Phase II study of avelumab and trastuzumab with FOLFOX chemotherapy in previously untreated HER2-amplified metastatic gastroesophageal adenocarcinoma.

Background: Trastuzumab and multiagent chemotherapy has been the standard of care for the 20-30% of metastatic gastric and esophageal adenocarcinomas that overexpress HER2. Preclinical data shows that trastuzumab requires a functional adaptive immune system for efficacy, suggesting synergy of trastuzumab combined with immune checkpoint inhibitors further supported by current clinical studies.

Methods: HCRN GI17-319 was a multicenter, single-arm, phase II clinical trial with a prespecified 6-subject safety run-in of the anti-PD-L1 antibody avelumab, combined with trastuzumab and mFOLFOX6, in previously untreated, metastatic, HER2-amplified gastric and esophageal adenocarcinomas. The primary endpoint was best overall response within 24 weeks. Subjects received 9 cycles of induction avelumab, trastuzumab, and mFOLFOX6, followed by maintenance avelumab + trastuzumab. The study was initially designed as a Simon's two stage trial, but enrollment was stopped after the 18-subject first stage for reasons unrelated to safety or efficacy.

Results: A total of 18 subjects, including the 6-subject safety run-in, were enrolled 4/2019-8/2020. The 24-week response rate was 11/18 (61%; 95% CI 39-84%), and the confirmed overall response rate is 9/18 (50%). With a median follow-up of 14.6 months, the median PFS was 8.0 mo (95% CI 5.3-NA) and median OS was 13.1 mo (95% CI 11.5-NA). The regimen was well tolerated, without any new safety signal.v The combination of avelumab, trastuzumab, and FOLFOX chemotherapy demonstrated some activity, with reasonable response rate and median PFS. These outcomes provide some support to other clinical trials of similar agents and support the future evaluation of adding avelumab in this setting.