Belzutifan Improves Disease-Specific Symptoms/QOL vs Everolimus in RCC

Least-squares mean change showed that from baseline to week 17, FKSI-DRS scores showed stability with belzutifan but worsened with everolimus.

Belzutifan (Welireg) improved disease-specific symptoms and quality-of-life (QOL) outcomes vs everolimus (Afinitor) in patients with advanced renal cell carcinoma (RCC), according to patient-reported outcome (PRO) results from the phase 3 LITESPARK-005 trial (NCT04195750)published in Lancet Oncology.1

Data from the trial revealed that among 720 patients in the PRO full analysis set, including 366 in the belzutifan group and 354 in the everolimus group, completion rates of both the Functional Assessment of Cancer Therapy-Kidney Cancer Symptom Index: Disease Related Symptoms (FKSI-DRS) and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) assessments were 96% and 94% in the respective groups. FKSI-DRS compliance rates were 90% in the belzutifan group and 91% in the everolimus group at week 17, with completion rates being 64% and 56%, respectively. EORTC QLQ-C30 compliance rates were 90% vs 91% in each respective group, with week 17 completion rates of 64% and 56%.

Least-squares mean change showed that from baseline to week 17, FKSI-DRS scores showed stability with belzutifan but worsened with everolimus (difference in least-squares mean, 1.5; 95% CI, 0.7-2.2). A similar trend was observed for EORTC QLQ-C30 (difference in least-squares mean, 6.4; 95% CI, 3.2-9.6). Additionally, least-squares mean change over the same period was similar between groups for physical functioning at 2.5 (95% CI, –0.6 to 5.5) and role functioning at 4.2 (95% CI, 0.1-8.4). Greater worsening with belzutifan vs everolimus was only observed for cognitive functioning.

“[Patients] with pretreated advanced [RCC] who received belzutifan reported better disease-specific symptoms and QOL than those who received everolimus,” lead investigator Thomas Powles, MBBS, MRCP, MD, professor of Genitourinary Oncology, lead for Solid Tumor Research, and director of the Barts Cancer Center at St. Bartholomew’s Hospital, wrote in the publication with study coinvestigators.1 “The PRO results are exploratory, and further research is required to support these findings. Taken together with efficacy and safety data from LITESPARK-005, belzutifan could offer a clinical benefit without compromising patient health-related QOL [HRQOL] in this setting.”

Patients with unresectable, locally advanced or metastatic clear cell RCC with disease progression following 1 to 3 lines of systemic therapy in the phase 3 LITESPARK-005 trial were randomly assigned 1:1 to receive either 120 mg of oral daily belzutifan or 10 mg of oral daily everolimus. Treatment was given until unacceptable toxicity, investigator-initiated treatment discontinuation, or patient withdrawal.

The primary end points included progression-free survival and overall survival. Secondary outcomes reported in the PRO analysis included changes in baseline in FKSI-DRS and EORTC QLQ-C30, as well as time to deterioration in physical functioning per EORTC QLQ-C30.

According to final analysis data from the LITESPARK-005 trial presented at the 2024 European Society for Medical Oncology Congress (ESMO),patient characteristics were well matched at baseline between the belzutifan and everolimus groups.2 The median age in the belzutifan group was 62 years (range, 22-90), and most patients were male (79.4%). Regarding International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk, 21.7% were considered favorable risk, 66.3% were considered intermediate risk, and 12.0% were consider poor risk. A total of 12.0% of patients received 1 prior line of therapy, 42.2% received 2, and 45.2% had received 3.

Median time to EORTC QLQ-C30 physical functioning deterioration was 19.3 months (95% CI, 11.1-not reached [NR]) in the belzutifan arm vs 13.8 months (95% CI, 10.6-NR) in the everolimus arm (HR, 0.93; 95% CI, 0.72-1.20). Additionally, the median time to deterioration for EORTC QLQ-C30 role functioning was 12.0 months (95% CI, 9.2-NR) vs 10.2 months (95% CI, 4.7-14.4) in the respective groups (HR, 0.88; 95% CI, 0.69-1.11).

Belzutifan received EU approval for adult patients with advanced clear cell RCC that progressed following 2 or more lines of therapy including PD-1 or PD-L1 inhibition and at least 2 VEGF-targeted therapies in February 2025 based on data from the LITESPARK-005 trial.3

References

1. Powles T, Choeriri 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;26:491-502. doi:10.1016/S1470-2045(25)00032-4
2. Rini B, Suarez C, Albiges L, et al. Final analysis of the phase 3 LITESPARK-005 study of belzutifan versus everolimus in participants with previously treated clear cell renal cell carcinoma. Ann Oncol. 2024;35(suppl 2):S1262-S1263. doi:10.1016/j.annonc.2024.08.2317