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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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