HER2-Related Biomarkers Confer Response to T-DXd in Advanced Gastric Cancer

“These exploratory biomarker analyses of patients from the primary and exploratory cohorts of the DESTINY-Gastric01 trial identified relevant prognostic or predictive biomarkers in patients with HER2-positive or HER2-low gastric and gastroesophageal junction [GEJ] cancer treated with T-DXd,” according to the study authors.

Biomarkers associated with HER2 appeared to confer improved objective response rates (ORRs) among patients with HER2-positive gastric cancer who received fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), according to exploratory analysis findings from the phase 2 DESTINY-Gastric01 trial (NCT03329690) published in Nature Medicine.

The ORR was 58.2% (95% CI, 47.8%-68.5%) in patients with HER2 immunohistochemistry (IHC) 3+ status vs 28.6% (95% CI, 13.2%-48.7%) in those with HER2 IHC 2+ or in situ hybridization (ISH)+ disease. Responses occurred in 81.2% (95% CI, 54.4%-96.0%) of those with HER2-high mRNA expression compared with 23.5% (95% CI, 6.8%-49.9%) of patients with HER2-low mRNA expression. In patients with and without plasma HER2 amplification in circulating tumor DNA (ctDNA), respectively, the ORR was 60.6% (95% CI, 48.3%-72.0%) vs 34.2% (95% CI, 19.6%-51.4%).

Investigators reported a 64% positive predictive agreement rate between tumor HER2 status and plasma amplification in ctDNA; the negative predictive agreement rate was 86%. Additionally, ctDNA plasma HER2 adjusted plasma copy number (apCN) correlated with HER2 status based on IHC or ISH, and higher HER2 levels in the tumor correlated with elevated HER2 apCN.

According to the investigators, ORRs following treatment with T-DXd were lower for patients with MET amplifications (25%; 95% CI, 3.2%-65.1%), EGFR amplifications (32.1%; 95% CI, 15.9%-52.4%), and FGFR2 amplifications (95% CI, 0.0%-45.9%). Moreover, treatment elicited an ORR of 50.0% (95% CI, 24.7%-75.3%) in patients with KRAS- or NRAS-activating variants vs 51.6% (95% CI, 41.0%-62.1%) in those with wild-type KRAS or NRAS.

“These exploratory biomarker analyses of patients from the primary and exploratory cohorts of the DESTINY-Gastric01 trial identified relevant prognostic or predictive biomarkers in patients with HER2-positive or HER2-low gastric and gastroesophageal junction [GEJ] cancer treated with T-DXd,” the study authors wrote. “Patients with higher levels of HER2-associated biomarkers, including HER2 IHC positivity, HER2 ISH positivity, tumor HER2 mRNA levels, plasma gene apCN and/or serum HER2 extracellular domain [HER2ECD], had numerically higher ORR compared with patients with lower HER2-associated biomarkers.”

In the open-label, multicenter phase 2 DESTINY-Gastric01 trial, patients with HER2-expressing advanced gastric or GEJ carcinoma were assigned to receive T-DXd at 6.4 mg/kg every 3 weeks (n = 125) or investigator’s choice of irinotecan or paclitaxel (n = 62). Those in the exploratory analysis cohorts had HER2 IHC 2+ or ISH– status (n = 20) or HER2 IHC 1+ status (n = 24) and received the same T-DXd treatment schedule.

The trial’s primary end point was ORR based on independent central review. Secondary end points included overall survival, duration of response, progression-free survival, and safety.

Of note, all patients enrolled on the DESTINY-Gastric01 trial—including 125 from the primary cohort and 42 from the exploratory cohorts—were evaluated for baseline HER2 status. Additionally, 114 and 37 patients from the primary and exploratory cohorts, respectively, had available samples for ctDNA assessment.

Data highlighted that 45% (n = 37/82) of patients with HER2 gene expression had amplified ctDNA prior to beginning treatment with T-DXd, which decreased to 33% (n = 27/82) at the end of treatment. Investigators reported comparable variances in patients with other gene variants.

Investigators identified 57 genes that demonstrated higher expression in patients with a response (absolute log₂ fold change ≥ 1; P ≤.01). Those with a response to T-DXd tended to have significantly higher expression of chromosome 17q12-21 genes, where HER2 is located. According to the investigators, a higher expression of genes in this chromosome correlated with improved responses.

Reference

Shitara K, Bang Y, Iwasa S, et al. Trastuzumab deruxtecan in HER2-positive advanced gastric cancer: exploratory biomarker analysis of the randomized, phase 2 DESTINY-Gastric01 trial. Nat Med. Published online May 14, 2024. doi:10.1038/s41591-024-02992-x