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nivolumab alone (n=316) vs. ipilimumab alone (n=315)
randomized controlled trial
nivolumab
nivolumab at a dose of 3 mg per kilogram every 2 weeks (plus ipilimumab-matched placebo)
ipilimumab
ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses (plus nivolumab-matched placebo)
mML - L1 - all population
Other eligibility criteria included known BRAF V600 mutation status
double-blind
137 cancer centres in 21 countries
P3/ two sided test procedure without interim analysis (but OS prolonged) (efficacy endpoints were based on the intent-to-treat population and formal co-primary endpoint analyses were conducted at two different prespecified time points (separately for progression-free survival and overall survival) per the study protocol, as described previously)3 arms // repartition : OS 0.02/ARM (N vs I, NI vs I), PFS 0.005/ARM (N vs I, NI vs I), and hierarchical testing procedure for ORR with PFS results (N vs I, NI vs I)
Nivolumab alone or combined with ipilimumab improved progression-free survival (no threshold), as compared with ipilimumab, among previously untreated patients with metastatic melanoma
nivolumab followed by ipilimumab (n=68) vs. ipilimumab followed by nivolumab (n=70)
randomized controlled trial
nivolumab followed by ipilimumab
nivolumab 3 mg/kg as a 60-min intravenous infusion every 2 weeks for up to six doses, followed by a planned switch to ipilimumab 3 mg/kg as a 90-min intravenous infusion every 3 weeks for up to four doses
ipilimumab followed by nivolumab
ipilimumab 3 mg/kg as a 90-min intravenous infusion every 3 weeks for up to four doses followed by a planned switch to nivolumab 3 mg/kg as a 60-min intravenous infusion every 2 weeks for up to six doses (reciprocal planned switch sequence)
time interval between drug sequences was 2 weeks for nivolumab followed by ipilimumab whereas it was 3 weeks for ipilimumab followed by nivolumab patient with clinical benefit were eligible to enter the continuation period and receive nivolumab 3 mg/kg every 2 weeks for up to 2 years
mML - L1 - all population
Patients with active brain metastases were excluded
open label
nine sites in the USA
P2/ No statistical hypothesis testing, sequentiel N=>I vs I=>N No statistical hypothesis testing was planned (PE = safety)
No statistical hypothesis testing was planned to assess differences between groups because the primary endpoint was safety
nivolumab plus ipilimumab (n=314) vs. ipilimumab alone (n=315)
randomized controlled trial
nivolumab plus ipilimumab
nivolumab at a dose of 1 mg per kilogram of body weight every 3 weeks plus ipilimumab at adose of 3 mg per kilogram every 3 weeks for four doses, followed by nivolumab at a dose of3 mg per kilogram every 2 weeks
ipilimumab
ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses (plus nivolumab-matched placebo).
Treatment was continued until disease progression, the occurrence of unacceptable toxicevents, or withdrawal of consent.
mML - L1 - all population
Adults, with known BRAF V600 mutation status,
double blind
137 cancer centres in 21 countries
P3/ two sided test procedure without interim analysis (but OS prolonged) (efficacy endpoints were based on the intent-to-treat population and formal co-primary endpoint analyses were conducted at two different prespecified time points (separately for progression-free survival and overall survival) per the study protocol, as described previously) 3 arms // repartition : OS 0.02/ARM (N vs I, NI vs I), PFS 0.005/ARM (N vs I, NI vs I), and hierarchical testing procedure for ORR with PFS results (N vs I, NI vs I)
Nivolumab alone or combined with ipilimumab improved progression-free survival (no threshold), as compared with ipilimumab, among previously untreated patients with metastatic melanoma
nivolumab plus ipilimumab (n=95) vs. ipilimumab alone (n=47)
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 - all population
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 safety in all randomized population (BRAF mutant and wild type). 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)
nivolumab plus ipilimumab (n=314) vs. nivolumab alone (n=316)
randomized controlled trial
nivolumab plus ipilimumab
nivolumab at a dose of 1 mg per kilogram of body weight every 3 weeks plus ipilimumab at adose of 3 mg per kilogram every 3 weeks for four doses, followed by nivolumab at a dose of3 mg per kilogram every 2 weeks
nivolumab
nivolumab at a dose of 3 mg per kilogram every 2 weeks (plus ipilimumab-matched placebo);
Treatment was continued until disease progression, the occurrence of unacceptable toxicevents, or withdrawal of consent.
mML - L1 - all population
Adults, with known BRAF V600 mutation status
double blind
137 cancer centres in 21 countries
P3/ two sided test procedure without interim analysis (but OS prolonged) (efficacy endpoints were based on the intent-to-treat population and formal co-primary endpoint analyses were conducted at two different prespecified time points (separately for progression-free survival and overall survival) per the study protocol, as described previously) 3 arms: hierarchical testing procedure and repartition : OS 0.02/ARM (N vs I, NI vs I), PFS 0.005/ARM (N vs I, NI vs I), ORR (N vs I, NI vs I) => exploratory for NI vs N
Nivolumab alone or combined with ipilimumab improved progression-free survival (no threshold), as compared with ipilimumab, among previously untreated patients with metastatic melanoma
relatlimab plus nivolumab (n=-9) vs. nivolumab alone (n=-9)
randomized controlled trial
relatlimab plus nivolumab
single fixed-dose intravenous (IV) infusion of 160 mg of relatlimab plus 480 in a fixed-dose coombination or 480 mg of IV nivolumab every 4 weeks.
nivolumab
480 mg of IV nivolumab every 4 weeks.
mML - L1 - all population
double blind
at 111 sites in North America, Central America, South America, Europe, Australia, and New Zealand
P2-3 /
tremelimumab (n=328) vs. Standard of Care (SoC) (n=327)
randomized controlled trial
tremelimumab
tremelimumab at 15 mg/kg once every 90 days for up to four cycles.
physician's choice of standard-of-care chemotherapy (temozolomide or dacarbazine)
either single-agent DTIC (1,000 mg/m2) IV on day 1 of a 21-day cycle or single-agent temozolomide (200 mg/m2) orally on days 1 to 5 of a 28-day cycle, up to 12 cycles. (64.5% dacarbazine and 33.0% temolozomide)
No dose reductions were permitted
mML - L1 - all population
Eligible patients had an Eastern Cooperative Oncology Group performance status of 0 or 1
open label
114 sites in 24 countries
P3/ two sided test procedure with two interim analysis. Repartition alpha with interim analysis (no IC for HR => CALCUL p value)
This study failed to demonstrate a statistically significant survival advantage of treatment with tremelimumab over standard-of-care chemotherapy in first-line treatment of patients with metastatic melanoma
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.
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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