Belzutifan-lenvatinib bests cabozantinib for RCC

A combination regimen comprising belzutifan and lenvatinib outdoes cabozantinib alone for the treatment of advanced clear cell renal cell carcinoma (ccRCC) in the phase III LITESPARK-011 study.

“Belzutifan plus lenvatinib demonstrated statistically superior progression-free survival (PFS) and objective response rate (ORR) vs cabozantinib in patients with advanced ccRCC following anti–PD-(L)1 therapy,” noted Dr Robert Motzer from the Memorial Sloan Kettering Cancer Center, New York, New York, US, who presented the findings at ASCO GU 2026.

The median PFS per RECIST 1.1 by blinded independent central review (BICR) was significantly longer with the combo regimen than with cabozantinib in the first interim analysis (IA1; 14.6 vs 10.6 months; hazard ratio [HR], 0.74; one-sided p=0.00095), which was sustained after 9 more months in the second interim analysis (IA2; 14.8 vs 10.7 months; HR, 0.70; one-sided p=0.00007).

The data cutoffs for IA1 and IA2 were June 26, 2024, and April 9, 2025, respectively. The median follow-up for IA2 was 29 months. [ASCO GU 2026, abstract LBA417]

The 24-month PFS rate was nearly twice as high with belzutifan plus lenvatinib as with cabozantinib (35.6 percent vs 19.1 percent).

Subgroup analyses generally favoured the combo over cabozantinib, with the most pronounced effects in participants with a favourable IMDC* prognostic risk category (HR, 0.47), in all other races (HR, 0.53), and those aged ≥65 years (HR, 0.59).

While there appears to be an overall survival (OS) trend favouring belzutifan plus lenvatinib over cabozantinib, this fell short of statistical significance in both IA1 (median not reached vs 27.4 months; HR, 0.90; p=0.19322) and IA2 (median 34.9 vs 27.6 months; HR, 0.85; one-sided p=0.06075). Motzer noted that the final OS analysis is pending.

Secondary, exploratory endpoints

The key secondary endpoint of ORR per RECIST 1.1 by BICR was higher with the experimental regimen than with cabozantinib in both IA1 (52.6 percent vs 39.6 percent; one-sided p=0.0002) and IA2 (52.6 percent vs 40.2 percent). These were primarily driven by the partial response rates (47.2 percent and 39.1 percent, respectively). Also, there were 20 complete responses in the combination arm compared with only four in the cabozantinib arm, Motzer noted.

“In addition to the higher response rates, the duration of response (DoR) at IA2 was essentially double with belzutifan plus lenvatinib compared with cabozantinib,” he continued. The 24-month rates were 49.5 percent vs 25.5 percent, respectively, and the median DoR was 23 vs 12.3 months.

“Some of the responses in the combination arm are ongoing for more than 3 years … These are some of the most striking aspects of the results of this trial – the durability of response,” Motzer emphasized.

The belzutifan plus lenvatinib and cabozantinib groups had similar rates of grade ≥3 treatment-emergent adverse events (TEAEs; 84.1 percent vs 82.7 percent), but the former was associated with a higher incidence of serious TEAEs than the latter (51.6 percent vs 43.9 percent).

Of the three treatment-related AEs that led to death, two were from the investigational group (thrombotic microangiopathy and pneumonitis), and one was from the cabozantinib group (haemoptysis).

“For the most part, the most common TEAEs … were attributable to the TKI, while some (eg, anaemia), were partially attributable to belzutifan,” Motzer noted. The most common TEAEs with the combo were diarrhoea, hypertension, and anaemia (52.7, 58.9, and 69.2 percent, respectively).

AEs of clinical interest in the combination arm were hypoxia (15.4 percent; 11.9 percent grade ≥3) and cardiac dysfunction (7 percent; 4.6 percent grade ≥3). Motzer noted that hypoxia is a well-recognized AE associated with belzutifan.

Time to worsening in disease-specific symptoms and quality of life were similar between the combo and cabozantinib arms, as reflected by the FKSI-DRS** (median 13.8 vs 10.6 months; HR, 1.02) and EORTC QLQ-C30 GHS/QOL*** (median 7.9 vs 10.1 months; HR, 1.07).

No SoC for advanced RCC

“No standard of care (SoC) exists for patients with advanced RCC after disease progression following anti–PD-(L)1 therapy,” Motzer said. Moreover, most of the frequently used targeted therapies^# were established before checkpoint inhibitors were SoC in the adjuvant and first-line advanced RCC settings, and none have been compared to a contemporary VEGFR-TKI in a randomized phase III trial, he added.

“There is a strong rationale for combining belzutifan, a first-in-class HIF-2α inhibitor, and lenvatinib, a potent VEGFR-TKI … Orthogonal inhibition of angiogenesis pathways with a HIF-2α inhibitor and a VEGFR-TKI may improve upon the efficacy of a VEGFR-TKI alone,” Motzer explained.

Hence, the team compared a regimen comprising belzutifan and lenvatinib with cabozantinib in individuals with unresectable, locally advanced, or metastatic ccRCC. The study included participants who had had ≤2 prior systemic therapies and progressed on or after an anti–PD-(L)1 inhibitor as first- or second-line therapy or within 6 months of the last dose of adjuvant treatment.

A total of 747 participants (median age 62.75 years, 75.65 percent women) were randomized 1:1 to oral belzutifan 120 mg plus lenvatinib 20 mg QD vs cabozantinib 60 mg QD. Approximately 59 percent of patients had an intermediate score in the IMDC prognostic risk categories, more than two-thirds had received one prior line of adjuvant-only therapy, and about half had been treated with one prior VEGFR-TKI.

Unmet need addressed

“[This] is the first phase III study of a HIF-2α inhibitor plus a VEGFR-TKI, and the first phase III study in RCC in the post–PD-(L)1 setting to show improved outcomes vs a contemporary VEGFR-TKI,” Motzer said.

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