A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer.

Mayer IA, Abramson VG, Formisano L, Balko JM, Estrada MV, Sanders ME, Juric D, Solit D, Berger MF, Won HH, Li Y, Cantley LC, Winer E, Arteaga CL
Clin Cancer Res. 2017 23 (1): 26-34

PMID: 27126994 · PMCID: PMC5085926 · DOI:10.1158/1078-0432.CCR-16-0134

PURPOSE - Alpelisib, a selective oral inhibitor of the class I PI3K catalytic subunit p110α, has shown synergistic antitumor activity with endocrine therapy against ER/PIK3CA-mutated breast cancer cells. This phase Ib study evaluated alpelisib plus letrozole's safety, tolerability, and preliminary activity in patients with metastatic ER breast cancer refractory to endocrine therapy.

EXPERIMENTAL DESIGN - Twenty-six patients received letrozole and alpelisib daily. Outcomes were assessed by standard solid-tumor phase I methods. Tumor blocks were collected for DNA extraction and next-generation sequencing.

RESULTS - Alpelisib's maximum-tolerated dose (MTD) in combination with letrozole was 300 mg/d. Common drug-related adverse events included hyperglycemia, nausea, fatigue, diarrhea, and rash with dose-limiting toxicity occurring at 350 mg/d of alpelisib. The clinical benefit rate (lack of progression ≥6 months) was 35% (44% in patients with PIK3CA-mutated and 20% in PIK3CA wild-type tumors; 95% CI, 17%-56%), including five objective responses. Of eight patients remaining on treatment ≥12 months, six had tumors with a PIK3CA mutation. Among evaluable tumors, those with FGFR1/2 amplification and KRAS and TP53 mutations did not derive clinical benefit. Overexpression of FGFR1 in ER/PIK3CA mutant breast cancer cells attenuated the response to alpelisib in vitro CONCLUSIONS: The combination of letrozole and alpelisib was safe, with reversible toxicities. Clinical activity was observed independently of PIK3CA mutation status, although clinical benefit was seen in a higher proportion of patients with PIK3CA-mutated tumors. Phase II and III trials of alpelisib and endocrine therapy in patients with ER breast cancer are ongoing. Clin Cancer Res; 23(1); 26-34. ©2016 AACR.

©2016 American Association for Cancer Research.

MeSH Terms (25)

Adult Aged Antineoplastic Combined Chemotherapy Protocols Aromatase Inhibitors Biomarkers, Tumor Breast Neoplasms Cell Line, Tumor DNA Mutational Analysis Female Humans In Situ Hybridization, Fluorescence Letrozole Maximum Tolerated Dose Middle Aged Mutation Neoplasm Metastasis Neoplasm Staging Nitriles Phosphatidylinositol 3-Kinases Receptor, ErbB-2 Receptor, Fibroblast Growth Factor, Type 1 Receptors, Estrogen Thiazoles Treatment Outcome Triazoles

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