Belzutifan plus lenvatinib (len) for Chinese patients (pts) with previously treated advanced clear cell renal cell carcinoma (ccRCC): Preliminary results of cohort 1 of the phase 1 LITESPARK-010 study.

4537 Background: Belzutifan, a first-in-class HIF-2α inhibitor, alone or in combination with a VEGFR-TKI, has shown durable antitumor activity in first- and subsequent-line settings of advanced ccRCC. LITESPARK-010 (NCT05030506) is a phase 1, 2-cohort, open-label study of belzutifan + len, with or without pembrolizumab, in Chinese pts with advanced ccRCC. We present preliminary results cohort 1. Methods: Chinese adults with histologically confirmed ccRCC who had 1-3 prior treatment regimens received belzutifan 120 mg PO QD for 3 wk followed by belzutifan 120 mg + len 20 mg PO QD until intolerable toxicity, disease progression, or pt withdrawal. The study included a dose-limiting toxicity (DLT) phase of 21 days after the start of combination treatment. Dual primary end points were safety and PK. Secondary end points included ORR, DOR, and PFS per RECIST v1.1 by investigator assessment and OS. Results: As of August 29, 2023, 24 pts were enrolled in cohort 1 and 23 received combination treatment; 1 pt discontinued in the monotherapy period because of treatment with non-study anti-cancer therapy. Median age was 61 years, 17 pts (71%) were male, and 14 (58%) had intermediate/poor IMDC risk. 14 pts (58%) received 1 prior line of therapy and 10 (42%) received ≥2 prior lines. Five pts (21%) received prior therapy with a PD-(L)1 inhibitor. As of the data cutoff date, 11 pts (46%) remained on treatment. Median follow up was 14.4 mo (range, 1.6-22.1). Ten pts were evaluated in the DLT phase, and 1 experienced a DLT (grade 2 treatment-related transient ischemic attack). All 24 pts (100%) experienced a treatment-related AE (TRAE) of any grade, most commonly anemia (100%) and proteinuria (88%). Grade 3 or 4 TRAEs occurred in 17 pts (71%), most commonly anemia (29%) and hypertension (29%). One pt (4%) experienced grade 3 hypoxia. No pts died (grade 5) due to a TRAE. After a single dose of belzutifan monotherapy, median T max was 1.8 h (range, 0.6-8.0), geometric mean AUC 0-24 was 22,400 h·ng/mL (90% CI, 19,600-25,500), and geometric mean C max was 1640 ng/mL (90% CI, 1490-1820). Steady-state concentration was reached after 14 days of belzutifan monotherapy treatment; the accumulation ratio of AUC 0-24 was 1.7 (90% CI, 1.5-1.9). Belzutifan + len treatment had similar PK to belzutifan monotherapy. In all 24 pts, confirmed ORR was 50% (95% CI, 29-71; all PRs). Median DOR was not reached (NR; range, 3.5-20.4+ months); 50% of responders remained in response for ≥12 mo per Kaplan-Meir estimate. Median PFS was 13.7 mo (95% CI, 8-NR) and median OS was NR (95% CI, NR-NR). The 12-mo PFS and OS rates were 57% and 75%, respectively. Conclusions: Preliminary data from the belzutifan + len showed promising antitumor activity in Chinese pts with previously treated ccRCC. The safety of belzutifan 120 mg + len 20 mg was consistent with the safety profiles of the individual drugs. Clinical trial information: NCT05030506 .