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-[L]1 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.