Online Resource Tables and Figures
Gastric Cancer
Exploration of predictors of benefit from nivolumab monotherapy for patients with pretreated advanced gastric and gastroesophageal junction cancer: Post-hoc subanalysis from the ATTRACTION-2 study
Yoon-Koo Kang, Satoshi Morita, Taroh Satoh, Min-Hee Ryu, Yee Chao, Ken Kato, Hyun Cheol Chung, Jen-Shi Chen, Kei Muro, Won Ki Kang, Kun-Huei Yeh, Takaki Yoshikawa, Sang Cheul Oh, Li-Yuan Bai, Takao Tamura, Keun-Wook Lee, Yasuo Hamamoto, Jong Gwang Kim, Keisho Chin, Do-Youn Oh, Keiko Minashi, Jae Yong Cho, Masahiro Tsuda, Hiroki Sameshima, Li-Tzong Chen, and Narikazu Boku
Corresponding author: Yoon-Koo Kang, MD, PhD. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
2
Online Resource Table S1 Covariates and their cutoff values.
Covariates Cutoff values
Age [<50 vs. ≥50] or [<55 vs. ≥55] or [<60 vs. ≥60] or [<65 vs. ≥65] or [<70 vs. ≥70]
Sex Male vs. Female
Body mass index [<17.0 vs. ≥17.0] or [<18.5 vs. ≥18.5]
ECOG PS 0 vs. 1
History of alcohol consumption Never vs. Former vs. Current History of smoking Never vs. Former vs. Current
Lesion site Gastric vs. gastroesophageal junction Borrman’s classification Type 4 vs. Others
Lauren classification Diffuse vs. Others
Metastatic organa Yes vs. No
Number of metastatic organs [<2 vs. ≥2] or [<3 vs. ≥3] or [<4 vs. ≥4]
Number of previous regimen [≤2 vs. >2] or [≤3 vs. >3] or [≤4 vs. >4]
Gastrectomy Yes vs. No
Radiotherapy Yes vs. No
Prior therapyb Yes vs. No
Last therapyb Yes vs. No
Best response to the last regimen Effective vs. Non-effective
Hemoglobin Lower than institutional standard value vs. Normal White blood cells Upper than institutional standard value vs. Normal
Neutrophils Median or Tertilec
Lymphocytes Lower than institutional standard value vs. Normal
Eosinophils Median or Tertilec
Basophils Median or Tertilec
Monocytes Median or Tertilec
Platelets Upper than institutional standard value vs. Normal Albumin Lower than institutional standard value vs. Normal Alkaline phosphatase Upper than institutional standard value vs. Normal Total bilirubin Upper than institutional standard value vs. Normal Protein Lower than institutional standard value vs. Normal Creatinine Upper than institutional standard value vs. Normal Lactate dehydrogenase Upper than institutional standard value vs. Normal Blood urea nitrogen Upper than institutional standard value vs. Normal Sodium Lower than institutional standard value vs. Normal Potassium Lower than institutional standard value vs. Normal Chloride Lower than institutional standard value vs. Normal C-reactive protein <1 mg/dL vs. ≥1 mg/dL
Neutrophil-lymphocyte ratio Median or Tertilec Platelet-lymphocyte ratio Median or Tertilec C-reactive protein-albumin ratio Median or Tertilec Prognostic nutritional index Median or Tertilec
ECOG PS, Eastern Cooperative Oncology Group Performance Status.
aMetastases to the bone, brain, liver, lung, lymph node, peritoneum, preural tissue, remnant stomach, and other organs were individually evaluated.
bPrior experiences with cisplatin, irinotevan, oxaliplatin, ramucirumab, taxanes, and trastuzumab were individually evaluated.
cDue to limitations of the conventional univariable analyses, the median was used as the cutoff value for these factors, whereas tertiles were used as the cutoff values of the factors in the BaPoFi analysis.
Online Resource Table S2 The factors showing significant associations with disease progression within 8 weeks in the nivolumab arm that were extracted by conventional logistic regression analysis.
Factors [Cutoff] N Odds ratio 95% CI
Univariable logistic regression analysis
Age [<60 vs. ≥60] 330 2.03 1.28–3.21
Age [<65 vs. ≥65] 330 2.19 1.40–3.43
Age [<70 vs. ≥70] 330 2.55 1.51–4.30
History of alcohol consumption [Current vs. Former or Never] 330 0.39 0.20–0.79
Metastasis (Liver) [Yes vs. No] 330 1.66 1.06–2.59
Metastasis (Lung) [Yes vs. No] 330 0.54 0.31–0.95
Metastasis (Lymph node) [Yes vs. No] 330 0.55 0.34–0.86
Metastasis (Peritoneum) [Yes vs. No] 330 2.03 1.30–3.17
Number of metastatic organs [<2 vs. ≥2] 330 0.56 0.34–0.93 Last therapy (Ramucirumab) [Yes vs. No] 330 0.39 0.17–0.89
White blood cells [Upper vs. Normal] 330 1.98 1.06–3.70
Neutrophils [<Median vs. ≥Median] 330 0.60 0.38–0.93
Platelets [Upper vs. Normal] 330 1.89 1.04–3.44
Lactate dehydrogenase [Upper vs. Normal] 330 1.65 1.03–2.63
Sodium [Lower vs. Normal] 330 2.33 1.24–4.38
Chloride [Lower vs. Normal] 330 2.31 1.13–4.75
C-reactive protein [<1 mg/dL vs. ≥1 mg/dL] 329 0.53 0.34–0.83 C-reactive protein-albumin ratio [<Median vs. ≥Median] 329 0.48 0.31–0.76 Prognostic nutrition index [<Median vs. ≥Median] 330 1.69 1.08–2.64
Multivariable logistic regression analysis
Age [<60 vs. ≥60] 330 2.16 1.15–4.05
Metastasis (Liver) [Yes vs. No] 330 2.09 1.11–3.93
Metastasis (Peritoneum) [Yes vs. No] 330 2.27 1.22–4.21
CI, confidence interval.
4
Online Resource Table S3 The factors showing significant associations with disease progression in the nivolumab arm that were extracted by conventional Cox analysis.
Factors [Cutoff] N Hazard ratio p value
Univariable Cox regression analysis
Age [<50 vs. ≥50] 330 1.50 0.0193
Age [<60 vs. ≥60] 330 1.59 0.0002
Age [<65 vs. ≥65] 330 1.37 0.0104
Metastasis (Liver) [Yes vs. No] 330 1.35 0.0147
Metastasis (Lymph node) [Yes vs. No] 330 0.66 0.0011
Metastasis (Peritoneum) [Yes vs. No] 330 1.52 0.0009
Number of metastatic organs [<2 vs. ≥2] 330 0.77 0.0497 Prior therapy (Ramucirumab) [Yes vs. No] 330 0.65 0.0338
Last therapy (Ramucirumab] [Yes vs. No] 330 0.59 0.024
White blood cells [Upper vs. Normal] 330 1.81 0.0002
Neutrophils [<Median vs. ≥Median] 330 0.74 0.0156
Platelets [Upper vs. Normal] 330 1.38 0.037
Alkaline phosphatase [Upper vs. Normal] 330 1.29 0.0345 Lactate dehydrogenase [Upper vs. Normal] 330 1.70 <0.0001
Sodium [Lower vs. Normal] 330 1.65 0.0025
Chloride [Lower vs. Normal] 330 1.58 0.0162
C-reactive protein [<1 mg/dL vs. ≥1 mg/dL] 329 0.76 0.0221 Neutrophil-lymphocyte ratio [<Median vs. ≥Median] 330 0.68 0.0019 Platelet-lymphocyte ratio [<Median vs. ≥Median] 330 0.76 0.023 C-reactive protein-albumin ratio [<Median vs. ≥Median] 329 0.76 0.0212 Prognostic nutrition index [<Median vs. ≥Median] 330 1.40 0.0054
Multivariable Cox regression analysis
Age [<60 vs. ≥60] 330 1.77 <0.0001
Metastasis (Lymph node) [Yes vs. No] 330 0.67 0.0063
Metastasis (Peritoneum] [Yes vs. No] 330 1.45 0.0115
White blood cells [Upper vs. Normal] 330 1.51 0.0326
Lactate dehydrogenase [Upper vs. Normal] 330 1.64 0.0007
Online Resource Table S4 RMST analysis of progression-free survival for patient subgroups classified by multiple cutoff values of age.
Low-benefit group High-benefit group ∆∆RMSTd,e
Cutoffa Nb ∆RMSTc,e Nb ∆RMSTc,e
[<50 vs. ≥50] 51/33 0.9 (-0.99–2.70) 279/128 2.5 (1.47–3.54) 1.7 (-0.47–3.77) [<60 vs. ≥60] 134/65 1.0 (-0.01–2.03) 184/90 2.9 (1.49–4.26) 1.9 (0.14–3.59) [<65 vs. ≥65] 180/89 1.9 (0.73–3.12) 138/66 2.3 (0.86–3.83) 0.4 (-1.49–2.32) [<70 vs. ≥70] 242/119 2.3 (1.24–3.36) 76/36 1.4 (-0.39–3.22) -0.9 (-2.97–1.21) RMST, restricted mean survival time.
aCutoff values listed on the left are classification values for the low-benefit group.
bNumbers of patients in the nivolumab/placebo arms.
c∆RMST is defined as the difference in RMST between the nivolumab and placebo arms. ∆RMST (months) with 95% confidence interval is shown.
d∆∆RMST is defined as the difference in ∆RMST between the low- and high-benefit groups.
∆∆RMST (months) with 95% confidence interval is shown.
eStatistically significant differences (p < 0.05) are highlighted in bold.
6
Online Resource Table S5 Top five factors in terms of the utility function identified in the BaPoFi analysis.
Rank Factors Class
High benefit group Corresponding low benefit group Overall survival
1 Na +
WBC Na: Normal
WBC: Normal Na: Lower than standard WBC: Higher than standard
2 Na +
NLR Na: Normal
NLR: Middle/Low Na: Lower than standard NLR: Highest tertile
3 Na +
Neutrophils Na: Normal
Neutrophils: Middle/Low Na: Lower than standard Neutrophils: Highest tertile
4 Na +
CL Na: Normal
CL: Normal Na: Lower than standard CL: Lower than standard
5 CL +
NLR CL: Normal
NLR: Mid/Low CL: Lower than standard NLR: Highest tertile Progression-free survival
1 CL +
NLR CL: Normal
NLR: Middle/Low CL: Lower than standard NLR: Highest tertile
2 Na +
NLR Na: Normal
NLR: Middle/Low Na: Lower than standard NLR: Highest tertile
3 Na +
CL Na: Normal
CL: Normal Na: Lower than standard CL: Lower than standard
4 Na +
Platelets Na: Normal
Platelets: Normal Na: Lower than standard Platelets: Higher than standard
5 Na +
WBC Na: Normal
WBC: Normal Na: Lower than standard WBC: Higher than standard
CL, serum chloride level; Na, serum sodium level; NLR, neutrophil-lymphocyte ratio; WBC, white blood cell count.
Low benefit High benefit Others (if present)
Online Resource Fig. S1
a Schematic representation of patient disposition. The number of patients in the intention-to-treat (ITT) population and that of patients who were included in the BaPoFi and restricted mean survival time (RMST) analyses are shown.
b (Upper panel) A single factor classified patients into two categories: a low-benefit group and a high-benefit group. (Lower panel) A double-factor combination classified patients into three categories: a low-benefit group, a high-benefit group, and the others.
c RMST is defined as the area under the curve. ∆RMST was defined as the difference of RMST between the nivolumab and placebo arms.
d ∆∆RMST was defined as the difference of ∆RMST between the low- benefit group and high-benefit group.
Nivolumab arm ITT: n=330 BaPoFi, RMST: n=318
Placebo arm ITT: n=163 BaPoFi, RMST: n=155
Classification using a single factor or a double-factor or triple-factor combination
Low Others
Others High
Survival (%)100 50
00 12 24 36
Time (months)
Survival (%)100 50
00 12 24 36
Time (months) 12 24
0 36
Time (months)
Cut-off Factor B Factor A
Low High
Cutoff Factor
a
b c
RMST in the
nivolumab arm RMST in the placebo arm
∆RMST
d ∆∆RMST = ∆RMST (High-benefit group) -∆RMST (Low-benefit group) poorer better
poorer
better Cutoff
poorer better
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Number at risk
Nivolumab 134 40 19 10 8 6 5 4 3 2 1 1 1 1 1 1 1 1 1 Placebo 65 16 7 2 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0
100 90 80 70 60 50 40 30 20 10 0
Nivolumab (n = 134) Placebo
(n = 65)
RMST, months 3.1 2.1
∆RMST, months
(95% CI) 1.0
(-0.01–2.03)
p-value 0.0525
Time (months)
Nivolumab Placebo
Progression-free survival (%)
Low-benefit group (Age, <60 years)
b
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Number at risk
Nivolumab 184 82 59 39 28 21 16 14 11 9 8 7 7 5 5 3 3 3 3 Placebo 90 24 10 7 6 4 2 2 1 1 0 0 0 0 0 0 0 0 0
100 90 80 70 60 50 40 30 20 10 0
Nivolumab (n = 184) Placebo
(n = 90)
RMST, months 5.4 2.6
∆RMST, months
(95% CI) 2.9
(1.49–4.26)
p-value <0.0001
Time (months)
Nivolumab Placebo
Progression-free survival (%)
High-benefit group (Age, ≥60 years)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Number at risk
Nivolumab 134 106 67 46 37 29 24 18 13 12 9 7 5 5 3 3 3 3 3 Placebo 65 46 35 25 14 9 4 2 1 1 1 0 0 0 0 0 0 0 0
100 90 80 70 60 50 40 30 20 10 0
Nivolumab (n = 134) Placebo
(n = 65)
RMST, months 7.3 5.5
∆RMST, months
(95% CI) 1.8
(0.13–3.47)
p-value 0.0347
Time (months)
Nivolumab Placebo
Overall survival (%)
Low-benefit group (Age, <60 years)
a
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Number at risk
Nivolumab 184 159 116 90 79 62 54 48 43 36 32 27 24 22 20 18 17 16 11 Placebo 90 69 43 26 20 14 13 8 8 5 5 5 5 4 4 4 3 3 3
100 90 80 70 60 50 40 30 20 10 0
Nivolumab (n = 184) Placebo
(n = 90) RMST, months 10.9 6.4
∆RMST, months
(95% CI) 4.5
(2.27–6.71)
p-value <0.0001
Time (months)
Nivolumab Placebo
Overall survival (%)
High-benefit group (Age, ≥60 years)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Number at risk
Nivolumab 168 51 28 11 6 4 3 3 3 3 3 3 3 1 1 0 0 0 0 Placebo 93 17 6 2 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0
100 90 80 70 60 50 40 30 20 10 0
Nivolumab (n = 168) Placebo
(n = 93)
RMST, months 3.3 1.8
∆RMST, months
(95% CI) 1.4
(0.50–2.38)
p-value 0.0027
Time (months)
Nivolumab Placebo
Progression-free survival (%)
Low-benefit group (with Peritoneal metastasis)
d
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Number at risk
Nivolumab 150 71 50 38 30 23 18 15 11 8 6 5 5 5 5 4 4 4 4 Placebo 62 23 11 7 6 4 2 2 1 1 0 0 0 0 0 0 0 0 0
100 90 80 70 60 50 40 30 20 10 0
Nivolumab (n = 150) Placebo
(n = 62)
RMST, months 5.6 3.2
∆RMST, months
(95% CI) 2.4
(0.79–3.94)
p-value 0.0032
Time (months)
Nivolumab Placebo
Progression-free survival (%)
High-benefit group (without Peritoneal metastasis)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Number at risk
Nivolumab 168 130 80 53 42 28 23 17 13 9 8 5 5 5 4 4 4 4 3 Placebo 93 65 42 25 18 10 8 4 3 2 2 1 1 1 1 1 1 1 1
100 90 80 70 60 50 40 30 20 10 0
Nivolumab (n = 168) Placebo
(n = 93)
RMST, months 6.5 5.2
∆RMST, months
(95% CI) 1.2
(-0.29–2.77)
p-value 0.1110
Time (months)
Nivolumab Placebo
Overall survival (%)
Low-benefit group (with Peritoneal metastasis)
c
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Number at risk
Nivolumab 150 135 103 83 74 63 55 49 43 39 33 29 24 22 19 17 16 15 11 Placebo 62 50 36 26 16 13 9 6 6 4 4 4 4 3 3 3 2 2 2
100 90 80 70 60 50 40 30 20 10 0
Nivolumab (n = 150) Placebo
(n = 62) RMST, months 12.7 7.2
∆RMST, months
(95% CI) 5.5
(2.85–8.13)
p-value <0.0001
Time (months)
Nivolumab Placebo
Overall survival (%)
High-benefit group (without Peritoneal metastasis)
Online Resource Fig. S2 Classification by single factors of age (a, b) and peritoneal metastasis (c, d). The Kaplan–Meier curves of overall survival (a, c) and progression-free survival (b, d) with RMST values in low-benefit groups (left) and in high-benefit groups (right) are shown. CI, confidence interval; RMST, restricted mean survival time; ∆RMST, difference of RMST between the nivolumab and placebo arms.
Time (months)
Nivolumab Placebo
Overall survival (%)
Others (Sodium; Chloride)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Number at risk
Nivolumab 29 7 3 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Placebo 12 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
100 90 80 70 60 50 40 30 20 10 0
Nivolumab (n = 29) Placebo
(n = 12)
RMST, months 2.6 1.3
∆RMST, months
(95% CI) 1.3
(0.10–2.57)
p-value 0.0334
Time (months)
Nivolumab Placebo
Progression-free survival (%)
Low-benefit group (Sodium, lower; Chloride, lower)
b
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Number at risk
Nivolumab 246 105 69 44 33 26 21 18 14 11 9 8 8 6 6 4 4 4 4 Placebo 123 37 15 9 7 4 2 2 1 1 0 0 0 0 0 0 0 0 0
100 90 80 70 60 50 40 30 20 10 0
Nivolumab (n = 246) Placebo
(n = 123)
RMST, months 5.1 2.6
∆RMST, months
(95% CI) 2.4
(1.25 – 3.55)
p-value <0.0001
Time (months)
Nivolumab Placebo
Progression-free survival (%)
High-benefit group (Sodium, normal; Chloride, normal)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Number at risk
Nivolumab 29 20 7 5 3 1 1 1 1 1 1 1 1 1 1 1 1 1 1
Placebo 12 5 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
100 90 80 70 60 50 40 30 20 10 0
Nivolumab (n = 29) Placebo
(n = 12)
RMST, months 4.7 2.1
∆RMST, months
(95% CI) 2.6
(-0.02–5.22)
p-value 0.0515
Time (months)
Nivolumab Placebo
Overall survival (%)
Low-benefit group (Sodium, lower; Chloride, lower)
a
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Number at risk
Nivolumab 246 217 161 119 105 84 72 61 52 44 38 31 27 25 21 19 18 17 13 Placebo 123 99 69 46 32 22 16 9 8 5 5 5 5 4 4 4 3 3 3
100 90 80 70 60 50 40 30 20 10 0
Nivolumab (n = 246) Placebo
(n = 123) RMST, months 10.6 6.7
∆RMST, months
(95% CI) 3.9
(2.17–5.70)
p-value <0.0001
Time (months)
Nivolumab Placebo
Overall survival (%)
High-benefit group (Sodium, normal; Chloride, normal)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Number at risk
Nivolumab 26 4 2 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Placebo 16 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
100 90 80 70 60 50 40 30 20 10 0
Nivolumab (n = 26) Placebo
(n = 16)
RMST, months 2.1 1.3
∆RMST, months
(95% CI) 0.8
(-0.21–1.82)
p-value 0.1216
Time (months)
Nivolumab Placebo
Progression-free survival (%)
Low-benefit group (Chloride, lower; NLR, high)
d
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Number at risk
Nivolumab 199 90 59 39 28 23 19 16 12 10 8 7 7 5 5 4 4 4 4 Placebo 96 34 15 8 7 4 2 2 1 1 0 0 0 0 0 0 0 0 0
100 90 80 70 60 50 40 30 20 10 0
Nivolumab (n = 199) Placebo
(n = 96)
RMST, months 5.3 2.9
∆RMST, months
(95% CI) 2.4
(1.11–3.76)
p-value 0.0003
Time (months)
Nivolumab Placebo
Progression-free survival (%)
High-benefit group (Chloride, normal; NLR, middle/low)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Number at risk
Nivolumab 26 15 6 4 3 2 2 2 1 1 0 0 0 0 0 0 0 0 0
Placebo 16 6 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
100 90 80 70 60 50 40 30 20 10 0
Nivolumab (n = 26) Placebo
(n = 16)
RMST, months 4.1 2.2
∆RMST, months
(95% CI) 1.9
(-0.03–3.82)
p-value 0.0537
Time (months)
Nivolumab Placebo
Overall survival (%)
Low-benefit group (Chloride, lower; NLR, high)
c
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Number at risk
Nivolumab 199 185 139 104 90 75 64 55 47 39 33 29 25 23 20 18 17 16 11 Placebo 96 85 59 42 30 20 15 9 8 6 6 5 5 4 4 4 3 3 3
100 90 80 70 60 50 40 30 20 10 0
Nivolumab (n = 199) Placebo
(n = 96) RMST, months 11.4 7.7
∆RMST, months
(95% CI) 3.7
(1.62–5.80)
p-value 0.0005
Time (months)
Nivolumab Placebo
Overall survival (%)
High-benefit group (Chloride, normal; NLR, middle/low)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Number at risk
Nivolumab 43 10 6 4 2 1 0 0 0 0 0 0 0 0 0 0 0 0 0
Placebo 20 2 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
100 90 80 70 60 50 40 30 20 10 0
Nivolumab (n = 43) Placebo
(n = 20)
RMST, months 2.4 1.6
∆RMST, months
(95% CI) 0.8
(-0.08–1.71)
p-value 0.0731
Time (months)
Nivolumab Placebo
Progression-free survival (%)
Others (Sodium; Chloride)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Number at risk
Nivolumab 43 28 15 12 8 6 5 4 3 3 2 2 1 1 1 1 1 1 0 Placebo 20 11 7 5 2 1 1 1 1 1 1 0 0 0 0 0 0 0 0
100 90 80 70 60 50 40 30 20 10 0
Nivolumab (n = 43) Placebo
(n = 20)
RMST, months 5.7 4.4
∆RMST, months
(95% CI) 1.3
(-1.67–4.20)
p-value 0.3979
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Number at risk
Nivolumab 93 28 17 9 7 4 2 2 2 1 1 1 1 1 1 0 0 0 0
Placebo 43 5 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
100 90 80 70 60 50 40 30 20 10 0
Nivolumab (n = 93) Placebo
(n = 43)
RMST, months 3.2 1.6
∆RMST, months
(95% CI) 1.6
(0.46–2.67)
p-value 0.0056
Time (months)
Nivolumab Placebo
Progression-free survival (%)
Others (Chloride; NLR)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Number at risk
Nivolumab 93 65 38 28 23 14 12 9 8 8 8 5 4 4 3 3 3 3 3 Placebo 43 24 16 9 4 3 2 1 1 0 0 0 0 0 0 0 0 0 0
100 90 80 70 60 50 40 30 20 10 0
Nivolumab (n = 93) Placebo
(n = 43)
RMST, months 6.5 3.8
∆RMST, months
(95% CI) 2.7
(0.77–4.64)
p-value 0.0062
Time (months)
Nivolumab Placebo
Overall survival (%)
Others (Chloride; NLR)
Online Resource Fig. S3 Classification by combinations of double factors of serum sodium level and serum chloride level (a, b) and of serum chloride level and neutrophil-lymphocyte ratio (NLR) (c, d). The Kaplan–Meier curves of overall survival (a, c) and progression-free survival (b, d) with RMST values in low-benefit groups (left), in high-benefit groups (right), and in others are shown. CI, confidence interval; RMST, restricted mean survival time; ∆RMST, difference of RMST between the nivolumab and placebo arms.
