Figure S1. A. B. Figure S1. Kaplan-Meier curve of progression-free survival by treatment group in soluble heregulin (HRG)-high population (A) and soluble.

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Figure S1. A. B. Figure S1. Kaplan-Meier curve of progression-free survival by treatment group in soluble heregulin (HRG)-high population (A) and soluble HRG-low population (B). A, In soluble HRG-high population each subject are treated in pooled High- and Low-dose patritumab arm (n=35) and Placebo arm (n=11). B, In soluble HRG-low population each subject are treated in pooled High- and Low-dose patritumab arm (n=97) and Placebo arm (n=51).

Figure S2. A. B. C. Figure S2. Kaplan-Meier curve of overall survival by treatment group in ITT population (A), soluble heregulin (HRG)-high population (B) and soluble HRG-low population (C). A, In ITT population each subject are treated in pooled High- and Low-dose patritumab arm (n=141) and Placebo arm (n=71). B, In soluble HRG-high population each subject are treated in pooled High- and Low-dose patritumab arm (n=35) and Placebo arm (n=11). C, In soluble HRG-low population each subject are treated in pooled High- and Low-dose patritumab arm (n=97) and Placebo arm (n=51).

Figure S3. Figure S3. Scatter plot for heregulin mRNA ∆CT vs. soluble heregulin serum concentration. Soluble heregulin expression level in serum and heregulin mRNA expression level in tumor was measured (number of pars = 94). The median ∆CT value was 3.9 and was used as the cutoff value between heregulin mRNA-high and heregulin mRNA-low subgroups. For soluble heregulin, a value of 980 pg/mL was used for the third quartile and thus as the cutoff value between soluble heregulin-high and -low subgroups.

soluble HRG-high population (n=46) Table S1. Subject baseline characteristics, ITT population and soluble heregulin-high population ITT population (n=212) soluble HRG-high population (n=46) High-dose arm (18 mg/kg) Low-dose arm (9 mg/kg) Placebo arm (n = 71) (n = 11) (n = 70) (n = 18) (n = 17) Age, median years (range) 62.0 (41–82) 65.0 (44–84) 60.0 (35–88) 62 (49-75) 63 (49-75) 51 (35-74) <60 28 (40.0) 24 (33.8) 33 (46.5) 7 (38.9) 8 (47.1) 8 (72.7) ≥60 42 (60.0) 47 (66.2) 38 (53.5) 11 (61.1) 9 (52.9) 3 (27.3) Male sex, n (%) 38 (54.3) 48 (67.6) 43 (60.6) 10 (55.6) 10 (58.8) 7 (63.6) Race, n (%) White 68 (97.1) 71 (100.0) 69 (97.2) 17 (94.4) 17 (100) 11 (100) Black or African American 1 (1.4) 1 (5.6) Asian Other Weight, median kg (range) 72 72.3 74 71.5 71 68 (44.0–121.0) (42.0–114.0) (42.6–108.6) 48.5 - 99 44 - 113 48.2 - 103 Smoking status, n (%) Never 10 (14.3) 11 (15.5) 5 (7.0) 3 (16.7) 2 (11.8) 2 (18.2) Current 12 (17.1) 9 (12.7) 13 (18.3) 2 (11.1) 3 (17.6) Former 48 (68.6) 51 (71.8) 53 (74.6) 13 (72.2) 12 (70.6) Pack-years, n (%) ≤15 9 (12.9) 7 (9.9) 4 (22.2) 3 (17.7) 1 (9.1) >15 43 (61.4) 50 (70.4) 9 (50.0) 11 (64.7) Missing 18 (25.7) 17 (23.9) 10 (14.1) 5 (27.8) Tumor histology subtype, n (%) Adenocarcinoma 46 (65.7) 44 (62.0) 42 (59.2) 14 (82.3) 10 (90.9) Squamous carcinoma 19 (27.1) 23 (32.4) 21 (29.6) 5 (7.1) 4 (5.6) 8 (11.3) 1 (5.9) EGFR mutation status from tissue, n (%) Sensitizing only 2 (2.8) Wild-type 17 (24.3) 4 (23.5) Unknown 53 (75.7) 13 (76.5) EGFR mutation status from tissue or plasma, n (%) 3 (4.2) Resistance only 45 (64.3) 14 (83.3) 9 (81.8) 24 (34.3) 22 (31.0) ECOG performance status, n (%) 33 (47.1) 30 (42.3) 25 (35.2) 5 (29.4) 5 (45.5) 1 37 (52.9) 41 (57.7) 46 (64.8) 8 (44.4) 6 (54.5) Time from initial diagnosis to study treatment (months), n (%) 　<6 months 16 (22.9) 14 (19.7) 　6–12 months 35 (49.3) 37 (52.1) 　>12 months 21 (30.0) Number of prior NSCLC therapies, n (%) 　1 50 (71.4) 　2 6 (35.3) 　3 Best response to prior chemotherapy, n (%) 　CR/PR 　SD 34 (47.9) 29 (40.8) 7 (41.2) 5 (45.4) 　PD 23 (32.9) 20 (28.2) 19 (26.8) ITT=intent-to-treat, HRG=heregulin, EGFR=epidermal growth factor receptor, NSCLC=non-small cell lung cancer, CR=complete response, PR=partial response, SD=stable disease, PD=progressive disease

Table S2. Hazard ration of overall survival in each population ITT population (n=212) soluble HRG-low population (n=148) soluble HRG-high population (n=46) High-dose arm Low-dose arm Placebo arm Pooled high and low dose (18 mg/kg) (9 mg/kg) (n = 71) (n = 51) (n = 11) (n = 70) (n = 48) (n = 49) (n = 97) (n = 18) (n = 17) (n = 35) Median OS, months 5.3 6.3 7.2 5.7 7.1 4.7 8.6 6.2 7.4 Hazard ratio (95% CI)* 1.23 0.93 — 1.31 0.98 1.13 1.27 0.69 0.92 (0.83-1.80) (0.63-1.37) 0.83-2.08 0.61-1.55 0.75-1.68 (0.50-3.23) (0.26-1.82) (0.40-2.16) p-value* 0.32 0.56 0.21 0.81 0.55 0.59 0.42 0.86 *Two-sided p-values was based on stratified log-rank test and HR was based on stratified Cox PH were stratified by best response to prior therapy (CR/PR, SD, PD) and histology subtype (Adenocarcinoma vs. Non-Adenocarcinoma). ITT = intent-to-treat, OS = overall survival, HRG = heregulin