Abstract 2971: Characterization of targeted ADC and small molecule therapy efficacy toward HER2-mutated XPDX models

Abstract Background: Somatic mutations in the human epidermal growth factor receptor 2 (HER2) gene occur in several cancer types, including bladder, colorectal, lung and cervical. Multiple antibody-drug conjugate (ADC) molecules and small molecule treatments targeting HER2 have been approved; however, comparative in vivo sensitivity of these therapies toward known and novel HER2 mutations is unclear. To better understand the effects of these targeted therapies on specific HER2 variants, we established and characterized a panel of XPDX models harboring various HER2 mutations and benchmarked in vivo sensitivity to targeting ADCs and small molecule therapies. Methods: 18 XPDX models were included in this study. Models representing the S310F mutation in the extracellular domain included ST174 (bile duct), ST524 (colorectal), ST1243 (lung) and ST5025B (bladder) and one cervical model (STM602) with a reported S310Y variant. Models harboring an R678Q mutation in the juxtamembrane domain included ST022 (ovary), ST026 (colorectal) and STF001 (pancreas). Models with mutations in the kinase domain included ST5960 breast (Y735C), STF117 lung (L755F), ST1616B breast (D769Y), ST2594 colorectal (D769Y), ST427 colorectal (V777L), ST4295 ovary (S792F), and ST1456 breast (V842I). Two models ST3107 (lung) and STF059 (colorectal), harboring a YVMA insertion, and the ST3013 (lung) with a 776-777 G/LC indel were also evaluated. Models were characterized for HER2 expression by immunohistochemistry and profiled using WES and RNAseq. For in vivo studies, T-DXd, T-DM1, neratinib, tucatinib, and afatinib were evaluated at standard treatment regimens. Study endpoints included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion; a %T/C of ≤ 20 versus control was considered sensitive. Tumor regression (%T/C<0%) versus Day 0 tumor volume was also reported. Results: The majority of models stained for HER2 at 2+ or 3+ and RNA based expression correlated with IHC results. In vivo, T-DXd or T-DM1 treatment resulted in regressions in ST1243 and ST3013 but were ineffective toward ST5025B. Neratinib reported activity toward ST5025B (%T/C=-80%), ST3107 (%T/C=1%), and ST3013 (%T/C=2%) while tucatinib was found efficacious toward ST5025B (%T/C=12%) and STF117 (%T/C=13%). Afatinib treatment resulted in regressions toward ST427 (%T/C=-25%) and was active in ST3013 (%T/C=8%). Conclusion: We have established and characterized a panel of XPDX models harboring various HER2 mutations and benchmarked in vivo sensitivity toward targeting ADCs and small molecule therapies. This data and model panel can be utilized as a valuable tool in better understanding the utility of HER2-targeting therapies in HER2-mutated cancers. Citation Format: Andre Villegas, Johnnie R. Flores, Alyssa Simonson, Anna Stackpole, Natalia Banos, Amy Fredrickson, Jim Lund, Rose Garcia, Ashley Jamison, Jennifer Garcia, Alexis Nunez, Karen Hernandez, Kyriakos P. Papadoupolos, Victor Moreno, Manish Sharma, Drew Rasco, Andrew Cunningham, Michael J. Wick. Characterization of targeted ADC and small molecule therapy efficacy toward HER2-mutated XPDX models [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 2971.