Addition of Ipatasertib to Dual Anti-HER2 Maintenance Therapy in HER2-Positive Metastatic Breast Tumors with PIK3CA Mutations: The Phase Ib SOLTI-1507 IPATHER Trial

Purpose: The aim of this study was to evaluate the safety and feasibility of ipatasertib combined with trastuzumab and pertuzumab (HP) as maintenance therapy after first-line treatment in patients with HER2-positive metastatic breast cancer harboring PIK3CA mutations (PIK3CAmut). Patients and methods: This prospective, multicenter, single-arm, phase Ib study evaluated the safety and preliminary efficacy of ipatasertib, an AKT inhibitor, combined with HP, with or without endocrine therapy as maintainance therapy, in patients with unresectable locally advanced or metastatic PIK3CAmut, HER2-positive breast cancer following first-line induction chemotherapy and HP. Results: Seventeen patients were enrolled, with a median follow-up of 27.7 months. During the dose-selection phase, ipatasertib at 400 mg daily (21 days on and 7 days off) with standard HP was established as the recommended phase II dosage. This decision was based on the absence of dose-limiting toxicities in the first six patients treated at this dosage during the initial 28-day cycle, which constituted the primary endpoint. Grade 3 treatment-related adverse events (TRAE) occurred in seven patients (41.2%), most commonly diarrhea and nausea. Two (11.8%) reported four serious TRAE (diarrhea, vomiting, ischemic stroke, and pneumonitis, one case each) related to ipatasertib, from which they recovered. The confirmed overall response rate was 31.1% [95% confidence interval (CI), 12.1%-58.5%], clinical benefit rate 84.6% (95% CI, 53.7%-97.3%), and median progression-free survival 16.4 months (95% CI, 9.4-NR); 47.3% of patients were progression free at 18 months. Conclusions: These results support ipatasertib plus HP as a safe and promising maintenance strategy for HER2-positive breast tumors harboring PIK3CAmut.