A Phase I Study of Alpelisib in Combination with Trastuzumab and LJM716 in Patients with PIK3CA-Mutated HER2-Positive Metastatic Breast Cancer

Abstract

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. Patients and Methods: This phase I study investigated the MTD of alpelisib given in combination with trastuzumab and LJM716 (a HER3-targeted antibody) in patients with PIK3CA-mutant HER2-positive (HER2+) 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 ≥3 adverse events seen in ≥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 250 mg daily. This prompted the opening of arm B in which 11 patients received intermittently dosed alpelisib. Grade ≥3 adverse events seen in ≥2 patients included diarrhea (n = 5), hypokalemia (n = 3), and hypomagnesemia (n = 2). The MTD of alpelisib in arm B was 350 mg 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.

Landscape of Epidermal Growth Factor Receptor Heterodimers in Brain Metastases

“…The NRG-HER3-HER2 axis has been strongly implicated in HER2+ breast cancer relapse [10,17,27,30,32,61], and preclinical studies have shown that pertuzumab and LJM716 (HER3-inactivating mAb) significantly reduce the outgrowth of experimental HER2+BM [27]. Further clinical development of LJM716 is underway [62,63], though it is unclear if planned clinical trials will assess intracranial progression as a specific endpoint.…”

Breast Cancer Treatments: Updates and New Challenges

“…Alpelisib and taselisib are PI3K isoform-specific inhibitors that were also evaluated in HR+ BC [ 235 , 236 , 238 , 253 , 254 ]. A phase I study evaluated alpelisib in combination with trastuzumab and LJM716 (a HER3-targeted antibody) in patients with PI3KCA mutant HER2+ metastatic BC [ 272 ]. Unfortunately, the results of this study were limited by high gastrointestinal toxicity.…”

Severe Lactic Acidosis Complicated by Insulin-Resistant Hyperosmolar Hyperglycemic Syndrome in a Patient With Metastatic Breast Cancer Undergoing AKT-Inhibitor Therapy

“…25,26 Twenty and twenty-eight percent of the patients with PIK3CA-mutated HER2-positive and hormone receptor-positive, HER2-negative metastatic breast cancer, respectively, developed high-grade hyperglycemia when treated with alpelisib in recent trials. 27,28 In most PAMi studies, hyperglycemia is controlled with metformin less frequently with a second oral agent or insulin and rarely with chemotherapy discontinuation. 3,[29][30][31][32] In 2012, an algorithm for screening and management of DM in PAMi-treated patients was proposed.…”

“…25,26 Twenty and twenty-eight percent of the patients with PIK3CA -mutated HER2-positive and hormone receptor–positive, HER2-negative metastatic breast cancer, respectively, developed high-grade hyperglycemia when treated with alpelisib in recent trials. 27,28…”