Published LITESPARK-011 data show PFS benefit with belzutifan plus lenvatinib in ccRCC

Results from the phase 3 LITESPARK-011 trial (NCT04586231) have been published in The Lancet, demonstrating that the combination of belzutifan (Welireg) plus lenvatinib (Lenvima) significantly improved progression-free survival (PFS) vs cabozantinib (Cabomety) in patients with previously treated advanced clear cell renal cell carcinoma (ccRCC).¹

Although there was no significant benefit in overall survival (OS), the authors note that the regimen “might be a new standard of care for patients with advanced clear-cell renal cell carcinoma with disease progression after previous anti-PD-1 or anti-PD-L1 therapy.” The FDA is currently reviewing supplemental new drug applications for belzutifan plus lenvatinib, with a target action data of October 4, 2026.

About the LITESPARK-011 trial

The phase 3, open-label LITESPARK-011 trial enrolled a total of 747 patients between March 5, 2021, and September 1, 2023. Patients were eligible for enrollment if they were 18 years or older and had unresectable, locally advanced, or metastatic stage IV ccRCC. Participants also needed to have a Karnofsky Performance Status score of at least 70%, disease progression on or after anti-PD-(L)1 monoclonal antibody as first- or second-line therapy, or progression 6 months or sooner after the last dose adjuvant anti-PD-(L)1 therapy. Patients were still eligible for inclusion if they had received prior treatment with a VEGFR-TKI.

Participants in the study were randomly assigned 1:1 to receive either 120 mg belzutifan plus 20 mg lenvatinib orally once daily or 60 mg cabozantinib orally once daily. The dual primary end points were PFS per RECIST 1.1 by blinded independent central review (BICR) and OS. The key secondary end point was objective response rate (ORR) per RECIST 1.1 by BICR. Other secondary end points included duration of response (DOR) per RECIST 1.1 by BICR and safety.

Efficacy and safety data

At a median follow-up of 29 months (IQR, 23.7 to 34.9), the combination of belzutifan plus lenvatinib demonstrated a 30% reduction in the risk of disease progression or death compared with cabozantinib (HR, 0.70; 95% CI, 0.59 to 0.84; P < .0001). The median PFS was 14.8 months (95% CI, 11.2 to 16.6) with the combination vs 10.7 months (95% CI, 9.2 to 11.1) with cabozantinib.

Related: Robert Motzer, MD, unpacks LITESPARK-011 results of belzutifan plus lenvatinib in advanced RCC

The results also showed a trend toward improvement in OS with belzutifan plus lenvatinib compared with cabozantinib (HR, 0.85; 95% CI, 0.68 to 1.05; P = .061), although the difference did not achieve statistical significance. The median OS was 34.9 months (95% CI, 27.5 to not reached) in the combination arm vs 27.6 months (95% CI, 24 to 31.4) with cabozantinib. OS will continue to be evaluated per the trial protocol.

Data from the trial’s key secondary end points were also reported. Results showed significantly higher ORR with the combination, with a rate of 53% (95% CI, 47 to 58) in the belzutifan–lenvatinib arm vs 40% (95% CI, 35 to 45) in the cabozantinib arm. Among patients with a partial or complete response, the median DOR was 23 months (95% CI, 18.3 to 29.3) in the combination arm vs 12.3 months (95% CI, 9.7 to 16.6) in the cabozantinib arm.

Overall, the median duration of therapy was 16.8 months (IQR, 6.4 to 25.6) for patients receiving belzutifan–lenvatinib and 13.2 months (IQR, 5.7 to 23.3) for patients receiving cabozantinib.

Grade 3 or worse treatment-emergent adverse events (TEAEs) were reported in 84% of patients in the belzutifan plus lenvatinib arm and 83% of patients in the cabozantinib arm. The most common grade 3 or worse TEAE in both arms was hypertension, reported in 31% and 29% of patients, respectively.

Treatment-related AEs led to 2 deaths in the belzutifan–lenvatinib arm and 1 death in the cabozantinib arm.

Overall, the authors concluded, “Although overall survival was not significantly different between the groups, these results highlight that combining drugs with different mechanisms of action can improve outcomes in a difficult-to-treat population. Belzutifan plus lenvatinib addresses an unmet clinical need and might represent a potential new standard of care in this disease setting.”

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