HER2-related biomarkers predict clinical outcomes with trastuzumab deruxtecan treatment in patients with HER2-expressing metastatic colorectal cancer: biomarker analyses of DESTINY-CRC01

Nat Commun. 2024 Nov 25;15(1):10213. doi: 10.1038/s41467-024-53223-3.

Abstract

DESTINY-CRC01 (NCT03384940) was a multicentre, open-label, phase 2 study that investigated the safety and efficacy of trastuzumab deruxtecan (T-DXd) in patients with human epidermal growth factor receptor 2 (HER2)-expressing metastatic colorectal cancer (CRC). The present exploratory biomarker analysis aims to investigate relationships between biomarkers and clinical outcomes in patients with HER2-positive (immunohistochemistry [IHC] 3+ or IHC 2+ and in situ hybridization [ISH] positive) Cohort A (N = 53) of DESTINY-CRC01. Higher levels of HER2 biomarkers in baseline tissue and liquid biopsies, including HER2 status (IHC/ISH), HER2/CEP17 ratio, HER2 ISH signals, HER2 H-score, plasma HER2 (ERBB2) amplification status, HER2 adjusted plasma copy number, and HER2 extracellular domain correlate with antitumor activity (indicated by objective response rate, progression-free survival, and overall survival) of T-DXd. Baseline circulating tumor DNA (ctDNA) analysis suggests antitumor activity of T-DXd in patients who had baseline activating RAS, PIK3CA, or HER2 mutations detected in ctDNA.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents, Immunological / therapeutic use
  • Biomarkers, Tumor* / blood
  • Biomarkers, Tumor* / genetics
  • Biomarkers, Tumor* / metabolism
  • Camptothecin* / analogs & derivatives
  • Camptothecin* / therapeutic use
  • Circulating Tumor DNA / blood
  • Circulating Tumor DNA / genetics
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • Class I Phosphatidylinositol 3-Kinases / metabolism
  • Colorectal Neoplasms* / drug therapy
  • Colorectal Neoplasms* / genetics
  • Colorectal Neoplasms* / metabolism
  • Colorectal Neoplasms* / pathology
  • Female
  • Humans
  • Immunoconjugates
  • Male
  • Middle Aged
  • Neoplasm Metastasis
  • Progression-Free Survival
  • Receptor, ErbB-2* / genetics
  • Receptor, ErbB-2* / metabolism
  • Trastuzumab* / therapeutic use
  • Treatment Outcome

Substances

  • Receptor, ErbB-2
  • Trastuzumab
  • Biomarkers, Tumor
  • ERBB2 protein, human
  • Camptothecin
  • trastuzumab deruxtecan
  • Circulating Tumor DNA
  • Antineoplastic Agents, Immunological
  • Class I Phosphatidylinositol 3-Kinases
  • Immunoconjugates

Associated data

  • ClinicalTrials.gov/NCT03384940