Editor’s Note: For patients with advanced renal cell carcinoma (RCC) who have progressed after anti-PD-(L)1 therapy, a consensus standard of care is currently lacking. Belzutifan, a first-in-class HIF-2α inhibitor, combined with the VEGFR-TKI lenvatinib, has emerged as a promising therapeutic strategy. At a recent academic conference, Professor Robert J. Motzer from Memorial Sloan Kettering Cancer Center (MSKCC) presented the latest results from the randomized, open-label, Phase 3 LITESPARK-011 study.01 Background:
The Therapeutic Dilemma Following Anti-PD-(L)1 Progression Currently, no globally recognized standard of care exists for advanced renal cell carcinoma (RCC) patients who progress after anti-PD-(L)1 therapy. While targeted therapies like cabozantinib or lenvatinib plus everolimus are commonly utilized, most were established as standards before immune checkpoint inhibitors (ICIs) became the frontline therapy. Belzutifan is the first approved HIF-2α inhibitor for specific RCC indications, and lenvatinib is a potent VEGFR-TKI. Based on the strong mechanistic rationale for combining these two pathways, the LITESPARK-011 study investigated “belzutifan + lenvatinib” versus “cabozantinib” in the post-ICI setting.
02 Study Design:
A Head-to-Head Comparison with Contemporary TKI LITESPARK-011 is an open-label, Phase 3 trial. Key eligibility criteria included:
- Advanced or metastatic clear cell RCC (ccRCC);
- Received ≤2 prior lines of systemic therapy;
- Disease progression on or after an anti-PD-1/L1 inhibitor administered as 1st- or 2nd-line therapy;
- Prior VEGFR-TKI therapy was permitted.
A total of 747 patients were randomized 1:1 to receive:
- Combination Arm: Belzutifan (120 mg QD) + lenvatinib (20 mg QD);
- Control Arm: Cabozantinib (60 mg QD).
The dual primary endpoints were progression-free survival (PFS) by Blinded Independent Central Review (BICR) and overall survival (OS). Objective response rate (ORR) was a key secondary endpoint.
03 Primary Endpoint:
Significant PFS Extension with 30% Reduced Risk of Progression At the second interim analysis (IA2), with a median follow-up of 29 months, the results demonstrated:
- PFS Benefit: The median PFS was 14.8 months for the combination arm versus 10.7 months for cabozantinib. The hazard ratio (HR) was 0.70 (95% CI, 0.57–0.86; P=0.0003).
- Subgroup Analysis: Benefits were generally consistent across all pre-specified subgroups, favoring the combination arm.
- 24-Month PFS Rate: 35.6% for the combination group compared to 19.1% for cabozantinib.
04 Response Quality:
Higher ORR and Doubled Duration of Response The combination therapy showed a marked advantage in both the depth and durability of response:
- ORR: The ORR was 52.6% in the combination arm (including 20 complete responses [CRs]) versus 40.2% in the cabozantinib arm (with only 4 CRs).
- DOR (Duration of Response): The median DOR nearly doubled, reaching 23.0 months in the combination arm compared to 12.3 months in the control arm.
- Response Durability: The proportion of patients remaining in response at 24 months was 50% for the combination arm versus 25% for cabozantinib.
05 Overall Survival (OS) and Safety Profile
- OS Data: At IA2, the median OS was 34.9 months for the combination arm vs. 27.6 months for cabozantinib (HR 0.85; 95% CI, 0.67–1.07; P=0.0811). While a positive trend was observed, statistical significance was not reached at this analysis; the final OS analysis is pending.
- Safety: The incidence of Grade ≥3 adverse events (AEs) was similar between the two arms (81.7% vs. 80.9%). Discontinuation rates of all study drugs due to AEs were identical at 11%.
- Specific AEs: Common AEs in the combination arm included diarrhea, hypertension, and anemia. Notably, hypoxia—a known side effect of belzutifan—occurred in 15.4% of patients. Cabozantinib was more frequently associated with skin toxicity (palmar-plantar erythrodysesthesia syndrome).
- Quality of Life (PRO): Based on FKSI-DRS and EORTC QLQ-C30 scales, the time to deterioration (TTD) was similar between arms (HR=1.0).
Conclusion and Outlook Professor Robert J. Motzer concluded that LITESPARK-011 is the first Phase 3 study to demonstrate that a HIF-2α inhibitor plus a VEGFR-TKI is superior to a contemporary TKI in the post-ICI setting for RCC. The trial achieved its primary endpoint of PFS and showed significantly improved ORR with exceptional durability. These findings address a critical unmet clinical need and establish belzutifan plus lenvatinib as a potent new treatment option for patients progressing after immunotherapy.
