Ipatasertib combined with non-taxane chemotherapy for patients with previously treated advanced triple-negative breast cancer: the PATHFINDER phase IIa trial

Abstract

BACKGROUND: The PI3K/AKT pathway is frequently altered in advanced triple-negative breast cancer (aTNBC), representing a promising target. Ipatasertib, a pan-AKT inhibitor, has shown activity with taxane-based chemotherapy and acceptable safety. This study evaluated the safety and efficacy of ipatasertib with non-taxane chemotherapy for aTNBC. METHODS: The PATHFINDER trial was a multicenter, open-label, non-comparative, phase IIa study with a safety run-in phase. Eligible patients had TNBC pretreated in the advanced setting with one or two chemotherapy regimens, including a taxane, and no prior exposure to PI3K/mTOR/AKT inhibitors. Patients received 21-day cycles of ipatasertib combined with capecitabine (arm A), eribulin (arm B), or carboplatin plus gemcitabine (arm C). The safety run-in phase determined feasibility and phase IIa doses. The primary endpoint was the incidence of treatment-emergent adverse events (TEAEs). Key secondary endpoints included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR). The analysis was exploratory without formal hypothesis testing. RESULTS: A total of 54 patients were assigned to arms A (N = 22), B (N = 25), and C (N = 7). Arm C was discontinued due to toxicity during the safety run-in phase. At data cut-off (November 2023), the overall median follow-up was 12.1 (range: 0.2-35.6) months. Common TEAEs in arm A were diarrhea (59.1%, 0.0% G ? 3), fatigue (36.4%, 0.0% G ? 3), and nausea (36.4%, 0.0% G ? 3); in arm B neutropenia (52.0%; 32.0% G ? 3), diarrhea (52.0%, 4.0% G3) and stomatitis (44.0%; 8.0% G3); and in arm C thrombocytopenia (85.7%, 85.7%G ? 3), anemia (85.7%, 57.1% G ? 3), neutropenia (71.4%, 71.4% G ? 3). No treatment-related deaths occurred. Median PFS was 2.7 (95%CI, 1.5-4.1) and 3.8 (95%CI, 1.5-9.6) months; median OS was 15.5 (95%CI, 11.8-19.3) and 11.5 (95%CI, 8.8-25.1) months; and ORR was 9.1% and 36.0% for arms A and B, respectively. No significant differences in efficacy were observed by PIK3CA mutational status. CONCLUSIONS: Ipatasertib combined with capecitabine or eribulin showed acceptable safety but was not tolerable with carboplatin plus gemcitabine. The addition of ipatasertib to capecitabine or eribulin shows a potential efficacy signal in this patient population, compared to historical monotherapy data of these treatments. Identifying biomarkers to predict response to AKT inhibitors in TNBC is crucial. TRIAL REGISTRATION: www. CLINICALTRIALS: gov , NCT04464174. Registered 09 July 2020.