title: Simulations to Predict Clinical Trial Outcome of Bevacizumab Plus Chemotherapy vs. Chemotherapy Alone in Patients With First-Line Gastric Cancer and Elevated Plasma VEGF-A.
abstract: To simulate clinical trials to assess overall survival (OS) benefit of bevacizumab in combination with chemotherapy in selected patients with gastric cancer (GC), a modeling framework linking OS with tumor growth inhibition (TGI) metrics and baseline patient characteristics was developed. Various TGI metrics were estimated using TGI models and data from two phase III studies comparing bevacizumab plus chemotherapy vs. chemotherapy as first-line therapy in 976 GC patients. Time-to-tumor-growth (TTG) was the best TGI metric to predict OS. TTG, Eastern Cooperative Oncology Group (ECOG) score, albumin level, and Asian ethnicity were significant covariates in the final OS model. The model correctly predicted a decreased hazard ratio favorable to bevacizumab in patients with high baseline plasma VEGF-A above the median of 113.4 ng/L. Based on trial simulations, in trials enrolling patients with elevated baseline plasma VEGF-A (500 patients per arm), the expected hazard ratio was 0.82 (95% prediction interval: 0.70-0.95), independent of ethnicity.
authors.affiliation: Genentech Inc, Clinical Pharmacology, South San Francisco, California, USA.
authors.forename: Kelong
authors.initials: K
authors.lastname: Han
authors.affiliation: Pharsight Consulting Services, Pharsight, a Certara Company, Marseille, France.
authors.forename: L
authors.initials: L
authors.lastname: Claret
authors.affiliation: Roche Product Development in Asia Pacific, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Piao
authors.affiliation: Genentech Inc, Biomarker, South San Francisco, California, USA.
authors.forename: P
authors.initials: P
authors.lastname: Hegde
authors.affiliation: Genentech Inc, Clinical Pharmacology, South San Francisco, California, USA.
authors.forename: A
authors.initials: A
authors.lastname: Joshi
authors.affiliation: Pharmaceutical Research and Early Development (pRED), Roche, Beijing, China.
authors.forename: J R
authors.initials: JR
authors.lastname: Powell
authors.affiliation: Genentech Inc, Clinical Pharmacology, South San Francisco, California, USA.
authors.forename: J
authors.initials: J
authors.lastname: Jin
authors.affiliation: Pharsight Consulting Services, Pharsight, a Certara Company, Marseille, France.
authors.forename: R
authors.initials: R
authors.lastname: Bruno
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000097:blood*; D001208:Asia / Q000453:epidemiology; D000068258:Bevacizumab / Q000008:administration & dosage / Q000097:blood*; D017326:Clinical Trials, Phase III as Topic / Q000379:methods / Q000706:statistics & numerical data*; D003198:Computer Simulation / Q000706:statistics & numerical data; D004311:Double-Blind Method; D006801:Humans; D007843:Latin America / Q000453:epidemiology; D009656:North America / Q000453:epidemiology; D011237:Predictive Value of Tests; D016032:Randomized Controlled Trials as Topic / Q000379:methods / Q000706:statistics & numerical data; D013274:Stomach Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000401:mortality; D015996:Survival Rate / Q000639:trends; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000097:blood*
chemical_list: C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab