Circulating Tumor DNA as a Predictive Biomarker for Clinical Outcomes With Margetuximab and Pembrolizumab in Pretreated HER2-Positive Gastric/ Gastroesophageal Adenocarcinoma

Oncology (Williston Park). 2023 Apr 25;37(4):176-183. doi: 10.46883/2023.25920992.


Purpose: To assess the ability of circulating tumor DNA (ctDNA)-based testing to identify patients with HER2 (encoded by ERBB2)-positive gastric/gastroesophageal adenocarcinoma (GEA) who progressed on or after trastuzumab-containing treatments were treated with combination therapy of anti-HER2 and anti-PD-1 agents.

Methods: ctDNA analysis was performed retrospectively using plasma samples collected at study entry from 86 patients participating in the phase 1/2 CP-MGAH22-05 study (NCT02689284).

Results: Objective response rate (ORR) was significantly higher in evaluable ERBB2 amplification-positive vs - negative patients based on ctDNA analysis at study entry (37% vs 6%, respectively; P = .00094). ORR was 23% across all patients who were evaluable for response. ERBB2 amplification was detected at study entry in 57% of patients (all HER2 positive at diagnosis), and detection was higher (88%) when HER2 status was determined by immunohistochemistry fewer than 6 months before study entry. ctDNA was detected in 98% (84/86) of patients tested at study entry. Codetected ERBB2-activating mutations were not associated with response.

Conclusions: Current ERBB2 status may be more effective than archival status at predicting clinical benefit from margetuximab plus pembrolizumab therapy. ctDNA testing for ERBB2 status prior to treatment will spare patients from repeat tissue biopsies, which may be reserved for reflex testing when ctDNA is not detected.

Keywords: gastric/gastroesophageal adenocarcinoma; HER2; ctDNA; and margetuximab plus pembrolizumab..

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma* / drug therapy
  • Adenocarcinoma* / genetics
  • Biomarkers, Tumor / genetics
  • Circulating Tumor DNA* / genetics
  • Humans
  • Receptor, ErbB-2 / genetics
  • Retrospective Studies
  • Stomach Neoplasms* / drug therapy
  • Stomach Neoplasms* / genetics
  • Trastuzumab / therapeutic use


  • Biomarkers, Tumor
  • Circulating Tumor DNA
  • margetuximab
  • pembrolizumab
  • Receptor, ErbB-2
  • Trastuzumab
  • ERBB2 protein, human

Associated data