Trastuzumab for HER2-Positive Gastroesophageal Cancer

Gastric cancer, although uncommon in the U.S., is the second leading cause of cancer-related mortality worldwide. Three-drug chemotherapy regimens (epirubicin or docetaxel plus cisplatin and 5-fluorouracil) have little advantage over either conventional 5-FU or capecitabine plus cisplatin (JW Oncol Hematol Jan 22 2008). Trastuzumab, a monoclonal antibody that blocks human epidermal growth factor receptor-2 (HER2), is an active adjuvant and advanced-disease treatment for patients with HER2-positive breast cancer (JW Oncol Hematol Feb 5 2007). Investigators now report results from a manufacturer-funded, multinational, phase III randomized trial of chemotherapy with or without trastuzumab for metastatic gastroesophageal cancer.

Of 3665 patients screened with fluorescence in situ hybridization or immunohistochemistry, 810 were HER2 positive. Of these patients, 594 were randomized to receive 3-week cycles of chemotherapy alone — oral capecitabine (1000 mg/m² twice daily for 14 days) and intravenous cisplatin (80 mg/m² on day 1) — or chemotherapy plus trastuzumab (8 mg/kg on day 1 of the first cycle and then 6 mg/kg in each subsequent cycle). More than 80% of patients had gastric cancer and the rest gastroesophageal (GE) junction cancer; tumors were intestinal in about three quarters of patients and diffuse or mixed in the rest. A minority of participants (13%) received intravenous 5-FU (800 mg/m² on days 1 to 5 of each cycle) in place of capecitabine.

Results with trastuzumab plus chemotherapy were significantly better than with chemotherapy alone in terms of overall survival (mean, 13.8 vs. 11.1 months; hazard ratio, 0.74; P=0.0046), progression-free survival (mean, 6.7 vs. 5.5 months; HR, 0.71; P=0.0004), and tumor response rate (47% vs. 35%; odds ratio, 1.70; P=0.0017). Although a ≥10% drop in left ventricular ejection fraction (to an absolute value <50%) was more common with trastuzumab than with chemotherapy alone (5% vs. 1%), the adverse event profile was similar in the two groups.