Welireg Delays Kidney Cancer Progression, Betters Quality of Life

Patients with advanced or metastatic clear cell renal cell carcinoma (RCC) treated with Welireg (belzutifan) tended to live longer before disease progression and had improved quality of life compared to those treated with Afinitor (everolimus), according to findings from the LITESPARK-005 trial that were presented at the 2024 Genitourinary Cancers Symposium.

A total of 366 participating patients were randomly assigned to receive Welireg, a first-in-class HIF-2 alpha inhibitor, and 354 patients were randomized to receive Afinitor in the randomized, open-label, phase 3 study and were included in the patient-reported outcomes (PRO) analysis population. Both the Welireg and Afinitor groups had high completion rates for the Functional Assessment of Cancer Therapy Kidney Cancer Symptom Index – Disease Related Symptoms (FKSI-DRS) and QLQ-C30 — both tools used to measure patient functioning and quality of life — at more than 90% at baseline and more than 55% at week 17.

The median time to disease progression (TTD) with Welireg 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 Afinitor.

“These patient-reported outcomes indicate better disease-specific symptoms and quality-of-life associated with (Welireg) compared to (Afinitor). … These types of analyses might be more useful to patients than looking at these very specific graded (side effects),” said Dr. Thomas Powles, professor of genitourinary oncology at Queen Mary University of London; director, Barts Cancer Center, in a presentation of the data.

Welireg's Background

Prior LITESPARK-005 data established Welireg's efficacy in terms of progression-free survival (PFS; time from treatment until disease worsening or death) and overall response rate (ORR; percentage of patients whose disease shrinks or disappears from treatment) compared to Afinitor 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 Welireg 120 mg orally once daily or Afinitor 10 mg orally once daily. Thecoprimary end points of the trial were PFS and overall survival (OS; time from treatment until death of any cause).

Investigators also evaluated secondary end points including ORR, duration of response, the number of patients who experienced side effects, the number of patients who discontinued study treatment as a result of side effects, 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.

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

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

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

Patient-Reported Outcomes

This analysis presented at the 2024 Genitourinary Symposium delved into the PROs within the same trial. PROs were assessed using FKSI-DRS and EORTC QLQ-C30 questionnaires in all randomized patients who received at least one dose of the study treatment and completed at least one PROs assessment. Questionnaires were administered electronically on day 1 of weeks 1, 3, 5 and 9, every four 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 side effects of drugs, whereas the EORTC QLQ-C30, that focuses more broadly actually on health-related and global quality-of-life,” Powles said.

With a median follow-up of 25.7 months at the data cutoff date at the second prespecified interim analysis of June 13, 2023, the median duration of treatment was 7.6 months with Welireg compared with 3.9 months with Afinitor. A total of 84 (22.6%) and 18 (5%) patients remained on treatment across the two 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 side effects in the two arms were similar, the pattern of side effects was different, including more patients reporting cough with Afinitor vs Welireg (20.6% versus 8.3%), rash (18.9% versus 4.6%), stomatitis (37.8% versus 3.5%) and hyperglycemia (15.0% versus 2.7%). More patients treated with Welireg (308 patients; 82.8%) had any grade anemia compared with those given Afinitor (204 patients; 56.7%).

Overall, patients treated with Welireg experienced less severe disease-specific symptoms and a higher QoL compared with those receiving Afinitor, 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 (Welireg) in heavily pretreated patients with advanced clear cell renal cancer,” concluded Powles.

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