Metastatic Gastric Cancer: Dual HER2-Targeting Study Does Not Meet Primary Endpoint

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Dual HER2 targeting in metastatic gastric and gastroesophageal junction cancers did not significantly improve outcomes over trastuzumab (Herceptin) alone—both in combination with chemotherapy—according to the results of the phase III JACOB study reported at the 2017 European Society for Medical Oncology (ESMO) Congress.1

Although a 3.3-month increase in survival was achieved, the study failed to meet the primary endpoint.
— Josep Tabernero, MD, PhD

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Targeting HER2 with trastuzumab plus chemotherapy significantly improved overall survival vs chemotherapy alone in patients with HER2-positive metastatic gastric or gastroesophageal junction cancer. In HER2-positive metastatic breast cancer, the addition of pertuzumab (Perjeta) to trastuzumab plus docetaxel, ie, the use of dual HER2 blockade, significantly improved overall survival (hazard ratio [HR] = 0.64; P = .005) in the CLEOPATRA trial,2 leading to the hypothesis that the same might be seen in HER2-positive metastatic gastric/gastroesophageal junction cancer.

In the JACOB trial, 780 patients were randomized to receive trastuzumab/chemotherapy (standard cisplatin/fluoropyrimidine regimen) with or without pertuzumab (840 mg). The HER2-targeted therapy was continued until disease progression. The primary endpoint was overall survival. JACOB was estimated to have 80% power to detect a significant improvement in overall survival (hazard ratio [HR] = 0.777) at the final efficacy analysis after 502 events.

3-Month Gain in Survival: Not Significant

After a median follow-up of approximately 2 years, median overall survival was 17.5 months in the experimental arm and 14.2 months in the standard treatment arm (HR = 0.84; P  = .0565). Although a 3.3-month increase in survival was achieved, the study narrowly failed to meet the primary endpoint, reported Josep Tabernero, MD, PhD, of the Institute of Oncology at Vall d’Hebron University Hospital in Barcelona, Spain. “Outcomes in the majority of subgroups were consistent with the overall analysis,” he added.

Pertuzumab Plus Trastuzumab in Gastric Cancer

  • Based on the efficacy in HER2-positive metastatic breast cancer, the phase III JACOB trial evaluated whether adding pertuzumab to trastuzumab plus chemotherapy would be more effective than trastuzumab/chemotherapy alone.
  • A 3.3-month improvement in overall survival was observed, but the outcome failed to achieve statistical significance.
  • Median overall survival was 17.5 months in the experimental arm and 14.2 months with standard treatment (HR = 0.84; P = .0565).

The safety profile was generally comparable between treatment arms except for diarrhea, which for all grades was 61.6% in the pertuzumab/trastuzumab plus chemotherapy arm vs 35.1% in control arm. The incidence of symptomatic and asymptomatic left ventricular systolic dysfunction was low and similar in both arms. ■

DISCLOSURE: Dr. Tabernero is an advisor to Amgen, Bayer, Boehringer--Ingelheim, Celgene, Chugai, Genentech, Lilly, MSD, Merck Serono, Novartis,
Pfizer, Roche, Sanofi, Symphogen, Taiho, and Takeda.


1. Tabernero J, Hoff PM, Shen L, et al: Pertuzumab + trastuzumab + chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer: Final analysis of a Phase III study (JACOB). 2017 ESMO Congress. Abstract 6160. Presented September 8, 2017.

2. Baselga J, Cortés J, Kim SB, et al: Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 366:109-119, 2012.

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