title: A phase III study evaluating the safety and efficacy of NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting over repeated cycles of chemotherapy.
abstract: BACKGROUND
  Safe, effective and convenient antiemetic regimens that preserve benefit over repeated cycles are needed for optimal supportive care during cancer treatment. NEPA, an oral fixed-dose combination of netupitant, a highly selective NK1 receptor antagonist (RA), and palonosetron (PALO), a distinct 5-HT3 RA, was shown to be superior to PALO in preventing chemotherapy-induced nausea and vomiting after a single cycle of highly (HEC) or moderately (MEC) emetogenic chemotherapy in recent trials. This study was designed primarily to assess the safety but also to evaluate the efficacy of NEPA over multiple cycles of HEC and MEC.
  
  
  METHODS
  This multinational, double-blind, randomized phase III study (NCT01376297) in 413 chemotherapy-naïve patients evaluated a single oral dose of NEPA (NETU 300 mg + PALO 0.50 mg) given on day 1 with oral dexamethasone (DEX). An oral 3-day aprepitant (APR) regimen + PALO + DEX was included as a control (3:1 NEPA:APR randomization). In HEC, DEX was administered on days 1-4 and in MEC on day 1. Safety was assessed primarily by adverse events (AEs), including cardiac AEs; efficacy by complete response (CR: no emesis, no rescue).
  
  
  RESULTS
  Patients completed 1961 total chemotherapy cycles (76% MEC, 24% HEC) with 75% completing ≥4 cycles. The incidence/type of AEs was comparable for both groups. Most frequent NEPA-related AEs included constipation (3.6%) and headache (1.0%); there was no indication of increasing AEs over multiple cycles. The majority of AEs were mild/moderate and there were no cardiac safety concerns based on AEs and electrocardiograms. The overall (0-120 h) CR rates in cycle 1 were 81% and 76% for NEPA and APR + PALO, respectively, and antiemetic efficacy was maintained over repeated cycles.
  
  
  CONCLUSIONS
  NEPA, a convenient single oral dose antiemetic targeting dual pathways, was safe, well tolerated and highly effective over multiple cycles of HEC/MEC.
authors.affiliation: Department of Medical Oncology, Albert Einstein College of Medicine, Jacobi Medical Center, Bronx, USA. Electronic address: richard.gralla@nbhn.net.
authors.forename: R J
authors.initials: RJ
authors.lastname: Gralla
authors.affiliation: Department of Supportive Oncology, Institute for Oncology and Radiology of Serbia, Belgrade, Serbia.
authors.forename: S M
authors.initials: SM
authors.lastname: Bosnjak
authors.affiliation: Chernivtsi Regional Cancer Hospital, Chernivtsi, Ukraine.
authors.forename: A
authors.initials: A
authors.lastname: Hontsa
authors.affiliation: OnkoNet Marburg GmbH, Marburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Balser
authors.affiliation: Department of Statistics and Data Management.
authors.forename: G
authors.initials: G
authors.lastname: Rizzi
authors.affiliation: Department of Corporate Clinical Development, Helsinn Healthcare SA, Lugano, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Rossi
authors.affiliation: Department of Corporate Clinical Development, Helsinn Healthcare SA, Lugano, Switzerland.
authors.forename: M E
authors.initials: ME
authors.lastname: Borroni
authors.affiliation: Department of Hematology and Oncology, University of Halle-Wittenberg, Halle, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Jordan
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects*; D004311:Double-Blind Method; D004338:Drug Combinations; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage* / Q000009:adverse effects; D009325:Nausea / Q000139:chemically induced / Q000517:prevention & control*; D009369:Neoplasms / Q000188:drug therapy; D000077924:Palonosetron; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects; D011812:Quinuclidines / Q000008:administration & dosage* / Q000009:adverse effects; D014839:Vomiting / Q000139:chemically induced / Q000517:prevention & control*; D010879:Piperazines; D044482:Benzeneacetamides
chemical_list: D000970:Antineoplastic Agents; D004338:Drug Combinations; D007546:Isoquinolines; D000077924:Palonosetron; D011725:Pyridines; D011812:Quinuclidines; C508854:netupitant; D010879:Piperazines; D044482:Benzeneacetamides
keywords: CINV; NEPA; multiple chemotherapy cycles; netupitant; neurokinin-1 receptor antagonist; palonosetron