title: A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Vanderbilt-Ingram Cancer Center (VICC), Vanderbilt University, Nashville, Tennessee. ingrid.mayer@vanderbilt.edu carlos.arteaga@vanderbilt.edu.
authors.forename: Ingrid A
authors.initials: IA
authors.lastname: Mayer
authors.affiliation: Vanderbilt-Ingram Cancer Center (VICC), Vanderbilt University, Nashville, Tennessee.
authors.forename: Vandana G
authors.initials: VG
authors.lastname: Abramson
authors.affiliation: Vanderbilt-Ingram Cancer Center (VICC), Vanderbilt University, Nashville, Tennessee.
authors.forename: Luigi
authors.initials: L
authors.lastname: Formisano
authors.affiliation: Vanderbilt-Ingram Cancer Center (VICC), Vanderbilt University, Nashville, Tennessee.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Balko
authors.affiliation: Vanderbilt-Ingram Cancer Center (VICC), Vanderbilt University, Nashville, Tennessee.
authors.forename: Mónica V
authors.initials: MV
authors.lastname: Estrada
authors.affiliation: Vanderbilt-Ingram Cancer Center (VICC), Vanderbilt University, Nashville, Tennessee.
authors.forename: Melinda E
authors.initials: ME
authors.lastname: Sanders
authors.affiliation: Massachusetts General Hospital (MGH), Boston, Massachusetts.
authors.forename: Dejan
authors.initials: D
authors.lastname: Juric
authors.affiliation: Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York.
authors.forename: David
authors.initials: D
authors.lastname: Solit
authors.affiliation: Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.affiliation: Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York.
authors.forename: Helen H
authors.initials: HH
authors.lastname: Won
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Li
authors.affiliation: Weill Cornell Medical College, New York, New York.
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.affiliation: Dana-Farber Cancer Institute (DFCI), Boston, Massachusetts.
authors.forename: Eric
authors.initials: E
authors.lastname: Winer
authors.affiliation: Vanderbilt-Ingram Cancer Center (VICC), Vanderbilt University, Nashville, Tennessee. ingrid.mayer@vanderbilt.edu carlos.arteaga@vanderbilt.edu.
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000008:administration & dosage; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D000077289:Letrozole; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009570:Nitriles / Q000008:administration & dosage; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D013844:Thiazoles / Q000008:administration & dosage; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage
chemical_list: D047072:Aromatase Inhibitors; D014408:Biomarkers, Tumor; D000077289:Letrozole; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D011960:Receptors, Estrogen; D013844:Thiazoles; D014230:Triazoles; C585539:Alpelisib