Abstract PS5-12-23: Herthena-breast01: a phase 1b/2, multicenter, open-label, dose-finding study to evaluate the safety and antitumor activity of patritumab deruxtecan (HER3-DXd) in HER2+ unresectable locally advanced or metastatic breast cancer

Abstract Background: Although HER2-targeted antibody-drug conjugates (ADCs) have improved outcomes in HER2+ advanced or metastatic breast cancer, safe and effective later-line therapies are needed for patients who have progressed on trastuzumab deruxtecan (T-DXd). Human epidermal growth factor receptor 3 (HER3) is expressed in many tumor types, including HER2+ breast cancer. Patritumab deruxtecan (HER3-DXd), a novel ADC that selectively binds HER3, is composed of a fully human anti-HER3 IgG1 antibody linked to a cytotoxic topoisomerase I inhibitor via a tetrapeptide-based cleavable linker (drug-to-antibody ratio, ∼8). In a phase 1/2 study, HER3-DXd monotherapy showed durable antitumor activity and manageable safety in heavily pretreated participants across breast cancer subtypes, including HER2+, HER3-expressing metastatic breast cancer. This phase 1b/2, multicenter, open-label, dose-finding HERTHENA-Breast01 study (NCT06686394) will evaluate safety, pharmacokinetic exposure parameters, and preliminary antitumor activity of HER3-DXd in combination with anti-HER2 agents in participants with HER2+ unresectable locally advanced or metastatic breast cancer. Methods: Eligible participants are ≥18 y with histologically confirmed HER2+ (per most recent ASCO/CAP guidelines: IHC 3+, IHC 2+/in situ hybridization positive [ISH+], or IHC undetermined/ISH+) unresectable locally advanced or metastatic breast cancer. Tumor tissue will be collected at study entry and assessed locally for HER2+ and hormone receptor status. Participants will have measurable disease per RECIST v1.1, ECOG PS of 0 or 1, and adequate organ function. Up to 27 participants will be enrolled in each arm of the study. Participants in Arm 1 will have received 2−5 lines of anti-HER2 therapy in the locally advanced or metastatic setting, including disease progression on prior T-DXd. Participants in Arm 2 will have received a maximum of 5 lines of anti-HER2 therapy in the locally advanced or metastatic setting, with no minimum prior lines of therapy. Participants in Arm 3 will have received 1-3 lines of anti-HER2 therapy in the locally advanced or metastatic setting, including disease progression on T-DXd as the most recent therapy. Participants in Arm 1 will receive HER3-DXd Q3W plus trastuzumab 8 mg/kg IV followed by 6 mg/kg IV Q3W. Participants in Arms 2 and 3 will receive the same regimen as Arm 1, with either pertuzumab 840 mg IV followed by 420 mg IV Q3W (Arm 2) or tucatinib 300 mg orally BID (Arm 3). Dose level decisions (i.e. escalation and de-escalation) will be performed based on the Bayesian Optimal Interval design. Treatment will continue until radiographic progression, unacceptable toxicity, or participant withdrawal. Primary endpoints are dose-limiting toxicities, safety, and treatment discontinuations due to AEs. Secondary endpoints are pharmacokinetics of HER3-DXd ADC, total HER3-DXd antidrug antibody, and free DXd payload. AEs are graded per National Cancer Institute Common Terminology Criteria for Adverse Events 5.0. Enrollment began in early 2025. Citation Format: S. Tolaney, C. Pinheiro, A. Sporchia, Q. Liu, K. M. Hirshfield, H. Iwata. Herthena-breast01: a phase 1b/2, multicenter, open-label, dose-finding study to evaluate the safety and antitumor activity of patritumab deruxtecan (HER3-DXd) in HER2+ unresectable locally advanced or metastatic breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-12-23.