Format

Send to

Choose Destination
See comment in PubMed Commons below
Lancet Oncol. 2015 Apr;16(4):375-84. doi: 10.1016/S1470-2045(15)70076-8. Epub 2015 Mar 18.

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.

Author information

1
Moffitt Cancer Center, Tampa, FL, USA. Electronic address: jeffrey.weber@moffitt.org.
2
Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA.
3
California Pacific Center for Melanoma Research, San Francisco, CA, USA.
4
Dana-Farber Cancer Institute, Boston, MA, USA.
5
Medizinische Hochschule Hannover, Hannover, Germany.
6
Universitair Ziekenhuis Brussel, Brussels, Belgium.
7
Medical University of Vienna, Vienna, Austria.
8
Roswell Park Cancer Institute, Buffalo, NY, USA.
9
Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC, Canada.
10
University of Michigan, Ann Arbor, MI, USA.
11
Washington University, St Louis, MO, USA.
12
Centre Hospitalier Universitaire de Lyon, Lyon, France.
13
Christie Hospital, Manchester, UK.
14
Huntsman Cancer Institute, Salt Lake City, UT, USA.
15
German Cancer Research Centre University Hospital, Heidelberg, Germany.
16
Medical Oncology and Immunotherapy, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy.
17
Yale Cancer Center, New Haven, CT, USA.
18
Istituto Nazionale Tumori Fondazione G Pascale, Naples, Italy.
19
Elbe Kliniken Buxtehude, Buxtehude, Germany.
20
Department of Medicine, University of California, Los Angeles, CA, USA.
21
Department of Medicine, Mayo Clinic, Scottsdale, AZ, USA.
22
Department of Oncology, Herlev Hospital, Copenhagen, Denmark.
23
Aix-Marseille University, Hopital de la Timone, Marseille, France.
24
Technische Universität München School of Medicine, II Medical Department, Munich, Germany.
25
Bristol-Myers Squibb, Princeton, NJ, USA.
26
Bristol-Myers Squibb, Braine-I'Alleud, Belgium.
27
Royal Marsden Hospital, London, UK.

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.

FINDINGS:

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.

INTERPRETATION:

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.

FUNDING:

Bristol-Myers Squibb.

PMID:
25795410
DOI:
10.1016/S1470-2045(15)70076-8
[Indexed for MEDLINE]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science
    Loading ...
    Support Center