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Ipilimumab (10 mg/kg) (n=511) vs. interferon alpha (n=636)
randomized controlled trial
ipilimumab 10 mg/kg
ipi3 or ipi10 was administeredintravenously every 3 weeks for 4 doses (induction),followed by the same dose every 12 weeks for up to4 additional doses (maintenance).
HDI high dose of interferon alpha
HDI was administered intravenously at 20 million units/m2 of body surface area per day, 5 days per week, for 4 weeks (induction), followed by 10 million units/m2 per day subcutaneously every other day, 3 days per week, for 48 weeks (maintenance).
mML - NA - all population
open label
United States and Canada.
P3/ one sided and four interim analysis (OS). A 2-step hierarchic approach first evaluated ipi3 versus HDI followed by ipi10 versus HDI. Because no interim analyses had been conducted before this revision, this change did not affectthe overall type I error rate of the study design. With a 1-sidedtype I error rate of 0.022 for OS and 0.003 for RFS.
Adjuvant therapy with ipi3 benefits survival versus HDI. The currently approved adjuvant ipilimumab dose (ipi10) was more toxic and not superior in efficacyto HDI.
Ipilimumab (10 mg/kg) (n=475) vs. placebo (n=476)
randomized controlled trial
ipilimumab
intravenous infusions of 10 mg/kg ipilimumab every 3 weeks for four doses, then every 3 months for up to 3 years.
placebo
intravenous infusions of placebo every 3 weeks for four doses, then every 3 months for up to 3 years.
No dose reductions or modifications were made.
mML - NA - all population
patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) with adequate resection of lymph nodes (ie, the primary cutaneous melanoma must have been completely excised with adequate surgical margins)
double-blind
91 hospitals located in 19 countries
P3/ two sided test procedure without interim analysis. Hierarchical testing procedure : RFS (0.05) then final analysis OS (0.049) and MFS (0.042)
Adjuvant ipilimumab significantly improved RFS, OS and MFS for patients with completely resected high-risk stage III melanoma.
ipilimumab alone (n=523) vs. interferon alpha (n=636)
randomized controlled trial
ipilimumab 3 mg/kg
ipi3 or ipi10 was administeredintravenously every 3 weeks for 4 doses (induction),followed by the same dose every 12 weeks for up to4 additional doses (maintenance).
HDI high dose of interferon alpha
HDI was administered intravenously at 20 million units/m2 of body surface area per day, 5 days per week, for 4 weeks (induction), followed by 10 million units/m2 per day subcutaneously every other day, 3 days per week, for 48 weeks (maintenance).
mML - NA - all population
open label
United States and Canada.
P3/ one sided and four interim analysis (OS). A 2-step hierarchic approach first evaluated ipi3 versus HDI followed by ipi10 versus HDI. Because no interim analyses had been conducted before this revision, this change did not affectthe overall type I error rate of the study design. With a 1-sidedtype I error rate of 0.022 for OS and 0.003 for RFS.
Adjuvant therapy with ipi3 benefits survival versus HDI. The currently approved adjuvant ipilimumab dose (ipi10) was more toxic and not superior in efficacyto HDI.
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
nivolumab plus ipilimumab (n=-9) vs. nivolumab alone (n=-9)
randomized controlled trial
nivolumab plus ipilimumab
240 mg of nivolumab intravenously every 2 weeks and 1 mg/kg of ipilimumab every 6 weeks for up to 1 year.
nivolumab
480 mg of nivolumab every 4 weeks for up to 1 year.
mML - NA - all population
double-blind
P3/
Qualitative results realeased in BMS news in october 2020 : Statistically significant benefit was not reached for the co-primary endpoint of recurrence-free survival (RFS) in patients whose tumors expressed PD-L1 <1% (2019 results) and in the all-comer (intent-to-treat) (2020 results).
nivolumab plus ipilimumab (n=56) vs. nivolumab alone (n=59)
randomized controlled trial
nivolumab plus ipilimumab
nivolumab plus ipilimumab group (1 mg/kg of intravenous nivolumab every 3 weeks plus 3 mg/kg of intravenous ipilimumab every 3 weeks for four doses, followed by 3 mg/kg of nivolumab every 2 weeks)
nivolumab
3 mg/kg of nivolumab every 2 weeks (plus ipilimumab-matching placebo during weeks 1–12
For patients with disease recurrence receiving nivolumab-matching placebo plus ipilimumabmatching placebo, crossover to nivolumab was allowed
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 )
exploratory results only
nivolumab plus ipilimumab (n=56) vs. placebo (n=52)
randomized controlled trial
nivolumab plus ipilimumab
nivolumab plus ipilimumab group (1 mg/kg of intravenous nivolumab every 3 weeks plus 3 mg/kg of intravenous ipilimumab every 3 weeks for four doses, followed by 3 mg/kg of nivolumab every 2 weeks)
placebo
double-matching placebo group
For patients with disease recurrence receiving nivolumab-matching placebo plus ipilimumabmatching placebo, crossover to nivolumab was allowed
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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