title: Exposure-Response and Tumor Growth Inhibition Analyses of the Monovalent Anti-c-MET Antibody Onartuzumab (MetMAb) in the Second- and Third-Line Non-Small Cell Lung Cancer.
abstract: The phase III trial comparing onartuzumab + erlotinib vs. erlotinib in the second- and third-line non-small cell lung cancer (NSCLC) did not meet its primary endpoint of overall survival (OS). The objective was to assess whether doses higher than the phase III dose (15 mg/kg) might yield better efficacy without compromising the safety profile. Data were from 636 patients from the phase II and III NSCLC studies. Tumor growth inhibition (TGI) models were fit to longitudinal tumor size data to estimate individual TGI metrics including time to tumor re-growth (TTG). Cox regression models were developed for time-to-event endpoints (progression-free survival (PFS), OS, and TTG) to investigate relationships with baseline prognostic factors and onartuzumab exposure. Incidence of adverse events was modeled by logistic regression. In the final models, higher onartuzumab exposure was associated with longer PFS, but not with longer OS. Longer OS was associated with higher baseline albumin, longer TTG, smaller number of metastatic sites, female gender, lower ECOG score, and younger age. TTG was the only TGI metric retained in the final OS model. Onartuzumab exposure was not significantly associated with TTG after adjusting for prognostic factors. Higher Cmin was associated with increased incidence of infusion reactions and peripheral edema. Higher onartuzumab exposure was not significantly associated with improved OS after adjusting for prognostic factors and TTG, and there was a trend of unknown clinical significance toward increased incidence of infusion reactions and peripheral edema. These results did not support testing higher onartuzumab doses.
authors.affiliation: Clinical Pharmacology Modeling & Simulations, GlaxoSmithKline, 709 Swedeland Rd, King of Prussia, Pennsylvania, 19406, USA. kelong.x.han@gsk.com.
authors.forename: Kelong
authors.initials: K
authors.lastname: Han
authors.affiliation: Clinical Pharmacology, Genentech/Roche, Lyon, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Chanu
authors.affiliation: qPharmetra, Stockholm, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Jonsson
authors.affiliation: Clinical Pharmacology, Genentech Inc., South San Francisco, California, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Winter
authors.affiliation: Clinical Pharmacology, Genentech/Roche, 84 Chemin des Grives, 13013, Marseille, France. rene.bruno@roche.com.
authors.forename: René
authors.initials: R
authors.lastname: Bruno
authors.affiliation: Clinical Pharmacology, Genentech Inc., South San Francisco, California, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Jin
authors.affiliation: Clinical Pharmacology, Genentech Inc., South San Francisco, California, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Stroh
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D005260:Female; D006801:Humans; D016015:Logistic Models; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012737:Sex Factors; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000069347:Erlotinib Hydrochloride; C584058:onartuzumab
keywords: Cox regression; NSCLC; exposure–response; onartuzumab; survival model; time to tumor re-growth; tumor growth inhibition