Belzutifan (bel) plus lenvatinib (lenva) versus cabozantinib (cabo) for advanced renal cell carcinoma (RCC) after anti–PD-(L)1 therapy: Open-label phase 3 LITESPARK-011 study.

LBA417 Background: There is no globally accepted standard of care (SOC) for advanced RCC after IO therapy. VEGFR-TKIs are often leveraged in this setting, but were primarily tested in phase 3 studies prior to PD-(L)1 inhibitors becoming SOC in earlier lines of therapy. The phase 3 LITESPARK-011 study (NCT04586231) investigates bel + lenva vs cabo in pts with advanced RCC progressing after anti–PD-(L)1 therapy in the 1L, 2L or adjuvant setting. Methods: Eligible pts were ≥18 yrs old with advanced clear cell RCC (ccRCC) that progressed on or after 1L or 2L anti–PD-(L)1 therapy or ≤6 mo of last dose of adjuvant anti–PD-(L)1 therapy. Pts were randomized 1:1 to bel 120 mg + lenva 20 mg QD vs cabo 60 mg QD. The dual primary endpoints were progression-free survival (PFS) by blinded independent central review (BICR) per RECIST 1.1 and overall survival (OS). Secondary endpoints included objective response rate (ORR, key) and duration of response (DOR) by BICR per RECIST 1.1, and safety. Results are reported for the first (IA1; data cutoff Jun 26, 2024) and second (IA2; data cutoff Apr 9, 2025) interim analysis. Results: 747 pts were randomized to bel + lenva (n = 371) or cabo (n = 376). Median (range) follow-up was 19.6 mo (9.9–39.8) at IA1, and 29.0 mo (19.3–49.2) at IA2. Bel + lenva showed statistically significant improvement in PFS (IA1, IA2) and ORR (IA1) vs cabo (Table). OS results did not reach statistical significance (Table); additional follow-up for OS is ongoing. Median (range) DOR was 23.0 mo (2.0–44.3+) with bel + lenva vs 12.3 mo (1.8+–35.9+) with cabo at IA2. Grade ≥3 TEAEs occurred in 84.1% of pts with bel + lenva and 82.7% with cabo; TEAEs led to death in 5.4% of pts (2 were treatment-related: 1 each thrombotic microangiopathy and pneumonitis) and 3.2% of pts (1 was treatment-related: hemoptysis), respectively. Conclusions: Bel + lenva demonstrated superior PFS and ORR vs cabo in pts with advanced ccRCC following anti–PD-(L)1 therapy. OS favored bel + lenva but did not reach statistical significance and will be tested further at final analysis. The safety profile of bel + lenva was consistent with the profiles of the individual drugs. LITESPARK-011 is the first phase 3 study of a HIF-2α inhibitor combined with a VEGFR-TKI, and the first phase 3 study in RCC to show improved outcomes vs a contemporary VEGFR-TKI. Clinical trial information: NCT04586231 . IA1 IA2 Bel + Lenva, N = 371 Cabo, N = 376 Bel + Lenva, N = 371 Cabo, N = 376 Median PFS (95% CI), mo 14.6 (11.1–16.6) 10.6 (9.2–11.1) 14.8 (11.2–16.6) 10.7 (9.2–11.1) HR (95% CI) 0.74 (0.61–0.89) 0.70 (0.59–0.84) P value (1-sided) .00095* .00007* Median OS (95% CI), mo NR (26.5–NR) 27.4 (23.6–31.4) 34.9 (27.5–NR) 27.6 (24.0–31.4) HR (95% CI) 0.90 (0.70–1.15) 0.85 (0.68–1.05) P value (1-sided) .19322 .06075 ORR, % (95% CI) 52.6 (47.3–57.7) 39.6 (34.6–44.8) 52.6 (47.3–57.7) 40.2 (35.2–45.3) P value (1-sided) .0002* NA NA, not applicable. *Denotes statistical significance.