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cemiplimab (n=356) vs. Standard of Care (SoC) (n=354)
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 - all population
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 to overall 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=374) vs. Standard of Care (SoC) (n=372)
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 (138 of 253 patients [54.5%]) and gemcitabine plus carboplatin (49 of 99 patients [49.5%])
3 arms: durvalumab with or without tremelimumab vs platinum-based doublet chemotherapy
mNSCLC - L1 - all population
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.
sintillimab plus SoC (n=266) vs. placebo plus SoC (n=131)
randomized controlled trial
Sintilimab plus pemetrexed plus platine
Sintilimab 200 mg was intravenously (IV) administered on day 1 of each cycle, once every 3 weeks (Q3W)
placebo plus pemetrexed plus platine
placebo was intravenously (IV) administered on day 1 of each cycle, once every 3 weeks (Q3W)
Patients in the placebo-combination group were eligible to cross over to receive sintilimab
mNSCLC - L1 - all population
including patient ineligible for radical surgery or radiotherapy, who had no sensitive EGFR mutations or anaplastic lymphoma kinase (ALK) rearrangements
double blind
47 hospitals in the People’s Republic of China.
P3/ one sided and one interim analysis. Only PFS tested stopped at AI1
AI 1 stopped : In Chinese patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC, the addition of sintilimab to chemotherapy with pemetrexed and platinum resulted in considerably longer PFS than with chemotherapy alone
nivolumab plus SoC (n=177) vs. pemetrexed plus platin (n=186)
randomized controlled trial
nivolumab plus pemetrexed plus platine
nivolumab (3 mg per kilogram of body weight every 2 weeks)
platinum based chemotherapy (pemetrexed plus platine)
platinum doublet chemotherapy based on tumor histologic type every 3 weeks for up to four cycles : pemetrexed (500 mg per square meter of body-surface area) plus cisplatin (75 mg per square meter) or carboplatin (area under the concentration-time curve [AUC], 5 or 6), every3 weeks for up to four cycles.Crossover between treatment groups within the trial was not permitted.
3 arms: Nivolumab, or Nivolumab Plus Ipilimumab.Crossover between treatment groups within the trial was not permitted.
mNSCLC - L1 - PDL1 negative
Patients with known EGFR mutations or ALK translocations sensitive to targeted therapy, an autoimmune disease, or untreated central nervous system metastases were excluded.Tumor mutational burden was determined by the FoundationOne CDx assay,
open label
NA
P3/ two sided and one interim analysis. Repartition between coprimary end point and hierarchy with secondary endpoint
Progression-free survival was significantly longer with first-line nivolumab plus ipilimumab than with chemotherapy among patients with NSCLC and a high tumor mutational burden, irrespective of PD-L1 expression level.
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=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=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=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
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
atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (n=400) vs. bevacizumab plus carboplatin and paclitaxel (n=400)
randomized controlled trial
atezolizumab and bevacizumab, carboplatin plus paclitaxel (ABCP)
atezolizumab 1200 mg every 3 weeks bevacizumab at a dose of 15 mg/kg,paclitaxel at a dose of 200 mg/m2 (175 mg for Asian patients), and carboplatin at an area under the concentration−time curve of 6 mg/ml/min
bevacizumab plus carboplatin plus paclitaxel (BCP)
bevacizumab at a dose of 15 mg per kilogram of body weight,paclitaxel at a dose of 200 mg per square meter of body-surface area (175 mg per square meter for Asian patients), and carboplatin at an areaunder the concentration−time curve of 6 mg per milliliter per minute. for four or six 21-day cycles
Crossover from the control arm to either of the experimental arms will not be permitted
non squamous - mNSCLC - L1 - all population
patients with wild type genotype (patients with EGFR or ALK genetic alterations were excluded, The Teff gene signature was defined as the expression of PD-L1, CXCL9, and IFN-γ messenger RNA
open label
240 sites in 26 countries
P3/ two sided and one interim analysis. Repartition between coprimary endoint (ABCP vs BCP) and hierarchical testing procedure with secondary endpoint and then ACP vs BCP results
The addition of atezolizumab to bevacizumab plus chemotherapy significantly improved progression-free survival and overall survival among patients with metastatic nonsquamous NSCLC, regardless of PD-L1 expression and EGFR or ALK genetic alteration status, among patient with wild type (WT) and only PFS among patients with WT Teff
atezolizumab plus carboplatin plus nab-paclitaxel (n=483) vs. atezolizumab plus carboplatin plus nab-paclitaxel (n=240)
randomized controlled trial
atezolizumab plus carboplatin plus nab-paclitaxel (ACnp)
atezolizumab (1200 mg intravenously every 3 weeks) plus carboplatin [area under the curve 6 mg/mL per min every 3 weeks] plus nab-paclitaxel [100 mg/m]
carboplatine plus nab-paclitaxel (CnP)
carboplatin [area under the curve 6 mg/mL per min every 3 weeks] plus nab-paclitaxel [100 mg/m]
Crossover to receive atezolizumab at disease progression was permitted only for patients in the chemotherapy group enrolled before June 15, 2016.
non squamous - mNSCLC - L1 - all population
PDL1 : VENTANA PD-L1 (SP142) Assay (Ventana Medical Systems, Tucson, AZ, USA), randomisation). Patients with unknown EGFR or ALK status were required to have had locally or centrally assessed testing at screening.
open label
131 academic medical centres and community oncology practices in North America, Europe and Israel
P3/ two sided one interim analysis. Alpha split between coprimary endpoints, reallocation and hierarchy testing procedure with secondary endpoints
this study showed a significant and clinically meaningful improvement in overall survival and a significant improvement in progression-free survival with atezolizumab plus chemotherapy versus chemotherapy as first-line treatment of patients with stage IV non-squamous non-small-cell lung cancer (ITT) and no ALK or EGFR mutations (WT)
atezolizumab plus carboplatin plus paclitaxel (n=402) vs. bevacizumab plus carboplatin and paclitaxel (n=400)
randomized controlled trial
atezolizumab plus carboplatin plus paclitaxel (ACP)
atezolizumab 1200 mg every 3 weeks,paclitaxel at a dose of 200 mg/m2 (175 mg for Asian patients), and carboplatin at an area under the concentration−time curve of 6 mg/ml/min
bevacizumab and caroplatin plus paclitaxel (BCP)
bevacizumab at a dose of 15 mg per kilogram of body weight,paclitaxel at a dose of 200 mg per square meter of body-surface area (175 mg per square meter for Asian patients), and carboplatin at an areaunder the concentration−time curve of 6 mg per milliliter per minute.
Crossover from the control arm to either of the experimental arms will not be permitted
non squamous - mNSCLC - L1 - all population
patients with wild type genotype (patients with EGFR or ALK genetic alterations were excluded, The Teff gene signature was defined as the expression of PD-L1, CXCL9, and IFN-γ messenger RNA
open label
240 sites in 26 countries
P3/ two sided and one interim analysis. Repartition between coprimary endoint (ABCP vs BCP) and hierarchical testing procedure with secondary endpoint and then ACP vs BCP results
The addition of atezolizumab to chemotherapy in the first-line treatment of extensive-stage small-cell lung cancer resulted in significantly longer overall survival and progression-free survival than chemotherapy alone.
atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (n=155) vs. bevacizumab plus carboplatin and paclitaxel (n=129)
randomized controlled trial
atezolizumab and bevacizumab, carboplatin plus paclitaxel (ABCP)
atezolizumab 1200 mg every 3 weeks bevacizumab at a dose of 15 mg/kg,paclitaxel at a dose of 200 mg/m2 (175 mg for Asian patients), and carboplatin at an area under the concentration−time curve of 6 mg/ml/min
bevacizumab plus carboplatin plus paclitaxel (BCP)
bevacizumab at a dose of 15 mg per kilogram of body weight,paclitaxel at a dose of 200 mg per square meter of body-surface area (175 mg per square meter for Asian patients), and carboplatin at an areaunder the concentration−time curve of 6 mg per milliliter per minute. for four or six 21-day cycles
Crossover from the control arm to either of the experimental arms will not be permitted
non squamous - mNSCLC - L1 - Wild Type (WT)
patients with wild type genotype (patients with EGFR or ALK genetic alterations were excluded, The Teff gene signature was defined as the expression of PD-L1, CXCL9, and IFN-γ messenger RNA
open label
240 sites in 26 countries
P3/ two sided and one interim analysis. Repartition between coprimary endoint (ABCP vs BCP) and hierarchical testing procedure with secondary endpoint and then ACP vs BCP results
The addition of atezolizumab to bevacizumab plus chemotherapy significantly improved progression-free survival and overall survival among patients with metastatic nonsquamous NSCLC, regardless of PD-L1 expression and EGFR or ALK genetic alteration status, among patient with wild type (WT) and only PFS among patients with WT Teff
atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (n=356) vs. bevacizumab plus carboplatin and paclitaxel (n=336)
randomized controlled trial
atezolizumab plus bevacizumab plus carboplatin plus paclitaxel (ABCP)
atezolizumab 1200 mg every 3 weeks bevacizumab at a dose of 15 mg/kg,paclitaxel at a dose of 200 mg/m2 (175 mg for Asian patients), and carboplatin at an area under the concentration−time curve of 6 mg/ml/min
bevacizumab and caroplatin plus paclitaxel (BCP)
bevacizumab at a dose of 15 mg per kilogram of body weight,paclitaxel at a dose of 200 mg per square meter of body-surface area (175 mg per square meter for Asian patients), and carboplatin at an areaunder the concentration−time curve of 6 mg per milliliter per minute.
Crossover from the control arm to either of the experimental arms will not be permitted
non squamous - mNSCLC - L1 - Wild Type (WT)
patients with wild type genotype only (patients with EGFR or ALK genetic alterations were excluded)
open label
240 sites in 26 countries
P3/ two sided and one interim analysis. Repartition between coprimary endoint (ABCP vs BCP) and hierarchical testing procedure with secondary endpoint and then ACP vs BCP results
The addition of atezolizumab to bevacizumab plus chemotherapy significantly improved progression-free survival and overall survival among patients with metastatic nonsquamous NSCLC, regardless of PD-L1 expression and EGFR or ALK genetic alteration status, among patient with wild type (WT) and only PFS among patients with WT Teff
atezolizumab plus carboplatin plus nab-paclitaxel (n=451) vs. carboplatin plus nab-paclitaxel (n=228)
randomized controlled trial
atezolizumab (ACnP) plus carboplatine plus nab-paclitaxel
atezolizumab (1200 mg intravenously every 3 weeks)
carboplatine plus nab-paclitaxel
carboplatin [area under the curve 6 mg/mL per min every 3 weeks] plus nab-paclitaxel [100 mg/m]
Crossover to receive atezolizumab at disease progression was permitted only for patients in the chemotherapy group enrolled before June 15, 2016.
non squamous - mNSCLC - L1 - Wild Type (WT)
PDL1 : VENTANA PD-L1 (SP142) Assay (Ventana Medical Systems, Tucson, AZ, USA), PDL1 : VENTANA PD-L1 (SP142) Assay (Ventana Medical Systems, Tucson, AZ, USA), randomisation). Patients with unknown EGFR or ALK status were required to have had locally or centrally assessed testing at screening.
open label
131 academic medical centres and community oncology practices in North America, Europe and Israel
P3/ two sided one interim analysis. Alpha split between coprimary endpoints, reallocation and hierarchy testing procedure with secondary endpoints
this study showed a significant and clinically meaningful improvement in overall survival and a significant improvement in progression-free survival with atezolizumab plus chemotherapy versus chemotherapy as first-line treatment of patients with stage IV non-squamous non-small-cell lung cancer (ITT) and no ALK or EGFR mutations (WT)
atezolizumab plus pemetrexed and platin (n=292) vs. pemetrexed plus platin (n=286)
randomized controlled trial
Atezolizumab (induction and maintenance) plus pemetrexed plus platine
Atezolizumab 1200 mg IV every 3 weeks plus carboplatin or cisplatin (Carboplatin: AUC 6 mg/mL/min IV q3w; Cisplatin: 75 mg/m2 IV q3w) plus pemetrexed (500 mg/m2 IV q3w) for 4 or 6 cyclesb for induction and permetrexed maintenance therapy
pemetrexed plus platine
carboplatin or cisplatin (Carboplatin: AUC 6 mg/mL/min IV q3w; Cisplatin: 75 mg/m2 IV q3w) plus pemetrexed (500 mg/m2 IV q3w) for 4 or 6 cyclesb for induction and permetrexed maintenance therapy
non squamous - mNSCLC - L1 - Wild Type (WT)
open-label
NA
P3
IMpower132 met its co-primary endpoint of investigator-assessed PFS in the ITT population but preliminary results on OS were not significant (IA)
pembrolizumab and pemetrexed plus platin (n=60) vs. pemetrexed plus platin (n=63)
randomized controlled trial
pembrolizumab with carboplatin plus pemetrexed
4 cycles of pembrolizumab 200 mg administered over 30 min, with carboplatin plus permetrexed, (pemetrexed 500 mg/m² and carboplatin AUC 5 mg/mL per min were given for 4 cycles followed by optional indefi nite pemetrexed maintenance) followed by pembrolizumab for 24 months,
carboplatin plus pemetrexed
carboplatin plus permetrexed, (pemetrexed 500 mg/m² and carboplatin AUC 5 mg/mL per min were given for 4 cycles followed by optional indefi nite pemetrexed maintenance)
Patients from control group could crossover to receive pembrolizumab monotherapy after a washout period of 21 days
non squamous - mNSCLC - L1 - Wild Type (WT)
eligibility critera stipulated the absence of targetable EGFR mutations or ALK translocations.
open label
26 medical centres in the USA and Taiwan
P2/one sided and no interim analysis, hierarchy with secondary endpoint PFS
Combination of pembrolizumab, carboplatin, and pemetrexed provides a significant and clinically relevant improvement in ORR and PFS compared with chemotherapy alone
pembrolizumab plus SoC (n=410) vs. placebo plus SoC (n=206)
randomized controlled trial
pembrolizumab plus pemetrexed plus platine
200 mg of pembrolizumab every 3 weeks for up to 35 cycles with four cycles of ICC : cisplatin (75 mg per square meter of bodysurface area) or carboplatin (area under the concentration–time curve, 5 mg per milliliter per minute) plus pemetrexed (500 mg per square meter), all administered intravenously every 3 weeks, followed by pemetrexed (500 mg per square meter) every 3 weeks
placebo plus pemetrexed plus platine
four cycles of ICC : cisplatin (75 mg per square meter of bodysurface area) or carboplatin (area under the concentration–time curve, 5 mg per milliliter per minute) plus pemetrexed (500 mg per square meter), all administered intravenously every 3 weeks, followed by pemetrexed (500 mg per square meter) every 3 weeks
placebo-combination group were eligible to cross over to receive pembrolizumab monotherapy.
non squamous - mNSCLC - L1 - Wild Type (WT)
patients with sensitizing EGFR or ALK mutations were excluded
double-blind
126 sites in 16 countries
P3/ one sided and two interim analysis. Repartition, reallocation between coprimary endpoint and hirarchy with secondary endpoint ORR
AI1 stopped/ addition of pembrolizumab to SOC chemotherapy resulted in significantly longer OS and PFS than chemotherapy alone. ORR was also significantly higher in pembrolizumab group.
atezolizumab plus carboplatin plus nab-paclitaxel (n=343) vs. carboplatin plus nab-paclitaxel (n=340)
randomized controlled trial
atezolizumab plus carboplatine plus nab-paclitaxel(ACnP)
Atezolizumab was administered at 1200 mg intravenously plus carboplatin at an area under the concentration-time curve of 6 mg/mL/min IV (day 1), nab-paclitaxel at 100 mg/m2 IV (days 1, 8, and 15).
carboplatine plus nab-paclitaxel (CnP)
carboplatin at an area under the concentration-time curve of 6 mg/mL/min IV (day 1), nab-paclitaxel at 100 mg/m2 IV (days 1, 8, and 15).
Crossover to atezolizumab was not allowed
squamous - mNSCLC - L1 - all population
Patients known to have EGFR mutations or ALK fusion oncogene were eligible
open label
317 study sites across 26 countries
P3/ two sided and two interim analysis. Alpha split between coprimary endpoint (ACnP) and hierarchy with OS/PFS (ACP)
Adding atezolizumab to platinum-based chemotherapy significantly improved PFS in patients with first-line squamous NSCLC; OS was similar between arms.
atezolizumab plus carboplatin plus paclitaxel (n=338) vs. nab-paclitaxel (n=340)
randomized controlled trial
atezolizumab plus carboplatine plus paclitaxel (ACP)
Atezolizumab was administered at 1200 mg intravenously and paclitaxel at 200 mg/m2 IV (175 mg/m2 for Asian race/ethnicity; day 1)
carboplatine plus nabpaclitaxel (CnP)
carboplatin at an area under the concentration-time curve of 6 mg/mL/min IV (day 1), nab-paclitaxel at 100 or 200 mg/m2 IV (days 1, 8, and 15)
Crossover to atezolizumab was not allowed
squamous - mNSCLC - L1 - all population
Patients known to have EGFR mutations or ALK fusion oncogene were eligible
open label
317 study sites across 26 countries
P3/ two sided and two interim analysis. Alpha split between coprimary endpoint (ACnP) and hierarchy with OS/PFS (ACP)
Adding atezolizumab to platinum-based chemotherapy significantly improved PFS in patients with first-line squamous NSCLC; OS was similar between the arms.No efficay results for this arm because of hierarchy
pembrolizumab plus SoC (n=278) vs. placebo plus SoC (n=281)
randomized controlled trial
pembrolizumab plus platine and (nab)paclitaxel
200 mg of pembrolizumab on day 1 for up to 35 cycles in 3-week cycles and for the first 4 cycles, carboplatin (at a dose calculated to produce an area under the concentration–time curve of 6 mg per milliliter per minute)on day 1 and either paclitaxel (200 mg per square meter of body-surface area) on day 1 or nab-paclitaxel (100 mg per square meter) on days 1, 8, and 15
placebo plus platine and (nab)paclitaxel
placebo on day 1 for up to 35 cycles in 3-week cycles and for the first 4 cycles, carboplatin (at a dose calculated to produce an area under the concentration–time curve of 6 mg per milliliter per minute)on day 1 and either paclitaxel (200 mg per square meter of body-surface area) on day 1 or nab-paclitaxel (100 mg per square meter) on days 1, 8, and 15
patients with progression will have the opportunity to crossover to receive open-label pembrolizumab monotherapy
squamous - mNSCLC - L1 - all population
no information about EGFR or ALK status
open-label
137 sites in 17 countries
P3/ one sided and three interim analysis. Repartition and reallocation between coprimary endpoint PFS OS and then ORR
AI2 (stopped) In patients with previously untreated metastatic, squamous NSCLC, the addition of pembrolizumab to chemotherapy with carboplatin plus paclitaxel or nab-paclitaxelresulted in significantly longer overall survival and progression-free survival than chemotherapyalone
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