Single-center phase 1b trial of ipatasertib plus endocrine therapy and a CDK4/6 inhibitor for HR+/HER2- metastatic breast cancer

PI3K/AKT pathway activation is implicated in CDK4/6 inhibitor resistance. The phase 1b TAKTIC trial, at Massachusetts General Hospital (Boston) evaluated the oral AKT inhibitor ipatasertib in combination with endocrine therapy with or without palbociclib in patients with treatment-refractory HR-positive, HER2-negative metastatic breast cancer (HR+ HER2- mBC). The trial included adult patients with an ECOG performance status 0-2 and disease progression on at least one previous therapy for metastatic disease. Median age of 77 patients was 62 years and median number of previous lines was 3. Patients received ipatasertib and fulvestrant (n=19), ipatasertib and aromatase inhibitor (AI; n=16), or ipatasertib plus fulvestrant and palbociclib (n=42). The recommended phase 2 dose was 400 mg ipatasertib on dayd 1-21 with 100 mg palbociclib on days 8-28 and standard fulvestrant 500 mg. Median follow-up was 12.5 months (IQR 7.6-19.7). Median progression-free survival was 5.5 months (95% CI 3.8-7.4). Serious adverse events related to study treatment were neutropenia, leukopenia, thrombocytopenia and hyperglycemia. Four death occurred during the study (one possibly treatment-related). The authors conclude that the combination of fulvestrant, ipatasertib, and palbociclib showed preliminary signs of clinical activity with expected adverse events in heavily pretreated patients with HR+ HER2- mBC.