Update further supports belzutifan use for advanced renal cell carcinoma


New efficacy and quality-of-life (QoL) data for belzutifan (Welireg) from the pivotal LITESPARK-005 trial (NCT04195750) further support use of the HIF-2 alpha inhibitor for its FDA-approved indication in advanced renal cell carcinoma.1

Thomas Powles, MD, MBBS, MRCP

Thomas Powles, MD, MBBS, MRCP

Specifically, belzutifan extended the time to disease progression (TTD) and was associated with improvements in QoL scores, as measured by the Functional Assessment of Cancer Therapy-Kidney Symptom Index Disease-Related Symptoms (FKSI-DRS) and the EORTC QLG Core Questionnaire (EORTC QLQ-C30), at 17 weeks compared with everolimus.

A total of 366 of 374 patients randomized to receive belzutifan and 354 of 372 patients randomized to receive everolimus in the randomized, open-label, phase 3 study were included in the patient-reported outcomes (PRO) analysis population. Both the belzutifan and everolimus groups had high completion rates for FKSI-DRS and QLQ-C30 (>90% at baseline and >55% at week 17).

The median TTD with belzutifan was not reached in FKSI-DRS, 19.35 months in QLQ-C30 global health status/quality of life (GHS/QoL), and 19.32 months in QLQ-C30 physical functioning (PF) compared with 11.99, 10.19, and 13.83 months with everolimus. Across the questionnaires, the TTD hazard ratios (HR) were 0.53 (95% CI, 0.41-0.69), 0.75 (95% CI, 0.58-0.96), and 0.93 (95% CI, 0.72-1.20) and the 2-sided nominal P-values were <.0001, .019, and .55.

“These patient-reported outcomes indicate better disease-specific symptoms and quality-of-life associated with belzutifan compared to everolimus…These types of analyses might be more useful to patients than looking at these very specific graded adverse events,” said Thomas Powles, MD, MBBS, MRCP, professor of genitourinary oncology at Queen Mary University of London; director, Barts Cancer Center, in a presentation of the data at the 2024 Genitourinary Cancers Symposium.


Prior LITESPARK-005 data established belzutifan's efficacy in terms of progression-free survival (PFS; HR, 0.75; 95% CI, 0.63-0.90; P <.001) and overall response rate (ORR; estimated difference, 18.4; 95% CI 14.0-23.2; P <.00001) vs everolimus in advanced kidney cancer. LITESPARK-005 randomized 746 patients with advanced RCC who progressed after treatment with anti-PD-1/PD-L1 and VEGF-targeted therapies to receive either belzutifan 120 mg orally once daily or everolimus 10 mg orally once daily.2,3 Thecoprimary end points of the trial were PFS and overall survival (OS).4

Investigators also evaluated a number of secondary end points, including ORR, duration of response, the number of patients who experience 1 or more adverse events (AEs), the number of patients who discontinued study treatment as a result of AEs, TTD of health-related QoL (HRQOL), TTD in PF, TTD in disease symptoms, change from baseline in HRQOL per the EORTC Core Quality of Life questionnaire C30 (EORTC QLQ-C30) items 29 and 30 score, change from baseline in physical functioning based on the EORTC QLQ-C30 items 1-5 score, change from baseline in disease symptoms according to the functional Assessment of Cancer Therapy Kidney Cancer Symptom Index-Disease Related Symptoms items 1-9 score, and change from baseline in European Quality of Life 5 Dimensions per the 5-level Questionnaire Health Utility score.4

Enrollment was open to patients with unresectable, locally advanced, or metastatic disease who had received no more than 3 prior systemic agents for locally advanced or metastatic RCC and had adequate organ function.

Based on findings from LITESPARK-005, the FDA approved belzutifan for the treatment of adult patients with advanced RCC whose disease progressed following PD-1/PD-L1 and VEGF tyrosine kinase inhibitor treatment in December 2023.

“The randomized phase 3 trial was positive for progression-free survival and response. Indeed, belzutifan now has FDA approval in pretreated patients, which is super exciting to have a new class of drug in our armory,” explained Powles.

PROs Analysis

This analysis presented at the 2024 Genitourinary Symposium delved into the PROs within the same trial.1 PROs were assessed using FKSI-DRS and EORTC QLQ-C30 questionnaires in all randomized patients who received at least 1 dose of the study treatment and completed at least 1 PROs assessment. Questionnaires were administered electronically on day 1 of weeks 1, 3, 5, and 9, every 4 weeks thereafter, at treatment discontinuation, and 30 days after the last dose.

“The FKSI-DRS stands for disease-related symptoms, so the questions we were asking focus on these symptoms with advanced cancer. They are not necessarily focused on [adverse] effects of drugs, whereas the EORTC QLQ-C30, that focuses more broadly actually on health-related and global quality-of-life,” Powles said.

TTD and least square (LS) mean change from baseline as measured by FKSI-DRS and QLQ-C30 GHS/QoL and PF scales were prespecified as secondary end points of the analysis. Further, PROs were not formally statistically tested, and 95% CI and P-values were nominal and descriptive.

With a median follow-up of 25.7 months (range, 16.8-39.1) at the data cutoff date at the second prespecified interim analysis of June 13, 2023, the median duration of treatment was 7.6 months (range, 0.1–35.8) with belzutifan compared with 3.9 months (range, 0.0–33.2) with everolimus. A total of 84 (22.6%) and 18 (5.0%) patients remained on treatment across the 2 arms.

“The good news is, over 90% of patients filled out the baseline questionnaire, and then 60% at week 17. As time goes by, it is harder and harder to get patients to continue to complete these questionnaires,” explained Powles.

Although AEs in the 2 arms were similar, the pattern of AEs was different, including more patients reporting cough with everolimus vs belzutifan (20.6% vs 8.3%), rash (18.9% vs 4.6%), stomatitis (37.8% vs 3.5%), and hyperglycemia (15.0% vs 2.7%). More patients treated with belzutifan (n = 308; 82.8%) had any grade anemia compared with those given everolimus (n = 204; 56.7%).

The belzutifan LS mean change was -0.17 (95% CI, -0.70 to 0.36) in FKSI-DRS, 0.28 (95% CI, -1.98 to 2.53) in QLQ-C30 GHS/QoL, and -4.75 (95% CI, -6.87 to -2.63) in QLQ-C30 PF. With everolimus, the LS mean change was -1.62 (95% CI, -2.17 to -1.06) in FKSI-DRS, -6.11 (95% CI, -8.51 to -3.70) in QLQ-C30 GHS/QoL, and -7.22 (95% CI, -9.47 to -4.98) in QLQ-C30 PF. The difference in LS mean change was 1.45 (95% CI, 0.70-2.19), 6.38 (95% CI, 3.21-9.55), and 2.47 (95% CI, -0.59 to 5.54) across the questionnaires.

Overall, patients treated with belzutifan experienced less severe disease-specific symptoms and a higher QoL compared with those receiving everolimus, as measured by patient-reported outcome tools.

“Along with the improved progression-free survival and overall response rates, I think the findings I presented today further support the use of belzutifan in heavily pretreated patients with advanced clear cell renal cancer,” concluded Powles.


  1. Powles T, Albiges L, Jalkanen KJ, et al. Belzutifan versus everolimus in participants (pts) with previously treated advanced renal cell carcinoma (RCC): Patient-reported outcomes (PROs) in the phase 3 LITESPARK-005 study. J Clin Oncol. 2024;42(suppl 4):361. doi:10.1200/JCO.2024.42.4_suppl.361.
  2. Jonasch E, Donskov F, Iliopoulos O, et al. Belzutifan for renal cell carcinoma in von Hippel-Lindau disease. N Engl J Med. 2021;385(22):2036-2046. doi:10.1056/NEJMoa2103425
  3. Merck announces Welireg® (belzutifan) phase 3 LITESPARK-005 trial met primary endpoint of progression-free survival in certain previously treated patients with advanced renal cell carcinoma. News release. Merck. August 18, 2023. Accessed January 27, 2024. https://tinyurl.com/5duv497t
  4. A study of belzutifan (MK-6482) versus everolimus in participants with advanced renal cell carcinoma (MK-6482-005). ClinicalTrials.gov. Updated August 1, 2022. Accessed January 27, 2024. https://tinyurl.com/3ejtc595

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