Abstract CT011: Genomic HER2 amplification predicts for complete clinical response in a phase II study of induction tucatinib and trastuzumab combined with chemotherapy in locally advanced rectal adenocarcinoma

Abstract Background: The standard treatment for locally-advanced rectal adenocarcinoma is trimodality therapy with neoadjuvant chemotherapy and chemoradiation, followed by surgery. A subset of these cases overexpress HER2; therapies that target HER2 signaling may improve therapeutic responses and organ preservation. Methods: We conducted a prospective investigator initiated single-arm study for patients with stage 2-3, HER2-overexpressed, RAS-wild-type, mismatch-repair-proficient rectal cancer. Patients received 6 weeks of induction HER2 targeted therapy with trastuzumab and tucatinib and then continued trastuzumab and tucatinib with the addition of 15 weeks of FOLFOX or CAPOX. Patients with a complete clinical response (cCR) transition to active surveillance without radiation or surgery. Patients with a non-cCR proceeded with SOC chemoradiation or surgery. The primary endpoint is cCR rate that exceeds 40% at completion of trastuzumab/tucatinib/chemotherapy. Overall response rate (ORR) is a key secondary endpoint. Results: Nine patients with stage II (n=2) and III (n=7) rectal adenocarcinoma with at least 2+ expression of HER2 by immunohistochemistry and Fluorescence in Situ Hybridization HER2-amplification were enrolled. Eight of nine patients completed 21 weeks of neoadjuvant therapy with combination HER2/chemotherapy. The study achieved an ORR of 78% (n=7/9) after 6 weeks of trastuzumab and tucatinib and 75% (n=6/8) after 15 additional weeks of combination HER2/chemotherapy. Four patients out of 8 exhibited a cCR after induction trastuzumab/tucatinib/chemotherapy and an additional patient achieved a cCR with subsequent radiation. All remain alive without metastatic recurrence after a median follow-up of 26 months (95% CI 15 mo - not reached). Only patients with 3+ HER2 expression achieved a cCR. Conclusion: Genomic HER2 amplification in early stage rectal adenocarcinoma predicts for complete clinical response to HER2 targeted therapy in combination with chemotherapy, which may guide non-operative management in this patient population. Citation Format: Michael B. Foote, Jinru Shia, Callahan Wilde, Marinela Capanu, Joanne Chou, Vetri Sudar Jayaprakasam, Marc Gollub, Miteshkumar Patel, Mina Ito, Leonard B. Saltz, Devika Rao, Neil Segal, Maliha Nusrat, Karuna Ganesh, Paul Romesser, Julio Garcia-Aguilar, Martin Weiser, Rona Yaeger, Luis A. Diaz, Andrea Cercek. Genomic HER2 amplification predicts for complete clinical response in a phase II study of induction tucatinib and trastuzumab combined with chemotherapy in locally advanced rectal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT011.