Supplementary information
Supplementary Table 1. Toxicities in the safety population (N=61).
Adverse Event a
Gastrointestinal
Diarrhea
Colonic perforation
Nausea
Vomiting
Constipation
Dysphagia
Dermatologicb
Endocrine
Hepatic
Hematologic
Anemia
Thrombocytopenia
Thrombocytosis
Asthenia
Pneumonia
Mood alteration
Otherc
Grade 1/2
N (%)
19 (31)
11
0
6
6
3
3
13 (21)
6 (10)
10 (16)
24 (39)
24
1
1
15 (25)
0
0
14 (23)
Grade 3/4
N (%)
2 (3)
1
1
0
0
0
0
0
0
0
3 (5)
2
1
0
1 (2)
1 (2)
1 (2)
0
a
Patients could have more than one adverse event.
b
This includes 18 AEs in 13 patients: pruritus (N=12), rash (N=4), alopecia (N=2).
c
This includes: pyrexia (N=4), dyspnea (N=3), pain (N=2), cough (N=1), aphasia (N=1),
vertigo (N=1), allergic reaction (N=1), sideropenia (N=1).
Abbreviation: N= number
1
Supplementary Table 2. The relationship between NLR thresholds and irPD
NLR cutoff Specificitya
3
68% (43-87)
4
89% (67-99)
5
95% (74-100)
Sensitivitya Likelihood ratio
78% (64-88)
2.47
52% (37-66)
4.94
44% (30-59)
8.36
Abbreviations: NLR= neutrophil to lymphocyte ratio; irPD= immune-related progressive
disease
a
Value and 95% confidence interval for each threshold are reported.
2
Supplementary Table 3. Univariate analysis of the associations of baseline patient
characteristics (N=69) and survival.
Disease progression
Parameter
HR
95% CI
P valuea
Overall survival
HR
95% CI
P valuea
Age (<65 vs ≥ 65 yrs)
1.06 0.64-1.77
0.80
0.81 0.46-1.43
0.52
Sex (F vs M)
0.74 0.45-1.22
0.22
0.70 0.40-1.21
0.22
LDH (<ULN vs ≥ ULN)
0.47 0.28-0.80
0.03
0.60 0.34-1.06
0.11
ECOG PS (0-1 vs 2)
0.16 0.05-0.53
<0.0001
0.08 0.02-0.30
<0.0001
NLR (<5 vs ≥5)
0.20 0.10-0.41
<0.0001
0.12 0.05-0.25
<0.0001
WBC (<ULN vs ≥ULN) 0.14 0.05-0.35
<0.0001
0.06 0.02-0.18
<0.0001
ANC (<ULN vs ≥ULN)
0.20 0.09-0.45
0.0004
0.12 0.05-0.28
<0.0001
ALC (≤LLN vs >LLN)
1.49 0.80-2.78
0.07
2.03 1.02-4.07
0.04
a
P values are from Wilcoxon test
Abbreviations: N= number; HR= hazard ratio; CI= confidence interval; F= female; M=
male; LDH= lactate dehydrogenase; ULN= upper limit of normal; LLN= lower limit of
normal; ECOG PS= European Cooperative Oncology Group performance status; NLR=
neutrophil to lymphocyte ratio; WBC= white blood cells; ANC= absolute neutrophil count;
ALC= absolute lymphocyte count.
3
Supplementary Table 4. Multivariate analysis of the associations of baseline
features and survival of patients receiving at least two drug infusions (N=59).
Disease progression
P valuea
HR
95% CI
P valuea
Parameter
HR
Age
0.99 0.97-1.02
0.46
1.00 0.97-1.03
0.98
Sex (F vs M)
0.85 0.48-1.50
0.57
0.73 0.38-1.39
0.34
LDH (<ULN vs ≥ ULN) 0.70 0.39-1.25
0.23
0.99 0.51-1.90
0.97
ECOG PS (0-1 vs 2)
0.78 0.18-3.44
0.74
0.55 0.12-2.48
0.44
NLR (<5 vs ≥5)
0.46 0.24-0.87
0.02
0.26 0.13-0.53
0.0002
a
95% CI
Overall survival
P values are from Cox model adjusted for age, gender, LDH and ECOG PS
Abbreviations: HR= hazard ratio; CI= confidence interval; F= female; M= male; LDH=
lactate dehydrogenase; ULN= upper limit of normal; ECOG PS= European Cooperative
Oncology Group performance status; NLR= neutrophil to lymphocyte ratio
4
Supplementary Table 5. Validation of the association of NLR and overall survival in
patients receiving 10 mg/kg ipilimumab (N=27).
HR
Age
1.02 0.97-1.07
0.49
Sex (F vs M)
0.63 0.23-1.72
0.37
LDH (<ULN vs ≥ ULN) 0.41 0.16-1.02
0.055
NLR (<5 vs ≥5)
0.03
a
95% CI
P valuea
Parameter
0.26 0.08-0.88
P values are from Cox model adjusted for age, gender and LDH
Abbreviations: HR= hazard ratio; CI= confidence interval; F= female; M= male; LDH=
lactate dehydrogenase; ULN= upper limit of normal; NLR= neutrophil to lymphocyte ratio
5
Legend to Supplementary Figure 1.
Baseline white blood cell counts (WBC, A), absolute neutrophil count (ANC, B), absolute
lymphocyte counts (ALC, C) and neutrophil to lymphocyte ratio (NLR, D) in patients that
experienced disease progression (irPD) or disease control (irDC) as best overall response
to ipilimumab therapy. P values were calculated with Mann-Whitney U test.
6