Authors: Kohei Shitara, Yung-Jue Bang, Satoru Iwasa, Naotoshi Sugimoto, Min-Hee Ryu, Daisuke Sakai, Hyun Cheol Cheol Chung, Yasushi Omuro, Hisato Kawakami, Hiroshi Yabusaki, Yasuhiro Sakamoto, Tomohiro Nishina, Koichiro Inaki, Yusuke Kuwahara, Fumitaka Suto, Masahiro Sugihara, Kaku Saito, Akihito Kojima, Kensei Yamaguchi
Published: 2022-01-19
DOI: 10.1200/jco.2022.40.4_suppl.322
Source: Full article
322 Background: T-DXd is a HER2-targeting antibody-drug conjugate. In primary analyses of DG-01 (NCT03329690), T-DXd showed clinically meaningful improvement in objective response rate (ORR) and overall survival (OS) vs chemotherapy in the primary cohort of pts with HER2+ advanced gastric cancer (AGC; IHC3+ or IHC2+/ISH+; Shitara K et al. NEJM 2020;382:2419). In the context of emerging first-line ICI-based regimens in AGC, we conducted a post hoc analysis of T-DXd clinical outcomes and baseline BMs in pts with or without prior ICI. Methods: DG-01 primary cohort enrolled pts who progressed on ≥2 prior lines with centrally confirmed HER2+ AGC. Efficacy and safety were assessed in pts with or without prior ICI (defined as any ICI-related treatment received prior to T-DXd). Exploratory BM analysis in the T-DXd arm assessed RNA sequencing (RNAseq) of tumor biopsies and ctDNA of liquid biopsies taken immediately before T-DXd treatment. A linear regression model and Wilcoxon rank-sum test were used to identify differentially expressed genes and signature scores between pts with or without prior ICI. Results: Prior ICI was received in 35.2% (44/125) of pts treated with T-DXd and 27.4% (17/62) treated with chemotherapy. The table shows efficacy in pts with or without prior ICI. Safety data in the T-DXd arm were similar between pts with or without prior ICI, including adjudicated drug-related interstitial lung disease/pneumonitis; 9.1% (4/44) of pts with prior ICI and 9.9% (8/81) of pts without prior ICI. Among 34 T-DXd-treated pts with RNAseq data, 12 received prior ICI. Searching for differentially expressing genes (fold change ≥2, P≤0.01) identified multiple genes with a higher trend for expression in tumors with prior ICI, 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 showed a concurrent higher trend of multiple chemokine gene expressions in the prior ICI group. Conclusions: This exploratory analysis suggests that treatment with T-DXd results in better outcomes than chemotherapy regardless of prior ICI. Given a relatively small sample size, the relationship between changes in IO-related signatures and efficacy of T-DXd warrants further evaluation in larger cohorts. Clinical trial information: NCT03329690. [Table: see text]