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Delayed Progression-Free Survival Benefit of Belzutifan Versus Everolimus in LITESPARK-005: A Reconstructed
Motohiro Fujiwara1, Soichiro Yoshida2, Shugo Yajima3
1Department of Urology, Teikyo University Hospital, Mizonokuchi, Kanagawa, Japan.
Introduction:
In the LITESPARK-005 trial, early crossing of the progression-free survival (PFS) Kaplan-Meier curves suggest nonproportional hazards, potentially obscuring time-dependent treatment effects when summarized by a single hazard ratio. To characterize time-varying effects of belzutifan versus everolimus on PFS and overall survival (OS) in LITESPARK-005 using reconstructed individual patient data.
Methods:
Reconstructed individual patient data for PFS and OS were reconstructed from published Kaplan-Meier curves. Proportional hazards were assessed using log (-log) plots and Schoenfeld residuals. Interval-specific hazards were modeled with a Bayesian piecewise-exponential approach using a diffuse Gamma (0.001, 0.001) prior. Absolute effects were summarized by 12- and 18-month landmark survival and 24-month restricted mean survival time.
Results:
Reconstructed PFS curves showed early crossing and delayed separation, and diagnostic analyses, including log (-log) plots and Schoenfeld residuals, indicated nonproportional hazards. For PFS, belzutifan showed an early hazard disadvantage at 0 to 3 months (hazard ratio [HR] 1.45; 95% credible interval [CrI], 1.12-1.88), followed by benefit at 3 to 6 months (HR 0.56; 95% CrI, 0.40-0.79), 6 to 12 months (HR 0.35; 95% CrI, 0.23-0.52), and 12 to 24 months (HR 0.30; 95% CrI, 0.17-0.54). About 12- and 18-month PFS rates (95% CrIs) were 35.0% (30.1%-40.2%) versus 18.2% (13.8%-23.2%), and 26.1% (21.4%-31.2%) versus 6.9% (4.1%-10.6%), with absolute differences of 16.8% (9.8%-23.6%) and 19.1% (13.2%-25.0%), respectively. The 24-month PFS restricted mean survival time difference was 2.68 months (95% CrI, 1.48-3.88). For OS, interval-specific HRs modestly favored belzutifan beyond 6 months, but the 24-month restricted mean survival time difference was small (0.48 months; 95% CrI, -0.70 to 1.65).
Conclusion:
Belzutifan showed delayed PFS benefit after an early hazard disadvantage, whereas OS differences were modest and uncertain.
