Japanese journal of clinical oncology · 2026
A Bayesian reanalysis of the THOR trial cohort 1 using reconstructed individual patient data: interval-specific effects and clinically interpretable estimands under non-proportional hazards.
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Okumura Gaku, Yoshida Soichiro, Hirose Kohei, Yajima Shugo, Chen Wei, Sato Hiroyuki, Hirakawa Akihiro, Fujiwara Motohiro, Arita Yuki, Fukushima Hiroshi, Yasuda Yosuke, Tanaka Hajime, Masuda Hitoshi, Fujii Yasuhisa
Аннотация
BACKGROUND: The phase 3 THOR trial (cohort 1) showed improved overall survival (OS) and progression-free survival (PFS) with erdafitinib versus chemotherapy in FGFR2/3-altered advanced urothelial carcinoma after prior programmed cell death protein 1 (PD-1) / programmed death-ligand 1 (PD-L1) inhibitor therapy. When the assumption of proportional hazards (PH) is violated, a single hazard ratio (HR) may be difficult to interpret.
METHODS: We derived reconstructed individual patient data (rIPD) for OS and PFS from published Kaplan-Meier curves. PH was assessed using scaled Schoenfeld residuals and log-log plots. We fit Bayesian piecewise-exponential models with administrative censoring at τ = 24 months (OS; cut-point 12 months) and τ = 12 months (PFS; cut-point 6 months). We reported interval-specific HRs, landmark survival differences (ΔOS, ΔPFS), number needed to treat (NNT), restricted-mean survival time (RMST), and posterior probabilities for clinically meaningful thresholds.
RESULTS: Statistical diagnostics indicated that the PH assumption was violated for both OS and PFS. For OS, HR was 0.59 (95% credible interval 0.41-0.84) in months 0-12 and 1.06 (0.48-2.48) in months 12-24. At 12 months, ΔOS(12) = 0.18 (0.06-0.30); conditional median NNT was 5.45. ΔRMST (0-24) = 3.02 months (0.74-5.23), with P(ΔRMST >0) = 99.5%. For PFS, the HR was 0.64 (0.45-0.89) in months 0-6 and 0.49 (0.25-1.00) in months 6-12; ΔPFS (6) = 0.16 (0.04-0.28) and ΔRMST (0-12) = 1.74 months (0.69-2.76).
CONCLUSION: This Bayesian rIPD-based reanalysis provides PH-robust estimands, indicating early OS benefit with uncertain later effects, and favorable PFS over 0-12 months with erdafitinib.
METHODS: We derived reconstructed individual patient data (rIPD) for OS and PFS from published Kaplan-Meier curves. PH was assessed using scaled Schoenfeld residuals and log-log plots. We fit Bayesian piecewise-exponential models with administrative censoring at τ = 24 months (OS; cut-point 12 months) and τ = 12 months (PFS; cut-point 6 months). We reported interval-specific HRs, landmark survival differences (ΔOS, ΔPFS), number needed to treat (NNT), restricted-mean survival time (RMST), and posterior probabilities for clinically meaningful thresholds.
RESULTS: Statistical diagnostics indicated that the PH assumption was violated for both OS and PFS. For OS, HR was 0.59 (95% credible interval 0.41-0.84) in months 0-12 and 1.06 (0.48-2.48) in months 12-24. At 12 months, ΔOS(12) = 0.18 (0.06-0.30); conditional median NNT was 5.45. ΔRMST (0-24) = 3.02 months (0.74-5.23), with P(ΔRMST >0) = 99.5%. For PFS, the HR was 0.64 (0.45-0.89) in months 0-6 and 0.49 (0.25-1.00) in months 6-12; ΔPFS (6) = 0.16 (0.04-0.28) and ΔRMST (0-12) = 1.74 months (0.69-2.76).
CONCLUSION: This Bayesian rIPD-based reanalysis provides PH-robust estimands, indicating early OS benefit with uncertain later effects, and favorable PFS over 0-12 months with erdafitinib.