title: Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial.
abstract: BACKGROUND
  Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, can result in durable responses in patients with melanoma who have progressed after ipilimumab and BRAF inhibitors. We assessed the efficacy and safety of nivolumab compared with investigator's choice of chemotherapy (ICC) as a second-line or later-line treatment in patients with advanced melanoma.
  
  
  METHODS
  In this randomised, controlled, open-label, phase 3 trial, we recruited patients at 90 sites in 14 countries. Eligible patients were 18 years or older, had unresectable or metastatic melanoma, and progressed after ipilimumab, or ipilimumab and a BRAF inhibitor if they were BRAF(V 600) mutation-positive. Participating investigators randomly assigned (with an interactive voice response system) patients 2:1 to receive an intravenous infusion of nivolumab 3 mg/kg every 2 weeks or ICC (dacarbazine 1000 mg/m(2) every 3 weeks or paclitaxel 175 mg/m(2) combined with carboplatin area under the curve 6 every 3 weeks) until progression or unacceptable toxic effects. We stratified randomisation by BRAF mutation status, tumour expression of PD-L1, and previous best overall response to ipilimumab. We used permuted blocks (block size of six) within each stratum. Primary endpoints were the proportion of patients who had an objective response and overall survival. Treatment was given open-label, but those doing tumour assessments were masked to treatment assignment. We assessed objective responses per-protocol after 120 patients had been treated with nivolumab and had a minimum follow-up of 24 weeks, and safety in all patients who had had at least one dose of treatment. The trial is closed and this is the first interim analysis, reporting the objective response primary endpoint. This study is registered with ClinicalTrials.gov, number NCT01721746.
  
  
  RESULTS
  Between Dec 21, 2012, and Jan 10, 2014, we screened 631 patients, randomly allocating 272 patients to nivolumab and 133 to ICC. Confirmed objective responses were reported in 38 (31·7%, 95% CI 23·5-40·8) of the first 120 patients in the nivolumab group versus five (10·6%, 3·5-23·1) of 47 patients in the ICC group. Grade 3-4 adverse events related to nivolumab included increased lipase (three [1%] of 268 patients), increased alanine aminotransferase, anaemia, and fatigue (two [1%] each); for ICC, these included neutropenia (14 [14%] of 102), thrombocytopenia (six [6%]), and anaemia (five [5%]). We noted grade 3-4 drug-related serious adverse events in 12 (5%) nivolumab-treated patients and nine (9%) patients in the ICC group. No treatment-related deaths occurred.
  
  
  CONCLUSIONS
  Nivolumab led to a greater proportion of patients achieving an objective response and fewer toxic effects than with alternative available chemotherapy regimens for patients with advanced melanoma that has progressed after ipilimumab or ipilimumab and a BRAF inhibitor. Nivolumab represents a new treatment option with clinically meaningful durable objective responses in a population of high unmet need.
  
  
  BACKGROUND
  Bristol-Myers Squibb.
authors: Moffitt Cancer Center, Tampa, FL, USA. Electronic address: jeffrey.weber@moffitt.org.
authors: Jeffrey S
authors: JS
authors: Weber
authors: Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA.
authors: Sandra P
authors: SP
authors: D'Angelo
authors: California Pacific Center for Melanoma Research, San Francisco, CA, USA.
authors: David
authors: D
authors: Minor
authors: Dana-Farber Cancer Institute, Boston, MA, USA.
authors: F Stephen
authors: FS
authors: Hodi
authors: Medizinische Hochschule Hannover, Hannover, Germany.
authors: Ralf
authors: R
authors: Gutzmer
authors: Universitair Ziekenhuis Brussel, Brussels, Belgium.
authors: Bart
authors: B
authors: Neyns
authors: Medical University of Vienna, Vienna, Austria.
authors: Christoph
authors: C
authors: Hoeller
authors: Roswell Park Cancer Institute, Buffalo, NY, USA.
authors: Nikhil I
authors: NI
authors: Khushalani
authors: Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC, Canada.
authors: Wilson H
authors: WH
authors: Miller
authors: University of Michigan, Ann Arbor, MI, USA.
authors: Christopher D
authors: CD
authors: Lao
authors: Washington University, St Louis, MO, USA.
authors: Gerald P
authors: GP
authors: Linette
authors: Centre Hospitalier Universitaire de Lyon, Lyon, France.
authors: Luc
authors: L
authors: Thomas
authors: Christie Hospital, Manchester, UK.
authors: Paul
authors: P
authors: Lorigan
authors: Huntsman Cancer Institute, Salt Lake City, UT, USA.
authors: Kenneth F
authors: KF
authors: Grossmann
authors: German Cancer Research Centre University Hospital, Heidelberg, Germany.
authors: Jessica C
authors: JC
authors: Hassel
authors: Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy.
authors: Michele
authors: M
authors: Maio
authors: Yale Cancer Center, New Haven, CT, USA.
authors: Mario
authors: M
authors: Sznol
authors: Istituto Nazionale Tumori Fondazione G Pascale, Naples, Italy.
authors: Paolo A
authors: PA
authors: Ascierto
authors: Elbe Kliniken Buxtehude, Buxtehude, Germany.
authors: Peter
authors: P
authors: Mohr
authors: Department of Medicine, University of California, Los Angeles, CA, USA.
authors: Bartosz
authors: B
authors: Chmielowski
authors: Department of Medicine, Mayo Clinic, Scottsdale, AZ, USA.
authors: Alan
authors: A
authors: Bryce
authors: Department of Oncology, Herlev Hospital, Copenhagen, Denmark.
authors: Inge M
authors: IM
authors: Svane
authors: Aix-Marseille University, Hopital de la Timone, Marseille, France.
authors: Jean-Jacques
authors: JJ
authors: Grob
authors: Technische Universität München School of Medicine, II Medical Department, Munich, Germany.
authors: Angela M
authors: AM
authors: Krackhardt
authors: Bristol-Myers Squibb, Princeton, NJ, USA.
authors: Christine
authors: C
authors: Horak
authors: Bristol-Myers Squibb, Braine-I'Alleud, Belgium.
authors: Alexandre
authors: A
authors: Lambert
authors: Bristol-Myers Squibb, Princeton, NJ, USA.
authors: Arvin S
authors: AS
authors: Yang
authors: Royal Marsden Hospital, London, UK.
authors: James
authors: J
authors: Larkin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D060908:CTLA-4 Antigen / Q000276:immunology / Q000627:therapeutic use; D016190:Carboplatin / Q000008:administration & dosage; D018572:Disease-Free Survival; D064420:Drug-Related Side Effects and Adverse Reactions / Q000473:pathology*; D005260:Female; D006801:Humans; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D000077594:Nivolumab; D017239:Paclitaxel / Q000008:administration & dosage; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; D000074324:Ipilimumab; D000077594:Nivolumab; D016190:Carboplatin; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D017239:Paclitaxel