Belzutifan plus lenvatinib maintains PFS benefit vs cabozantinib in advanced ccRCC

In the final prespecified analysis of the phase 3 LITESPARK-011 trial (NCT04586231), belzutifan (Welireg) plus lenvatinib (Lenvima) continued to demonstrate progression-free survival (PFS) and objective response rate (ORR) benefits compared with cabozantinib (Cabometyx) in patients with advanced clear cell renal cell carcinoma (ccRCC) whose disease progressed after anti–PD-(L)1 therapy. Overall survival (OS), the trial’s other dual primary end point, numerically favored the combination but did not reach statistical significance.¹

The data were presented by Daniel Y.C. Heng, MD, MPH, FRCPC, of the Arthur J.E. Child Comprehensive Cancer Centre in Calgary, Alberta, Canada, at the 2026 European Society for Medical Oncology (ESMO) Congress in Madrid, Spain, and published concurrently in Annals of Oncology.^1,2 The results follow the FDA’s September 2026 approval of the combination in this setting.

About the LITESPARK-011 trial

LITESPARK-011 is an open-label, randomized, phase 3 trial that enrolled 747 patients March 5, 2021, and September 1, 2023. Eligible patients had unresectable, locally advanced, or metastatic ccRCC; a Karnofsky Performance Status score of at least 70%; no more than 2 prior systemic regimens; and disease progression on or after an anti–PD-(L)1 antibody given as first- or second-line therapy, or within 6 months of the last dose of adjuvant anti–PD-(L)1 therapy. Prior VEGF receptor tyrosine kinase inhibitor (VEGFR-TKI) therapy was permitted.

Patients were randomly assigned 1:1 to belzutifan 120 mg plus lenvatinib 20 mg orally once daily (n = 371) or cabozantinib 60 mg orally once daily (n = 376). Randomization was stratified by International Metastatic RCC Database Consortium (IMDC) risk score, line of prior anti–PD-(L)1 therapy, and geographic region. The dual primary end points were PFS per RECIST 1.1 by blinded independent central review (BICR) and OS; ORR by BICR was the key secondary end point.

PFS and ORR met statistical significance at earlier interim analyses. Because the trial met 1 of its dual primary end points, it was considered positive. The final analysis, with a February 2, 2026, data cutoff, was designed to evaluate OS after approximately 383 events.

Efficacy

At a median time from randomization to data cutoff of 38.8 months (range, 29.1 to 59.0), median PFS was 14.8 months (95% CI, 11.2 to 16.6) with belzutifan plus lenvatinib vs 10.8 months (95% CI, 9.2 to 11.1) with cabozantinib (HR, 0.74; 95% CI, 0.62 to 0.88; nominal 1-sided P = .00035). Estimated 24-month PFS rates were 35.2% vs 20.0%, and 36-month rates were 20.5% vs 12.6%, respectively.

Median OS was 33.7 months (95% CI, 29.0 to 46.9) with the combination vs 28.6 months (95% CI, 24.1 to 31.4) with cabozantinib (HR, 0.85; 95% CI, 0.70 to 1.03). The 1-sided P value of .04689 did not cross the prespecified boundary of .0223. Estimated 36-month OS rates were 48.9% vs 40.6%, respectively.

ORR was 53.1% (95% CI, 47.9 to 58.3) vs 40.2% (95% CI, 35.2 to 45.3), representing an estimated difference of 12.9% (95% CI, 5.8 to 19.8). Complete responses occurred in 6.7% vs 1.3% of patients. The median duration of response was 22.0 months with the combination (range, 2.0 to 52.2+) vs 11.9 months with cabozantinib (range, 1.8+ to 44.1+).

In an exploratory analysis of PFS2, defined as time from randomization to progression on next-line therapy or death from any cause, median PFS2 was 28.7 months vs 23.4 months (HR, 0.80; 95% CI, 0.67 to 0.96).

Exploratory analyses by prior first-line regimen showed PFS and ORR advantages for the combination both in patients who had received dual immune checkpoint inhibitor (IO) therapy (n = 261; median PFS, 20.1 vs 10.0 months; HR, 0.56; 95% CI, 0.41 to 0.75) and in those who had received an IO–TKI combination (n = 214; median PFS, 10.9 vs 7.5 months; HR, 0.66; 95% CI, 0.49 to 0.90). The corresponding OS HRs were 0.77 (95% CI, 0.55 to 1.06) and 0.82 (95% CI, 0.58 to 1.15).

Safety

Median duration of therapy was 16.8 months with the combination vs 13.2 months with cabozantinib. Grade 3 or higher adverse events (AEs) occurred in 85.4% and 83.0% of patients, and serious AEs in 55.1% and 46.9%. Treatment-related grade 3 or higher AEs occurred in 73.2% and 66.6%, and treatment-related serious AEs in 28.1% and 17.8%. Treatment-related AEs led to death in 2 patients (0.5%) in the combination arm and 1 patient (0.3%) in the cabozantinib arm.

In the combination arm, AEs led to discontinuation of both drugs in 11.6% of patients, of lenvatinib in 24.1%, and of belzutifan in 17.3%. In the cabozantinib arm, 12.7% of patients discontinued cabozantinib because of AEs.

Anemia (70.8% vs 27.0%) and hypoxia (15.7% vs 0%) were more frequent with the combination, whereas diarrhea (54.3% vs 71.2%), palmar-plantar erythrodysesthesia (20.5% vs 51.8%), and stomatitis (14.3% vs 28.3%) were more frequent with cabozantinib. Hypertension was common in both arms (59.5% vs 57.1%).

Cardiac dysfunction, an AE of clinical interest, occurred in 13.0% vs 8.1% of patients.

“This may be higher because of a mandated increase in ejection fraction echocardiogram frequency halfway through the protocol, and so we detected more,” Heng explained during his presentation. “Most of these are related to asymptomatic decreases in ejection fraction.”

Overall, Heng concluded, “These results continue to support the use of belzutifan and lenvatinib in patients with advanced clear cell renal cell carcinoma.”

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REFERENCES

1. Heng DYC, McDermott RS, Park SH, et al. Final analysis of the phase 3 LITESPARK-011 study: Belzutifan (bel) plus lenvatinib (len) versus cabozantinib (cabo) for advanced renal cell carcinoma (RCC) after anti–PD-(L)1 therapy. Presented at: European Society for Medical Oncology Congress 2026; October 23-27, 2026, Madrid, Spain. Abstract 35870. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2026_abstracts/3587O.html.pdf

2. Heng DYC, Schmidinger M, McDermott R, et al. Final prespecified analysis of the phase 3 LITESPARK-011 study: belzutifan plus lenvatinib versus cabozantinib for advanced renal cell carcinoma after anti–PD-(L)1 therapy. Ann Oncol. 2026 Oct 25:S0923-7534(26)06893-6. doi:10.1016/j.annonc.2026.10.109