Efficacy and safety of immune checkpoint inhibitors in patients with advanced non–small cell lung cancer (NSCLC): a systematic literature review

Figures & data

Table 1. Eligibility criteria.

	Inclusion	Exclusion
Population:	Adults with histologically confirmed unresectable NSCLC (stages IIIA, IIIB, and IV)	Adults with NSCLC stage I–II or SCLC
Interventions:	PD-1 inhibitors (nivolumab, pembrolizumab), PD-L1 inhibitors (atezolizumab, durvalumab) as: monotherapy combination of two or more combination therapy with targeted therapy combination therapy with chemotherapy	Other treatments
Comparators:	Chemotherapy Targeted therapy small molecule inhibitors for EGFR, ROS1, ALK, and MET Placebo Best Supportive Care	Other treatment, no treatment
Outcomes:	Progression-free survival Overall survival Overall adverse events (any cause, treatment related) Serious adverse events (any cause, treatment related)	Other outcomes
Study design:	Randomized controlled trial	All other study designs
Publication language:	English German	Other languages
Search period:	2000–beginning of search	Before 2000

Abbreviations: ALK = anaplastic lymphoma kinase; EGFR = epidermal growth factor receptor; MET = mesenchymal–epithelial transition factor; NSCLC = non–small cell lung cancer; PD-1 = programmed cell death protein-1; PD-L1 = programmed cell death ligand-1; ROS1 = proto-oncogene tyrosine-protein kinase; SCLC = small cell lung cancer

Figure 1. PRISMA flow diagram modified from Moher et al.²⁹

Table 2. Characteristics of included studies.

Author, year, trial name, NCT Therapy line	Study design, phase Funding/Support	Recruiting Period	Countries	Follow-up	N total randomized	Key inclusion criteria Primary outcome(s)	Intervention N randomized	Comparison N randomized
ATEZOLIZUMAB
Fehrenbacher et al. 2016^Citation40 POPLAR NCT01903993 Second-line therapy	Randomized, controlled, open-label, phase 2 F. Hoffmann-La Roche/Genentech	August 2013 – March 2014	61 academic medical centers, 13 countries, Europe and North America	Median: Atezolizumab: 14.8 months Docetaxel: 15.7 months	287	Key inclusion criteria: NSCLC with progression after platinum-based CHT ECOG status of 0 or 1 Measurable disease Adequate hematological and end-organ function Primary endpoints: Overall survival in the intention-to-treat population and PD-L1 subgroups	Atezolizumab 1200 mg every 3 weeks N = 144	Docetaxel 75 mg/m^2 of BSA every 3 weeks N = 143
Rittmeyer et al. 2017^Citation48 Fehrenbacher et al. 2018^Citation41 OAK NCT02008227 Second-line therapy	Randomized, controlled, open-label, phase 3 F. Hoffmann-La Roche/Genentech	March 2014 – April 2015	194 academic or community oncology centers, 31 countries, Europe, North and South America, New Zealand, and Asia	Median: 21 months	1225 (secondary efficacy population) 850 (primary efficacy population)	Key inclusion criteria: Stage IIIB or IV squamous or nonsquamous NSCLC ECOG status of 0 or 1 1–2 previous cytotoxic chemotherapy regimens Patients with EGFR mutations or an ALK fusion oncogene were additionally required to have received previous tyrosine kinase inhibitor therapy Primary endpoints: Overall survival	Atezolizumab 1200 mg every 3 weeks N = 425 (primary efficacy population) N = 613 (secondary efficacy population)	Docetaxel 75 mg/m^2 of BSA every 3 weeks N = 425 (primary efficacy population) N = 612 (secondary efficacy population)
West et al.2019^Citation50 IMpower130 NCT02367781 First-line therapy	Randomized, controlled, open-label, phase 3 F. Hoffmann-La Roche/Genentech	April 2015 – February 2017	131 centers, 8 countries, North America, Europe and Israel	Median: (wild-type population)^a Atezolizumab plus Chemotherapy: 18.5 months Chemotherapy: 19.2 months	724 Wild-type population:^a 679	Key inclusion criteria: Stage IV nonsquamous NSCLC ECOG status of 0 or 1 No previous chemotherapy for stage IV disease Primary endpoints: Overall survival Progression-free survival	Atezolizumab 1200 mg every 3 weeks + carboplatin at an AUC of 6 mg/mL per minute every 3 weeks + nab-paclitaxel 100 mg/m^2 of BSA every week for four or six 21-day cycles N = 483 N = 451 (wild-type population)^a	Carboplatin at an AUC of 6 mg/mL per minute every 3 weeks + nab-paclitaxel 100 mg/m^2 of BSA every week for four or six 21-day cycles N = 240 N = 228 (wild-type population) ^a
Socinski et al. 2018^Citation49 IMpower150 NCT02366143 First-line therapy	Randomized, controlled, open-label, phase 3 F. Hoffmann-La Roche/Genentech	March 2015 – December 2016	240 sites, 26 countries, Australia, Asia, Europe, and North and South America	Median: (wild-type population)^a ABCP: 15.4 months BCP: 15.5 months	1202 Wild-type population:^a 1040	Key inclusion criteria: Previously untreated stage IV or recurrent metastatic nonsquamous NSCLC ECOG status of 0 or 1 Patients with EGFR or ALK genomic alterations if they had disease progression with or unacceptable side effects from treatment with at least one approved tyrosine kinase inhibitor Primary endpoints: Overall survival Progression-free survival	ABCP: Atezolizumab 1200 mg + bevacizumab 15 mg/kg BW + carboplatin at an AUC of 6 mg/mL per minute + paclitaxel 200 mg/m^2 of BSA (175 mg/m^2 for Asian patients) for four or six 21-day cycles N = 400 N = 356 (wild-type population)^a ACP: Atezolizumab 1200 mg + carboplatin at an AUC of 6 mg/mL per minute + paclitaxel 200 mg per m^2 of BSA (175 mg per m^2 for Asian patients) for four or six 21-day cycles N = 402 N = 348 (wild-type population)^a	BCP: Bevacizumab 15 mg/kg BW + carboplatin at an AUC of 6 mg/mL per minute for four or six 21-day cycles + paclitaxel 200 mg per m^2 of BSA (175 mg/m^2 for Asian patients) N = 400 N = 336 (wild-type population)^a
DURVALUMAB
Antonia et al. 2017^Citation22 Antonia et al. 2018^Citation36 Gray et al. 2019^Citation26 PACIFIC NCT02125461 First-line therapy (consolidation after radiochemotherapy)	Randomized, double-blind, placebo-controlled, phase 3 Astra Zeneca	May 2014 – April 2016	Australia, Asia, Europe, North and South America, and South Africa	Antonia et al. 2017:^Citation22 Median: 14.5 months Antonia et al. 2018:^Citation36 Median: 25.2 months Gray et al. 2019:^Citation26 Median: 33.3 months	713	Key inclusion criteria: Histologically or cytologically documented stage III, locally advanced, unresectable NSCLC Patients had received two or more cycles of platinum-based chemotherapy concurrent with definitive radiotherapy No disease progression after this therapy WHO performance status of 0 or 1 Life expectancy of 12 weeks or longer Primary endpoints: Overall survival Progression-free survival	Durvalumab 10 mg/kg BW every 2 weeks for up to 12 months N = 476 (	Placebo every 2 weeks for up to 12 months N = 237
NIVOLUMAB
Wu et al. 2019^Citation51 CheckMate 078 NCT02613507 Second-line therapy	Randomized, controlled, open-label, phase 3 Bristol-Myers Squibb	December 2015 – November 2016	32 hospitals and cancer/medical centers, China, Russia, Singapore	Median: Nivolumab: 10.4 months Docetaxel: 8.8 months	504	Key inclusion criteria: Patients with stage IIIB or IV or recurrent squamous or nonsquamous NSCLC progressing during or after one previous platinum-based doublet chemotherapy regime ECOG status of 0 or 1 Primary endpoint: Overall survival	Nivolumab 3 mg/kg BW every 2 weeks N = 338	Docetaxel 75 mg/m^2 of BSA every 3 weeks N = 166
Borghaei et al. 2015^Citation37 CheckMate 057 NCT01673867 Second-line therapy	Randomized, controlled, open-label, phase 3 Bristol-Myers Squibb	November 2012 – December 2013	Europe and North and South America	Minimum: 13.2 months	582	Key inclusion criteria: Previously untreated stage IIIB or IV nonsquamous NSCLC No activating EGFR mutations or ALK receptor tyrosine kinase gene translocations ECOG status of 0 or 1 Primary endpoint: Overall response rate	Nivolumab 3 mg/kg BW every 2 weeks N = 292	Docetaxel 75 mg/m^2 of BSA every 3 weeks N = 290
Brahmer et al. 2015^Citation38 CheckMate 017 NCT01642004 Second-line therapy	Randomized, controlled, open-label, phase 3 Bristol-Myers Squibb	October 2012 – December 2013	Australia, Europe, and North and South America	Minimum: 11 months	272	Key inclusion criteria: Patients with stage IIIB or IV squamous cell NSCLC who had disease recurrence after one prior platinum containing regimen ECOG status of 0 or 1 Primary endpoint: Overall survival	Nivolumab 3 mg/kg BW every 2 weeks N = 135	Docetaxel 75 mg/m^2 of BSA every 3 weeks N = 137
Carbone et al. 2017^Citation39 CheckMate 026 NCT02041533 First-line therapy	Randomized, controlled, open-label, phase 3 Bristol-Myers Squibb	March 2014 – April 2015	Australia, Asia, Europe, and North and South America	Median: 13.5 months	541	Key inclusion criteria: Histologically confirmed squamouscell or nonsquamous stage IV or recurrent NSCLC ECOG status of 0 or 1 No previous systemic anti-cancer therapy as primary therapy for advanced or metastatic disease PD-L1 expression level ≥1 Primary endpoint: Progression-free survival among patients with a PD-L1 expression level of ≥5%	Nivolumab 3 mg/kg BW every 2 weeks N = 271	Platinum-based doublet CHT every 3 weeks for 4 to 6 cycles: carboplatin + pemetrexed, cisplatin + pemetrexed, carboplatin + gemcitabine, cisplatin + gemcitabine, or carboplatin + paclitaxel N = 270
Hellmann et al. 2018^Citation24 Hellmann et al. 2019^Citation23 CheckMate 227 NCT02477826 First-line therapy	Randomized, controlled, open-label, phase 3 Bristol-Myers Squibb	August 2015 – November 2016	Europe, North and South America, Australia, Asia, and Africa	Minimum: 29.3 months	1739 PD-L1 expression of ≥1%: 1189 PD-L1 expression of <1%: 550	Key inclusion criteria: Histologically confirmed squamous or nonsquamous stage IV or recurrent NSCLC No previous systemic anticancer therapy as primary therapy for advanced or metastatic disease ECOG status of 0 or 1 Primary endpoints: Overall survival in a patient population selected on the basis of the PD-L1 expression level Progression-free survival in a patient population on the basis of the tumor mutational burden	PD-L1 expression of ≥1%: Nivolumab 3 mg/kg BW every 2 weeks + ipilimumab 1 mg/kg every 6 weeks N = 396 or Nivolumab 240 mg every 2 weeks N = 396 PD-L1 expression of <1%: Nivolumab 3 mg/kg BW every 2 weeks + ipilimumab 1 mg/kg BW every 6 weeks N = 187 or Nivolumab 360 mg every 3 weeks + platinum-doublet CHT based on histologic tumor type every 3 weeks or up to four cycles N = 177	PD-L1 expression of ≥1%: Platinum-doublet CHT based on histologic tumor type every 3 weeks for up to four cycles N = 397 PD-L1 expression of <1%: Platinum-doublet CHT based on histologic tumor type every 3 weeks for up to four cycles N = 186
PEMBROLIZUMAB
Herbst et al. 2016^Citation43 KEYNOTE-010 NCT01905657 Second-line therapy	Randomized, controlled, open-label, phase 2/3 Merck & Co.	August 2013 – February 2015	202 academic centers, 24 countries, Africa, Australia, Asia, Europe, and North and South America	Median: 13.1 months	1034	Key inclusion criteria: Advanced NSCLC Disease progression after two or more cycles of platinum-doublet chemotherapy An appropriate tyrosine kinase inhibitor for those with an EGFR-sensitizing mutation or ALK gene rearrangement ECOG status of 0 or 1 PD-L1 TPS >1% Primary endpoints: Overall survival in the total population and in patients with TPS>50% Progression-free survival in the total population and in patients with TPS>50%	Pembrolizumab 2 mg/kg BW every 3 weeks N = 345 Pembrolizumab 10 mg/kg BW every 3 weeks N = 346	Docetaxel 75 mg per m^2 of BSA every 3 weeks N = 343
Mok et al. 2019^Citation45 KEYNOTE-042 NCT02220894 First-line therapy	Randomized, controlled, open-label, phase 3 Merck Sharp & Dohme	December 2014 – March 2017	213 centers, 32 countries, North and South America, Europe, Asia and South Africa	Median: 12.8 months	1274	Key inclusion criteria: Previously untreated locally advanced or metastatic NSCLC ECOG status of 0 or 1 No EGFR mutation or ALK translocation PD-L1 TPS ≥1% Life-expectancy 3 months or longer Primary endpoints: Overall survival in patients with PD-L1 TPS ≥50%, ≥20% or ≥1%	Pembrolizumab 200 mg every 3 weeks for up to 35 cycles N = 637	Platinum-based CHT of the investigator’s choice for 4–6 cycles: carboplatin at an AUC of 5–6 mg/mL/min + paclitaxel 200 mg/m^2 of BSA or pemetrexed 500 mg/m^2 N = 637
Reck et al. 2016^Citation47 Reck et al. 2019^Citation27 KEYNOTE-024 NCT2142738 First-line therapy	Randomized, controlled, open-label, phase 3 Merck & Co.	September 2014 – October 2015	142 sites, 16 countries, Australia, Europe, and North America	Reck et al. 2016: Median: 11.2 months Reck et al. 2019: Median: 25.2 months	305	Key inclusion criteria: Stage IV NSCLC No sensitizing EGFR mutations or ALK translocations No previous systematic therapy for metastatic disease ECOG status of 0 or 1 Life expectancy of at least 3 months PD-L1 tumor proportion score of 50% or more Primary endpoint: Progression-free survival	Pembrolizumab 200 mg every 3 weeks for 35 cycles N = 154	Platinum-based CHT for 4 to 6 cycles: carboplatin + pemetrexed, cisplatin + pemetrexed, carboplatin + gemcitabine, cisplatin + gemcitabine, or carboplatin + paclitaxel N = 151
Paz-Ares et al. 2018^Citation46 KEYNOTE-407 NCT02775435 First-line therapy	Randomized, controlled, double-blind, phase 3 Merck Sharp & Dohme	August 2016 – December 2017	125 sites, 17 countries, Australia, Europe, and North and Central America, Asia	Median: 7.8 months	559	Key inclusion criteria: Stage IV squamous NSCLC ECOG status of 0 or 1 No previous chemotherapy for metastatic disease Primary endpoints: Overall survival Progression-free survival	Pembrolizumab 200 mg every 3 weeks for up to 35 cycles + carboplatin at an AUC of 6 mg/mL + paclitaxel 200 mg/m^2 of BSA or nab-paclitaxel 100 mg/m^2 of BSA for the first 4 cylces N = 278	Placebo for up to 35 cycles + carboplatin at an AUC of 6 mg/mL + paclitaxel 200 mg/m^2 of BSA or nab-paclitaxel 100 mg/m^2 of BSA for the first 4 cylces N = 281
Langer et al. 2016^Citation44 Borghaei et al. 2019^Citation25 KEYNOTE-021 NCT02039674 First-line therapy	Randomized, controlled, open-label, phase 2 Merck & Co.	November 2014 – January 2016	26 medical centers, 2 countries, Taiwan and USA	Langer et al. 2016: Median: 10.6 months Borghaiei et al. 2019: Median: 23.9 months	123	Key inclusion criteria: Nonsquamous stage IIIB or IV NSCLC No previous systemic treatment for stage IIIB or IV NSCLC Absence of targetable EGFR mutations or ALK translocations ECOG status of 0 or 1 Primary endpoint: Objective response rate	Pembrolizumab 200 mg + Platinum-based doublet CHT: carboplatin + pemetrexed every 3 weeks for 4 cycles N = 60	Platinum-based doublet CHT: carboplatin + pemetrexed for 4 cycles N = 63
Gandhi et al. 2018^Citation42 KEYNOTE-189 NCT02578680 First-line therapy	Randomized, controlled, double-blind, phase 3 Merck & Co.	February 2016 – March 2017	126 sites, 16 countries, Europe, North America, Australia, Asia, and Japan	Median: 10.5 months	616	Key inclusion criteria: Metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations No previous systematic therapy for systematic disease ECOG status of 0 or 1 Primary endpoints: Overall survival Progression-free survival	Pembrolizumab 200 mg every 3 weeks for 35 cycles + Platinum-based CHT: four cycles of the investigator’s choice of IV cisplatin (75 mg/m2 of BSA) or carboplatin (AUC, 5 mg per ml per minute) plus pemetrexed (500 mg/m^2), all administered IV every 3 weeks, N = 410	Placebo every 3 weeks for up to 35 cycles + Platinum-based CHT: four cycles of the investigator’s choice of IV cisplatin (75 mg/m^2 of BSA) or carboplatin (AUC, 5 mg per ml per minute) plus pemetrexed (500 mg per m^2), all administered IV every 3 weeks, N = 206

Abbreviations: ABCP = atezolizumab plus bevacizumab plus carboplatin plus paclitaxel; ACP = atezolizumab plus carboplatin plus paclitaxel; ALK = anaplastic lymphoma kinase; AUC = area under the concentration−time curve; BSA = body surface area; BCP = bevacizumab plus carboplatin plus paclitaxel; BW = body weight; CHT = chemotherapy; ECOG = Eastern Cooperative Oncology Group; EGFR = epidermal growth factor receptor; IV = intravenously; ITT = intention-to-treat; N = number of patients; NCT = National Clinical Trial; NR = not reported; NSCLC = non–small cell lung cancer; PD-L1 = programmed death ligand-1; mg = milligram; ml = milliliter; kg = kilogram; TPS = tumor proportion score; WHO = World Health Organization

^aWild-type genotype: patients with no EGFR or ALK genomic alterations

Figure 2. Forest plots for (a) overall survival and (b) progression-free survival in studies assessing immune checkpoint inhibitors as first-line therapy.

Hellmann 2019 CheckMate 227, Nivolumab + CHT vs. CHT: We converted 97.72% CI (0.60–1.02) for overall survival and 97.72% CI (0.56–0.95) for progression free survival to 95% CI. Hellmann 2019 CheckMate 227, Nivolumab + Ipilimumab vs. CHT: We converted 97.72% CI (0.65–0.96) for overall survival to 95% CI. Abbreviations: CHT = chemotherapy; CI = confidence interval; ICI = immune checkpoint inhibitor; N = number of patients; PD-L1 = programmed cell death ligand-1.

Figure 3. Forest plots for (a) overall survival and (b) progression-free survival in studies assessing immune checkpoint inhibitors as second-line therapy.

Wu 2019 CheckMate 078: We converted 97.7% CI (0.52–0.90) for overall survival to 95% CI. Herbst 2016 KEYNOTE-010:intention-to-treat N = 1033 including all three study arms (pembrolizumab 2 mg, N = 344, pembrolizumab 10 mg, N = 346, docetaxel 75 mg, N = 343). Percentage of randomized patients with quantifiable tumor PD-L1 expression: Borghaei 2015 CheckMate 057: 78%; Brahmer 2015 CheckMate 017: 83%; Wu 2019 CheckMate 078: 9%. Abbreviations: CI = confidence interval; D + L = DerSimonian and Laird method; ICI = immune checkpoint inhibitor; kg = kilogram; mg = milligram; N = number of patients; PD-L1 = programmed cell death ligand-1.

Figure 4. Forest plots for adverse events in studies assessing immune checkpoint inhibitors as (a) first-line and (b) second-line therapy.

Herbst 2016 KEYNOTE-010: docetaxel arm (N = 343) was split upAbbreviations: CHT = chemotherapy; CI = confidence interval; ICI = immune checkpoint inhibitor; N = number of patients; TRAE = treatment-related adverse events.

Figure 4. (Continued).

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