A new quality-adjusted time without symptoms or toxicity (Q-TWiST) analysis from the phase 3 LITESPARK-005 trial has demonstrated that belzutifan (Welireg) provides clinically meaningful and statistically significant improvements in quality-adjusted survival time compared to everolimus (Afinitor) in patients with advanced renal cell carcinoma (RCC). The findings were presented at the 2025 Kidney Cancer Research Summit.
Primary Q-TWiST Analysis Results
The main analysis revealed that patients receiving belzutifan (n = 374) achieved a mean Q-TWiST of 17.47 months compared to 14.81 months for those receiving everolimus (n = 372), representing a difference of 2.66 months (95% CI, 1.06-4.49). This translated to a relative gain in Q-TWiST of 11.32% (range, 4.49%-19.09%) with belzutifan treatment.
A sensitivity analysis that included grade 1 to 4 serious adverse events showed consistent results, with belzutifan achieving a mean Q-TWiST of 17.50 months versus 15.03 months for everolimus (difference, 2.47; 95% CI, 0.81-4.28), corresponding to a relative Q-TWiST gain of 10.50% (range, 3.44%-18.18%).
Time in Health States Analysis
The analysis divided patient survival time into three mutually exclusive states: time with grade 3/4 adverse effects before disease progression (TOX), time without symptoms and progression of grade 3/4 toxicity (TWiST), and time from progression until death (REL). While the mean TOX time was numerically longer with belzutifan at 1.45 months versus 1.22 months with everolimus (difference, 0.23; 95% CI, −0.29 to 0.76), this was offset by significantly longer time in TWiST.
Belzutifan patients experienced a mean TWiST of 10.73 months compared to 6.07 months with everolimus, driven by prolonged periods without progression (difference, 4.66 months; 95% CI, 3.28-6.02).
Clinical Significance and Expert Perspective
"In conclusion, belzutifan outperformed everolimus from a response and a progression-free-survival [PFS] perspective. The toxicity profile was distinct, the quality of life was better, and so was the TWiST and the Q-TWiST analysis," stated lead study investigator Thomas Powles, MBBS, MCRP, MD, professor of genitourinary oncology, lead for Solid Tumor Research, and director of Barts Cancer Institute at St. Bartholomew's Hospital, Queen Mary University of London.
Powles emphasized the clinical utility of this analysis, noting, "This [Q-TWiST analysis] does help patients and doctors make decisions. I quite like this type of exploratory analysis, and I'm happy to be involved in future projects with it."
Trial Design and Patient Population
The multicenter, open-label phase 3 LITESPARK-005 trial (NCT04195750) randomly assigned patients 1:1 to receive either belzutifan at 120 mg or everolimus at 10 mg orally once daily until progressive disease or unacceptable toxicity. The trial's dual primary endpoints were progression-free survival based on blinded independent central review per RECIST v1.1 criteria and overall survival.
Eligible patients were 18 years and older with stage IV clear cell RCC, a Karnofsky performance status of 70 or higher, at least one measurable lesion per RECIST v1.1 guidelines, and disease progression after prior treatment with a PD-(L)1 inhibitor and a VEGFR tyrosine kinase inhibitor. Patients were required to have received three or fewer prior lines of systemic therapy.
Safety Profile Comparison
Prior safety data from the trial showed distinct toxicity profiles between the two treatments. The most common any-grade adverse events in the belzutifan and everolimus arms, respectively, included anemia (83.1% vs 57.2%), fatigue (32.3% vs 25.8%), nausea (18.5% vs 12.2%), edema peripheral (17.2% vs 18.1%), and constipation (16.9% vs 8.3%).
Methodology
Investigators calculated Q-TWiST as the sum-product of restricted mean time spent in individual health states and state-specific utility weights. Standard utility weights used in literature—1 for TWiST and 0.5 for TOX and REL—were applied, and threshold utility analysis was performed to determine the impact of differing health state utility. The study employed nonparametric bootstrapping methods to generate 95% confidence intervals for treatment differences related to health states and Q-TWiST.
