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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
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
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 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
nivolumab alone (n=453) vs. Ipilimumab (10 mg/kg) (n=453)
randomized controlled trial
nivolumab
nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks
ipilimumab
ipilimumab at a dose of 10 mg per kilogram every 3 weeks for four doses and then every 12 weeks
traetment along with corresponding matching placebo
mML - NA - all population
double-blind
130 centers in 25 countries
P3/ two sided test procedure with one interim analysis. The critical hazard ratio was 0.78 with an adjusted alpha level of 0.0244 (two-sided). (no other strategy in SAP)
Among patients undergoing resection of stage IIIB, IIIC, or IV melanoma, adjuvant therapy with nivolumab resulted in significantly longer recurrence-free survival and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab
nivolumab alone (n=59) vs. placebo (n=52)
randomized controlled trial
nivolumab
nivolumab monotherapy group (3 mg/kg of intravenous nivolumab every 2 weeks plus ipilimumab-matching placebo during weeks 1–12)
placebo
double-matching placebo group
mML - NA - all population
double-blind
20 german academic medical centres
P2/ two sided and one interim analysis. Repartition alpha between two arms (0.025/arm) (nivolumab plus ipilimumab and nivolumab versus placebo) no statistical plan for the comparaison between nivolumab plus ipilimumab and nivolumab )
Adjuvant therapy with nivolumab alone or in combination with ipilimumab increased recurrence-free survival significantly compared with placebo in patients with stage IV melanoma with no evidence of disease
pembrolizumab alone (n=514) vs. placebo (n=505)
randomized controlled trial
pembrolizumab
pembrolizumab 200 mg intravenously (IV) on Day 1 of each 21-day cycle for up to 1 year
placebo
placebo every 3 weeks for a total of 18 doses (approximately 1 year)
patients were eligible for crossover or repeat treatment with pembrolizumab
mML - NA - all population
Membranous PD-L1 expression in tumor and tumor-associated immune cells was assessed by an immunohistochemistry assay and scored on a scale of 0-5; a score >=2 (staining on . 1% of cells) was considered PD-L1 positive
double-blind
123 centers in 23 countries
P3/ one sided test procedure with one interim analysis. Hierarchy RFS (ITT then PDL1) DMFS (ITT then PDL1) AND OS (ITT then PDL1) A SUIVRE
As adjuvant therapy for high-risk stage III melanoma, pembrolizumab resulted in significantly longer RFS and DMFS than placebo and provided a sustained and clinically meaningful improvement in RFS at 5-year median follow-up
pembrolizumab alone (n=428) vs. placebo (n=425)
randomized controlled trial
pembrolizumab
pembrolizumab 200 mg intravenously (IV) on Day 1 of each 21-day cycle for up to 1 year
placebo
placebo every 3 weeks for a total of 18 doses (approximately 1 year)
patients were eligible for crossoveror repeat treatment with pembrolizumab
mML - NA - PDL1 positive
Membranous PD-L1 expression in tumor and tumor-associated immune cells was assessed by an immunohistochemistry assay and scored on a scale of 0-5; a score >=2 (staining on . 1% of cells) was considered PD-L1 positive
double-blind
123 centers in 23 countries
P3/ one sided test procedure with one interim analysis. Hierarchy RFS (ITT then PDL1) MFS (ITT then PDL1) AND OS (ITT then PDL1) A SUIVRE
As adjuvant therapy for high-risk stage III melanoma, pembrolizumab resulted in significantly longer RFS and DMFS than placebo and provided a sustained and clinically meaningful improvement in RFS at 5-year median follow-up. Same results were observed in the PDL1 positive population.
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