A Phase I study of alpelisib in combination with trastuzumab and LJM716 in patients with PIK3CA-mutated HER2-positive metastatic breast cancer.

Purpose Activating mutations in PIK3CA promote resistance to HER2-targeted therapy in breast cancer, however inhibition of PI3K alone leads to escape via feedback upregulation of HER3. Combined inhibition of HER2, HER3 and PI3K overcomes this mechanism preclinically. Experimental design This phase I study investigated the maximum tolerated dose (MTD) of alpelisib given in combination with trastuzumab and LJM716 (a HER3-targeted antibody) in patients with PIK3CA-mutant HER2-positive metastatic breast cancer (MBC) using the continual reassessment method. Secondary analyses included efficacy and exploratory correlative studies. Results Ten patients were treated initially with daily alpelisib (Arm A). Grade {greater than or equal to}3 adverse events seen in {greater than or equal to}2 patients included diarrhea (n=6), hypokalemia (n=3), abnormal liver enzymes (n=3), hyperglycemia (n=2), mucositis (n=2), and elevated lipase (n=2). The MTD of alpelisib in Arm A was 250mg daily. This prompted the opening of Arm B in which 11 patients received intermittently dosed alpelisib. Grade {greater than or equal to}3 adverse events seen in {greater than or equal to}2 patients included diarrhea (n=5), hypokalemia (n=3), and hypomagnesemia (n=2). The MTD of alpelisib in Arm B was 350mg given 4 days on, 3 days off. Among 17 patients assessed, 1 had a partial response, 14 had stable disease, and 2 had disease progression at best response. Five patients had stable disease for >30 weeks. mRNA profiling of pre-and on-treatment tissue demonstrated PIK3CA target engagement by alpelisib via induction of downstream signaling and feedback pathways. Conclusions Combination treatment with alpelisib, trastuzumab and LJM716 was limited by gastrointestinal toxicity. Further efforts are warranted to target the PI3K pathway in HER2+ MBC.