Abstract CT155: Long term results and ctDNA correlatives for CAPOX BETR: A multi-center phase II trial of capecitabine, oxaliplatin, bevacizumab and trastuzumab for previously untreated HER2 positive metastatic gastroesophageal adenocarcinoma
Authors: Singh Harshabad , Lowder Kristen E. , Kapner Kevin , Kelly Ronan J. , Zheng Hui , McCleary Nadine J. , Abrams Thomas A. , Chan Jennifer A. , Regan Eileen M. , Klempner Samuel J. , Hannigan Alison M. , Brais Lauren K. , Andrews Elizabeth A. , Yurgelun Matthew B. , Cleary James M. , Rubinson Douglas A. , Ritterhouse Lauren L. , Maron Garrett E. , Aguirre Andrew J. , Tan Lu , Du Pan , Meyerhardt Jeffrey A. , Gardecki Emma , Lennerz Jochen K. , Jia Shidong , Wolpin Brian M. , Enzinger Peter C. 
Published: April 2023

Abstract
Introduction: Preclinical studies suggest cooperativity between blocking the human epidermal growth factor receptor 2 (HER2) and the vascular endothelial growth factor (VEGF) pathways in gastroesophageal adenocarcinomas (GEAs).
Methods:Patients with previously untreated advanced HER2 positive GEAs were treated with standard of care chemotherapy capecitabine 1,200 mg/m2 days 1-14 and oxaliplatin 130 mg/m2 day 1 (CAPOX) plus trastuzumab 6 mg/kg day 1, once every 3 weeks. Investigational agent bevacizumab (7.5 mg/kg, VEGF mAb) was added on day 1 of each cycle for all patients. The primary endpoint was radiographic objective response rate by RECIST 1.1. ctDNA was extracted and profiled from serially banked plasma samples (every other treatment cycle) using CLIA certified 152-gene next generation sequencing (NGS) panel assay, PredicineCARETM.
Results:Sixty one patients were screened for the study of whom 24 were ineligible. Thirty-seven patients were enrolled, and one withdrew consent prior to starting. Thirty-six patients were evaluable for efficacy and safety. The median follow-up was 23.2 months (IQR: 11.0 - 46.9 months). All enrolled patients are now off study. Radiographic objective response rate was 81%. Median progression-free survival (PFS) and overall survival (OS) were 14.0 months (95% CI, 11.3 -36.4) and 23.2 months (95% CI, 16.6-36.4), respectively. The most common grade 3-4 toxicities were diarrhea, peripheral neuropathy, and hypertension. Baseline ctDNA profiling identified HER2 amplifications in 76.7% of tested cases (23/30). Baseline ctDNA based tumor fraction (TF) was highly prognostic and TF &gt; 50th centile had a statistically significantly worse PFS of 11.3 months (95% CI 5.2-18) vs. 22.7 months (95% CI 18.1-NA), p value = 0.0013, and OS of 15.4 months (95% CI 8.0-27.6) vs. 28.0 months (95% CI 17.8-NA), p value = 0.022. 56.7% of cases (17/30) had alternative MAPK drivers present in pretreatment ctDNA, most commonly amplifications in EGFR, FGFR1, MET, and KRAS. Additional MAPK alterations were associated with worse PFS of 12.5 months (95% CI 5.2-NA) vs. 22.7 months (95% CI 8.5-NA), p-value = 0.0067, and OS of 16.5 months (95% CI 8.0-27.6) vs. 32.3 months (95% CI 17.8-NA), p-value = 0.015. 19 cases had plasma profiled at time of clinical resistance of whom 10 showed new oncogenic mutations not detectable in the matched baseline sample. These included mutations in MAPK pathway (KRAS, NRAS, BRAF, HER2; n = 1 each) and PI3K pathway (PTEN, PIK3CA; n = 1 each), suggesting a role in therapeutic resistance.
Conclusions:The combination of CAPOX, trastuzumab and bevacizumab shows striking clinical activity comparable to novel triplet regimens that include PD1 blockade for HER2+ GEAs. Further evaluation of VEGF mAb in combination with chemoimmunotherapy and anti-PD1 regimens is warranted. Diagnostic ctDNA profiling identifies cases with high TF and alternative MAPK drivers who have worse outcomes. Serial measurement of ctDNA may allow early identification of novel genetic resistance mechanisms which can aid attempts at early intervention.
Citation Format: Harshabad Singh, Kristen E. Lowder, Kevin Kapner, Ronan J. Kelly, Hui Zheng, Nadine J. McCleary, Thomas A. Abrams, Jennifer A. Chan, Eileen M. Regan, Samuel J. Klempner, Alison M. Hannigan, Lauren K. Brais, Elizabeth A. Andrews, Matthew B. Yurgelun, James M. Cleary, Douglas A. Rubinson, Lauren L. Ritterhouse, Garrett E. Maron, Andrew J. Aguirre, Lu Tan, Pan Du, Jeffrey A. Meyerhardt, Emma Gardecki, Jochen K. Lennerz, Shidong Jia, Brian M. Wolpin, Peter C. Enzinger. Long term results and ctDNA correlatives for CAPOX BETR: A multi-center phase II trial of capecitabine, oxaliplatin, bevacizumab and trastuzumab for previously untreated HER2 positive metastatic gastroesophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT155.