title: Safety of an Oral Fixed Combination of Netupitant and Palonosetron (NEPA): Pooled Data From the Phase II/III Clinical Program.
abstract: BACKGROUND
  Standard prophylaxis for chemotherapy-induced nausea and vomiting (CINV) with highly emetogenic and anthracycline-cyclophosphamide-based chemotherapy includes a 5-hydroxytryptamine-3 receptor antagonist, a neurokinin-1 receptor antagonist (NK1RA), and corticosteroid therapy. NEPA is a fixed combination of netupitant and palonosetron. The primary objective of this analysis was to document the safety profile, including cardiac safety, of NEPA + dexamethasone in comparison with current therapies across all phase II/III trials.
  
  
  METHODS
  This pooled analysis was based on data from 3,280 patients in 4 randomized, double-blind clinical trials. Patients were categorized into 1 of 3 pooled groups on the basis of actual treatment received: NEPA + dexamethasone, palonosetron + dexamethasone, and aprepitant + ondansetron/palonosetron + dexamethasone. Safety was assessed by number and frequency of adverse events (AEs) and changes from baseline electrocardiogram measures.
  
  
  RESULTS
  Most patients were female and younger than 65 years of age. Demographic characteristics varied among studies and pooled groups. Frequencies of treatment-emergent AEs (TEAEs) and treatment-related AEs (TRAEs) were similar across groups. TEAEs were mostly mild and consistent with expected chemotherapy and disease-related AEs (hematologic events, hair loss, general weakness). TRAEs in ≥2% of patients were headache and constipation. Frequencies of cardiac TEAEs were similar across groups, with QT prolongation (1.6%), tachycardia (1.1%), and dyspnea (0.9%) the most common. Serious cardiac TEAEs were rare.
  
  
  CONCLUSIONS
  NEPA was well-tolerated, with an AE profile as expected for the regimen. Sample size, demographic characteristics, study design, chemotherapy, and antiemetic regimen differences across the four studies may have contributed to differences in frequencies of neutropenia and alopecia. Adding an NK1RA to a CINV prophylaxis regimen can improve outcomes without additional toxicity.
  
  
  CONCLUSIONS
  Supportive care for cancer should ideally be efficacious, convenient, and well-tolerated. There have been concerns about cardiac safety with current antiemetic prophylactic agents, namely dolasetron and ondansetron. This pooled safety analysis demonstrates that the new oral fixed combination therapy NEPA can be safely added to an antiemetic regimen without increased toxicity.
authors.affiliation: Clinique de Genolier, Genolier, Switzerland maapro@genolier.net.
authors.forename: Matti
authors.initials: M
authors.lastname: Aapro
authors.affiliation: Lahey Hospital and Medical Center, Burlington, Massachusetts, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hesketh
authors.affiliation: University of Halle, Halle, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Jordan
authors.affiliation: Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gralla
authors.affiliation: Helsinn Healthcare, Lugano, Switzerland.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Rossi
authors.affiliation: Helsinn Healthcare, Lugano, Switzerland.
authors.forename: Giada
authors.initials: G
authors.lastname: Rizzi
authors.affiliation: Helsinn Healthcare, Lugano, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Palmas
mesh_terms: D000328:Adult; D000368:Aged; D000932:Antiemetics / Q000627:therapeutic use*; D054316:Biomarkers, Pharmacological; D003907:Dexamethasone / Q000008:administration & dosage / Q000009:adverse effects; D004338:Drug Combinations; D004358:Drug Therapy; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D009369:Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D064729:Neurokinin-1 Receptor Antagonists / Q000627:therapeutic use; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D011812:Quinuclidines / Q000009:adverse effects / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000627:therapeutic use; D014839:Vomiting / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control
chemical_list: D000932:Antiemetics; D054316:Biomarkers, Pharmacological; D004338:Drug Combinations; D007546:Isoquinolines; D064729:Neurokinin-1 Receptor Antagonists; D011725:Pyridines; D011812:Quinuclidines; D058831:Serotonin 5-HT3 Receptor Antagonists; C000595957:netupitant, palosentron drug combination; D003907:Dexamethasone
keywords: Antiemetics; Chemotherapy; Nausea; Neurokinin-1 receptor antagonists; Safety; Serotonin 5-hydroxytryptamine-3 receptor antagonists; Vomiting