Clinical outcomes and ctDNA correlates for CAPOX BETR: a phase II trial of capecitabine, oxaliplatin, bevacizumab, trastuzumab in previously untreated advanced HER2+ gastroesophageal adenocarcinoma

Harshabad Singh (), Kristen E. Lowder, Kevin Kapner, Ronan J. Kelly, Hui Zheng, Nadine Jackson McCleary, Thomas A. Abrams, Jennifer A. Chan, Eileen M. Regan, Samuel J. Klempner, Alison M. Hannigan, Joshua Remland, Lauren K. Brais, Elizabeth Andrews, Matthew Yurgelun, James M. Cleary, Douglas A. Rubinson, Lauren L. Ritterhouse, Garrett Maron, Andrew J. Aguirre, Jeffrey A. Meyerhardt, Emma Gardecki, Jochen K. Lennerz, Brian M. Wolpin and Peter C. Enzinger ()
Additional contact information
Harshabad Singh: Dana-Farber Cancer Institute
Kristen E. Lowder: Dana-Farber Cancer Institute
Kevin Kapner: Dana-Farber Cancer Institute
Ronan J. Kelly: Johns Hopkins Hospital & School of Medicine
Hui Zheng: Harvard Medical School
Nadine Jackson McCleary: Dana-Farber Cancer Institute
Thomas A. Abrams: Dana-Farber Cancer Institute
Jennifer A. Chan: Dana-Farber Cancer Institute
Eileen M. Regan: Dana-Farber Cancer Institute
Samuel J. Klempner: Harvard Medical School
Alison M. Hannigan: Dana-Farber Cancer Institute
Joshua Remland: Dana-Farber Cancer Institute
Lauren K. Brais: Dana-Farber Cancer Institute
Elizabeth Andrews: Dana-Farber Cancer Institute
Matthew Yurgelun: Dana-Farber Cancer Institute
James M. Cleary: Dana-Farber Cancer Institute
Douglas A. Rubinson: Dana-Farber Cancer Institute
Lauren L. Ritterhouse: Harvard Medical School
Garrett Maron: Massachusetts General Hospital
Andrew J. Aguirre: Dana-Farber Cancer Institute
Jeffrey A. Meyerhardt: Dana-Farber Cancer Institute
Emma Gardecki: Harvard Medical School
Jochen K. Lennerz: Harvard Medical School
Brian M. Wolpin: Dana-Farber Cancer Institute
Peter C. Enzinger: Dana-Farber Cancer Institute

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract Preclinical studies suggest that simultaneous HER2/VEGF blockade may have cooperative effects in gastroesophageal adenocarcinomas. In a single-arm investigator initiated clinical trial for patients with untreated advanced HER2+ gastroesophageal adenocarcinoma, bevacizumab was added to standard of care capecitabine, oxaliplatin, and trastuzumab in 36 patients (NCT01191697). Primary endpoint was objective response rate and secondary endpoints included safety, duration of response, progression free survival, and overall survival. The study met its primary endpoint with an objective response rate of 81% (95% CI 65–92%). Median progression free and overall survival were 14.0 (95% CI, 11.3–36.4) and 23.2 months (95% CI, 16.6–36.4), respectively. The median duration of response was 14.9 months. The regimen was well tolerated without unexpected or severe toxicities. In post-hoc ctDNA analysis, baseline ctDNA features were prognostic: Higher tumor fraction and alternative MAPK drivers portended worse outcomes. ctDNA at resistance identified oncogenic mutations and these were detectable 2–8 cycles prior to radiographic progression. Capecitabine, oxaliplatin, trastuzumab and bevacizumab shows robust clinical activity in HER2+ gastroesophageal adenocarcinoma. Combination of VEGF inhibitors with chemoimmunotherapy and anti-PD1 regimens is warranted.

Date: 2024
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DOI: 10.1038/s41467-024-51271-3

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