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atezolizumab alone (n=107) vs. Standard of Care (SoC) (n=98)
randomized controlled trial
atezolizumab
Atezolizumab 1200 mg once every 3 weeks.
platinum chemotherapy
platinum-based chemotherapy (4 or 6 cycles) once every 3 weeks. (either cisplatin (75 mg per square meter of body-surface area) or carboplatin (area under the concentration−time curve [AUC], 6) in addition to pemetrexed (500 mg per square meter) (75.6%) or gemcitabine ( 1000 to 1250 mg per square meter) (24.4%) intravenously)
No crossover to the atezolizumab group was permitted.
mNSCLC - L1 - PDL1 positive
Initially, patients with a knownsensitizing EGFR mutation or ALK translocation were eligible provided they had received previous targeted therapy. The protocol was subsequently amended to exclude these patients from the analysis (18 patients) because emerging data suggested that they may not benefit from immune-checkpoint inhibitor monotherapy
open label
144 centers in 19 countries
P3/two sided with one interim analysis. Hierachical testing procedure OS (PDL1 TC3 then TC2/3 then TC 1/2/3)
IA1 stopped: Atezolizumab treatment resulted in significantly longer overall survival than platinum-based chemotherapy among patients with NSCLC with high PD-L1 expression (TC3 or IC3), regardless of histologic type
atezolizumab alone (n=166) vs. Standard of Care (SoC) (n=162)
randomized controlled trial
atezolizumab
Atezolizumab 1200 mg once every 3 weeks.
platinium chemotherapy
platinum-based chemotherapy (4 or 6 cycles) once every 3 weeks. (either cisplatin (75 mg per square meter of body-surface area) or carboplatin (area under the concentration−time curve [AUC], 6) in addition to pemetrexed (500 mg per square meter) (72.5%) or gemcitabine ( 1000 to 1250 mg per square meter) intravenously) (27.4%)
No crossover to the atezolizumab group was permitted.
mNSCLC - L1 - PDL1 positive
Initially, patients with a knownsensitizing EGFR mutation or ALK translocation were eligible provided they had received previous targeted therapy. The protocol was subsequently amended to exclude these patients from the analysis (18 patients) because emerging data suggested that they may not benefit from immune-checkpoint inhibitor monotherapy
open label
144 centers in 19 countries
P3/two sided with one interim analysis. Hierachical testing procedure OS (PDL1 TC3 then TC2/3 then TC 1/2/3)
IA1 stopped: Atezolizumab treatment resulted in significantly longer overall survival than platinum-based chemotherapy among patients with NSCLC with high PD-L1 expression, regardless of histologic type
atezolizumab alone (n=277) vs. Standard of Care (SoC) (n=277)
randomized controlled trial
atezolizumab
Atezolizumab 1200 mg once every 3 weeks.
platinium chemotherapy
platinum-based chemotherapy (4 or 6 cycles) once every 3 weeks. (either cisplatin (75 mg per square meter of body-surface area) or carboplatin (area under the concentration−time curve [AUC], 6) in addition to pemetrexed (500 mg per square meter) (69.5%) or gemcitabine ( 1000 to 1250 mg per square meter) (30.5%) intravenously
No crossover to the atezolizumab group was permitted.
mNSCLC - L1 - PDL1 positive
Initially, patients with a knownsensitizing EGFR mutation or ALK translocation were eligible provided they had received previous targeted therapy. The protocol was subsequently amended to exclude these patients from the analysis (18 patients) because emerging data suggested that they may not benefit from immune-checkpoint inhibitor monotherapy
open label
144 centers in 19 countries
P3/two sided with one interim analysis. Hierachical testing procedure OS (PDL1 TC3 then TC2/3 then TC 1/2/3)
IA1 stopped: Atezolizumab treatment resulted in significantly longer overall survival than platinum-based chemotherapy among patients with NSCLC with high PD-L1 expression, regardless of histologic type
cemiplimab (n=283) vs. Standard of Care (SoC) (n=280)
randomized controlled trial
cemiplimab
cemiplimab 350 mg administered intravenously over aperiod of 30 min every 3 weeks (for up to 108 weeks[ie, up to 36 treatment cycles]) Cemiplimab dose modification was not allowed
ICC
four to six cycles ofinvestigator’s choice of platinum-doublet chemotherapy (n=128 paclitaxel plus carboplatin102 pemetrexed plus carboplatin39 pemetrexed plus cisplatin37 gemcitabine plus carboplatin37 gemcitabine plus cisplatin11 paclitaxel plus cisplatin) 74% crossed over to cemiplimab
Crossover from chemotherapy tocemiplimab was allowed following disease progression
mNSCLC - L1 - PDL1 positive
Patients were ineligible if they had never smoked
open label
138 clinics in 24 countries
P3/ two sided and 5 interim analysis. To control type 1 error, two sided alpha 0.05 split between the analyses of overall survival (0·04)and progression-free survival (0·01). The α allocated to progression-free survival was subject to reallocation tooverall survival, provided the progression-free survival analysis was positive, and vice versa. The key secondary endpoint of objective response rate was tested hierarchically when both analyses of overall survival and progression-free survival were significant
Cemiplimab monotherapy significantly improved overall survival and progression-free survival compared with chemotherapy in patients with advanced non-small-cell lung cancer with PD-L1 of at least 50%,providing a potential new treatment option for this patient population.
durvalumab alone (n=163) vs. Standard of Care (SoC) (n=162)
randomized controlled trial
durvalumab
durvalumab (20 mg/kg every 4 weeks)
platinum-based doublet chemotherapy
4 to 6 cycles of platinum-based doublet chemotherapy of the investigator’s choice : pemetrexed plus carboplatin and gemcitabine plus carboplatin (no % for this sub-population)
3 arms: durvalumab with or without tremelimumab vs platinum-based doublet chemotherapy
mNSCLC - L1 - PDL1 positive
only patient with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) wild-type were included
open-label
203 cancer treatment centers in 17 countries
P3/ two sided and two interim analysis. A hierarchical multiple testing procedure with a gatekeeping strategy was used to control family-wise type I error at a twosided 5% significance level.
The phase 3 MYSTIC study did not meet its primary end points of improved OS with durvalumab vs chemotherapy or improved OS or PFS with durvalumab plus tremelimumab vs chemotherapy in patients with ≥25% of tumor cells expressing PD-L1.
nivolumab alone (n=271) vs. Standard of Care (SoC) (n=270)
randomized controlled trial
Nivolumab
Nivolumab solution for Injection 3 mg/kg Intravenous every 2 weeks until disease progression
platinium doublet chemotherapy
investigator’s choice of platinum doublet chemotherapy (every 3 weeks for four to six cycles) Squamous: gemcitabine 1250 mg/m2 plus cisplatin 75 mg/m2 (11.1%); gemcitabine 1000 mg/m2 plus carboplatin AUC 5 (12.5%); paclitaxel 200 mg/m2 plus carboplatin AUC 6(6.1%); nonsquamous: pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 (32.7%); pemetrexed 500 mg/m2 plus carboplatin AUC 6(43.7%)
Patients who progressed on chemotherapy could crossover to nivolumab as second line treatment. Maintenance therapy with pemetrexed was allowed in patients with nonsquamous NSCLC
mNSCLC - L1 - PDL1 positive
Patients with EGFR activating mutations and ALK translocations, which are sensitive to targeted therapy, were excluded.
open label
NA
P3/ two sided no interim analysis planned. no specific testing procedure for secondary endpoints
nivolumab monotherapy did not result in longer progression-free survival than platinum-based chemotherapy as first-line treatment for stage IV or recurrent NSCLC in a broad population of patients with a PD-L1 expression level of 5% or more.
nivolumab alone (n=211) vs. Standard of Care (SoC) (n=212)
randomized controlled trial
Nivolumab
Nivolumab solution for Injection 3 mg/kg Intravenous every 2 weeks until disease progression
platinum-based chemotherapy
investigator’s choice of platinum doublet chemotherapy (every 3 weeks for four to six cycles) Squamous: gemcitabine 1250 mg/m2 plus cisplatin 75 mg/m2 (11.1%); gemcitabine 1000 mg/m2 plus carboplatin AUC 5 (12.5%); paclitaxel 200 mg/m2 plus carboplatin AUC 6(6.1%); nonsquamous: pemetrexed 500 mg/m2 plus cisplatin 75 mg/m2 (32.7%); pemetrexed 500 mg/m2 plus carboplatin AUC 6(43.7%) (% for ITT pop)
Patients who progressed on chemotherapy could crossover to nivolumab as second line treatment.
mNSCLC - L1 - PDL1 positive
Patients with EGFR activating mutations and ALK translocations, which are sensitive to targeted therapy, were excluded. Determination of PD-L1 status using the analytically validated IHC assay.
open label
NA
P3/ two sided no interim analysis planned. no specific testing procedure for secondary endpoints
nivolumab monotherapy did not result in longer progression-free survival than platinum-based chemotherapy as first-line treatment for stage IV or recurrent NSCLC in a broad population of patients with a PD-L1 expression level of 5% or more.
pembrolizumab alone (n=413) vs. Standard of Care (SoC) (n=405)
randomized controlled trial
pembrolizumab
pembrolizumab 200 mg alone every 3 weeks.
platinium based chemotherapy
investigator’s choice of carboplatin to achieve an area under the curve of 5–6 mg/mL per minplus paclitaxel 200 mg/m² or pemetrexed 500 mg/m² every 3 weeks. (no % for this sub-population)
No crossover from the chemotherapy group to pembrolizumab was allowed as part of the study.
mNSCLC - L1 - PDL1 positive
Patients without a sensitising EGFR mutation or ALK translocation were included
open label
213 sites in 32 countries
P3/ one sided and two interim analysis. Hierarchy between coprimary endpoints and secondary endpoint
IA2 results (stopped)/this trial meet its primary endpoint of OS in PDL1 >50, >20% and >1% but not its secondary endpoints PFS or ORR in each group
pembrolizumab alone (n=637) vs. Standard of Care (SoC) (n=637)
randomized controlled trial
pembrolizumab
pembrolizumab 200 mg alone every 3 weeks.
platinium based chemotherapy
investigator’s choice of carboplatin to achieve an area under the curve of 5–6 mg/mL per minplus paclitaxel 200 mg/m² (47.6%) or pemetrexed 500 mg/m² (49.0%) every 3 weeks.
No crossover from the chemotherapy group to pembrolizumab was allowed as part of the study.
mNSCLC - L1 - PDL1 positive
Patients without a sensitising EGFR mutation or ALK translocation were included
open label
213 sites in 32 countries
P3/ one sided and two interim analysis. Hierarchy between coprimary endpoints and secondary endpoint
IA2 results (stopped)/this trial meet its primary endpoint of OS in PDL1 >50, >20% and >1% but not its secondary endpoints PFS or ORR in each group
pembrolizumab alone (n=154) vs. Standard of Care (SoC) (n=151)
randomized controlled trial
Pembrolizumab
(200 mg) administered as intravenous (IV) infusion on Day 1 of each 21-day cycle for up to 35 cycles or until documented PD
ICC platinum-based chemotherapies regimens
for 4 to 6 cycles (carboplatin plus pemetrexed (44.4%), cisplatin plus pemetrexed (23.8%), carboplatin plus gemcitabine (13.2%), cisplatin plus gemcitabine (7.3%), or carboplatin plus paclitaxel(11.3%))
Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression
mNSCLC - L1 - PDL1 positive
Patients were excluded if they had sensitizing EGFR mutations, ALK translocations
open label
142 sites in 16 countries
P3/ one sided and two interim analysis. The statistical test strategy foresees a repartition between PFS (2%) and ORR (0.5%) and a hierarchy with the PFS and the OS(0.0118% AI)
In patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells,pembrolizumab was associated with significantly longer progression-free and overallsurvival and with fewer adverse events than was platinum-based chemotherapy
pembrolizumab alone (n=299) vs. Standard of Care (SoC) (n=300)
randomized controlled trial
pembrolizumab
pembrolizumab 200 mg alone every 3 weeks.
platinium based chemotherapy
investigator’s choice of carboplatin to achieve an area under the curve of 5–6 mg/mL per minplus paclitaxel 200 mg/m² or pemetrexed 500 mg/m² every 3 weeks. (no % for this sub-population)
No crossover from the chemotherapy group to pembrolizumab was allowed as part of the study.
mNSCLC - L1 - PDL1 positive
Patients without a sensitising EGFR mutation or ALK translocation were included
open label
213 sites in 32 countries
P3/ one sided and two interim analysis. Hierarchy between coprimary endpoints and secondary endpoint
IA2 results (stopped)/this trial meet its primary endpoint of OS in PDL1 >50, >20% and >1% but not its secondary endpoints PFS or ORR in each group
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