Belzutifan Regimen Boosts Responses, PFS in Clear Cell RCC

Combining belzutifan (Welireg) with lenvatinib (Lenvima) in the phase 3 LITESPARK-011 trial (NCT04586231) improved the objective response rate (ORR) and progression-free survival (PFS) compared with cabozantinib (Cabometyx) among those with advanced clear cell renal cell carcinoma (RCC) after prior immune checkpoint inhibitor therapy, according to a presentation at the 2026 ASCO Genitourinary Cancers Symposium.¹

The first interim analysis (cutoff date June 26, 2024) and second interim analysis (cutoff date April 9, 2025) were presented, but Robert J. Motzer, MD, focused his presentation on the second interim analysis.

The median PFS was 14.8 months in the belzutifan/lenvatinib arm vs 10.7 months in the cabozantinib arm (HR, 0.70; 95% CI, 0.59-0.84; P = .00007).

“For both of these analyses, there was statistically superior benefit in [PFS] for belzutifan plus lenvatinib compared with cabozantinib,” Motzer, the Jack and Dorothy Byrne Chair in Clinical Oncology, and section head, kidney cancer, at Memorial Sloan Kettering Cancer Center, said. “ORR was only studied at the first interim analysis and showed a statically higher rate of ORR for the combination as well.”

At 24 months, patients in the treatment arm had an OS of 62.8% vs 55.4% in the control arm. The median OS in the belzutifan/lenvatinib arm was 34.9 months (95% CI, 27.5-not reached) vs 27.6 months (95% CI, 24.0-31.4) with a hazard ration of 0.85 (95% CI, 0.68-1.05; P =.06075), which was not statistically significant. “This will be studied in the final OS analysis,” Motzer said.

ORR was 52.6% (95% CI, 47.3-57.7) for belzutifan/lenvatinib compared with 40.2% (95% CI, 35.2-45.3) for cabozantinib. “Note that there were 20 complete responses in the belzutifan/lenvatinib arm compared with only 4 in the cabozantinib arm,” Motzer said.

Duration of response (DOR) also favored the treatment arm. At 24 months, DOR was 49.5% in the belzutifan/lenvatinib arm vs 25.5% in the cabozantinib arm. Median DOR was 23.0 months for belzutifan/lenvatinib vs 12.3 months for cabozantinib. “To me, these are some of the most striking aspects of the results of this trial,” Motzer said.

Study Design

LITESPARK-011 evaluated patients with locally advanced or metastatic ccRCC who had progressed in immune checkpoint inhibitor as first- or second-line therapy. A total of 747 patients were randomly assigned to 120 mg of belzutifan and 20 mg of lenvatinib (n = 371) or 60 mg of cabozantinib (n = 376). Dual primary end points were PFS and OS and the secondary end points were ORR and DOR.

Investigators sought to determine the potential of combining a first-in-class HIF inhibitor with a VEGF-TKI. Because belzutifan is already approved² for advanced disease following both immunotherapy and VEGF-TKI treatment, the trial provides critical data on moving this combination into earlier lines of therapy for patients whose disease has progressed on checkpoint inhibition.

Patients were on belzutifan/lenvatinib longer than cabozantinib with the median duration of therapy of 16.8 months vs 13.2 months, respectively. Nearly everyone in both arms experienced adverse events (AEs), and the number of patients who experienced a grade 3 or higher AE was nearly identical. There were 2 deaths reported in the belzutifan/lenvatinib arm and 1 death in the cabozantinib arm.

Baseline characteristics were balanced between the arms and were typical of a patient population with RCC.

Safety and Toxicity

The most common treatment-emergent AEs (TEAEs) reflect those associated with the individual agents. The most common TEAEs in the combination arm were anemia (69.2%), diarrhea (52.7%), and hypertension (58.8%). In the control arm, the most common TEAEs were diarrhea (70.1%), hypertension (56.6%), and skin toxicity (51.2%).

Time to worsening in disease-specific symptoms and quality of life were similar between belzutifan/lenvatinib vs cabozantinib.

“Belzutifan plus lenvatinib addresses an unmet clinical need and represents a potential new treatment option for patients with RCC that has progressed after anti–PD-(L)1 therapy,” Motzer concluded.

DISCLOSURES: Motzer has served in a consulting or advisory role to Merck. He has received research funding from Aveo (Inst); Bristol-Myers Squibb (Inst); Eisai (Inst); Exelixis (Inst); Merck (Inst); and Pfizer (Inst).

Referneces

1. Motzer RJ, Park SH, McDermott RS, et al. 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. J Clin Oncol. 2026;44(suppl 7):417. Doi:10.1200/JCO.2026.44.7_suppl417
2. FDA approves belzutifan for advanced renal cell carcinoma. News release. US FDA. December 14, 2023. Accessed February 28, 2026. https://tinyurl.com/mtxm3fju