Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial.
Kohei ShitaraYung-Jue BangSatoru IwasaNaotoshi SugimotoMin-Hee RyuDaisuke SakaiHyun Cheol ChungHiasto KawakamiHiroshi YabusakiYasuhiro SakamotoTomohiro NishinaKoichiro InakiYusuke KuwaharaNaoya WadaFumitaka SutoTakeo AritaMasahiro SugiharaZenta TsuchihashiKaku SaitoAkihito KojimaKensei YamaguchiPublished in: Nature medicine (2024)
Trastuzumab deruxtecan (T-DXd) showed statistically significant clinical improvement in patients with human epidermal growth factor receptor 2-positive (HER2 + ) gastric cancer in the DESTINY-Gastric01 trial. Exploratory results from DESTINY-Gastric01 suggested a potential benefit in patients with HER2-low gastric cancer. Spatial and temporal heterogeneity in HER2 expression or gene alteration, an inherent characteristic of gastric cancer tumors, presents a challenge in identifying patients who may respond to T-DXd. Specific biomarkers related to therapeutic response have not been explored extensively. Exploratory analyses were conducted to assess baseline HER2-associated biomarkers in circulating tumor DNA and tissue samples, and to investigate mechanisms of resistance to T-DXd. Baseline HER2-associated biomarkers were correlated with objective response rate (ORR) in the primary cohort of patients with HER2 + gastric cancer. The primary cohort had 64% concordance between HER2 positivity and HER2 (ERBB2) plasma gene amplification. Other key driver gene amplifications, specifically MET, EGFR and FGFR2, in circulating tumor DNA were associated with numerically lower ORR. Among 12 patients with HER2 gain-of-function mutations, ORR was 58.3% (7 of 12). ORR was consistent regardless of timing of immunohistochemistry sample collection. Further investigations are required in larger studies.
Keyphrases
- circulating tumor
- epidermal growth factor receptor
- tyrosine kinase
- cell free
- circulating tumor cells
- advanced non small cell lung cancer
- phase iii
- genome wide
- phase ii
- copy number
- clinical trial
- study protocol
- open label
- endothelial cells
- genome wide identification
- double blind
- small cell lung cancer
- squamous cell carcinoma
- dna methylation
- gene expression
- binding protein
- risk assessment
- placebo controlled
- long non coding rna
- induced pluripotent stem cells
- neoadjuvant chemotherapy
- rectal cancer
- climate change
- nucleic acid
- case control
- pluripotent stem cells
- single molecule