A phase II study evaluating treatment discontinuation of dual anti-HER2 therapy in metastatic HER2-positive breast cancer after five years of sustained complete response (FREEDOME-trial).

TPS1143 Background: Dual anti-HER2 therapy with trastuzumab (T) and pertuzumab (P) has transformed outcomes in HER2-positive metastatic breast cancer (mBC), with approximately 20% of patients maintaining response beyond 8 years based on CLEOPATRA trial data. Current practice continues anti-HER2 therapy indefinitely in responding patients, despite lack of evidence supporting necessity of lifelong treatment in long-term responders. This approach is associated with cumulative financial burden, and quality of life impact from indefinite therapy requirements. No prospective data exist regarding optimal duration of anti-HER2 therapy in long-term responders, nor are there validated biomarkers to guide treatment discontinuation decisions. Minimal residual disease (MRD) assessment has shown promise in other malignancies for identifying patients at low risk of recurrence. This study addresses an unmet need for evidence on safety of treatment discontinuation in long-term responders. Methods: This prospective, multicenter, single-arm phase II trial enrolls patients with HER2-positive mBC who have maintained CR for ≥5 years on dual anti-HER2 therapy (T plus P). Target enrollment is 40 patients based on Fleming's single-stage design to detect median progression-free survival (mPFS) >12 months with 80% power (α=0. 05). Key eligibility criteria include: confirmed HER2-positive mBC, sustained CR by RECIST 1. 1 for ≥5 years, normal tumor markers (CA125, CEA, CA15-3), and no evidence of progression on baseline PET-CT. Patients with concurrent malignancies requiring systemic therapy are excluded. Following enrollment, participants discontinue T+P therapy but should continue endocrine therapy (if given). Surveillance includes PET-CT at baseline, 3, 6, 12 months, then annually; annual mammography/ultrasound per institutional standards; and blood collection for tumor markers at baseline, 3, 6, 12 months, then annually. Patients resuming anti-HER2 therapy upon progression remain on study for survival assessment. Primary endpoint is mPFS post-discontinuation. Secondary endpoints include 6-month PFS, 12-month PFS, and median overall survival. Exploratory analyses examine tumor markers as predictive biomarkers. Kaplan-Meier methodology will estimate survival probabilities with 95% confidence intervals. As of January 2026, one site is open for recruitment. Minimal residual disease analysis is planned and will be submitted to the IRB committee for approval. Study completion is anticipated by 2031 with interim analysis planned after 2 years. Clinical trial information: MOH₂025-12-27₀15564.