BACKGROUND Trastuzumab is a monoclonal antibody targeting HER2 standardly administered with multi-agent chemotherapeutics in 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. Moreover, cytotoxic chemotherapy facilitates tumor antigen presentation, and the combination of anti-PD-1 therapy and chemotherapy was recently found to improve progression-free survival (PFS) and overall survival (OS) compared to chemotherapy alone in HER2-negative metastatic gastric cancer. We hypothesized that the addition of the anti-PD-L1 antibody avelumab to trastuzumab and FOLFOX chemotherapy would result in a greater response rate than expected with trastuzumab + FOLFOX alone in HER2-amplified gastroesophageal cancer. METHODS HCRN GI17-319 was a multicenter, single-arm, phase II clinical trial with a prespecified 6-subject safety run-in of avelumab, trastuzumab, and mFOLFOX6 in previously untreated, metastatic, HER2-amplified gastric and esophageal adenocarcinomas (NCT03783936). The primary endpoint was best response rate within the first 24 weeks. Secondary endpoints included PFS and adverse events (AEs). Subjects received 9 cycles of induction avelumab, trastuzumab, and mFOLFOX6 every 14 days, followed by maintenance avelumab + trastuzumab every 14 days. 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%), including one complete response. The confirmed overall response rate is 7/18 (39%), but 3 unconfirmed responders are still on treatment. With 11 progression events, median PFS was 8.0 mo (95% CI 4.2-11.9). The regimen was well tolerated, with most common treatment-related grade 3-4 AEs of decreased neutrophil count (28%), decreased platelet count (11%), anemia (11%), and hypokalemia (11%). CONCLUSIONS The combination of avelumab, trastuzumab, and FOLFOX chemotherapy demonstrated evidence of activity, and response rate and median PFS compared favorably to results expected with trastuzumab + chemotherapy from historical data. These outcomes corroborate with results from prior small studies of chemotherapy, trastuzumab, and immune checkpoint inhibitors in patients with HER2-amplified metastatic gastroesophageal adenocarcinoma and demonstrate the exciting potential for addition of immune checkpoint inhibitors in this setting. Correlative studies from tumor specimens and peripheral blood collected on study are in progress.

Citation Format: Michael S. Lee, Joseph Chao, Mary F. Mulcahy, Pashtoon M. Kasi, Angela T. Alistar, Sarbajit Mukherjee, Mehmet Akce, Dominic T. Moore, Cheryl A. Carlson, Autumn J. McRee. Phase II study of avelumab and trastuzumab with FOLFOX chemotherapy in previously untreated HER2-amplified metastatic gastroesophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT174.