Dr. Kohei Shitara is a Chief of Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa in Japan. In this interview, he speaks about the ASCO GI 2022 Abstract – Exploratory analysis of the impact of prior immune checkpoint inhibitor (ICI) on trastuzumab deruxtecan (T-DXd; DS-8201) clinical outcomes and biomarkers (BM) in DESTINY-Gastric01 (DG-01), a randomized, phase 2, multicenter, open-label study in patients (pts) with HER2+ advanced gastric or gastroesophageal junction adenocarcinoma.
Context:
T-DXd is an antibody-drug combination that targets HER2. T-DXd showed clinically meaningful improvements in objective response rate (ORR) and overall survival (OS) compared to chemotherapy in the primary cohort of patients with HER2+ advanced gastric cancer (AGC; IHC3+ or IHC2+/ISH+; Shitara K et al. NEJM 2020;382:2419; Shitara K et al. NEJM 2020;382:2419). We conducted a post hoc analysis of T-DXd clinical outcomes and baseline BMs in pts with or without prior ICI in the context of evolving first-line ICI-based regimens in AGC.
Methodologies:
The DG-01 primary cohort included patients who had advanced on at least two prior treatments and had HER2+ AGC verified centrally. Efficacy and safety were evaluated in patients who had or had not had prior ICI (defined as any ICI-related treatment received prior to T-DXd). In the T-DXd arm, exploratory BM analysis looked at RNA sequencing (RNAseq) of tumor samples and ctDNA of liquid biopsies taken right before T-DXd treatment. To identify differentially expressed genes and signature scores between pts with and without prior ICI, a linear regression model and Wilcoxon rank-sum test were utilized.
Findings:
Prior ICI was found in 35.2 percent (44/125) of T-DXd patients and 27.4 percent (17/62) of chemotherapy patients. The table depicts efficacy in patients who had or had not had prior ICI. In the T-DXd arm, safety data were similar in patients with and without prior ICI, including adjudicated drug-related interstitial lung disease/pneumonitis; 9.1 percent (4/44) of patients with prior ICI and 9.9 percent (8/81) of patients without prior ICI had adjudicated drug-related interstitial lung disease/pneumonitis. Twelve of the 34 T-DXd-treated pts with RNAseq data had previously received ICI. Multiple genes with a higher trend for expression in tumors with prior ICI were identified by searching for differentially expressed genes (fold change 2, P0.01), including immune-oncology (IO)-related molecules CXCL9 and PD-1 (log2 fold change 2.3 and 1.4, P=7.3e-05 and 2.8e-03, respectively). Furthermore, gene signature analysis revealed that the preceding ICI group had a greater trend of numerous chemokine gene expressions.
Outcomes:
Regardless of prior ICI, this exploratory analysis reveals that T-DXd treatment produces better results than chemotherapy. The connection between changes in IO-related markers and T-DXd effectiveness justifies future investigation in larger cohorts, notwithstanding the modest sample size. NCT03329690 is the number for the clinical trial.