Abstract P5-03-11: DEMETHER: A single-arm phase II trial to evaluate the efficacy & safety of subcutaneous pertuzumab & trastuzumab maintenance after induction treatment w/ trastuzumab deruxtecan (T-DXd) for previously untreated HER2-positive advanced breast cancer

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Abstract Background: HER2 (human epidermal growth factor receptor 2) is overexpressed in 15-20% of all breast cancers. Pertuzumab combined with trastuzumab and taxanes is the standard first-line therapy for HER2-positive advanced breast cancer (ABC) based on the results from CLEOPATRA trial. T-DXd has demonstrated unprecedented antitumor activity in patients (pts) with previously treated HER2-positive ABC and has the potential to move into the first-line treatment of this patient population (DESTINY-Breast09). Despite a manageable toxicity profile, prior studies have raised safety concerns about potential serious adverse events associated with its use and a potential negative impact on quality of life (QoL). Taking this into consideration, the rationale of the DEMETHER study is to find the right balance between T-DXd shorter treatment duration and subcutaneous fixed-dose combination of pertuzumab and trastuzumab maintenance therapy to ensure efficacy and tolerance in previously untreated HER2-positive ABC pts. Trial Design DEMETHER (NCT06172127) is an international, multicenter, open-label, single-arm phase II trial. Key inclusion criteria include: (a) Pts aged ≥18 years with centrally-confirmed HER2-positive ABC; (b) No prior chemotherapy and/or HER2-targeted therapy for advanced disease. Participants who have received chemotherapy and/or HER2-targeted therapy in the neo(adjuvant) setting are eligible if ≥ 12 months from completion of systemic treatment to metastatic diagnosis; (c) ECOG performance status of 0-1; (d) Evaluable disease according to RECIST v.1.1. Pts will first receive an induction treatment consisting of 6 cycles of T-DXd (5.4 mg/kg, intravenously, on day 1 of each 21-day cycle). If any T-DXd unacceptable toxicity occurs during the induction phase, participants may receive taxane-based chemotherapy concomitantly with subcutaneous fixed-dose combination of pertuzumab and trastuzumab treatment at the discretion of the Investigator. In the maintenance phase, all participants will be treated with a subcutaneous fixed-dose combination of pertuzumab and trastuzumab each 21-day cycle until disease progression, unacceptable toxicity, patient withdrawal, or up to 3 years after T-DXd initiation. During the maintenance phase, hormone receptor-positive pts will also receive concomitant endocrine therapy. The primary objectives are: 1-year (1-y) progression-free survival (PFS) rate, as locally determined by the Investigator according to RECIST v.1.1; and 3-year (3-y) overall survival (OS) rate. Secondary objectives are median PFS and OS, objective response rate, clinical benefit rate, time to response, duration of response, best percentage of change in tumor burden as per RECIST v.1.1, changes in health-related QoL assessments from baseline (EORTC QLQ-C30, QLQ-BR45, and EQ-5D-5L), and safety and toxicity profiles according to the NCI-CTCAE v.5.0. The primary analyses will be performed using the maximum likelihood method for exponential distributions, with a one-sided significance level of 2.5% for both endpoints. Applying sequentially rejective test, the type I error will be controlled at 5% level. A sample size of 165 patients will allow to achieve 80% power. Date of registration: May (Europe), July-August (FDA-IRB, US), December (Brazil), 2024. First patient enrolled: June (Europe), September (US), December (Brazil), 2024. Citation Format: Javier Cortés, Juan José García-Mosquera, Gabriele Antonarelli, Alessandra Gennari, Carlos Barrios, Giuseppe Curigliano, Hope Rugo, Joseph Gligorov, Nadia Harbeck, Sara M. Tolaney, William J. Gradishar, Peter Schmid, María Gion, Rui Rui Zhan, Emilia Szosta, Paula González-Alonso, Michela Verbeni, José Manuel Pérez-García, Antonio Llombart-Cussac. DEMETHER: A single-arm phase II trial to evaluate the efficacy & safety of subcutaneous pertuzumab & trastuzumab maintenance after induction treatment w/ trastuzumab deruxtecan (T-DXd) for previously untreated HER2-positive advanced breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-03-11.

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