Phase I study of LJM716, BYL719, and trastuzumab in patients (pts) with HER2-amplified (HER2+) metastatic breast cancer (MBC).

590 Background: HER2+ breast cancer is driven by HER2/HER3/PI3K signaling. Single agent targeted therapy (tx) is limited by redundant mechanisms of pathway activation and feedback loops; preclinical models support combinatorial tx. This phase I trial examined HER2, HER3 and PI3K inhibition in pts with HER2+ MBC (NCT02167854). Methods: Pts received weekly intravenous (IV) trastuzumab (T) at 2 mg/kg, LJM716 (L, HER3 inhibitor) at 20 mg/kg, and escalating dose cohorts of daily oral BYL719 (B, PI3Kα inhibitor) starting at 250 mg. Eligible pts had HER2+ MBC with a PIK3CA mutation and prior ado-trastuzumab emtansine and pertuzumab. Endpoints were: to define MTD (toxicity based on CTCAE 4.0) using the Continual Reassessment Method, to assess efficacy (RECIST v1.1), to evaluate genomics and proteomics of pre- and on-tx tumor biopsies, and to quantify cell-free DNA and PIK3CA mutant allele fraction (MAF). Results: 8 pts have been treated with a median (M) age 56y (range (R): 46-68), M ECOG of 1 (R: 0-1), and M of ...