Abstract Introduction: The HER2-targeted doublet, tucatinib and trastuzumab, recently received FDA approval for previously treated HER2-positive metastatic colorectal cancer (mCRC). While the intensity of HER2 IHC staining and ERBB2 amplification have been proposed as potential markers of response, our understanding of the role of the tumor microenvironment remains limited. Methods: The phase II MOUNTAINEER Trial (NCT03043313) enrolled patients for tucatinib plus trastuzumab based on HER2 positivity (IHC or NGS amplification). Patients from cohort A with available HER2 IHC and H50%. Tumors with below median iTIL or sTIL had significantly shorter PFS. Notably, tumors with sTIL density in the bottom quantile had an ORR of 0% and PFS HR of 4.40 (P=0.002) despite including cases with high AI-H3+. TIL densities and AI-H3+ percentage were not correlated. Conclusion: These findings confirm AI-quantified HER2 intensity as a marker of response and suggests the importance of TILs, which may have a role through immunogenic cell death. Stratification by HER2 and TIL may be an approach to consider as this regimen progresses into the first-line setting. Citation Format: Mitsuho Imai, John H. Strickler, Woochan Hwang, Kara Bonneau, Andrew B. Nixon, Jongchan Park, Chang Ho Ahn, Tanios Bekaii-Saab, Takayuki Yoshino. HER2 expression and tumor-infiltrating lymphocytes predict response to tucatinib plus trastuzumab in HER2-positive metastatic colorectal cancer (MOUNTAINEER): Exploratory analysis of a multicenter, Phase II trial abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7735.
Imai et al. (Fri,) studied this question.