1. 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).

2. 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).

3. 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.

4. 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)
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

5. 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
( )
( )
( )
( )
( )
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