Belzutifan Combo Exhibits Comparable HRQoL Vs Cabozantinib in RCC

Belzutifan (Welireg) plus lenvatinib (Lenvima) produced patient-reported outcomes (PROs) comparable with those of cabozantinib (Cabometyx) in patients with clear cell renal cell carcinoma (RCC) that progressed after anti–PD-(L)1 therapy, according to results from the phase 3 LITESPARK-011 trial (NCT04586231) presented at the 2026 Kidney Cancer Research Summit (KCRS) in Boston, Massachusetts.¹

The health-related quality-of-life (HRQoL) findings follow previously reported efficacy data from the trial presented at the 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), where belzutifan plus lenvatinib significantly improved progression-free survival (PFS) and objective response rate (ORR) compared with cabozantinib.²

At a median follow-up of 29.0 months (range, 19.3-49.2) from a data cutoff of April 9, 2025, the time to deterioration in disease-specific symptoms per the Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease-Related Symptoms (FKSI-DRS) was similar between arms (HR, 1.02; 95% CI, 0.82-1.28), with a median of 13.8 months (95% CI, 6.4-20.3) with belzutifan plus lenvatinib vs 10.6 months (95% CI, 7.4-20.2) with cabozantinib. Time to deterioration in HRQoL per the EORTC QLQ-C30 Global Health Status (GHS)/QoL scale was also comparable (HR, 1.07; 95% CI, 0.86-1.34), at a median of 7.9 months (95% CI, 5.5-13.1) vs 10.1 months (95% CI, 6.5-19.3), respectively. Time to deterioration in physical functioning (HR, 1.13; 95% CI, 0.91-1.40) and role functioning (HR, 1.10; 95% CI, 0.90-1.35) were similar between arms.

Least squares mean (LSM) score changes from baseline to week 45 were generally comparable between arms across QLQ-C30 functional and symptom domains, with 1 notable exception: cabozantinib was associated with a marked, clinically meaningful worsening in the QLQ-C30 diarrhea symptom scale relative to belzutifan plus lenvatinib.

PRO questionnaire completion rates at baseline were 87.4% with belzutifan/lenvatinib vs 87.7% with cabozantinib for the FKSI-DRS assessment, with EORTC QLQ-C30 completion rates of 86.9% vs 87.3%. Completion rates for the FKSI-DRS and EORTC QLQ-C30 assessments declined by week 45, with rates of 59.2% vs 59.3% and 58.6% vs 59.0% in each arm, respectively. Moreover, the compliance rates at baseline and by week 45 remained high, generally staying around 90% in each arm across both assessments.

These PRO findings follow previously reported efficacy results from LITESPARK-011 presented at ASCO GU. Among 747 patients enrolled, belzutifan plus lenvatinib improved median PFS to 14.8 months compared with 10.7 months with cabozantinib (HR, 0.70; 95% CI, 0.59-0.84; P = .00007). The ORR was 52.6% (95% CI, 47.3%-57.7%) with belzutifan plus lenvatinib vs 40.2% (95% CI, 35.2%-45.3%) with cabozantinib, including 20 complete responses vs 4 in each arm, respectively. The 24-month duration of response (DOR) rate was 49.5% with belzutifan plus lenvatinib vs 25.5% with cabozantinib, with a median DOR of 23.0 months vs 12.3 months. Overall survival (OS) numerically favored belzutifan plus lenvatinib, though this had not reached statistical significance as of the interim analysis.

“Patient-reported outcomes were generally comparable between treatment arms and showed no additional HRQoL burden with belzutifan plus lenvatinib,” Manuela Schmidinger, MD, professor of medicine and program director of Renal Cell Carcinoma Research at the Medical University of Vienna, and coinvestigators wrote in the poster.¹ “Together with the previously reported efficacy (superior PFS and ORR) and safety results, these findings further support belzutifan plus lenvatinib as a promising new treatment option for patients with advanced RCC following anti–PD-(L)1 therapy.”

LITESPARK-011 is a randomized, open-label phase 3 trial that enrolled patients with unresectable, locally advanced, or metastatic clear cell RCC; a Karnofsky performance status score of 70% or higher; who received no more than 2 prior systemic regimens; and experienced disease progression on or after anti–PD-(L)1 monoclonal antibody therapy as first- or second-line treatment, or within 6 months of the last dose of adjuvant anti–PD-(L)1 therapy. Prior VEGFR-tyrosine kinase inhibitor therapy was permitted.

Patients were randomly assigned 1:1 to belzutifan 120 mg orally once daily plus lenvatinib 20 mg orally once daily (n = 371) or cabozantinib 60 mg orally once daily (n = 376), stratified by International Metastatic RCC Database Consortium prognostic score, line of prior anti–PD-(L)1 treatment, and geographic region. The PRO analysis population comprised all patients who had been randomly assigned and who received at least 1 dose of study treatment and completed at least 1 PRO assessment (365 in the belzutifan plus lenvatinib arm and 366 in the cabozantinib arm for the FKSI-DRS analysis).

The dual primary end points of LITESPARK-011 are PFS per RECIST v1.1 by blinded independent central review and OS. The key secondary end point is ORR per RECIST v1.1 by blinded independent central review. PROs were assessed as an exploratory end point using the FKSI-DRS and EORTC QLQ-C30 instruments, with between-group differences in LSM score change evaluated descriptively via a constrained longitudinal data analysis model rather than formal statistical testing.

The investigators noted that declining PRO questionnaire completion rates over time raise the potential for informative missingness related to disease progression, treatment discontinuation, adverse effects, or death, which should be factored into the interpretation of long-term PRO findings.

The investigators noted that these results build on prior findings from the phase 3 LITESPARK-005 trial (NCT04195750), in which belzutifan monotherapy was associated with less worsening of disease-specific symptoms and better HRQoL compared with everolimus in patients with post–PD-(L)1 RCC.³

References

1. Schmidinger M, Heng DYC, McDermott R, et al. Belzutifan plus lenvatinib versus cabozantinib in post–PD-(L)1 renal cell carcinoma: health-related quality-of-life outcomes in the phase 3 LITESPARK-011 study. Presented at: Kidney Cancer Research Summit (KCRS); July 23-24, 2026; Boston, MA. Abstract 23.
2. 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):LBA417. doi:10.1200/JCO.2026.44.7_suppl.LBA417
3. Powles T, Choueiri TK, Albiges L, et al. Health-related quality of life with belzutifan versus everolimus for advanced renal cell carcinoma (LITESPARK-005): patient-reported outcomes from a randomised, open-label, phase 3 trial. Lancet Oncol. 2025;26(4):491-502. doi:10.1016/S1470-2045(25)00032-4