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The Efficacy and Plasma ctDNA as a Biomarker of Dual PD-1 and HER2 Blockade in HER2-Positive Gastric or Gastroesophageal Junction Cancers
25 Pages Posted: 10 Aug 2022
More...Abstract
Purpose: To assess the efficacy of dual PD-1 and HER2 blockade in HER2-positive gastric or gastroesophageal junction (G/GEJ) cancers and explore the potential predictors of this regimen efficacy.
Methods: Here, we investigated: (i) the consistency of HER2 status by tissue-based IHC/FISH assay and circulating tumor DNA (ctDNA)-based NGS; (ii) the antitumor activity of dual PD-1 and HER2 blockade in histologically HER2-positive G/GEJ cancer patients; and (iii) the potential biomarkers of this regimen efficacy utilizing ctDNA NGS.
Findings: ctDNA-based NGS and IHC/FISH displayed a high concordance of 84.4% (38/45) with an 82.5% sensitivity and a 100% specificity for identifying HER2 status. Anti-PD-1 plus trastuzumab treatment obtained an objective response rate (ORR) of 45.9% and a median progression-free survival (PFS) of 7.5 months in 37 histologically HER2-positive patients. The patients receiving chemotherapy-containing had a numerically higher ORR (P=0.103), which reached significance in the first-line setting (P=0.036) compared to those treated with chemotherapy-free. Despite all patients being histologically HER2-positive, those with HER2 amplification in ctDNA displayed a significantly higher ORR (P=0.009) than those without. POLE mutations were also linked to a significantly higher ORR (P=0.036). Besides, the patients carrying immunonegative_gene_set alterations had a significantly decreased ORR (P=0.02) and PFS (P<0.001) versus those without.
Interpretation: Dual PD-1 and HER2 blockade provided an alternative treatment option for HER2-positive G/GEJ cancers, which tended to be more effective when combined with chemotherapy. Additionally, HER2 amplification, POLE mutations, and immunonegative_gene_set alterations were identified as potential biomarkers of dual PD-1 and HER2 blockade efficacy in HER2-positive G/GEJ cancers.
Funding Information: This study was supported by Capital's Funds for Health Improvement and Research (2020-1-1022) and Beijing Municipal Medical Research Institutes, Beijing Medical Research Institute (No. Z20J00105).
Declaration of Interests: Z. Yan, J. Cai, H. Chen, S. Chen, and X. Zhao are employees of 3D Medicines Inc. No other disclosures are reported.
Ethics Approval Statement: This study was approved by the Ethics Committee of Peking University Cancer Hospital &Institute (Beijing, China) (approval ID: 2020KT46). was conducted in accordance with the principles of the Declaration of Helsinki. Consent was obtained directly from patients.
Keywords: circulating tumor DNA, HER2 amplification, gastric or gastroesophageal junction cancers, trastuzumab, anti-PD-1 immunotherapy
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