DESTINY-Gastric01 was a pivotal randomised study of trastuzumab deruxtecan versus third- or later-line chemotherapy in patients with HER2-positive gastric or gastro-oesophageal (GEJ) tumours. The objective of the exploratory biomarker analyses of patients from the primary and exploratory cohorts of the DESTINY-Gastric01 study was to identify patients who may benefit from treatment with trastuzumab deruxtecan based on relevant biomarkers in tumour or circulating tumour DNA (ctDNA).
Baseline HER2-associated biomarkers in ctDNA or tissue samples were associated with therapeutic response in patients with HER2-positive tumours, and these analyses identify potential drivers of resistance according to Dr. Kohei Shitara of the National Cancer Center Hospital East in Kashiwa; Department of Immunology, Nagoya University Graduate School of Medicine in Nagoya, Japan and colleagues who published the findings on 14 May 2024 in the Nature Medicine.
DESTINY-Gastric01 was an open-label, multicentre, randomised, phase II study that included patients with HER2-expressing advanced gastric or GEJ carcinoma that had progressed on two or more previous lines of therapy, including fluoropyrimidine, a platinum agent and trastuzumab. In the DESTINY-Gastric01 primary cohort of patients with HER2-positive gastric cancer centrally confirmed as immunohistochemistry (IHC) score 3+ or IHC 2+/in situ hybridisation (ISH)-positive using the most recent archival or fresh biopsy tumour tissues, trastuzumab deruxtecan significantly improved objective response rate (ORR) compared with physician choice of chemotherapy and led to significantly improved overall survival. These findings supported the regulatory approval of trastuzumab deruxtecan.
Trastuzumab deruxtecan activity was also suggested in the HER2-low (IHC 2+/ISH-negative or IHC 1+) exploratory cohorts of DESTINY-Gastric01. The activity of trastuzumab deruxtecan was further confirmed in the phase II DESTINY-Gastric02 study; this study enrolled patients with HER2-positive status, measured using fresh biopsy samples obtained following trastuzumab treatment. Trastuzumab deruxtecan is now recommended as a second- or third-line treatment following trastuzumab treatment. Furthermore, trastuzumab deruxtecan versus second-line paclitaxel plus ramucirumab is being investigated in the ongoing phase III DESTINY-Gastric04 study.
The authors wrote in the background that spatial and temporal heterogeneity may make it challenging to identify patients with gastric or GEJ cancer who have the potential to respond to trastuzumab deruxtecan treatment. Intratumoural heterogeneity is a more common phenomenon in HER2-positive gastric cancer compared with HER2-positive breast cancer. Moreover, decreased HER2 expression following treatment with trastuzumab or other HER2-targeted agents has been observed in 16–32% of patients. The relationship between gene alterations in ctDNA and the efficacy of antibody drug conjugates that target specific oncoproteins has not been thoroughly evaluated.
Exploratory analyses of patients from the primary and exploratory cohorts of the DESTINY-Gastric01 study were conducted to assess baseline HER2-associated biomarkers in ctDNA and tissue samples, and to investigate mechanisms of resistance to trastuzumab deruxtecan. Baseline HER2-associated biomarkers were correlated with ORR in the primary cohort of patients with HER2-positive 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 ctDNA 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 IHC sample collection.
The authors emphasised that these biomarker analyses were either exploratory or post hoc analyses with a small sample size conducted in the absence of external validation and data from a control arm. Further investigations are required in larger studies. The biomarkers identified in this analysis are being investigated and validated in additional studies, including DESTINY-Gastric02, DESTINY-Gastric03, DESTINY-Gastric04 and EPOC2203.
This study was sponsored and designed by Daiichi Sankyo in collaboration with AstraZeneca. It was funded by Daiichi Sankyo and AstraZeneca. Results were previously presented in part at the ESMO World Congress on Gastrointestinal Cancer (30 June‒3 July 2021).
Reference
Shitara K, Bang Y-J, Iwasa S, et al. Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial. Nature Medicine; Published online 14 May 2024. DOI: https://doi.org/10.1038/s41591-024-02992-x