title: Stand up to cancer phase Ib study of pan-phosphoinositide-3-kinase inhibitor buparlisib with letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer.
abstract: OBJECTIVE
  Buparlisib, an oral reversible inhibitor of all class I phosphoinositide-3-kinases, has shown antitumoral activity against estrogen receptor (ER)-positive breast cancer cell lines and xenografts, alone and with endocrine therapy. This phase Ib study evaluated buparlisib plus letrozole's safety, tolerability, and preliminary activity in patients with metastatic ER-positive breast cancer refractory to endocrine therapy.
  
  
  METHODS
  Patients received letrozole and buparlisib in two different administration schedules. Outcomes were assessed by standard solid-tumor phase I methods. [(18)F]fluorodeoxyglucose-positron emission tomography/computed tomography ([(18)F]FDG-PET/CT) scans were done at baseline and 2 weeks after treatment initiation. Tumor blocks were collected for phosphoinositide-3-kinase pathway mutation analysis.
  
  
  RESULTS
  Fifty-one patients were allocated sequentially to continuous or intermittent (five on/two off days) buparlisib administration on an every-4-week schedule. Buparlisib's maximum-tolerated dose (MTD) was 100 mg/d. Common drug-related adverse events included ≤ grade 2 hyperglycemia, nausea, fatigue, transaminitis, and mood disorders. The clinical benefit rate (lack of progression ≥ 6 months) among all patients treated at the MTD was 31%, including two objective responses in the continuous dose arm. Of seven patients remaining on treatment ≥ 12 months, three had tumors with PIK3CA hot-spot mutation. Patients exhibiting metabolic disease progression by [(18)F]FDG-PET/CT scan at 2 weeks progressed rapidly on therapy.
  
  
  CONCLUSIONS
  The letrozole and buparlisib combination was safe, with reversible toxicities regardless of schedule administration. Clinical activity was observed independent of PIK3CA mutation status. No metabolic response by [(18)F]FDG-PET/CT scan at 2 weeks was associated with rapid disease progression. Phase III trials of buparlisib and endocrine therapy in patients with ER-positive breast cancer are ongoing.
authors.affiliation: Ingrid A. Mayer, Vandana G. Abramson, Justin M. Balko, María Gabriela Kuba, Melinda E. Sanders, and Carlos L. Arteaga, Vanderbilt University, Nashville, TN; Steven J. Isakoff, Massachusetts General Hospital, Boston, MA; Andres Forero, University of Alabama, Birmingham, AL; Jeffrey T. Yap, Huntsman Cancer Institute, Salt Lake City, UT; Annick D. Van den Abbeele and Eric Winer, Dana-Farber Cancer Institute, Boston, MA; Yisheng Li, MD Anderson Cancer Center, Houston, TX; and Lewis C. Cantley, Weill Cornell Medical College, New York, NY.
authors.forename: Ingrid A
authors.initials: IA
authors.lastname: Mayer
authors.forename: Vandana G
authors.initials: VG
authors.lastname: Abramson
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Isakoff
authors.forename: Andres
authors.initials: A
authors.lastname: Forero
authors.forename: Justin M
authors.initials: JM
authors.lastname: Balko
authors.forename: María Gabriela
authors.initials: MG
authors.lastname: Kuba
authors.forename: Melinda E
authors.initials: ME
authors.lastname: Sanders
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Yap
authors.forename: Annick D
authors.initials: AD
authors.lastname: Van den Abbeele
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Li
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.forename: Eric
authors.initials: E
authors.lastname: Winer
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
mesh_terms: D000328:Adult; D000368:Aged; D000631:Aminopyridines / Q000008:administration & dosage / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D000077289:Letrozole; D008875:Middle Aged; D009025:Morpholines / Q000008:administration & dosage / Q000009:adverse effects; D064847:Multimodal Imaging; D009570:Nitriles / Q000008:administration & dosage / Q000009:adverse effects; D000081082:Phosphoinositide-3 Kinase Inhibitors; D049268:Positron-Emission Tomography; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D019275:Radiopharmaceuticals; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000096:biosynthesis; D014057:Tomography, X-Ray Computed; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D058534:Class I Phosphatidylinositol 3-Kinases; D019788:Fluorodeoxyglucose F18; D000077289:Letrozole; D009025:Morpholines; D009570:Nitriles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D019275:Radiopharmaceuticals; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D014230:Triazoles; C571178:NVP-BKM120; C484760:PIK3CA protein, human; C508053:ERBB2 protein, human