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

• Published in: The oncologist (Dayton, Ohio) Vol. 30; no. 7
• Main Authors: Lee, Michael S, Chao, Joseph, Mulcahy, Mary F, Kasi, Pashtoon M, Alistar, Angela T, Mukherjee, Sarbajit, Akce, Mehmet, Moore, Dominic T, McRee, Autumn J, Somasundaram, Ashwin
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 04.07.2025
• Subjects: Adenocarcinoma - drug therapy; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Adult; Aged; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - pharmacology; Antibodies, Monoclonal, Humanized - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Clinical Trial Results; Esophageal Neoplasms - drug therapy; Esophageal Neoplasms - genetics; Esophageal Neoplasms - pathology; Female; Fluorouracil - pharmacology; Fluorouracil - therapeutic use; Humans; Leucovorin - pharmacology; Leucovorin - therapeutic use; Male; Middle Aged; Organoplatinum Compounds - pharmacology; Organoplatinum Compounds - therapeutic use; Receptor, ErbB-2 - genetics; Stomach Neoplasms - drug therapy; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Trastuzumab - administration & dosage; Trastuzumab - pharmacology; Trastuzumab - therapeutic use; trastuzumab; esophageal cancer; gastric cancer; HER2; immunotherapy
• ISSN: 1083-7159; 1549-490X; 1549-490X
• DOI: 10.1093/oncolo/oyaf195

Trastuzumab and multiagent chemotherapy have been the standard of care for the 20-30% of metastatic gastric and esophageal adenocarcinomas that overexpress HER2. Preclinical data show 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. 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 the 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 2-stage trial, but enrollment was stopped after the 18-subject first stage for reasons unrelated to safety or efficacy. 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 months (95% CI: 5.3-NA) and median OS was 13.1 months (95% CI: 11.5-NA). The regimen was well tolerated, without any new safety signals. The combination of avelumab, trastuzumab, and FOLFOX chemotherapy demonstrated some activity, with a 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. NCT03783936.