Dual HER2 blockade did not significantly improve overall survival, compared with standard treatment of metastatic HER2-positive gastric cancer, according to final readouts from the international, double-blind JACOB trial.
After a median of 24.4 months of follow-up, median overall survival times were 17.5 months among patients who received pertuzumab in addition to standard trastuzumab therapy plus chemotherapy versus 14.2 months in the control arm (hazard ratio, 0.84; 95% confidence interval, 0.71-1.00; P = .057). The pertuzumab arm also had a higher incidence of moderate to severe diarrhea and more interruptions and dose modifications of chemotherapy, perhaps because of overlapping toxicities, wrote Josep Tabernero, MD. of Vall d’Hebron University Hospital and Centro de Investigación Biomedica en Red Cancer, Barcelona, and his colleagues. The report is in Lancet Oncology.
Gastric cancer remains the fifth most common cancer globally and the third most common cause of cancer-related death. For patients whose metastatic gastric tumors express high levels of HER2, targeted trastuzumab therapy can significantly improve overall survival when added to standard chemotherapy with capecitabine or fluorouracil plus a platinum-based drug. Pertuzumab binds to a HER2 receptor protein epitope different from trastuzumab, and combination treatment with trastuzumab plus pertuzumab has been found to significantly increase overall survival for patients with HER2-positive breast cancer. Although gastric cancer displays more HER2 heterogeneity than does breast cancer, Dr. Tabernero and his associates hypothesized that dual HER2 blockade might show a similar result.
Accordingly, in the phase 3 JACOB trial, 780 patients with HER2-positive metastatic gastric or gastroesophageal junction cancer were randomly assigned to receive treatment every 3 weeks with intravenous pertuzumab (840 mg) or placebo in addition to intravenous trastuzumab (8 mg/kg loading dose, then 6 mg/kg) plus either oral capecitabine (1,000 mg/m2 twice daily), intravenous cisplatin (80 mg/m2), or intravenous 5-fluorouracil (800 mg/m2; 120-hour continuous infusion).
The two groups had similar rates of serious adverse events, most commonly diarrhea. Grade 3 or worse diarrhea affected 13% of pertuzumab patients versus 6% of control patients. There were no treatment-related deaths in the pertuzumab group and seven (2%) in the control group. “The study was not powered to assess efficacy endpoints in clinical and biomarker subgroups and there was no multiplicity control for subgroup analyses, so we cannot assess which patients might be more likely to benefit from pertuzumab treatment,” the investigators wrote. They recommended further evaluating other first-line treatments for advanced HER2-positive gastric cancer, predictors of benefit from dual HER2 blockade, and the best chemotherapy backbone for anti-HER2 regimens.
F. Hoffman-La Roche Ltd. sponsored the work. Dr. Tabernero disclosed advisory board relationships with Genentech/Roche, Roche, Sanofi, Symphogen, and other pharmaceutical companies outside the submitted work. Three coinvestigators also disclosed ties to Roche and several other pharmaceutical companies and one reported owning stock in F. Hoffmann-La Roche. The remaining two investigators reported having no conflicts of interest.
SOURCE: Taberno J, et al. Lancet Oncol. 2018 Sep 11. doi: 10.1016/S1470-2045(18)30481-9.