Nivolumab in previously untreated melanoma without BRAF mutation.
BACKGROUND
Nivolumab was associated with higher rates of objective response than chemotherapy in a phase 3 study involving patients with ipilimumab-refractory metastatic melanoma. The use of nivolumab in previously untreated patients with advanced melanoma has not been tested in a phase 3 controlled study.


METHODS
We randomly assigned 418 previously untreated patients who had metastatic melanoma without a BRAF mutation to receive nivolumab (at a dose of 3 mg per kilogram of body weight every 2 weeks and dacarbazine-matched placebo every 3 weeks) or dacarbazine (at a dose of 1000 mg per square meter of body-surface area every 3 weeks and nivolumab-matched placebo every 2 weeks). The primary end point was overall survival.


RESULTS
At 1 year, the overall rate of survival was 72.9% (95% confidence interval [CI], 65.5 to 78.9) in the nivolumab group, as compared with 42.1% (95% CI, 33.0 to 50.9) in the dacarbazine group (hazard ratio for death, 0.42; 99.79% CI, 0.25 to 0.73; P<0.001). The median progression-free survival was 5.1 months in the nivolumab group versus 2.2 months in the dacarbazine group (hazard ratio for death or progression of disease, 0.43; 95% CI, 0.34 to 0.56; P<0.001). The objective response rate was 40.0% (95% CI, 33.3 to 47.0) in the nivolumab group versus 13.9% (95% CI, 9.5 to 19.4) in the dacarbazine group (odds ratio, 4.06; P<0.001). The survival benefit with nivolumab versus dacarbazine was observed across prespecified subgroups, including subgroups defined by status regarding the programmed death ligand 1 (PD-L1). Common adverse events associated with nivolumab included fatigue, pruritus, and nausea. Drug-related adverse events of grade 3 or 4 occurred in 11.7% of the patients treated with nivolumab and 17.6% of those treated with dacarbazine.


CONCLUSIONS
Nivolumab was associated with significant improvements in overall survival and progression-free survival, as compared with dacarbazine, among previously untreated patients who had metastatic melanoma without a BRAF mutation. (Funded by Bristol-Myers Squibb; CheckMate 066 ClinicalTrials.gov number, NCT01721772.).
The authors' affiliations are listed in the Appendix.
Caroline
C
Robert
Georgina V
GV
Long
Benjamin
B
Brady
Caroline
C
Dutriaux
Michele
M
Maio
Laurent
L
Mortier
Jessica C
JC
Hassel
Piotr
P
Rutkowski
Catriona
C
McNeil
Ewa
E
Kalinka-Warzocha
Kerry J
KJ
Savage
Micaela M
MM
Hernberg
Celeste
C
Lebbé
Julie
J
Charles
Catalin
C
Mihalcioiu
Vanna
V
Chiarion-Sileni
Cornelia
C
Mauch
Francesco
F
Cognetti
Ana
A
Arance
Henrik
H
Schmidt
Dirk
D
Schadendorf
Helen
H
Gogas
Lotta
L
Lundgren-Eriksson
Christine
C
Horak
Brian
B
Sharkey
Ian M
IM
Waxman
Victoria
V
Atkinson
Paolo A
PA
Ascierto
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D003606:Dacarbazine / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000556:secondary; D008875:Middle Aged; D000077594:Nivolumab; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D015996:Survival Rate; D055815:Young Adult
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D000077594:Nivolumab; D003606:Dacarbazine; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf