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

Abstract Background 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 o...

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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: US Oxford University Press 01.07.2025
Subjects:
Adenocarcinoma
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
Cancer
Care and treatment
Chemotherapy
Clinical Trial Results
Drug therapy
Esophageal cancer
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
Pharmacology, Experimental
Physiological aspects
Receptor, ErbB-2 - genetics
Stomach cancer
Stomach Neoplasms - drug therapy
Stomach Neoplasms - genetics
Stomach Neoplasms - pathology
Trastuzumab - administration & dosage
Trastuzumab - pharmacology
Trastuzumab - therapeutic use
United States
trastuzumab
esophageal cancer
gastric cancer
HER2
immunotherapy
ISSN:1083-7159, 1549-490X, 1549-490X
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Summary:Abstract Background 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. 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 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. 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 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. Conclusions 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.
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ISSN:1083-7159
1549-490X
1549-490X
DOI:10.1093/oncolo/oyaf195