atezolizumab plus SoC (n=256) vs. placebo plus SoC (n=258)
randomized controlled trial
atezolizumab plus cobimetinib plus vemurafenib
intravenous atezolizumab 840 mg (day 1 and 15) and twice daily oral vemurafenib 960 mg for 21 days plus oncedaily oral cobimetinib 60 mg followed by either twice daily vemurafenib 720 mg in the atezolizumab group or 960 mg for 7 days in the control group. THEN in cycle 2 twice daily vemurafenib 720 mg, and once daily cobimetinib 60 mg (21 days on–7 days off)
placebo plus cobimetinib plus vemurafenib
intravenous placebo (day 1 and 15) and twice daily oral vemurafenib 960 mg for 21 days plus oncedaily oral cobimetinib 60 mg followed by either twice daily vemurafenib 720 mg in the atezolizumab group or 960 mg for 7 days in the control group. THEN in cycle 2 twice daily vemurafenib 720 mg, and once daily cobimetinib 60 mg (21 days on–7 days off)
Patients in the control arm are not eligible for crossover to the treatment arm at diseaseprogression.
mML - L1 - BRAF mutant
Patients with untreated or actively progressing brain metastases, active malignancy other than melanoma, or history of serious autoimmune disease were excluded.
double-blind
112 institutes in 20 countries
P3/two sided and No interim analysis for primary EP. Hierarchical testing procedure (PFS then OS)
The addition of atezolizumab to targeted therapy with vemurafenib and cobimetinib was safe and tolerable and significantly increased progression-free survival in patients with BRAF
nivolumab plus ipilimumab (n=23) vs. ipilimumab alone (n=10)
randomized controlled trial
nivolumab and ipilimumab
nivolumab (1 mg per kilogram) and ipilimumab (3 mg per kilogram of body weight) combined once every 3 weeks for four doses followed by nivolumab (3 mg per kilogram) every 2 weeks until the occurrence of disease progression or unacceptable toxic effects
ipilimumab
ipilimumab (3 mg per kilogram of body weight) combined once every 3 weeks, nivolumab was replaced with matched placebo during both the combination and maintenance portions of the trial.
After the fourth dose of both agents, ipilimumab was discontinued, and thereafter (maintenance phase), nivolumab was administered as a single agent at a dose of 3 mg per kilogram over a period of 60 minutes, once every 2 weeks.
mML - L1 - BRAF mutant
Other inclusion criteria included a known BRAF V600 mutation status and the availability for immunohistochemical assessment of PD-1 ligand (PD-L1) expression
double-blind
United States and France
P2/ two sided test procedure without interim analysis. The primary end point was the rate of investigator-assessed, confirmed objective response among patients with BRAF V600 wild-type tumors. In order to preserve an experiment-wide type I error rate of 5%, a hierarchical testing approach was applied to key secondary end points. a hierarchical testing approach was applied to key secondary end points : ORR WT then ORR ITT then PFS WT then PFS ITTNo statistical analysis planned for BRAF mutant population
The objective-response rate and the progression-free survival among patients with advanced melanoma who had not previously received treatment were significantly greater with nivolumab combined with ipilimumab than with ipilimumab monotherapy.