 2023;34(suppl_2):S1013-S1031. doi:10.1016/annonc/annonc1312.
