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atezolizumab plus cometinib (n=222) vs. pembrolizumab alone (n=224)
randomized controlled trial
cometinib plus atezolizumab
cobimetinib (60 mg once daily, days 1-21) plus intravenous atezolizumab (840 mg, days 1 plus 15) in 28-day cycles
pembrolizumab
intravenous pembrolizumab (200 mg every 3 weeks)
Dose reductions for atezolizumab or pembrolizumab were not permitted.
mML - L1 - BRAF wild
open label
multicenter
P3/ two sided and no interim analysis. Hierarchical testing procedure (PFS(IRC) then OS then ORR)
Cobimetinib plus atezolizumab did not improve PFS compared with pembrolizumab monotherapy in patients with BRAF mutation
nivolumab alone (n=210) vs. dacarbazine (n=208)
randomized controlled trial
nivolumab
Nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks, plus a dacarbazine-matched placebo every 3 weeks
dacarbazine
1000 mg of dacarbazine per square meter of body-surface area every 3 weeks, plus a nivolumab-matched placebo every 2 weeks.
Treatment continued until there was disease progression, as assessed by the investigator, or an unacceptable level of toxic effects. As a result, the monitoring committee recommended that the study be unblinded and amended to allow patients enrolled in the dacarbazine group to receive nivolumab.
mML - L1 - BRAF wild
exclusion criteria were active brain metastases, ans patients who had received adjuvant therapy previously were not excluded.
double-blind
Europe, Israel, Australia, Canada, and South America
P3/ two sided test procedure with interim analysis. Hierarchy OS then PFS then ORR
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
nivolumab plus ipilimumab (n=72) vs. ipilimumab alone (n=37)
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 wild
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. (in BRAFwild and all population)
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