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

Abstract

Purpose: To evaluate the safety and feasibility of ipatasertib combined with trastuzumab and pertuzumab as maintenance therapy after first-line treatment in patients with HER2-positive metastatic breast cancer harboring PIK3CA mutations (PIK3CAmut). Experimental Design: This prospective, multicenter, single-arm, phase 1b study evaluated the safety and preliminary efficacy of ipatasertib, an AKT inhibitor, combined with trastuzumab and pertuzumab (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, 7 days off) with standard HP was established as the recommended phase 2 dose (RP2D). This decision was based on the absence of dose-limiting toxicities in the first six patients treated at this dose during the initial 28-day cycle, which constituted the primary endpoint. Seven (41.2%) patients experienced grade 3 treatment-related adverse events (TRAEs), with diarrhea and nausea being the most frequent. Two (11.8%) reported four serious TRAEs (diarrhea, vomiting, ischemic stroke, and pneumonitis, one case each) related to ipatasertib, from which they recovered. Confirmed overall response rate was 31.1% (95% 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), with 47.3% of patients being 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. Clinicaltrials.gov registration: NCT04253561