Targeting HER2 with H + CT significantly improves overall survival (OS) vs CT alone in patients (pts) with HER2-positive mGC/GEJC. In HER2-positive metastatic breast cancer, P + H + docetaxel significantly improves progression-free survival (PFS) and OS vs placebo (PLA) + H + docetaxel. We therefore assessed the efficacy and safety of adding P to H + CT in pts with HER2-positive mGC/GEJC.
JACOB (NCT01774786) is a double-blind, randomised, PLA-controlled, Phase III study in mGC/GEJC. Pts were randomised 1:1 to PLA + H + CT (standard cisplatin/fluoropyrimidine regimen) or P + H + CT. P and H were given every 3 weeks until disease progression or unacceptable toxicity (P at 840 mg, H: 8 mg/kg loading and 6 mg/kg maintenance doses). CT was given as per standard regimens/doses. Stratification factors were world region, prior gastrectomy and HER2 immunohistochemistry score. Primary endpoint was OS. Secondary endpoints included PFS and safety. JACOB was estimated to have 80% power to detect a significant improvement in OS (hazard ratio [HR] 0.777) at the final efficacy analysis after 502 events (overall two-sided α-level 5%).
From 10 Jun 2013 to 12 Jan 2016, 388 pts were randomised to P + H + CT and 392 to PLA + H + CT. After a median OS follow-up of approx. 2 years, 504 patients had died, 242 in the P + H + CT arm (median OS 17.5 months) and 262 in the PLA + H + CT arm (median OS 14.2 months) (HR 0.84, 95% confidence interval [CI] 0.71–1.00; p = 0.0565). Median PFS was 8.5 months and 7.0 months respectively (HR 0.73, 95% CI 0.62–0.86). The safety profile was generally comparable between treatment arms except for diarrhoea (all grades: 61.6% in P + H + CT vs 35.1% in PLA + H + CT). Incidence of symptomatic and asymptomatic left ventricular systolic dysfunction was low and similar in both arms.
The study failed to demonstrate a statistically significant improvement in OS with the addition of P to H + CT, although a 3.3-month increase in median OS was observed. P was generally well tolerated and no new safety signals were identified. Further analyses will be presented.
Clinical trial identification
Protocol number: BO25114; ClinicalTrials.gov NCT01774786
Legal entity responsible for the study
F. Hoffmann-La Roche Ltd
F. Hoffmann-La Roche Ltd.
J. Tabernero: Advisory board: Amgen, Bayer, Boehringer-Ingelheim, Celgene, Chugai, Genentech, Lilly, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Symphogen, Taiho, and Takeda. P.M. Hoff: Corporate-sponsored research: Roche. L. Shen: Advisory board: Hengrui, Merck, Roche, BMS. Corporate-sponsored research: Taiho, Hengrui, Merck, Roche AZ. A. Ohtsu: Corporate-sponsored research: BMS. M.A. Shah: Advisory board: Lilly, Inc. Corporate-sponsored research to institution: Roche, Boston Biomedical, Gilead. K. Cheng: Stock ownership: Genentech. Employee of Genentech. C. Song: Stock ownership: Roche. Corporate-sponsored research: Roche. Employee of Roche. H. Wu: Employee of Roche (China) Holding Ltd. J. Eng-Wong: Employee of Genentech. Y-K. Kang: Advisory board: Roche, Novartis, Ono, Daehwa, LSK Biopharma, Blueprint, Taiho, BMS.