Effect of Fluorouracil, Leucovorin, and Oxaliplatin With or Without Onartuzumab in HER2-Negative, MET-Positive Gastroesophageal Adenocarcinoma: The METGastric Randomized Clinical Trial

Abstract

Importance: Dysregulation of the mesenchymal-epithelial transition (MET) signaling pathway is associated with poor prognosis in gastroesophageal adenocarcinoma (GEC). We report results of METGastric, a phase 3 trial of the MET inhibitor onartuzumab plus standard first-line chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative, MET-positive, advanced GEC.

Objective: To determine whether the addition of onartuzumab to first-line fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) improves efficacy compared with mFOLFOX6 plus placebo in HER2-negative, MET-positive GEC.

Design, setting, and participants: Randomized, double-blind, multicenter trial conducted from November 2012 to March 2014. Patients were 18 years or older with an adenocarcinoma of the stomach or gastroesophageal junction with metastatic disease not amenable for curative therapy. Tumor samples were centrally tested for MET expression using Ventana anti-Total c-MET (SP44) rabbit monoclonal antibody, HER2 status, and Lauren histologic subtype. MET-positive tumors were defined as at least 50% of tumor cells showing weak, moderate, and/or strong staining intensity (MET 1+/2+/3+, respectively) by immunohistochemistry.

Interventions: Patients with HER2-negative, MET-positive GEC were enrolled and randomized 1:1 to receive mFOLFOX6 with or without onartuzumab (10 mg/kg).

Main outcomes and measures: Co-primary end points: overall survival in the intent-to-treat (ITT) population and in patients with MET 2+/3+ GEC. Secondary end points: progression-free survival (PFS), overall response rate (ORR), and safety.

Results: Enrollment was stopped early due to sponsor decision, which was agreed with an independent data monitoring committee. At the data cutoff (April 25, 2014) there were 562 patients in the ITT population (n = 283 placebo plus mFOLFOX6 [median age, 58 y; 65% male]; n = 279 onartuzumab plus mFOLFOX6 [median age, 60 y; 67% male]); 109 (38.5%) and 105 (37.6%) of the ITT population were MET 2+/3+, respectively. Addition of onartuzumab to mFOLFOX6 did not significantly improve OS, PFS, or ORR vs placebo plus mFOLFOX6 in the ITT (OS hazard ratio [HR], 0.82; 95% CI, 0.59-1.15; P = .24; PFS HR, 0.90; 95% CI, 0.71-1.16; P = .43; ORR, 46.1% vs 40.6%) or MET 2+/3+ populations (OS HR, 0.64; 95% CI, 0.40-1.03; P = .06; PFS HR, 0.79; 95% CI, 0.54-1.15; P = .22; ORR, 53.8% vs 44.6%). Safety was as expected for onartuzumab.

Conclusions and relevance: Addition of onartuzumab to first-line mFOLFOX6 did not significantly improve clinical benefits in the ITT or MET 2+/3+ populations.

Trial registration: clinicaltrials.gov Identifier: NCT01662869.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Shah has acted in a consulting or advisory role to Lilly Inc, and received research funding from Berg Pharma, Merck, Roche, and Sanofi. Dr Bang has received honoraria from, acted in a consulting or advisory role to, and received research funding from Roche/Genentech. Dr Lordick has received honoraria from Amgen, Bristol-Myers Squibb, Lilly, Merck Sharp & Dohme, Nordic Group, and Roche Pharma AG, acted in a consulting or advisory role to BioNTech AG, Ganymed Pharmaceuticals, and Roche, received research funding from Boehringer Ingelheim, Fresenius Biotech, GlaxoSmithKline, and Merck Serono, and travel, accommodation, or other expenses from Bayer, Roche, and Taiho Pharmaceutical. Dr Chen is an employee of Roche/Genentech. Dr Hack is an employee of, and holds stock in, Genentech. Dr Bruey is an employee of Genentech and holds stock in Roche Holding. Dr Smith is an employee of, and holds stock in, Genentech, and has received travel, accommodation, or other expenses from Genentech. Dr McCaffery was an employee of Genentech at the time this work was conducted, he holds stock in Roche, has patent or intellectual property interest in Amgen, Celera Genomics, and Genentech, and has received travel, accommodation, or other expenses from Corvus Pharma and Genentech. Dr Shames is an employee of Genentech, holds stock in Roche Holding, and has patent or intellectual property interest in UT Southwestern. Dr Phan is an employee of Genentech. Prof Cunningham has received research funding from Amgen, AstraZeneca, Bayer, Celgene, Medimmune, Merck Serono, Merrimack, and Sanofi. No other disclosures are reported.

Figures

Figure 1.. Consolidated Standards of Reporting Trials Diagram

Safety population indicates all randomized patients who received at least 1 dose of study treatment; intent-to-treat (ITT) population, all randomized patients. mFOLFOX6 indicates fluorouracil, leucovorin, and oxaliplatin.

Figure 2.. Kaplan-Meier Plots of Overall and Progression-Free Survival

Median overall survival was 11.3 months for placebo plus fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) vs 11.0 months for onartuzumab plus mFOLFOX6, and median progression-free survival was 6.8 vs 6.7 months, respectively. Dashed lines indicate median survival, and HR, hazard ratio.

Figure 3.. Subgroup Analysis of Overall Survival in the Intent-to-Treat Population

Size of the data marker corresponds to the number of patients in each subgroup. ECOG indicates Eastern Cooperative Oncology Group; IHC, immunohistochemistry; MET, mesenchymal-epithelial transition; NE, not estimable.