Abstract 7148: Exploratory biomarker analysis of trastuzumab deruxtecan (T-DXd) treatment for HER2-positive (HER2+) metastatic colorectal cancer (mCRC) in DESTINY-CRC02 (DC-02)

Abstract Background: T-DXd showed clinically meaningful antitumor activity in patients (pts) with HER2+ mCRC in the phase 2 DC-02 trial (NCT04744831). Exploratory baseline circulating tumor DNA (ctDNA) analyses of HER2 (ERBB2), PIK3CA, and RAS mutation (mut) status and blood-based tumor mutational burden were reported previously (Raghav et al. 2024). This study reports the relationship between other CRC-related genes and efficacy of T-DXd in HER2+ mCRC. Methods For this analysis, data were combined from 122 pts enrolled in the 5.4 and 6.4 mg/kg T-DXd cohorts. Transcriptome analysis by RNA sequencing with ribosome depletion was performed on 102/107 available baseline (BL) archival tissue samples. ctDNA from blood collected at BL (n = 120/120) and after 2 T-DXd treatment cycles (C3D1; n = 97/103 paired BL/C3D1 samples) was analyzed at Guardant Health to determine genomic landscape (OMNI, ∼500 genes) and molecular response (MR; G360, ∼74 genes). Results: By ctDNA, alterations (any) in TP53 (84.2%), APC (77.5%), FLT3 (63.3%), and PREX2 (52.5%) were most common; 82.5% and 24.2% of pts had HER2 amplification (amp) or mut, respectively. Pts with APC mut or ≥ median ABCB1 (P-gp) transporter gene expression tended to have lower objective response rate (ORR) and shorter median progression-free survival (PFS; Table). PFS appeared to be shorter in pts with EGFR amp (Table), although this group also had higher ctDNA levels, which is negatively prognostic. Complete MR at C3D1 was associated with the highest ORR and longest PFS, while ORR was lowest and PFS shortest when MR was absent (Table). Conclusions: Several genetic biomarkers with known prognostic effects in CRC, including EGFR or APC alterations, were potentially associated with T-DXd efficacy. MR analyses suggested magnitude of ctDNA reduction at C3D1 could be predictive of T-DXd clinical response. Further analysis is needed to assess these biomarkers’ predictive vs prognostic value. Citation Format: Salvatore Siena, Kanwal Raghav, Atsuo Takashima, Takeshi Kato, Marc Van den Eynde, Filippo Pietrantonio, Yoshito Komatsu, Hisato Kawakami, Marc Peeters, Thierry Andre, Sara Lonardi, Kensei Yamaguchi, Jeanne Tie, Cristina Gravalos Castro, John H. Strickler, Yoshinobu Shiose, Makito Koga, Aislyn Boran, Dipica Haribhai, Hiroki Goto, Daniel Barrios, Kodai Abe, Takayuki Yoshino. Exploratory biomarker analysis of trastuzumab deruxtecan (T-DXd) treatment for HER2-positive (HER2+) metastatic colorectal cancer (mCRC) in DESTINY-CRC02 (DC-02) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7148.