Figure 1. Kaplan–Meier estimates of overall survival based on response evaluation after two cycles and based on 1-year progression-free survival. Responded, complete response, and partial response; controlled, complete response, partial response, and disease control. HR, hazard ratio; brackets, 95% confidence interval.

Figure 1. Kaplan–Meier estimates of overall survival based on response evaluation after two cycles and based on 1-year progression-free survival. Responded, complete response, and partial response; controlled, complete response, partial response, and disease control. HR, hazard ratio; brackets, 95% confidence interval.

Figure 2. Study-level correlation. Each circle represents one randomized trial. Circle size represents study weight. Red circles indicate the point-symmetry of the original samples (black circles) to produce reciprocal duplication. N, number of trials; r, weighted rank correlation coefficient. ORR, objective response rate; DCR, disease control rate; PFS, progression-free survival.

Figure 2. Study-level correlation. Each circle represents one randomized trial. Circle size represents study weight. Red circles indicate the point-symmetry of the original samples (black circles) to produce reciprocal duplication. N, number of trials; r, weighted rank correlation coefficient. ORR, objective response rate; DCR, disease control rate; PFS, progression-free survival.

Figure 3. Study level-surrogacy following reciprocal duplication, subgroup analysis. Each circle represents one trial. Circle size represents study weight. Red circles indicate the point-symmetry of the original samples (black circles) for reciprocal duplication. N, number of trials; r, weighted rank correlation coefficient. ORR, odds ratio; DCR, disease control rate; PFS, progression-free survival. 1L, first-line subgroup; 2L-, second- or later-line subgroup.

Figure 3. Study level-surrogacy following reciprocal duplication, subgroup analysis. Each circle represents one trial. Circle size represents study weight. Red circles indicate the point-symmetry of the original samples (black circles) for reciprocal duplication. N, number of trials; r, weighted rank correlation coefficient. ORR, odds ratio; DCR, disease control rate; PFS, progression-free survival. 1L, first-line subgroup; 2L-, second- or later-line subgroup.

Table 1. Patient characteristics for independent patient data analysis.

Table 1. Patient characteristics for independent patient data analysis.

1st Line2nd or Later LineN20031309Age (year)64 (58–70)63 (57–70)Sex  Men1328 (66.3%)803 (61.3%) Women675 (33.7%)506 (38.7%)Race  Asian199 (9.9%)199 (15.2%) Black or African American36 (1.8%)24 (1.8%) White1693 (84.5%)1027 (78.5%) Other/unknown75 (3.7%)59 (4.5%)Pathology  Squamous677 (33.8%)364 (27.8%) Non-squamous1309 (65.4%)945 (72.2%) Unknown17 (0.8%)0 (0.0%)Stage  IA60 (3.0%)39 (3.0%) IB44 (2.2%)56 (4.3%) IIA46 (2.3%)49 (3.7%) IIB48 (2.4%)75 (5.7%) IIIA134 (6.7%)193 (14.7%) IIIB96 (4.8%)159 (12.1%) IV (not specified for A/B)1489 (74.3%)55 (4.2%) IVA27 (1.3%)310 (23.7%) IVB24 (1.2%)346 (26.4%) Unknown35 (1.7%)27 (2.1%)TD-L1 (IC)  0–0.9917 (45.8%)326 (24.9%) 1–4.9645 (32.2%)315 (24.1%) 5–9.9212 (10.6%)207 (15.8%) 10–49.9191 (9.5%)321 (24.5%) 50–10038 (1.9%)131 (10.0%) Unknown0 (0.0%)9 (0.7%)PD-LI (TC)  0–0.91229 (61.4%)550 (42.0%) 1–4.9205 (10.2%)292 (22.3%) 5–9.973 (3.6%)61 (4.7%) 10–49.9241 (12.0%)181 (13.8%) 50–100255 (12.7%)218 (16.7%) Unknown0 (0.0%)7 (0.5%)Smoking history  Never290 (14.5%)239 (18.3%) Previous1224 (61.1%)901 (68.8%) Current489 (24.4%)169 (12.9%)

Table 2. Characteristics of trials used in the study-level analysis.

Table 2. Characteristics of trials used in the study-level analysis.

CountryPhasePathoStagePD-L1 StatusDriverPSLineImaging EvaluationTreatmentROB
H/U/LAntonia (2017)
PACIFICUSAIIINSCLCIIIa, IIIbAnyANY0–1After CCRRECIST
ICRDur (10 mg/kg) q2w
No active treatment0/0/6Barlesi (2018)
JAVELIN Lung 200South KoreaIIINSCLCIIIb, IV, RecTC > 1%EGFR(-), ALK(-)0–12–4RECIST
ICRAvel (10 mg/kg) q2w
Dtx (75 mg/m2) q3w1/0/5Borghaei (2015)
CheckMate057USAIIINSQIIIb, IVAnyAny0–12–3RECISTNiv (3 mg/kg) q2w
Dtx (75 mg/m2) q3w2/0/4Boyer (2021)
KEYNOTE-598AustraliaIIINSCLCIVTC > 50%EGFR(-), ALK(-)0–11RECIST,
ICRPemb (200 mg) q3w + Ipi (1 mg/kg) q6w
Pemb (200 mg) q3w 0/0/6Brahmer (2015)
CheckMate017USAIIISQIIIb, IVAnyAny0–12RECIST, Niv (3 mg/kg) q2w
Dtx (75 mg/m2) q3w2/0/4Carbone (2017)
CheckMate026USAIIINSCLCIV, RecTC > 5%EGFR(-), ALK(-)0–11RECIST,
ICRNiv (3 mg/kg) q2w
Platinum doublet1/0/5Fehrenbacher (2016)
POPLARUSAIINSCLCAdv, MetAnyAny0–12–3RECISTAtz (1200 mg) q3w
Dtx (75 mg/m2) q3w2/0/4Gandhi (2018)
KEYNOTE-189USAIIINSQMetAnyEGFR(-), ALK(-)0–11RECIST,
ICRPemb (200 mg) + Platinum + Pemt (500 mg/m2) q3w
Platinum + Pemt (500 mg/m2) q3w1/0/5Gettinger (2021)
Lung-MAP S1400I USAIIISQIVAnyAny0–1 (Z)2-RECISTNiv (3 mg/kg) q2w + Ipi (1 mg/kg) q6w
Niv (3 mg/kg) q2w 2/0/4Govindan (2017)
Study 104USAIIISQIV, RecAnyAny0–11mWHOIpi (10 mg/kg) + Cbdca (AUC 6) + Ptx (175 mg/m2) q3w
Cbdca (AUC 6) + Ptx (175 mg/m2) q3w 0/0/6Hellmann (2019)
CheckMate227USAIIINSCLCIV, RecTC >1%EGFR(-), ALK(-)0–11RECIST
ICRNiv (3 mg/kg) q2w + Ipi (1 mg/kg) q6w
Platinum doublet1/0/5Hensing (2021)
Alliance 09USAIINSCLCIVAnyEGFR(-), ALK(-)0–1no previous ICIRECIST,
ICRCbdca doublet q3w x4 followed by Pemb (200 mg) q3w x4
Pemb (200 mg) q3w x4 followed by Cbdca doublet q3w x41/0/5Herbst (2016)
KEYNOTE-010USAII/IIINSCLCAdvTC >1%Any0–12-RECIST,
ICRPemb (10 mg/kg) q3w
Dtx (75 mg/m2) q3w1/0/5Herbst (2020)
IMpower110USAIIINSCLCIVIC>10% or TC>50%EGFR(-), ALK(-)0–11RECISTAtz (1200 mg) q3w
Dtx (75 mg/m2) q3w1/0/5Jotte (2020)
IMpower131USAIIISQIVAnyAny0–11RECISTAtz (1200 mg) + Cbdca (AUC 6) + nPtx (100 mg/m2) q3w
Cbdca (AUC 6) + nPtx (100 mg/m2) q3w1/0/5Jung (2022)
NCT03656094South KoreaIINSCLCAdvAnyEGFR(-), ALK(-)0–12–3RECISTPemb (200 mg) q3w + Single-agent Chemotherpay
Single-agent Chemotherpay0/0/6Langer (2016)
KEYNOTE-021USAIINSQIII, IVAnyEGFR(-), ALK(-)0–11RECISTPemb (200 mg) + Cbdca (AUC 5) + Pemt (500 mg/m2) q3w
Cbdca (AUC 5) + Pemt (500 mg/m2) q3w2/0/4Leighl (2021)
CCTG BR34CanadaIINSCLCIVa, IVbAnyEGFR(-), ALK(-)0–11RECISTDurv (1500 mg) + Trem (75 mg) + Platinum doublet q3w
Durv (1500 mg) + Trem (75 mg) 2/0/4Lynch (2012)
NCT00527735NetherlandsIINSCLCIIIb, IVAnyEGFR(-), ALK(-)0–11mWHO, ICRIpi (10 mg/kg) + Cbdca (AUC 6) + Ptx (175 mg/m2) q3w
Cbdca (AUC 6) + Ptx (175 mg/m2) q3w 0/0/6Mok (2019)
KEYNOTE-042HKIIINSCLCLocAdv, MetTC>1%EGFR(-), ALK(-)0–11RECIST,
ICRPemb (200 mg) q3w
Cbdca doublet1/0/5Nishio (2021)
IMpower132JapanIIINSQIVAnyAny0–11RECISTAtz (1200 mg) + Platinum + Pemt (500 mg/m2) q3w
Platinum + Pemt (500 mg/m2) q3w2/0/4Paz-Ares (2018)
KEYNOTE-407SpainIIISQIVTC >50%Any0–11RECIST,
ICRPemb (200 mg) +Cbdca (AUC 6) + (Ptx (200 mg/m2) or nPtx (100 mg/m2)) q3w
Cbdca (AUC 6) + (Ptx (200 mg/m2) or nPtx (100 mg/m2)) q3w0/0/6Paz-Ares (2021)
CheckMate9LASpainIIINSCLCIV, RecAnyEGFR(-), ALK(-)0–11RECIST,
ICRNiv (360 mg) q3w + Ipi (1 mg/kg) q6w + Platinum doublet q3w
Platinum doublet q3w1/0/5Planchard (2020)
ARCTIC-AFranceIIINSCLCIIIb, IVTC >25%EGFR(-), ALK(-)0–13-RECISTDurv (10 mg/kg) q2w
Gem and Vin or Erl2/0/4Planchard (2020)
ARCTIC-BFranceIIINSCLCIIIb, IVTC <25%EGFR(-), ALK(-)0–13-RECISTDurv (20 mg/kg) + Trem (1 mg/kg) q4w
Gem and Vin or Erl2/0/4Reck (2016)
KEYNOTE-024USAIIINSCLCIVTC>50%EGFR(-), ALK(-)0–11RECIST,
ICRPemb (200 mg) q3w
Platinum doublet1/0/5Rittmeyer (2017)
OAKUSAIIINSCLCIIIb-IVIC>1% or TC>1%Any0–12–3RECISTAtz (1200 mg)
Dtx (75 mg/m2) q3w2/0/4Rizvi (2020)
MYSTICUSAIIINSCLCIVTC>25%EGFR(-), ALK(-)0–11RECIST,
ICRDurv (20 mg/kg) q4w
Platinum doublet1/0/5Sezer (2021)
EMPOWER-Lung 1TurkeyIIINSCLCIIIb, IIIc, IVTC >50%EGFR(-), ALK(-), ROS1(-)0–11RECIST,
ICRCemi (350 mg) q3w
Platinum doublet1/0/5Socinski (2018)
IMpower150GermanyIIINSQIV, RecAnyEGFR(-), ALK(-)0–11RECIST,
ICRAtz (1200 mg) + Bev (15 mg/kg) + Cbdca (AUC 6) + Ptx (200 mg/m2)
Bev (15 mg/kg) + Cbdca (AUC 6) + Ptx (200 mg/m2)1/0/5Sugawara (2021)
ONO-4538-52/TASUKI-52JapanIIINSQIIIb, IVAnyEGFR(-), ALK(-), ROS1(-)0–11RECIST,
ICRNiv (360 mg) + Cbdca (AUC 6) + Ptx (200 mg/m2) + Bev (15 mg/kg)
Cbdca (AUC 6) + Ptx (200 mg/m2) + Bev (15 mg/kg)0/0/6West (2019)
IMpower130ItalyIIINSQIVAnyEGFR(-), ALK(-)0–11RECIST,
ICRAtz (1200 mg) q3w + Cbdca (AUC 6) q3w + nPtx (100 mg/m2) q1w
Cbdca (AUC 6) q3w + nPtx (100 mg/m2) q1w1/0/5Wu (2019)
CheckMate078ChinaIIINSCLCIIIb, IVAnyEGFR(-), ALK(-)0–12RECISTNiv (3 mg/kg) q2w
Dtx (75 mg/m2) q3w2/0/4Yang (2020)
ORIENT-11 ChinaIIINSQIIIb, IIIc, IVAnyEGFR(-), ALK(-)0–11RECISTSint (200 mg) + Platinum +Pemt (500 mg/m2) q3w
Platinum + Pemt (500 mg/m2) q3w0/0/6ZhouC (2021)
ORIENT-12ChinaIIISQIIIb, IIIc, IVAnyEGFR(-), ALK(-)0–11RECIST,
ICRSint (200 mg) + Platinum +Gem (1000 mg/m2, d 1, 8) q3w
Platinum +Gem (1000 mg/m2, d 1, 8) q3w0/0/6ZhouC (2022)
GEMSTONE-302ChinaIIINSCLCIVAnyEGFR(-), ALK(-), ROS1(-), RET(-)0–11RECIST,
ICRSuge (1200 mg) + Cbdca doublet q3w
Cbdca doublet q3w0/0/6ZhouQ (2022)
GEMSTONE-301ChinaIIINSCLCIIIAnyEGFR(-), ALK(-), ROS1(-)0–1After CCRRECIST,
ICRSuge (1200 mg)
No active treatment0/0/6ZhouC (2021)
CameLChinaIIINSQIIIb, IVAnyEGFR(-), ALK(-)0–11RECIST,
ICRCamr (200 mg) + Cbdca (AUC 5) + Pemt (500 mg/m2) q3w
Cbdca (AUC 5) + Pemt (500 mg/m2) q3w1/0/5