No Survival Benefit From Pertuzumab Plus Trastuzumab and Chemotherapy as First-Line Therapy for HER2-Positive Gastric/Gastroesophageal Junction Cancer

End-of-Study Analysis of the Phase 3 JACOB Trial

There was no improvement of overall survival demonstrated from the addition of pertuzumab to trastuzumab and chemotherapy for patients with HER2-positive metastatic gastric or gastroesophageal junction cancer, according to the final analysis of a phase 3 trial.

While adding pertuzumab to trastuzumab and chemotherapy “has been shown to significantly improve clinical outcomes in patients with HER2-positive early and metastatic breast cancer,” Josep Tabernero, MD, Vall d’Hebron Hospital Campus and Institute of Oncology, Barcelona, Spain, and colleagues noted, “there are several differences in tumor biology between [breast cancer] and [gastric cancer].”

The double-blind, international, parallel-arm, phase 3 JACOB trial enrolled 780 patients with previously untreated HER2-positive metastatic gastric or gastroesophageal cancer. Patients were randomized on a 1-to-1 basis to receive either 840 mg pertuzumab (n = 385) or placebo (n = 388) every 3 weeks, in combination with trastuzumab and cisplatin and fluoropyrimidine chemotherapy regimen. The primary end point of the trial was overall survival (OS), with progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and safety among the secondary end points.

Primary results that have been previously reported showed that there was no improvement of OS in the pertuzumab arm at ≥24.4 months median follow-up. The current, end-of-study report evaluates the long-term efficacy and safety of pertuzumab plus trastuzuamb and chemotherapy in this patient population.

At the clinical cutoff of January 24, 2020, the median follow-up duration was 46.1 months in the pertuzumab arm and 44.4 months in the placebo arm. In the pertuzumab arm, the median OS was increased by 3.9 months (hazard ratio [HR]: 0.85; 95% confidence interval [CI], 0.72 to 0.99), the median PFS was increased by 1.3 months (HR 0.73; 95% CI, 0.62 to 0.85) and the median DoR was 1.8 months longer, compared to the placebo arm. The ORR of the pertuzumab arm was numerically higher than that of the placebo arm (57.0% vs 48.6%). While there were no clear differences in hazard ratios observed in any of the biomarker subgroups, the study authors noted “there was a trend for more favorable HRs in certain subgroups related to HER2 amplification/overexpression.”

Grade ≥3 adverse events and any-grade diarrhea were more frequent in the pertuzumab group, but safety was otherwise comparable between the 2 groups.

While JACOB did not meet its primary end point, Dr Tabernero and colleagues wrote that “the study continues to demonstrate some, albeit limited, evidence of treatment activity and an acceptable safety profile for pertuzumab plus trastuzumab and chemotherapy in previously untreated HER2-positive metastatic gastric or gastroesophageal junction cancer after long-term follow-up.”

Source:

Tabernero J, Hoff PM, Shen L, et al. Pertuzumab, trastuzumab, and chemotherapy in HER2-positive gastric/gastroesophageal junction cancer: end-of-study analysis of the JACOB phase III randomized clinical trial. Gastric Cancer. Published online September 6, 2022. doi:10.1007/s10120-022-01335-4