immune checkpoint inhibition

Description Results NMA

OS 0.63 [0.51; 0.78] median 5.26 vs. 4.14

nivolumab at 3 mg/kg every 2 weeks (n=330)

vs.

placebo (n=163)

double blind

Parallel groups

Sample size: 330/163

Primary endpoint: OS

FU duration:

(n=-9)

vs.

(n=-9)

Single-arm study

Sample size: -9/-9

Primary endpoint:

FU duration:

PFS 1.27 [1.03; 1.57] median 1.5 mo vs. 4.1 mo

OS 0.82 [0.66; 1.02] median 9.1 mo vs. 8.3 mo

pembrolizumab (n=-9)

vs.

paclitaxel (n=-9)

open label

Sample size: -9/-9

Primary endpoint:

FU duration:

OS 0.70 [0.51; 0.96] median 7.5 mo vs. 5.1 mo Demonstrated

PFS 0.89 [0.70; 1.13] median 2.0 mo vs. 2.3 mo

nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks (n=361)

vs.

standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). (n=0)

open-label

Parallel groups

Sample size: 361/0

Primary endpoint: overall survival

FU duration:

OS 0.81 [0.66; 0.99]

pembrolizumab 200 mg intravenous (IV) on Day 1 of each 3-week cycle (n=-9)

vs.

standard treatment (methotrexate, docetaxel or cetuximab) (n=-9)

open-design

Sample size: -9/-9

Primary endpoint: OS

FU duration:

PFS 0.62 [0.52; 0.74] median 8.3 mo vs. 6.8 mo

ORR 1.01 [0.99; 1.02]

atezo + bev + C + P; (n=356)

vs.

bev + C + P (n=336)

3 arms : atezo 1200 mgþC AUC 6þP 200 mg/m2 (Arm A) or atezo þbev 15 mg/kg þC þ P (Arm B) versus bev þ C þP (Arm C) IV q3w for 4 or 6 cycles per investigator (INV) discretion, then maintenance atezo, atezo þ bev or bev, respectively.

open label

Parallel groups

Sample size: 356/336

Primary endpoint: PFS, OS

FU duration:

PFS 0.51 [0.38; 0.68] median 11.3 mo vs. 6.8 mo

ORR 1.00 [0.97; 1.03]

atezo + bev + C + P (n=155)

vs.

bev + C + P (n=129)

3 arms : atezo 1200 mgþC AUC 6þP 200 mg/m2 (Arm A) or atezo þbev 15 mg/kg þC þ P (Arm B) versus bev þ C þP (Arm C) IV q3w for 4 or 6 cycles per investigator (INV) discretion, then maintenance atezo, atezo þ bev or bev, respectively.

open label

Parallel groups

Sample size: 155/129

Primary endpoint: PFS, OS

FU duration:

overall survival 0.73 [0.53; 1.00] median 12.6 mo vs. 9.7 mo

overall survival 0.73 [0.62; 0.86] median 13.8 mo vs. 9.6 mo

PFS 0.95 [0.82; 1.10]

Atezolizumab (n=144)

vs.

docetaxel 75 mg/m(2) once every 3 weeks (n=143)

open label

Parallel groups

Sample size: 144/143

Primary endpoint: OS

FU duration:

phase 2

atelozumab (n=425)

vs.

docetaxel (n=425)

open label

Parallel groups

Sample size: 425/425

Primary endpoint: OS

FU duration: minimum 19 months

combination of MEDI4736 (durvalumab) plus tremelimumab (n=-9)

vs.

Standard of Care (n=-9)

Sample size: -9/-9

Primary endpoint: Overall Survival ,

FU duration:

PFS 0.52 [0.42; 0.65] median 16.8 mo vs. 5.6 mo Demonstrated

Durvalumab (at a dose of 10 mg per kilogram of body weight intravenously) every 2 weeks for up to 12 months, administered 1 to 42 days after the patients had received chemoradiotherapy (n=473)

vs.

placebo (n=236)

double-blind

Parallel groups

Sample size: 473/236

Primary endpoint: PFS, OS

FU duration:

concurrent ipilimumab (four doses of ipilimumab plus paclitaxel and carboplatin followed by two doses of placebo plus paclitaxel and carboplatin) or phased ipilimumab (two doses of placebo plus paclitaxel and carboplatin followed by four doses of ipilimum (n=204)

vs.

paclitaxel (175 mg/m(2)) and carboplatin (area under the curve, 6) (n=0)

double-blind

Parallel groups

Sample size: 204/0

Primary endpoint: immune-related progression-free survival

FU duration:

OS 0.91 [0.77; 1.07] median 13.4 mo vs. 12.4 mo

ipilimumab 10 mg/kg + paclitaxel and carboplatin (n=388)

vs.

placebo + paclitaxel and carboplatin (n=361)

double-blind

Parallel groups

Sample size: 388/361

Primary endpoint: OS

FU duration:

ipilimumab 10 mg/kg plus etoposide and platinum (cisplatin or carboplatin) (n=478)

vs.

placebo plus etoposide and platinum (cisplatin or carboplatin) (n=476)

double-blind

Parallel groups

Sample size: 478/476

Primary endpoint:

FU duration:

PFS 0.58 [0.41; 0.82] median 7.2 mo vs. 5.5 mo

nivolumab plus ipilimumab (n=139)

vs.

chemotherapy (n=160)

4 arms: Nivolumab, or Nivolumab Plus Ipilimumab, or Nivolumab Plus Platinum-doublet Chemotherapy, Compared to Platinum Doublet Chemotherapy

Tumor mutational burden was determined by the FoundationOne CDx assay

No masking

Parallel groups

Sample size: 139/160

Primary endpoint: PFS, OS

FU duration:

PFS 0.74 [0.58; 0.94] median 5.6 vs. 4.7

Nivolumab + chemotherapy (n=177)

vs.

chemotherapy (n=186)

4 arms: Nivolumab, or Nivolumab Plus Ipilimumab, or Nivolumab Plus Platinum-doublet Chemotherapy, Compared to Platinum Doublet Chemotherapy

No masking

Sample size: 177/186

Primary endpoint: Overall survival (OS)

FU duration:

overall survival 1.02 [0.80; 1.30] median 14.4 mo vs. 13.2 mo

PFS 1.15 [0.91; 1.45] median 4.2 mo vs. 5.9 mo

Nivolumab solution for Injection 3 mg/kg Intravenous every 2 weeks until disease progression (n=271)

vs.

platinum-based chemotherapy (administered once every 3 weeks for up to six cycles). (n=270)

Patients who progressed on chemotherapy could crossover to nivolumab as second line treatment.

open design

Parallel groups

Sample size: 271/270

Primary endpoint: PFS

FU duration:

cross over were permitted, a total of 128 of 212 patients (60%) in the chemotherapy group received nivolumab as subsequent therapy

overall survival 0.73 [0.59; 0.90] median 12.2 mo vs. 9.4 mo

grade 3–5 drug-related AEs 0.19 [0.14; 0.28]

PFS 0.92 [0.77; 1.10] median 2.3 mo vs. 4.2 mo

Nivolumab 3 mg/kg solution intravenously every 2 weeks until documented disease progression (n=292)

vs.

Docetaxel 75 mg/m² concentrate for solution for intravenous infusion every 3 weeks until documented disease progression (n=290)

open

Parallel groups

Sample size: 292/290

Primary endpoint: OS

FU duration:

overall survival 0.59 [0.44; 0.79] median 9.2 mo vs. 6.0 mo

PFS 0.62 [0.47; 0.81] median 3.5 mo vs. 2.8 mo

ORR 2.28 [1.21; 4.32]

grade 3–5 drug-related AEs 0.12 [0.07; 0.24]

Endocrine disorders ∞ [NaN; ∞]

Hypothyroidism ∞ [NaN; ∞]

Pneumonitis or interstitial lung disease 6.89 [0.86; 55.24]

Severe skin reactions 1.07 [0.49; 2.35]

Colitis ∞ [NaN; ∞]

Nivolumab 3 mg/kg solution intravenously every 2 weeks until documented disease progression (n=135)

vs.

Docetaxel 75 mg/m2 solution intravenously every 3 weeks until documented disease progression (n=137)

open

Sample size: 135/137

Primary endpoint: OS

FU duration:

overall survival 0.54 [0.33; 0.88] median 19 mo vs. 8.9 mo

PFS 0.53 [0.31; 0.91] median 13.0 mo vs. 8.9 mo

24 months treatment with pembrolizumab (200mg every three weeks)+ CT (n=60)

vs.

four cycles of carboplatin and pemetrexed (500 mg/m2 every three weeks) (n=63)

open design

Parallel groups

Sample size: 60/63

Primary endpoint: ORR

FU duration:

phase 1/2

overall survival 0.49 [0.38; 0.64] median 11.3 mo vs. not reached Demonstrated

PFS 0.52 [0.43; 0.63] median 8.8 mo vs. 4.9 mo Demonstrated

pemetrexed and a platinum-based drug plus 200 mg of pembrolizumab, followed by pembrolizumab for up to a total of 35 cycles plus pemetrexed maintenance therapy (n=410)

vs.

pemetrexed and a platinum-based drug plus placebo every 3 weeks for 4 cycles, followed by placebo (n=206)

double-blind

Parallel groups

Sample size: 410/206

Primary endpoint: PFS, OS

FU duration: 10.5 mo median

crossover permited

overall survival 0.64 [0.49; 0.84] median 15.9 mo vs. 11.2 mo

pembrolizumab + carboplatin and paclitaxel or nano particle albumin-bound paclitaxel (nab-paclitaxel) (n=278)

vs.

carboplatin and paclitaxel or nano particle albumin-bound paclitaxel (nab-paclitaxel) (n=281)

open-label

Parallel groups

Sample size: 278/281

Primary endpoint: OS, PFS

FU duration: 7?7 mo (median)

overall survival 0.69 [0.56; 0.85] median 20.0 mo vs. 12.2 mo

overall survival 0.77 [0.64; 0.92] median 17.7 mo vs. 13.0 mo

pembrolizumab (n=299)

vs.

SOC Treatment (Platinum-based Chemotherapy) (n=300)

open label

Sample size: 299/300

Primary endpoint: Overall survival

FU duration: 12.8-mo median

pembrolizumab (n=413)

vs.

SOC Treatment (Platinum-based Chemotherapy) (n=405)

open label

Parallel groups

Sample size: 413/405

Primary endpoint: Overall survival

FU duration: 12.8-mo median

overall survival 0.81 [0.71; 0.93] median 16.7 mo vs. 12.1 mo

overall survival 0.60 [0.41; 0.88] median not reached vs. not reached

PFS 0.50 [0.37; 0.68] median 10.3 mo vs. 6.0 mo

pembrolizumab 200 mg every 3 wk for 35 cycles or until disease progression, intolerable toxicity (n=637)

vs.

investigator's choice of carboplatin plus paclitaxel or carboplatin plus pemetrexed for a maximum of 6 cycles (n=637)

open label

Parallel groups

Sample size: 637/637

Primary endpoint: Overall survival

FU duration: 12.8-mo median

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 (n=154)

vs.

standard of care (SOC) platinum-based chemotherapies (n=151)

crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression

open label

Parallel groups

Sample size: 154/151

Primary endpoint: PFS, OS

FU duration: 11.2 months (median)

in the chemotherapy group, 66 patients (43.7%) crossed over to receive pembrolizumab after disease progression

overall survival 0.71 [0.58; 0.87] median 10.4 mo vs. 8.5 mo

PFS 0.88 [0.74; 1.05] median 3.9 mo vs. 4.0 mo

overall survival 0.61 [0.49; 0.75] median 12.7 mo vs. 8.5 mo

PFS 0.79 [0.66; 0.94] median 4.0 mo vs. 4.0 mo

pembrolizumab 2 mg/kg (n=345)

vs.

docetaxel 75 mg/m² every 3 weeks (n=343)

open-label

Parallel groups

Sample size: 345/343

Primary endpoint: OS

FU duration:

pembrolizumab 10 mg/kg (n=346)

vs.

docetaxel 75 mg/m² every 3 weeks (n=343)

open-label

Sample size: 346/343

Primary endpoint: OS

FU duration:

OS 0.72 [0.59; 0.87] median 11.2 mo vs. 9.1 mo Demonstrated

ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per square meter of body-surface area) (n=-9)

vs.

dacarbazine (850 mg per square meter) (n=-9)

double blind

Parallel groups

Sample size: -9/-9

Primary endpoint: OS

FU duration:

OS 0.64 [0.49; 0.84] median 10.1 mo vs. 6.4 mo

vitiligo all grade -9.00 [NaN; NaN]

vitiligo (grade 3-4) -9.00 [NaN; NaN]

OS 0.69 [0.56; 0.85] median 10.0 mo vs. 6.4 mo

vitiligo all grade -9.00 [NaN; NaN]

vitiligo (grade 3-4) -9.00 [NaN; NaN]

ipilimumab 3mg/kg every 3 weeks up to 4 treatments (n=137)

vs.

gp100 alone (n=136)

3 arms: ipilimumab plus gp100, ipilimumab alone, or gp100 alone

open-label

Parallel groups

Sample size: 137/136

Primary endpoint: overall surviva

FU duration:

Ipilimumab, at a dose of 3 mg per kilogram of body weight, was administered with gp100 every 3 weeks for up to four treatments (n=403)

vs.

gp100 alone (n=136)

3 arms: ipilimumab plus gp100, ipilimumab alone, or gp100 alone

open-label

Parallel groups

Sample size: 403/136

Primary endpoint: overall surviva

FU duration:

recurrence free survival 0.76 [0.64; 0.90] Demonstrated

OS 0.72 [0.58; 0.89]

PFS 0.76 [0.64; 0.90]

distant metastasis free survival 0.76 [0.63; 0.91]

grade 3-4 2.07 [1.74; 2.46]

ipilimumab at a dose of 10 mg per kilogram every 3 weeks for four doses, then every 3 months for up to 3 years or until disease recurrence or an unacceptable level of toxic effects occurred (n=475)

vs.

placebo (n=476)

double-blind

Parallel groups

Sample size: 475/476

Primary endpoint: RFS

FU duration: 5.3 years

phase 3

Nivolumab + ipilumab (n=314)

vs.

nivolumab alone (n=316)

3 arms: nivolumab alone, nivolumab combined with ipilimumab, ipilumab alone

double-blind

Parallel groups

Sample size: 314/316

Primary endpoint: PFS, OS

FU duration:

this comparison (nivo+ipi versus nivo) was not planned and could not be considered as interential

OS 0.42 [0.25; 0.71] median not reached vs. 10.8 mo Demonstrated

PFS 0.43 [0.34; 0.55] median 5.1 mo vs. 2.2 mo

Vitiligo any grade 21.89 [2.98; 160.92]

Adverse events leading to discontinuation of drug 0.58 [0.31; 1.09]

Grade 3 or 4 drug-related adverse events 0.66 [0.41; 1.07]

Vitiligo grade 3-4 NaN [NaN; NaN]

nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks (n=210)

vs.

dacarbazine at a dose of 1000 mg per square meter of body-surface area every 3 weeks (n=208)

double-blind

Parallel groups

Sample size: 210/208

Primary endpoint: OS

FU duration:

PFS 0.42 [0.31; 0.57] median 11.5 mo vs. 2.9 mo Demonstrated

Adverse events leading to discontinuation of drug 2.46 [1.82; 3.34]

Grade 3 or 4 drug-related adverse events 2.01 [1.63; 2.47]

PFS 0.57 [0.43; 0.76] median 6.9 mo vs. 2.9 mo Demonstrated

Adverse events leading to discontinuation of drug 0.52 [0.32; 0.83]

Grade 3 or 4 drug-related adverse events 0.60 [0.44; 0.81]

1mg of nivolumab per kilogram every 3 weeks plus 3 mg of ipilimumab per kilogram every 3 weeks for 4 doses, followed by 3 mg of nivolumab per kilogram every 2 weeks for cycle 3 and beyond (n=314)

vs.

3 mg of ipilimumab per kilogram every 3 weeks for 4 doses (n=315)

3 arms: nivolumab alone, nivolumab combined with ipilimumab, ipilumab alone

double-blind

Parallel groups

Sample size: 314/315

Primary endpoint: PFS, OS

FU duration:

nivolumab (1 mg per kilogram)and ipilimumab (3 mg per kilogram of body weight) combined once every 3 weeks for four doses followed by nivolumab (3 mg per kilogram) every 2 weeks until the occurrence of disease progression or unacceptable toxic effects (n=-9)

vs.

(n=-9)

double-blind

Parallel groups

Sample size: -9/-9

Primary endpoint: investigator-assessed, confirmed objective response

FU duration:

phase 2. The primary end point was the rate of investigator-assessed, confirmed objective response among patients with BRAF V600 wild-type tumors

3 mg of nivolumab per kilogram of body weight every 2 weeks (n=316)

vs.

3 mg of ipilimumab per kilogram every 3 weeks for 4 doses (n=315)

3 arms: nivolumab alone, nivolumab combined with ipilimumab, ipilumab alone

double-blind

Parallel groups

Sample size: 316/315

Primary endpoint: PFS, OS

FU duration:

overall response rate 3.72 [1.41; 9.85]

Grade 3 or 4 drug-related adverse events 0.29 [0.18; 0.46]

ntravenous infusion of nivolumab 3 mg/kg every 2 weeks until progression or unacceptable toxic eff ects (n=272)

vs.

investigator’s choice of chemotherapy (dacarbazine 1000 mg/m² every 3 weeks or paclitaxel 175 mg/m² combined with carboplatin area under the curve 6 every 3 weeks) (n=133)

open-label

Parallel groups

Sample size: 272/133

Primary endpoint: ORR, OS

FU duration:

phase 3

recurrence free survival 0.65 [0.51; 0.83] Demonstrated

PFS 0.65 [0.51; 0.83]

Adverse events leading to discontinuation of drug 0.23 [0.17; 0.31]

Grade 3 or 4 drug-related adverse events 0.31 [0.24; 0.40]

nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks (n=453)

vs.

ipilimumab at a dose of 10 mg per kilogram every 3 weeks for four doses and then every 12 weeks (n=453)

double-blind

Parallel groups

Sample size: 453/453

Primary endpoint: Recurrence free survival

FU duration: 18 months (median)

OS 0.68 [0.53; 0.87] median NA vs. 16 months

PFS 0.58 [0.46; 0.73]

Grade 3 or 4 drug-related adverse events 0.67 [0.45; 0.98]

Vitiligo any grade 5.76 [2.03; 16.31]

Vitiligo grade 3-4 NaN [NaN; NaN]

OS 0.68 [0.53; 0.87] median NA vs. 16 months

PFS 0.58 [0.47; 0.72]

Grade 3 or 4 drug-related adverse events 0.51 [0.33; 0.78]

Vitiligo any grade 7.16 [2.56; 20.01]

Vitiligo grade 3-4 NaN [NaN; NaN]

pembrolizumab (at a dose of 10 mg per kilogram of body weight) every 2 weeks or every 3 weeks (n=-9)

vs.

four doses of ipilimumab (at 3 mg per kilogram) every 3 weeks (n=-9)

3 arms: pembrolizumab (at a dose of 10 mg per kilogram of body weight) every 2 weeks or every 3 weeks or four doses of ipilimumab (at 3 mg per kilogram) every 3 weeks

12% of second line patients was included

open-label

Parallel groups

Sample size: -9/-9

Primary endpoint: PFS, OS

FU duration:

Pembrolizumab Every 3 Weeks (n=277)

vs.

Ipilimumab (Participants receive ipilimumab, 3 mg/kg IV, once every 3 weeks for a total oPembrolizumab Every 2 Weeks (Participants receive pembrolizumab, 10 mg intravenously (IV), once every 2 weeks for up to 2 years) 2/ Pembrolizumab Every 3 Weeks (P (n=278)

3 arms: pembrolizumab (at a dose of 10 mg per kilogram of body weight) every 2 weeks or every 3 weeks or four doses of ipilimumab (at 3 mg per kilogram) every 3 weeks.

12% of second line patients was included

open label

Parallel groups

Sample size: 277/278

Primary endpoint: PFS, OS

FU duration:

OS 1.09 [0.68; 1.75]

PFS 0.84 [0.57; 1.23]

Adverse events leading to discontinuation of drug 0.63 [0.23; 1.69]

overall response rate 0.99 [0.58; 1.67]

Grade 3 or 4 drug-related adverse events 1.75 [0.73; 4.18]

serious drug-related adverse events 6.61 [0.83; 52.57]

intravenous pembrolizumab at 2 mg/kg every 3 weeks (n=89)

vs.

intravenous pembrolizumab at 10 mg/kg every 3 weeks (n=84)

open-label

Parallel groups

Sample size: 89/84

Primary endpoint: ORR

FU duration:

PFS 0.57 [0.45; 0.73] median 2.9 mo vs. 2.7 mo

Vitiligo any grade 4.80 [1.07; 21.61]

Vitiligo grade 3-4 NaN [NaN; NaN]

PFS 0.50 [0.39; 0.64] median 2.9 mo vs. 2.7 mo

Vitiligo any grade 4.30 [0.94; 19.61]

Vitiligo grade 3-4 NaN [NaN; NaN]

Pembrolizumab 2 mg/kg IV Q3W (n=180)

vs.

investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide) (n=179)

3 arms ntravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy

open design

Parallel groups

Sample size: 180/179

Primary endpoint: PFS

FU duration:

phase 2

intravenous pembrolizumab 10 mg/kg every 3 weeks (n=181)

vs.

investigator-choice chemotherapy (paclitaxel plus carboplatin, paclitaxel, carboplatin, dacarbazine, or oral temozolomide) (n=179)

3 arms ntravenous pembrolizumab 2 mg/kg or 10 mg/kg every 3 weeks or investigator-choice chemotherapy

open design

Parallel groups

Sample size: 181/179

Primary endpoint: PFS

FU duration:

phase 2

recurrence free survival 0.57 [0.43; 0.75] Demonstrated

PFS LP-D1 positif 0.54 [0.42; 0.69]

PFS PD-L1 negatif 0.47 [0.26; 0.85]

PFS 0.57 [0.43; 0.75]

Grade 3 or 4 drug-related adverse events 4.35 [2.61; 7.26]

Vitiligo any grade 2.96 [1.34; 6.52]

Vitiligo grade 3-4 NaN [NaN; NaN]

Pembrolizumab (Participants receive pembrolizumab 200 mg intravenously (IV) on Day 1 of each 21-day cycle for up to 1 year) (n=514)

vs.

placebo (n=505)

double-blind

Parallel groups

Sample size: 514/505

Primary endpoint: Recurrence-free survival ,

FU duration: 15 months (median)

(n=151)

vs.

lenalidomide and low-dose dexamethasone (n=150)

Only 301 of the 640 planned had been enrolled when the trial was halted

open-design

Parallel groups

Sample size: 151/150

Primary endpoint:

FU duration:

PFS 1.53 [1.05; 2.22] median 7.8 mo vs. 8.6 mo

OS 1.61 [0.91; 2.85] median NR vs. 15.2 mo

pembrolizumab, Pomalidomide and low-dose Dexamethasone (n=125)

vs.

Pomalidomide and low-dose Dexamethasone (n=124)

open-design

Parallel groups

Sample size: 125/124

Primary endpoint:

FU duration: 7.8 mo / 8.6 mo (median)

OS 0.68 [0.49; 0.95] median not reached vs. 32.9 mo Demonstrated

PFS 0.82 [0.64; 1.05] median 11.56 mo vs. 8.38 mo

nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for 4 doses followed by Opdivo 3 mg/kg every 2 weeks (n=-9)

vs.

sunitinib 50 mg once daily for 4 weeks, followed by 2 weeks off before continuation of treatment (n=-9)

open-label

Parallel groups

Sample size: -9/-9

Primary endpoint: ORR, PFS, OS

FU duration:

phase 3

OS 0.73 [0.57; 0.93] median 25.0 mo vs. 19.6 mo

PFS 0.88 [0.75; 1.03] median 4.6 mo vs. 4.4 mo

3 mg of nivolumab per kilogram of body weight intravenously every 2 weeks (n=-9)

vs.

10-mg everolimus tablet orally once daily (n=-9)

open-label

Parallel groups

Sample size: -9/-9

Primary endpoint: OS

FU duration:

Atezolizumab (n=-9)

vs.

single arm study (n=-9)

Single-arm study

Sample size: -9/-9

Primary endpoint:

FU duration:

phase 2

grade 3-4 treatment-related adverse events 0.46 [0.38; 0.58]

OS 0.87 [0.63; 1.21] median 11.1 months vs. 10.6 months

ORR 1.07 [0.66; 1.73]

atezolizumab (n=467)

vs.

chemotherapy (n=464)

IC2/3 patients as planned as step 1 of the hierarchical testing

open label

Parallel groups

Sample size: 467/464

Primary endpoint: OS

FU duration:

sequential testing of IC2/3 population in first then IC1/2/3 population; and finaly all-comers population

Atezolizumab+Gemcitabine+Carboplatin/Cisplatin (n=-9)

vs.

Placebo+Gemcitabine+Carboplatin/Cisplatin (n=-9)

3rd arm with Atezolizumab Monotherapy

open-design

Sample size: -9/-9

Primary endpoint:

FU duration:

durvalumab at 10 mg/kg body weight administered as an intravenous infusion over 60 minutes every two weeks until disease progression or unacceptable toxicity (n=-9)

vs.

(n=-9)

Single-arm study

Sample size: -9/-9

Primary endpoint:

FU duration:

phase 1/2

nivolumab 3 mg/kg intravenously every 2 weeks until disease progression and clinical deterioration, unacceptable toxicity, or other protocol-defined reasons (n=270)

vs.

(n=-9)

Single-arm study

Sample size: 270/-9

Primary endpoint: ORR

FU duration:

intravenous pembrolizumab 200 mg every 3 weeks (n=374)

vs.

(n=-9)

open-design

Single-arm study

Sample size: 374/-9

Primary endpoint: ORR

FU duration: 5 months (median)

phase 2, single arm

OS 0.73 [0.59; 0.91] median 10.3 months vs. 7.4 months

PFS 0.98 [0.81; 1.19]

pembrolizumab (n=270)

vs.

investigator's choice of chemotherapy with paclitaxel, docetaxel, or vinflunine (n=272)

open-label

Parallel groups

Sample size: 270/272

Primary endpoint: OS

FU duration:

pembrolizumab 200 mg every 3 weeks (Q3W) (n=990)

vs.

chemotherapy alone (n=0)

3 arms: pembrolizumab ± chemotherapy versus chemotherapy

Sample size: 990/0

Primary endpoint:

FU duration: