Lapatinib Fails to Improve Survival in HER2-Positive Gastroesophageal Cancer

The addition of lapatinib to capecitabine and oxaliplatin did not prolong overall survival (OS) among patients with previously untreated HER2-amplified gastroesophageal adenocarcinoma, according to a new randomized phase III trial. There was some benefit seen in certain subgroups, such as those who lived in Asia and those of a younger age.

HER2 is associated with about 20% of gastroesophageal adenocarcinomas, wrote study authors led by J. Randolph Hecht, MD, of the David Geffen School of Medicine at UCLA in Santa Monica, California. “Targeted inhibition of HER2 has been shown to significantly improve outcomes in patients with breast cancer overexpressing or amplifying HER2.”

In the new study, this effect was tested in a total of 545 patients with gastroesophageal adenocarcinoma across 22 countries; 487 of those made up the primary efficacy analysis. Patients were randomized to either capecitabine plus oxaliplatin along with lapatinib (249 patients) or along with placebo (238 patients). The results were published online ahead of print in the Journal of Clinical Oncology.

After a median follow-up of 23 months, the OS in the lapatinib group was 12.2 months, compared with 10.5 months in the placebo group. This yielded a hazard ratio (HR) of 0.91 (95% confidence interval [CI], 0.73–1.12; P = .3492).

The median progression-free survival (PFS) was significantly different, at 6 months in the lapatinib group and 5.4 months in the placebo group for an HR of 0.82 (95% CI, 0.68–1.00; P = .0381). Response rate was also better with lapatinib, at 53% vs 39% (P = .0031). The median duration of response was 7.3 months with lapatinib and 5.6 months with placebo.

The study included preplanned exploratory subgroup analyses, and these yielded some differences with lapatinib. The median OS among patients in Asia was 16.5 months with lapatinib and 10.9 months with placebo, for an HR of 0.68 (95% CI, 0.48–0.96; P = .0261). Patients under age 60 also saw benefit with lapatinib, with a median OS of 12.9 months compared with 9 months with placebo for an HR of 0.69 (95% CI, 0.51–0.94; P = .0141).

There were more adverse events (AEs) in the lapatinib group than in the placebo group, and more patients experienced serious AEs with the study drug. Diarrhea in particular was more common with lapatinib, experienced by 58% compared with only 29% of placebo patients. Twelve percent of lapatinib patients experienced grade 3 or greater diarrhea compared with 3% of placebo patients.

The authors wrote that several factors may explain why lapatinib failed to improve outcomes in HER2-amplified gastroesophageal adenocarcinoma when it does so in HER2-amplified breast cancer, including potential biologic differences between HER2-positive breast and other tumors.

“The use of lapatinib in combination with [capecitabine and oxaliplatin] in patients with HER2-positive gastric cancer cannot be recommended,” the authors concluded. “Future research may identify a subgroup of patients who benefit from such treatment, although there are several new anti-HER2 agents, such as pertuzumab and ado-trastuzumab, that are being tested in HER2-positive gastric cancer.”