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Early decision making in a randomized phase II trial of atezolizumab in biliary tract cancer using a tumor growth inhibition-survival modeling framework.

Colby S ShemeshPhyllis ChanMathilde MarchandAntonio GonçalvesShweta VadhavkarBenjamin WuChunze LiJin Y JinStephen P HackRené Bruno
Published in: Clinical pharmacology and therapeutics (2023)
We assess the longitudinal tumor growth inhibition (TGI) metrics and overall survival (OS) predictions applied to patients with advanced biliary tract cancer (BTC) enrolled in IMbrave151 a multicenter randomized phase II, double-blind, placebo-controlled trial evaluating the efficacy and safety of atezolizumab with or without bevacizumab in combination with cisplatin plus gemcitabine. Tumor growth rate (KG) was estimated for patients in IMbrave151. A pre-existing TGI-OS model for patients with hepatocellular carcinoma (HCC) in IMbrave150 was modified to include available IMbrave151 study covariates and KG estimates and used to simulate IMbrave151 study outcomes. At the interim progression free survival (PFS) analysis (98 patients, 27 weeks follow up), clear separation in tumor dynamic profiles with a faster shrinkage rate and slower KG (0.0103 vs 0.0117 week -1 ; tumor doubling time 67 vs 59 weeks; KG geometric mean ratio of 0.84) favoring the bevacizumab containing arm was observed. At the first interim analysis for PFS, the simulated OS HR 95% prediction interval (PI) of 0.74 (95% PI: 0.58-0.94) offered an early prediction of treatment benefit later confirmed at the final analysis, observed HR of 0.76 based on 159 treated patients and 34 weeks of follow up. This is the first prospective application of a TGI-OS modeling framework supporting gating of a Phase III trial. The findings demonstrate the utility for longitudinal TGI and KG GMR as relevant endpoints in oncology studies to support go/no-go decision-making and facilitate interpretation of the IMbrave151 results to support future development efforts for novel therapeutics for patients with advanced BTC.
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