Pertuzumab (P) + trastuzumab (H) + chemotherapy (CT) for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (mGC/GEJC): Final analysis of a Phase III study (JACOB)

Abstract

Background: 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 toH + CT in pts with HER2‐positivemGC/GEJC. Methods: 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 andH 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 twosided a‐level 5%). Results: 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. Conclusions: The study failed to demonstrate a statistically significant improvement in OS with the addition of P toH + 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.