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avelumab alone (n=350) vs. placebo (n=347)
randomized controlled trial
avelumab plus chemoradiotherapy
avelumab10 mg/kg intravenously on day 1 of the1-week lead-in phase followed by 10 mg/kg avelumab every 2 weeks maintenance therapy for up to 12 months.
placebo plus chemoradiotherapy
placebo intravenously on day 1 of the1-week lead-in phase followed by placebo every 2 weeks maintenance therapy for up to 12 months.
all patient were treated with standard-of-care chemoradiotherapy,consistingof intensity-modulated radiotherapy (IMRT) of 70 Gy. Dose modifications of avelumab, placebo or IMRT werenot permitted.
laHNSCC - 1st line (L1)
double-blind
196 hospitals and cancer treatment centres in 22 countries
P3/ one sided and one interim analysis. Overall survival was planned to be tested by means of ahierarchical testing procedure provided that a significantimprovement in progression-free survival was achievedfavouring the avelumab group. To protect the integrity of the study and to preserve the type I error rate, a fraction of alpha (0.0097) for PFS efficacy will be spent at the interim analysis
The primary objective of prolonging progression-free survival with avelumab plus chemoradiotherapy followed by avelumab maintenance in patients with locally advanced squamous cell carcinoma of the head and neck was not met.
pembrolizumab alone (n=301) vs. cetuximab plus platin plus 5FU (n=300)
randomized controlled trial
pembrolizumab
pembrolizumab (200 mg) was administered once every 3weeks (max 35 cycles)
cetuximab with chemotherapy (platine plus 5FU)
cetuximab (400 mg/m2 loading dose, then 250 mg/m2 per week) with chemotherapy : carboplatin (57%) (area under the curve 5 mg/m2) or cisplatin (43%) (100 mg/m2) and 5fluorouracil (1000 mg/m2 per day for 4 consecutive days) every 3 weeks for six cycles
patients receiving the comparator may switch to another anti PD-1 treatment following confirmation of progressive disease, adjustment for the effect of crossover on OS may be performed
mHNSCC - L1 - all population
open-label
200 sites in 37 countries
P3 / one-sided test procedure with TWO interim analysis. Repartition and hierarchy between interim analysis and endpoints : 14 hypothesis (primary and secondary)
First-line therapy with pembrolizumab monotherapy significantly improved overall survival in the PD-L1 CPS of 20 or more and CPS of 1 or more populations, and had non-inferior overall survival in the total population
pembrolizumab plus 5FU plus platin (n=281) vs. cetuximab plus platin plus 5FU (n=278)
randomized controlled trial
pembrolizumab plus 5 FU plus platine
pembrolizumab (200 mg) was administered once every 3weeks (max 35 cycles) plus carboplatin (area under the curve 5 mg/m2) or cisplatin (100 mg/m2) and 5fluorouracil (1000 mg/m2 per day for 4 consecutive days) every 3 weeks for six cycles.
cetuximab plus 5 FU plus platine
cetuximab (400 mg/m2 loading dose, then 250 mg/m2 per week) plus carboplatin (area under the curve 5 mg/m2) or cisplatin (100 mg/m2) and 5fluorouracil (1000 mg/m2 per day for 4 consecutive days) every 3 weeks for six cycles.
Patients receiving the comparator may switch to another anti PD-1 treatment following confirmation of progressive disease, adjustment for the effect of crossover on OS may be performed
mHNSCC - L1 - all population
open-label
200 sites in 37 countries
P3 / one-sided test procedure with TWO interim analysis. Repartition and hierarchy between interim analysis and endpoints : 14 hypothesis (primary and secondary)
First-line therapy with pembrolizumab monotherapy significantly improved overall survival in the PD-L1 CPS of 20 or more and CPS of 1 or more populations, and had non-inferior overall survival in the total population
pembrolizumab alone (n=133) vs. cetuximab plus platin plus 5FU (n=122)
randomized controlled trial
pembrolizumab
pembrolizumab (200 mg) was administered once every 3weeks (max 35 cycles)
cetuximab with chemotherapy (platine plus 5FU)
cetuximab (400 mg/m2 loading dose, then 250 mg/m2 per week) with chemotherapy : carboplatin (area under the curve 5 mg/m2) or cisplatin (100 mg/m2) and 5fluorouracil (1000 mg/m2 per day for 4 consecutive days) every 3 weeks for six cycles
patients receiving the comparator may switch to another anti PD-1 treatment following confirmation of progressive disease, adjustment for the effect of crossover on OS may be performed
mHNSCC - L1 - PDL1 positive
open-label
200 sites in 37 countries
P3 / one-sided test procedure with TWO interim analysis. Repartition and hierarchy between interim analysis and endpoints : 14 hypothesis (primary and secondary)
First-line therapy with pembrolizumab monotherapy significantly improved overall survival in the PD-L1 CPS of 20 or more and CPS of 1 or more populations, and had non-inferior overall survival in the total population
pembrolizumab alone (n=257) vs. cetuximab plus platin plus 5FU (n=255)
randomized controlled trial
pembrolizumab
pembrolizumab (200 mg) was administered once every 3weeks (max 35 cycles)
platinium based chemotherapy (cetuximab plus 5FU and platine)
cetuximab (400 mg/m2 loading dose, then 250 mg/m2 per week) with chemotherapy : carboplatin (area under the curve 5 mg/m2) or cisplatin (100 mg/m2) and 5fluorouracil (1000 mg/m2 per day for 4 consecutive days) every 3 weeks for six cycles
patients receiving the comparator may switch to another anti PD-1 treatment following confirmation of progressive disease, adjustment for the effect of crossover on OS may be performed
mHNSCC - L1 - PDL1 positive
open-label
200 sites in 37 countries
P3 / one-sided test procedure with TWO interim analysis. Repartition and hierarchy between interim analysis and endpoints : 14 hypothesis (primary and secondary)
First-line therapy with pembrolizumab monotherapy significantly improved overall survival in the PD-L1 CPS of 20 or more and CPS of 1 or more populations, and had non-inferior overall survival in the total population
pembrolizumab plus 5FU plus platin (n=126) vs. cetuximab plus platin plus 5FU (n=110)
randomized controlled trial
pembrolizumab plus 5FU plus platine
pembrolizumab (200 mg) was administered once every 3weeks (max 35 cycles)
cetuximab plus 5FU plus platine
cetuximab (400 mg/m2 loading dose, then 250 mg/m2 per week) plus carboplatin (area under the curve 5 mg/m2) or cisplatin (100 mg/m2) and 5fluorouracil (1000 mg/m2 per day for 4 consecutive days) every 3 weeks for six cycles
Patients receiving the comparator may switch to another anti PD-1 treatment following confirmation of progressive disease, adjustment for the effect of crossover on OS may be performed
mHNSCC - L1 - PDL1 positive
Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1;
open-label
200 sites in 37 countries
P3 / one-sided test procedure with TWO interim analysis. Repartition and hierarchy between interim analysis and endpoints : 14 hypothesis (primary and secondary)
First-line therapy with pembrolizumab monotherapy significantly improved overall survival in the PD-L1 CPS of 20 or more and CPS of 1 or more populations, and had non-inferior overall survival in the total population
pembrolizumab plus 5FU plus platin (n=242) vs. cetuximab plus platin plus 5FU (n=226)
randomized controlled trial
pembrolizumab plus 5FU plus platine
pembrolizumab (200 mg) was administered once every 3weeks (max 35 cycles) plus carboplatin (area under the curve 5 mg/m2) or cisplatin (100 mg/m2) and 5fluorouracil (1000 mg/m2 per day for 4 consecutive days) every 3 weeks for six cycles.
cetuximab plus 5FU plus platine
cetuximab (400 mg/m2 loading dose, then 250 mg/m2 per week) plus carboplatin (area under the curve 5 mg/m2) or cisplatin (100 mg/m2) and 5fluorouracil (1000 mg/m2 per day for 4 consecutive days) every 3 weeks for six cycles.
Patients receiving the comparator may switch to another anti PD-1 treatment following confirmation of progressive disease, adjustment for the effect of crossover on OS may be performed
mHNSCC - L1 - PDL1 positive
open-label
200 sites in 37 countries
P3 / one-sided test procedure with TWO interim analysis. Repartition and hierarchy between interim analysis and endpoints : 14 hypothesis (primary and secondary)
First-line therapy with pembrolizumab monotherapy significantly improved overall survival in the PD-L1 CPS of 20 or more and CPS of 1 or more populations, and had non-inferior overall survival in the total population
durvalumab alone (n=240) vs. Standard of Care (SoC) (n=249)
randomized controlled trial
durvalumab
durvalumab 10 mg/kg IV every 2 weeks (Q2W)
investigator’s choice: cetuximab, taxane, methotrexate, or fluoropyrimidine-based regimen
Each SoC agent (cetuximab (35.7%),docetaxel (10.8%), paclitaxel (36.9%), methotrexate (14.5%), Fluoropyrimidine regimen: (2.0%) [5-fluorouracil, TS-1, or capecitabine] was dosed and administered according to local regulations
3 arms: durvalumab, durvalumab plus tremelimumab, SOC
mHNSCC - L2 - all population
open-label
156 sites
P3 / two-sided test procedure with one interim analysis. Alpha splitting between coprimary endpoint and recycling strategy with OS (PDL1 TC<25 in DT)
There were no statistically significant differences in OS for durvalumab or durvalumab plus tremelimumab versus SoC in pts with R/M HNSCC
durvalumab plus tremelimumab (n=247) vs. Standard of Care (SoC) (n=249)
randomized controlled trial
durvalumab plus tremelimumab
durvalumab plus tremelimumab (Durvalumab 20 mg/kg IV Q4W and Tremelimumab 1 mg/kg IV Q4W for 4 doses, then Durvalumab 10 mg/kg IV Q2W)
investigator’s choice: cetuximab, taxane, methotrexate, or fluoropyrimidine-based regimen
Each SoC agent (cetuximab (35.7%),docetaxel (10.8%), paclitaxel (36.9%), methotrexate (14.5%), Fluoropyrimidine regimen: (2.0%) [5-fluorouracil, TS-1, or capecitabine] was dosed and administered according to local regulations
3 arms: durvalumab, durvalumab plus tremelimumab, SOC
mHNSCC - L2 - all population
open-label
156 sites
P3 / two-sided test procedure with one interim analysis. Alpha splitting between coprimary endpoint and recycling strategy with OS (PDL1 TC<25 in DT)
There were no statistically significant differences in OS for durvalumab or durvalumab plus tremelimumab versus SoC in pts with R/M HNSCC
nivolumab alone (n=240) vs. Standard of Care (SoC) (n=121)
randomized controlled trial
nivolumab
nivolumab at a dose of 3 mg per kilogram of body weight) every 2 weeks
ICC (methotrexate, docetaxel or cetuximab)
weekly intravenous administration of methotrexate (38.0%) at a dose of 40 to 60 mg/m2, docetaxel (43.0%)at 30 to 40 mg/m2, or cetuximab (10.7%)at 250 mg/m2 after a loading dose of 400 mg/m2
Dose modifications were not permitted for nivolumab but were specified for methotrexate, docetaxel, and cetuximab on the basis of the type and grade of the toxic effect.
mHNSCC - L2 - all population
an age of at least 18 years; an Eastern Cooperative Oncology Group performance-status score of 0 or 1
open-label
66 sites in 15 countries in North America, Asia, Europe, and South America
P3 / two-sided test procedure with one interim analysis. Hierarchical testing procedure for secondary endpoints PFS and ORR
Among patients with platinum-refractory, recurrent squamous-cell carcinoma of the head and neck, treatment with nivolumab resulted in longer overall survival than treatment with standard, single-agent therapy
pembrolizumab alone (n=247) vs. Standard of Care (SoC) (n=248)
randomized controlled trial
pembrolizumab
pembrolizumab 200 mg every 3 weeks intravenously
chemotherapy (methotrexate, docetaxel or cetuximab)
standard treatment per week (methotrexate, docetaxel or cetuximab) methotrexate (26.2%) 40 mg/m2 intravenously (could be increased to 60 mg/m2), docetaxel (44.4%)75 mg/m2 every 3 weeks intravenously, or cetuximab (29.4%) 250 mg/m2
There was no planned crossover on disease progression.
mHNSCC - L2 - all population
open-label
97 medical centres in 20 countries.
P3/ one-sided test procedure with two interim analysis. Hierarchy and split between secondary endpoints : one sided 0.025
pembrolizumab provides a clinically meaningful overall survival benefit compared with investigator’s choice of methotrexate, docetaxel, or cetuximab in patients with recurrent or metastatic head- and-neck squamous cell carcinoma that progressed during or after platinum-based therapy (in all population and CPS>1)
durvalumab plus tremelimumab (n=133) vs. durvalumab alone (n=67)
randomized controlled trial
durvalumab plus tremelimumab
durvalumab (20 mg/kg every 4 weeks) plus tremelimumab (1 mg/kg every 4 weeks) for 4 cycles, followed by durvalumab (10 mg/kg every 2 weeks)
durvalumab monotherapy
durvalumab (10 mg/kg every 2 weeks) monotherapy
mHNSCC - L2 - PDL1 negative
PD-L1–low/negative disease
open-label
127 sites in north america, europe, and asia pacific
P2 / no formal statistical plan to evaluate comparison between groups. No formal statistical comparison were planned
Treatment with durvalumab monotherapy and durvalumab tremelimumab resulted in clinical benefit in patients with PD-L1–low/negative tumor cell expression, but no significant difference in efficacy
durvalumab plus tremelimumab (n=133) vs. tremelimumab (n=67)
randomized controlled trial
durvalumab plus tremelimumab
durvalumab (20 mg/kg every 4 weeks) tremelimumab (1 mg/kg every 4 weeks) for 4 cycles, followed by durvalumab (10 mg/kg every 2 weeks)
tremelimumab monotherapy
tremelimumab (10 mg/kg every 4 weeks for 7 doses then every 12 weeks for 2 doses) monotherapy.
mHNSCC - L2 - PDL1 negative
PD-L1–low/negative disease
open-label
127 sites in north america, europe, and asia pacific
P2: no statistic plan to evaluate comparison between groups. No formal statistical comparison were planned
Treatment with durvalumab monotherapy and durvalumab tremelimumab resulted in clinical benefit in patients with PD-L1–low/negative tumor cell expression, but no significant difference in efficacy
pembrolizumab alone (n=196) vs. Standard of Care (SoC) (n=191)
randomized controlled trial
pembrolizumab
pembrolizumab 200 mg every 3 weeks intravenously
chemotherapy (methotrexate, docetaxel or cetuximab)
standard treatment per week (methotrexate, docetaxel or cetuximab) methotrexate (26.2%) 40 mg/m2 intravenously (could be increased to 60 mg/m2), docetaxel (44.4%)75 mg/m2 every 3 weeks intravenously, or cetuximab (29.4%) 250 mg/m2 (% for ITT population)
There was no planned crossover on disease progression.
mHNSCC - L2 - PDL1 positive
open-label
97 medical centres in 20 countries.
P3/ one-sided test procedure with two interim analysis. Hierarchy and split between secondary endpoints : one sided 0.025
pembrolizumab provides a clinically meaningful overall survival benefit compared with investigator’s choice of methotrexate, docetaxel, or cetuximab in patients with recurrent or metastatic head- and-neck squamous cell carcinoma that progressed during or after platinum-based therapy (in all population and CPS>1)
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