Ascending dose escalation of belzutifan plus palbociclib for previously treated advanced clear cell renal cell carcinoma (ccRCC): Phase 1/2 LITESPARK-024 study part 1.

423 Background: Novel MoAs remain an unmet need for patients with advanced ccRCC with PD after multiple therapies. Combination of HIF-2α and CDK4/6 inhibitors showed synthetic lethality in preclinical ccRCC models (Nicholson, Sci Signal 2019). The phase 1/2 LITESPARK-024 study (NCT05468697) evaluates safety and efficacy of belzutifan (bel) + palbociclib (palbo) in pts with advanced ccRCC with PD after ≥2 systemic regimens, including both anti-PD-(L)1 and VEGFR-TKI therapy, and no prior HIF-2α and CDK4/6 inhibitors. Methods: Eligible adults had unresectable stage IV ccRCC, radiographic PD on/after most recent treatment, and ≥2 prior systemic regimens (including both anti–PD-L1 and VEGFR-TKI). Part 1 aimed to determine the recommended phase 2 dose (RP2D) by evaluating DLTs (based on a list of prespecified terms if treatment-related and occurring ≤28 days after first dose) and safety (evaluated in all pts who received ≥1 dose study drug). Pts received bel 120 mg QD + palbo 75 mg, 100 mg, or 125 mg QD for 21 days followed by 7 days off until PD, unacceptable AEs, pt withdrawal, or bel discontinuation. Exploratory efficacy (ORR, disease control rate DCR, and PFS by investigator per RECIST 1.1) in all enrolled pts is also reported. Results: 59 pts were enrolled; 58 pts received ≥1 dose study drug (n = 20 in 75 mg palbo group, n = 19 each in 100 mg and 125 mg groups). 1 pt in the 100 mg group was enrolled but not treated. Data cutoff date was 28 July 2025. Median follow-up was 8.7 mo (range, 3.0–35.0). Total median (range) duration of therapy was 4.4 mo (0.2–23.4) for bel and 3.5 mo (0.2–23.4) for palbo. 2 DLTs occurred: 1 gr 3 anemia, and 1 gr 3 hypoxia (both in 125 mg group). Safety summary is shown in the Table. Most common grade ≥3 TRAE was anemia (50.0% in 75 mg group, 52.6% in 100 mg group, 57.9% in 125 mg group). ORR and DCR (95% CI) were 15.0% (3.2–37.9) and 70.0% (45.7–88.1) in 75 mg group, 0.0% (0.0–17.6) and 57.9% (33.5–79.7) in 100 mg group, and 21.1% (6.1–45.6) and 73.7% (48.8–90.9) in 125 mg group. Median PFS (95% CI) was 7.2 mo (1.9–NR), 5.4 mo (1.8–NR), and 9.1 mo (3.7–NR); estimated 12-mo PFS rates were 29.2%, 30.7%, and 44.4%. Conclusions: Bel + palbo had a manageable safety profile. Gr ≥3 TRAEs were frequent. No new safety signals occurred. In a population with heavily pretreated biomarker-unselected RCC, clear differentiation in efficacy outcomes with bel + palbo compared with historical bel monotherapy data was not observed. Interpretation of these results is limited by the sample size and the single-arm design. Clinical trial information: NCT05468697 . Pts with ≥1 event, % Bel +75 mg palbo Bel +100 mg palbo Bel +125 mg palbo Any AE 100.0 94.7 100.0 Gr ≥3 AE 85.0 84.2 100.0 Serious AE 60.0 47.4 36.8 AE led to discontinuation 15.0 26.3 10.5 AE led to death 0 0 5.3* Any TRAE 95.0 94.7 100.0 Gr ≥3 TRAE 65.0 78.9 78.9 Serious TRAE 15.0 15.8 10.5 TRAE led to discontinuation 15.0 26.3 5.3 TRAE led to death 0 0 0 *Cerebral hemorrhage.