Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial.
BACKGROUND
Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone. We report 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma.


METHODS
In this multicentre, double-blind, randomised, controlled, phase 2 trial (CheckMate 069) we recruited patients from 19 specialist cancer centres in two countries (France and the USA). Eligible patients were aged 18 years or older with previously untreated, unresectable stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 2:1 to receive an intravenous infusion of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or ipilimumab 3 mg/kg plus placebo, every 3 weeks for four doses. Subsequently, patients assigned to nivolumab plus ipilimumab received nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity, whereas patients allocated to ipilimumab alone received placebo every 2 weeks during this phase. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by BRAF mutation status. The study funder, patients, investigators, and study site staff were masked to treatment assignment. The primary endpoint, which has been reported previously, was the proportion of patients with BRAFV600wild-type melanoma achieving an investigator-assessed objective response. Overall survival was an exploratory endpoint and is reported in this Article. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all treated patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01927419, and is ongoing but no longer enrolling patients.


RESULTS
Between Sept 16, 2013, and Feb 6, 2014, we screened 179 patients and enrolled 142, randomly assigning 95 patients to nivolumab plus ipilimumab and 47 to ipilimumab alone. In each treatment group, one patient no longer met the study criteria following randomisation and thus did not receive study drug. At a median follow-up of 24·5 months (IQR 9·1-25·7), 2-year overall survival was 63·8% (95% CI 53·3-72·6) for those assigned to nivolumab plus ipilimumab and 53·6% (95% CI 38·1-66·8) for those assigned to ipilimumab alone; median overall survival had not been reached in either group (hazard ratio 0·74, 95% CI 0·43-1·26; p=0·26). Treatment-related grade 3-4 adverse events were reported in 51 (54%) of 94 patients who received nivolumab plus ipilimumab compared with nine (20%) of 46 patients who received ipilimumab alone. The most common treatment-related grade 3-4 adverse events were colitis (12 [13%] of 94 patients) and increased alanine aminotransferase (ten [11%]) in the combination group and diarrhoea (five [11%] of 46 patients) and hypophysitis (two [4%]) in the ipilimumab alone group. Serious grade 3-4 treatment-related adverse events were reported in 34 (36%) of 94 patients who received nivolumab plus ipilimumab (including colitis in ten [11%] of 94 patients, and diarrhoea in five [5%]) compared with four (9%) of 46 patients who received ipilimumab alone (including diarrhoea in two [4%] of 46 patients, colitis in one [2%], and hypophysitis in one [2%]). No new types of treatment-related adverse events or treatment-related deaths occurred in this updated analysis.


CONCLUSIONS
Although follow-up of the patients in this study is ongoing, the results of this analysis suggest that the combination of first-line nivolumab plus ipilimumab might lead to improved outcomes compared with first-line ipilimumab alone in patients with advanced melanoma. The results suggest encouraging survival outcomes with immunotherapy in this population of patients.


BACKGROUND
Bristol-Myers Squibb.
Dana-Farber Cancer Institute, Boston, MA, USA. Electronic address: stephen_hodi@dfci.harvard.edu.
F Stephen
FS
Hodi
University of Louisville, Louisville, KY, USA.
Jason
J
Chesney
New York University, New York, NY, USA.
Anna C
AC
Pavlick
Gustave Roussy, INSERM U981, Paris, France.
Caroline
C
Robert
Huntsman Cancer Institute, Salt Lake City, UT, USA.
Kenneth F
KF
Grossmann
Beth Israel Deaconess Medical Center, Boston, MA, USA.
David F
DF
McDermott
Washington University School of Medicine, St Louis, MO, USA.
Gerald P
GP
Linette
Institut Universitaire du Cancer, Toulouse, France.
Nicolas
N
Meyer
Greenville Health System Cancer Institute, Greenville, SC, USA.
Jeffrey K
JK
Giguere
St Luke's Cancer Center and Temple University, Bethlehem, PA, USA.
Sanjiv S
SS
Agarwala
University of New Mexico, Albuquerque, NM, USA.
Montaser
M
Shaheen
Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA.
Marc S
MS
Ernstoff
California Pacific Center for Melanoma Research, San Francisco, CA, USA.
David R
DR
Minor
Duke University Medical Center, Durham, NC, USA.
April K
AK
Salama
Oregon Health & Science University, Portland, OR, USA.
Matthew H
MH
Taylor
Dana-Farber Cancer Institute, Boston, MA, USA.
Patrick A
PA
Ott
Bristol-Myers Squibb, Princeton, NJ, USA.
Christine
C
Horak
Bristol-Myers Squibb, Princeton, NJ, USA.
Paul
P
Gagnier
Bristol-Myers Squibb, Princeton, NJ, USA.
Joel
J
Jiang
Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA.
Jedd D
JD
Wolchok
Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA.
Michael A
MA
Postow
D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D004311:Double-Blind Method; D006801:Humans; D000074324:Ipilimumab; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D009154:Mutation; D000077594:Nivolumab; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics
D000911:Antibodies, Monoclonal; D000074324:Ipilimumab; D000077594:Nivolumab; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf