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Ipilimumab (10 mg/kg) (n=40) vs. ipilimumab alone (n=42)
randomized controlled trial
ipilimumab
10 mg/kg ipilimumab every 3 weeks (Q3W) × 4 induction doses
ipilimumab
3 mg/kg ipilimumab every 3 weeks (Q3W) × 4 induction doses
At Week 24 (W24), eligible patients could receive ipilimumab maintenance treatment every 12 weeks (Q12W) or enter a companion study for follow-up and/or extended therapy
mML - L2 - all population
24.4% pretreated with adjuvant and 65.9 pretreated for metastatic disease
double blind
14 sites in 7 European, North American, and South American countries
P2/ no alpha no interim analysis/ objectives did not estimate clinical benefits
PILOT STUDY : objectives did not estimate clinical benefits
Ipilimumab (10 mg/kg) (n=365) vs. ipilimumab alone (n=362)
randomized controlled trial
ipilimumab 10 mg
10 mg/kg ipilimumab was administered by intravenous infusion for 90 min every 3 weeks for four doses. Treatment was continued for a maximum of four doses
Ipilimumab 3 mg
3 mg/kg dose groups, ipilimumab was administered by intravenous infusion for 90 min every 3 weeks for four doses. Treatment was continued for a maximum of four doses
mML - L2 - all population
with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1,
double blind
87 centres in 21 countries worldwide
P3/ two sided test procedure with one interim analysis / hierarchy : OS then PFS, ORR, DCR
In patients with advanced melanoma, ipilimumab 10 mg/kg resulted in significantly longer overall survival than did ipilimumab 3 mg/kg
ipilimumab alone (n=137) vs. gp100 (n=136)
randomized controlled trial
ipilimumab
ipilimumab, at a dose of 3 mg per kilogram of body weight administered once every 3 weeks for four treatments.
gp100
a gp100:209- 217(210M) peptide, 1 mg injected in the right anterior thigh, and a gp100:280-288(288V) peptide, 1 mg injected in the left anterior thigh administered once every 3 weeks for four treatments.
all administered once every 3 weeks for four treatments.
mML - L2 - all population
therapeutic regimen containing one or more of the following: dacarbazine, temozolomide, fotemustine, carboplatin, or interleukin-2.
double blind
25 centers in 13 coun- tries in North America, South America, Europe, and Africa
P3/ two sided test procedure without interim analysis. Hierarchy : OS ipi gp100 vs gp100 alone than OS ipi alone vs gp100 alone
Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma.
ipilimumab plus gp100 (n=403) vs. gp100 (n=136)
randomized controlled trial
ipilimumab plus a gp100 peptide vaccine
ipilimumab, at a dose of 3 mg per kilogram of body weight, plus a gp100 peptide vaccine
gp100
gp100:209- 217(210M) peptide, 1 mg injected in the right anterior thigh, and a gp100:280-288(288V) pep- tide, 1 mg injected in the left anterior thigh.
all administered once every 3 weeks for four treatments.
mML - L2 - all population
therapeutic regimen containing one or more of the following: dacarbazine, temozolomide, fotemus- tine, carboplatin, or interleukin-2.
double blind
25 centers in 13 countries in North America, South America, Europe, and Africa
P3/ two sided test procedure without interim analysis. hierarchy : OS ipi gp100 vs gp100 alone than OS ipi alone vs gp100 alone
Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma.
ipilimumab plus gp100 (n=403) vs. ipilimumab alone (n=137)
randomized controlled trial
ipilimumab plus gp100
ipilimumab, at a dose of 3 mg per kilogram of body weight plus gp100:209- 217(210M) peptide, 1 mg injected in the right anterior thigh, and a gp100:280-288(288V) pep- tide, 1 mg injected in the left anterior thigh.
Ipilimumab
ipilimumab, at a dose of 3 mg per kilogram of body weight
all administered once every 3 weeks for four treatments.
mML - L2 - all population
therapeutic regimen containing one or more of the following: dacarbazine, temozolomide, fotemus- tine, carboplatin, or interleukin-2.
double blind
25 centers in 13 coun- tries in North America, South America, Europe, and Africa
P3/ two sided test procedure without interim analysis. Hierarchy : OS ipi gp100 vs gp100 alone than OS ipi alone vs gp100 alone
Ipilimumab, with or without a gp100 peptide vaccine, as compared with gp100 alone, improved overall survival in patients with previously treated metastatic melanoma.
ipilimumab plus SoC (n=250) vs. placebo plus SoC (n=252)
randomized controlled trial
ipilimumab plus dacarbazine
ipilimumab plus dacarbazine (10 mg per kilogram plus 850 mg per square meter of body-surface area) given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeksthrough week 22.
dacarbazine plus placebo
dacarbazine (850 mg per square meter) plus placebo given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22.
No cross over, they were eligible to enter a maintenance phase in which they received placebo or ipilimumab every 12 weeks.
mML - L2 - all population
patients were ineligible if they had evidence of brain metastasis (as confirmed on imaging), primary ocular or mucosal melanoma, or autoimmune disease
double-blind
multinational
P3/ two sided test procedure without interim analysis. A hierarchical testing procedure was implemented in the order of the following end points: overall survival, progression- free survival, rate of disease control, and rate of best overall response
Ipilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, ascompared with dacarbazine plus placebo, improved overall survival in patients withpreviously untreated metastatic melanoma.
nivolumab alone (n=272) vs. Standard of Care (SoC) (n=133)
randomized controlled trial
nivolumab
nivolumab 3 mg/kg every 2 weeks until progression or unacceptable toxic effects. We allowed treatment with nivolumab beyond progression for patients experiencing clinical benefit and tolerating the drug as established by the investigator.
chemotherapy (investigator’s choice)
dacarbazine 1000 mg/m² every 3 weeks or paclitaxel 175 mg/m² combined with carboplatin area under the curve 6 every 3 weeks). (dacarbazine,33.8%; paclitaxel,42.9%) Treatment was given open-label because of the choices available to the investigators in the ICC group
We did not allow dose reductions with nivolumab treatment (dose reductions for chemotherapy were per institutional standards of care); however, we allowed dose delays
mML - L2 - all population
patients with active brain metastases and individuals who had had previous treatment with anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies;were excluded
open-label
90 sites in 14 countries
P3/ two sided test procedure with one interim analysis. Repartition between coprimary endpoint, and hierarchy for secondary endpoints
Nivolumab demonstrated higher, more durable responses but no difference in survival compared with ICC.
pembrolizumab (10mg/kg) (n=277) vs. ipilimumab alone (n=278)
randomized controlled trial
pembrolizumab every 3 wk
pembrolizumab at a dose of 10 mg per kilogram of body weight every 3 weeks
ipilimumab
ipilimumab at a dose of 3 mg per kilogram every 3 weeks.
Although crossover was not allowed per protocol, after the second interim analysis, an external data monitoring committee recommended making pembrolizumab available to patients in KEYNOTE-006
mML - L2 - all population
Known BRAF V600 mutational status was required. Excluded from the study were patients with ocular melanoma, active brain metastases, or a history of serious autoimmune disease.
open label
16 countries
P3/ one sided test procedure with two interim analysis. 3 arms pembrolizumab 2 weeks or 3 weeks versus ipilimumab - Subgroup BRAFV600E/K status (mutant previously treated) repartition between coprimary endpoint PFS OS
Substantiating the results of the interim analyses of KEYNOTE-006, pembrolizumab continued to provide significantly superior overall survival and progression free survival versus ipilimumab, with no difference between pembrolizumab dosing schedules
pembrolizumab (10mg/kg) (n=181) vs. Standard of Care (SoC) (n=179)
randomized controlled trial
pembrolizumab
pembrolizumab 10 mg/kg given intravenously every 3 weeks
ICC (carboplatin plus paclitaxel, dacarbazine, paclitaxel alone or oral temozolomid)
(paclitaxel plus carboplatin (23.4%), paclitaxel (15.6%), carboplatin (7.2%) [eliminated with protocol amendment one], dacarbazine (25.1%) , or oral temozolomide (24.0%))
the patient could cross over (48%) to receive pembrolizumab after a washout period
mML - L2 - all population
We excluded patients with known active brain metastases.
open label
73 hospitals, clinics, and academic medical centres in 12 countries
P2/ one sided test procedure with two interim analysis. 3 arms pembrolizumab 2mg/kg, 10mg/kg vs chemotherapy. repartition PFS (0.0025/arm) and OS (0.01/arm) in one-sided
Improvement in OS with pembrolizumab was not statistically significant at either dose versus chemotherapy.
pembrolizumab (10mg/kg) 2 weeks (n=279) vs. ipilimumab alone (n=278)
randomized controlled trial
pembrolizumab every 2 wk
pembrolizumab at a dose of 10 mg per kilogram of body weight every 2 weeks
ipilimumab
ipilimumab at a dose of 3 mg per kilogram every 3 weeks.
Although crossover was not allowed per protocol, after the second interim analysis, an external data monitoring committee recommended making pembrolizumab available to patients in KEYNOTE-006
mML - L2 - all population
Known BRAF V600 mutational status was required. Excluded from the study were patients with ocular melanoma, active brain metastases, or a history of serious autoimmune disease.
open label
16 countries
P3/ one sided test procedure with two interim analysis. 3 arms pembrolizumab 2 weeks or 3 weeks versus ipilimumab - Subgroup BRAFV600E/K status (mutant previously treated) repartition between coprimary endpoint PFS OS
Substantiating the results of the interim analyses of KEYNOTE-006, pembrolizumab continued to provide significantly superior overall survival and progression free survival versus ipilimumab, with no difference between pembrolizumab dosing schedules
pembrolizumab (2mg/kg) (n=180) vs. Standard of Care (SoC) (n=179)
randomized controlled trial
pembrolizumab
pembrolizumab 2 mg/kg given intravenously every 3 weeks
ICC (carboplatin plus paclitaxel, dacarbazine, paclitaxel alone or oral temozolomid)
(paclitaxel plus carboplatin (23.4%), paclitaxel (15.6%), carboplatin (7.2%) [eliminated with protocol amendment one], dacarbazine (25.1%) , or oral temozolomide (24.0%))
A designated pharmacist at each site who was unmasked prepared the pembrolizumab dose so that it could be administered to the patient in a masked fashionthey could cross over to receive pembrolizumab after a washout period
mML - L2 - all population
Randomisation was stratifi ed by ECOG performance status (0 vs 1), lactate dehydrogenaseconcentration, and BRAF status
open label
73 hospitals, clinics, and academic medical centres in 12 countries
P2/ one sided test procedure with two interim analysis. 3 arms pembrolizumab 2mg/kg, 10mg/kg vs chemotherapy. repartition PFS (0.0025/arm) and OS (0.01/arm) in one-sided
Improvement in OS with pembrolizumab was not statistically significant at either dose versus chemotherapy.
pembrolizumab plus SoC (n=60) vs. placebo plus SoC (n=60)
randomized controlled trial
pembrolizumab, with dabrafenib and trametinib
pembrolizumab 2 mg/kg intravenously every 3 weeks intravenously every 3 weeks with dabrafenib and trametinib (dabrafenib 150 mg bid plus trametinib 2 mg qd)
placebo with dabrafenib and trametinib
Placebo Q3W with dabrafenib and trametinib (dabrafenib 150 mg bid plus trametinib 2 mg qd)
mML - L2 - BRAF mutant
BRAF mutation-positive and has received prior systemic therapy for metastatic or advanced melanoma. those who had received previous systemic therapy for metastatic or advanced melanoma were not eligible to participate
double blind
22 sites in seven countries (Australia, New Zealand, Canada, Denmark, Italy, Israel, and USA)
P2/ one sided test procedure without interim analysis. No statistic plan found exept for PE (P value of 0.0025 to be declared a statistically significant improvement in this small randomized trial. Therefore, the improvement in progressionfreesurvival is numerical and not statistically significant in the current clinical trial.)OR (Assuminga hazard ratio of 0.5, approximately 74 progression-free survival events were necessary to have 80% power to reject the null hypothesis at one-sided 0.025 type I error.)
triplet therapy with dabrafenib, trametinib and pembrolizumab did not meet its primary endpoint PFS compared with the doublet therapyof dabrafenib, trametinib and placebo
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