title: A randomized, phase II trial of cetuximab with or without PX-866, an irreversible oral phosphatidylinositol 3-kinase inhibitor, in patients with relapsed or metastatic head and neck squamous cell cancer.
abstract: BACKGROUND
  The phosphotidylinositol-3 kinase (PI3K)/serine-threonine kinase/mammalian target of rapamycin signaling pathway is frequently altered in head and neck squamous cell cancer (HNSCC). PX-866 is an oral, irreversible, pan-isoform inhibitor of PI3K. A phase I trial demonstrated tolerability of this combination. This randomized phase II study evaluated PX-866 combined with cetuximab in patients with advanced, refractory HNSCC.
  
  
  METHODS
  Patients with recurrent or metastatic HNSCC who had received at least one and no more than two prior systemic treatment regimens were randomized (1 : 1) to cetuximab with or without PX-866 (8 mg p.o. daily; arms A and B, respectively). The primary end point was progression-free survival (PFS). Secondary end points included objective response rate (ORR), overall survival (OS), toxicity, and correlation of key biomarkers with efficacy outcomes.
  
  
  RESULTS
  Eighty-three patients were enrolled. There was a similar response rate between arms (10% versus 7%). Of patients for whom tissue was assessable, 57% were human papillomavirus (HPV) positive. Median PFS was 80 days in both arms and there was no difference in OS between the two arms (211 versus 256 days). Overall toxicity was higher in arm A compared with arm B, especially in terms of nausea (53% versus 23%), vomiting (45% versus 15%), fatigue (43% versus 23%), diarrhea (40% versus 21%), and hypokalemia (25% versus 10%). Grade 3 or higher adverse events were infrequent, but more common in the combination arm although without a specific pattern. PIK3CA mutations were observed in 17% of the cases assessed, and PTEN loss was infrequently observed.
  
  
  CONCLUSIONS
  The addition of PX-866 to cetuximab did not improve PFS, RR, or OS in patients with advanced, refractory HNSCC enrolled without molecular preselection. In this contemporary cohort, HPV-positive patients comprised the majority, and neither HPV-positive nor HPV-negative patients derived clinical benefit for the addition of cetuximab plus PX-866.
authors.affiliation: Division of Medical Oncology, University of Colorado School of Medicine, Aurora antonio.jimeno@ucdenver.edu roger.cohen@uphs.upenn.edu.
authors.forename: A
authors.initials: A
authors.lastname: Jimeno
authors.affiliation: Medical University of South Carolina, Charleston.
authors.forename: K
authors.initials: K
authors.lastname: Shirai
authors.affiliation: Karmanos Cancer Institute, Detroit, USA.
authors.forename: M
authors.initials: M
authors.lastname: Choi
authors.affiliation: Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Laskin
authors.affiliation: Oncology and Hematology Associates of South West Virginia, Roanoke.
authors.forename: M
authors.initials: M
authors.lastname: Kochenderfer
authors.affiliation: Department of Medical Oncology, Virginia Cancer Specialists, Fairfax US Oncology Research, The Woodlands.
authors.forename: A
authors.initials: A
authors.lastname: Spira
authors.affiliation: Texas Oncology, Round Rock, USA.
authors.forename: V
authors.initials: V
authors.lastname: Cline-Burkhardt
authors.affiliation: London Health Sciences Centre, London, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Winquist
authors.affiliation: Oncothyreon, Inc., Seattle.
authors.forename: D
authors.initials: D
authors.lastname: Hausman
authors.affiliation: Oncothyreon, Inc., Seattle.
authors.forename: L
authors.initials: L
authors.lastname: Walker
authors.affiliation: Abramson Cancer Center of the University of Pennsylvania, Philadelphia, USA antonio.jimeno@ucdenver.edu roger.cohen@uphs.upenn.edu.
authors.forename: R B
authors.initials: RB
authors.lastname: Cohen
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000188:drug therapy*; D000068818:Cetuximab / Q000008:administration & dosage*; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D006067:Gonanes / Q000008:administration & dosage*; D006258:Head and Neck Neoplasms / Q000175:diagnosis / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000188:drug therapy*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D004791:Enzyme Inhibitors; D006067:Gonanes; C496788:PX-866; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000068818:Cetuximab
keywords: PI3K; PIK3CA; cetuximab; combination therapy; head and neck squamous cell cancer