title: Efficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy: a randomized dose-ranging pivotal study.
abstract: BACKGROUND
  NEPA is a novel oral fixed-dose combination of netupitant (NETU), a new highly selective neurokinin-1 (NK1) receptor antagonist (RA) and palonosetron (PALO), a pharmacologically and clinically distinct 5-hydroxytryptamine type 3 (5-HT3) RA. This study was designed to determine the appropriate clinical dose of NETU to combine with PALO for evaluation in the phase 3 NEPA program.
  
  
  METHODS
  This randomized, double-blind, parallel group study in 694 chemotherapy naïve patients undergoing cisplatin-based chemotherapy for solid tumors compared three different oral doses of NETU (100, 200, and 300 mg) + PALO 0.50 mg with oral PALO 0.50 mg, all given on day 1. A standard 3-day aprepitant (APR) + IV ondansetron (OND) 32 mg regimen was included as an exploratory arm. All patients received oral dexamethasone on days 1-4. The primary efficacy endpoint was complete response (CR: no emesis, no rescue medication) during the overall (0-120 h) phase.
  
  
  RESULTS
  All NEPA doses showed superior overall CR rates compared with PALO (87.4%, 87.6%, and 89.6% for NEPA100, NEPA200, and NEPA300, respectively versus 76.5% PALO; P < 0.050) with the highest NEPA300 dose studied showing an incremental benefit over lower NEPA doses for all efficacy endpoints. NEPA300 was significantly more effective than PALO and numerically better than APR + OND for all secondary efficacy endpoints of no emesis, no significant nausea, and complete protection (CR plus no significant nausea) rates during the acute (0-24 h), delayed (25-120 h), and overall phases. Adverse events were comparable across groups with no dose response. The percent of patients developing electrocardiogram changes was also comparable.
  
  
  CONCLUSIONS
  Each NEPA dose provided superior prevention of chemotherapy-induced nausea and vomiting (CINV) compared with PALO following highly emetogenic chemotherapy; however, NEPA300 was the best dose studied, with an advantage over lower doses for all efficacy endpoints. The combination of NETU and PALO was well tolerated with a similar safety profile to PALO and APR + OND.
authors.affiliation: Lahey Hospital & Medical Center, Burlington, USA. Electronic address: paul.hesketh@lahey.org.
authors.forename: P J
authors.initials: PJ
authors.lastname: Hesketh
authors.affiliation: Corporate Clinical Development and Statistics & Data Management, Helsinn Healthcare SA, Lugano, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Rossi
authors.affiliation: Corporate Clinical Development and Statistics & Data Management, Helsinn Healthcare SA, Lugano, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Rizzi
authors.affiliation: Corporate Clinical Development and Statistics & Data Management, Helsinn Healthcare SA, Lugano, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Palmas
authors.affiliation: Federal State Institution, Privolzhsky District Medical Center under the Federal Medical-Biological Agency of Russia, Nizhny Novgorod, Russia.
authors.forename: A
authors.initials: A
authors.lastname: Alyasova
authors.affiliation: Dnepropetrovsk Medical Academy, Dnepropetrovsk, Ukraine.
authors.forename: I
authors.initials: I
authors.lastname: Bondarenko
authors.affiliation: City Clinical Oncology Dispensary, Saint Petersburg, Russia.
authors.forename: A
authors.initials: A
authors.lastname: Lisyanskaya
authors.affiliation: Albert Einstein College of Medicine, Bronx, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Gralla
mesh_terms: D000284:Administration, Oral; D000970:Antineoplastic Agents / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D006801:Humans; D007546:Isoquinolines / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced / Q000517:prevention & control*; 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; highly emetogenic; netupitant; neurokinin-1 receptor antagonist; palonosetron