Dynamic Risk Prediction for Disease Control
with Nivolumab in Advanced or Recurrent
Non-Small Cell Lung Cancer Patients:
A Prospective observational study (NewEpoch)
T. Fukui1, S. Igawa1, Y. Goto2, K. Yoh3, Y. Hosomi4, T. Kato5, K. Usui6, K. Hirano7, H. Tanaka8, R. Saito9,
A. Bessho10, H. Aono11, A. Tamura12, Y. Ohashi13, M. Taguri14, J. Sasaki1, K. Naoki1, H. Kunitoh15
1Kitasato University School of Medicine, Kanagawa, Japan, 2National Cancer Center Hospital, Tokyo, Japan, 3National Cancer

Center Hospital East, Kashiwa, Japan, 4Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo,Japan, 5Kanagawa Cancer Center, Kanagawa, Japan, 6NTT Medical Center Tokyo, Tokyo, Japan, 7Hyogo Prefectural Amagasaki
General Medical Center, Amagasaki, Japan, 8Niigata Cancer Center Hospital, Niigata, Japan, 9Tohoku University Hospital, Sendai,Japan, 10Japanese Red Cross Okayama Hospital, Okayama, Japan, 11Mitsui Memorial Hospital, Tokyo, Japan, 12National Hospital
Organization Tokyo National Hospital, Tokyo, Japan, 13Chuo University, Tokyo, Japan, 14Yokohama City University School of Data
Science, Yokohama, Japan, 15Japanese Red Cross Medical Center, Tokyo, JapanPresenter Name, Institution, Country

DISCLOSURES
I do not have any relevant financial
relationships to disclose.
This study is an investigator initiated multicenter cohort study．This
study is conducted by Comprehensive Support Project forOncology Research(CSPOR) of Public Health Research Foundation.
This study fund is provided to CSPOR with research support fromOno Pharmaceutical Co., Ltd. and Bristol Myers Squibb Co., Ltd.

共同演者の先生方のCOI確認

Background

Immune checkpoint inhibitors (ICI) have been widely used for treatment of advanced
or recurrent non-small cell lung cancer (NSCLC).

After randomized phase III trials in patients with advanced NSCLC,1, 2) nivolumab wasapproved as second or subsequent line of therapy in Japan in December 2015.

The PD-1 inhibitor produced durable response in approximately 20% of NSCLC
patients, although 30% to 40% had no response.1-3)

However, prediction of their efficacy remains difficult before and at early phases oftherapy.
1) Brahmer J, et al. NEJM 2015;373:123-135.

2) Borghaei H, et al. NEJM 2015;373:1627-1639.

3) Horn L, et al. JCO 2017:Jco2017743062.

PurposeWe aimed to clarify early clinical predictors for disease control in patients with NSCLC
treated with nivolumab.
Primary endpoint:
・ Disease control rate (DCR) at 25 weeks after the start of nivolumab
Secondary endpoint: Dynamic risk prediction for・ Overall response rate (ORR）・ Overall survival (OS)・ Clinical factors predicting 2-year survival
・ QOL by EQ-5D-5L

Methods


We prospectively collected a cohort of patients with advanced or recurrent NSCLC
who received nivolumab every two weeks as second or third-line treatment at 32
medical institutions in Japan.

Disease control was defined as continuing CR/PR/SD according to the RECIST at 25weeks after the start of nivolumab.

QOL score by EQ-5D-5L was collected at baseline and at weeks 5, 9, 13 and 25 (after12 cycles).

Potential clinical biomarkers included patient characteristics, laboratory data,
performance status (PS) and QOL score before and at nivolumab week 9 (after 4cycles), and immune-related adverse event (irAE) at week 9.

Consort

Advanced or recurrent NSCLC patients
Received nivolumab every two weeks
As second or third-line treatment
From July 2016 to December 2017
Obtained consent, n=244
Nivolumab treatment, n=243
Full analysis set, n=243
After 9th weeks, n=231
After 25th weeks, n=152

At two years after the start of the last registered caseContinued treatment, n=14Discontinued, n=229・Disease progression, n=176
・Adverse events, n=43・Others, n=10

Patient Characteristics and Clinical Data at Baseline
n%meanSD

minmaxGenderMele / Female

193 / 5079 / 21Age, years

67.79.532

85

PS

0/1
2/3/4

72 / 149
19 / 3 / 030/ 61
8/1/0Hight, cm

163.1

8.2

139

183

Smoking status

Never / Former / Current

30 / 204 / 912 / 84 / 4

Body weight, kg

58.9

11.3

32

96

Co-morbidity

ILD / COPD
Liver disease

8 / 745

3.3 / 30.5
2.1

BMI

18

3.1

1128

WBC, /μL

6856

2575

2500

22810

Stage

Advanced / Recurrent

183 / 60

75 / 25

Lymphocyte, /μL

1406

770

2106850

Histology

Ad / SqNOS / Others

148 / 80
10 / 561 / 33
4/2Alb, g/dL

3.6

0.6

1.44.9ALT, U/L

243

184111

PD-L1>50% / 1-49% / <1%Unknown

14 / 41 / 28
61

10 / 29 / 1942

ALP, U/L304

18876

1943

Treatment line

2nd / 3rd

175 / 67

72.3 / 27.7

Cr, mg/dL

0.84

0.31

0.43

4.39

Stage, TNM

I / II / III / IV

6 / 6 / 63 / 137

3 / 3 / 26 / 56

LDH, U/L248

124

461109

CRP, mg/dL

2648

4.5

0.01

29.7

Response According to the RECISTn (% [95%CI])

CRPRSDPDNE

ORR

DCR

9 weeks(5 cycles)1(0.4)

42(17.3)

97(39.9)68(28.0)35(14.4)

n=43(17.7% [13.1-23.1])

n=140(57.6% [51.1-63.9])25 weeks(13 cycles)3(1.2)

42(17.3)

55(22.6)

71(29.2)

72(29.6)

n=45(18.5% [13.8-24.0])

n=100(41.2% [34.9-47.6])

1 year(25 cycles)4(1.6)

37(15.2)30(12.3)40(16.5)132(54.3)

n=41(16.9% [12.4-22.2])

n=71(29.2% [23.6-35.4])

Progression Free Survival (PFS), n=243

PFSMedian: 3.9 months [95%CI, 3.3-5.5]
1-year PFS rate: 26.2% [95%CI, 20.9-31.9]
2-year PFS rate: 21.2% [95%CI, 16.3-26.6]

Overall Survival (OS), n=243

OS

Median: 13.0 months [95%CI, 11.4-16.5]
1-year OS rate: 53.3% [95%CI, 46.7-59.4]
2-year OS rate: 32.1% [95%CI, 26.2-38.1]

Association Between Disease Control at Week 25 andPatient Characteristics / Clinical Data at Baseline
Logistic regression

Univariate

Multivariate

OR

95%CI

pOR

95%CI

pGender, female vs male

0.35

0.19-0.66

0.00130.29

0.13-0.65

0.0027

Age0.995

0.97-1.02

0.73---BMI1.111.02-1.21

0.018

0.98

0.88-1.09

0.72

PS, 1 vs. 0

0.45

0.24-0.84

0.85

0.54

0.26-1.10

0.60

PS, >2 vs. 0

0.18

0.06-0.49

0.00480.42

0.12-1.49

0.33

Smoking, yes vs. no2.06

0.95-4.45

0.066

-

-

-

Co-morbidity, yes vs. no0.63

0.37-1.57

0.45

-

-

-

Radiotherapy, yes vs. no1.19

0.70-2.00

0.52

-

-

-

Line, 3rd vs. 2nd

1.02

0.57-2.82

0.95

-

-

-

Lymphocyte, /μL

2.64

1.61-4.33

0.00011.65

0.80-3.42

0.18

Association Between Disease Control at Week 25 andPatient Characteristics / Clinical Data at Week 9
Logistic regression

Univariate

Multivariate

OR95%CI

pOR

95%CI

pGender, female vs male

0.51

0.25-1.05

0.067

-

--

Lymphocyte, /μL

2.47

1.41-4.31

0.00151.03

0.38-3.00

0.91

Alb, g/U/L

1.00

0.98-1.02

0.91

-

-

-

ALT, U/L

0.999

0.998-1.00

0.13

-

-

-

Cr, mg/dL

0.99

0.986-0.996

0.0003

0.995

0.99-1.003

0.24

LDH, U/L

0.85

0.76-0.97

0.013

0.98

0.78-1.22

0.82

CRP, mg/dL

1.050.74-1.49

0.79---

irAEs, yes vs. no1.45

0.85-2.48

0.17

-

--

RECIST, CR/PR vs.SD/PD/NE

9.09

3.99-20.69<0.0001---

RECIST, CR/PR/SD vs. PD/NE

40.07

15.3-105.2<0.0001

11.8

3.4-40.7<0.0001

Association Between Tumor Response at Week 25 andPatient Characteristics / Clinical Data at Baseline
Univariate

Logistic regression

Multivariate

OR

95%CI

p

OR

95%CI

p

Gender, female vs male

0.37

0.15-0.92

0.032

0.41

0.16-1.04

0.060

Age

0.99

0.96-1.02

0.36---BMI

1.08

0.98-1.180.14---

PS, 1 vs. 0

0.39

0.21-0.72

0.47

-

-

-

Smoking, yes vs. no3.13

0.91-10.7

0.069

-

-

-

Line, 3rd vs. 2nd

0.79

0.40-1.55

0.49

-

-

-

Lymphocyte, /μL

2.87

1.55-5.33

0.00082.28

1.08-4.81

0.03

Alb, g/U/L

1.02

0.997-1.04

0.093

-

-

-

ALT, U/L

0.996

0.993-0.999

0.021

0.998

0.995-1.001

0.18

Cr, mg/dL

0.999

0.997-1.002

0.60

-

-

-

Association Between Tumor Response at Week 25 andPatient Characteristics / Clinical Data at Week 9Univariate

Logistic regression

Multivariate

OR95%CI

p

OR

95%CI

pGender, female vs male

0.26

0.077-0.89

0.031

0.51

0.099-2.57

0.41

Lymphocyte, /μL

4.44

2.03-9.73

0.0002

6.63

1.43-30.8

0.016

Alb, g/U/L

1.01

0.991-1.04

0.26

-

--

ALT, U/L

0.999

0.997-1.001

0.20-

--

Cr, mg/dL

0.991

0.98-0.998

0.00770.99

0.98-0.999

0.028

LDH, U/L

0.78

0.62-0.97

0.028

1.09

0.76-1.55

0.64

CRP, mg/dL

0.980.64-1.52

0.94---

irAEs, yes vs. no1.16

0.59-2.27

0.66

---

RECIST, CR/PR vs.SD/PD/NE

64.9

25.0-168.4<0.001

68.3

19.4-240.8<0.0001

RECIST, CR/PR/SD vs. PD/NE

21.9

5.17-93.0<0.001---OSstarting from week 25

Landmark Analysis of OS Starting from Week 25, n=152
Median: 12.2 months [95%CI, 9.6-16.8]
1-year OS rate: 50.9% [95%CI, 42.6-58.5]
2-year OS rate: 36.5% [95%CI, 28.7-44.3]

Association Between OS from Week 25 andPatient Characteristics / Clinical Data at Week 25
Cox proportional hazard modelUnivariate

Multivariate

HR95%CIp

HR95%CIp

Gender, female vs male

1.97

1.19-3.25

0.0087

5.64

1.46-21.9

0.012

Age

0.99

0.97-1.02

0.44

-

-

-

BMI

0.97

0.90-1.05

0.42

-

-

-

Smoking, yes vs. no0.93

0.50-1.73

0.81

-

-

-

Co-morbidity, yes vs. no1.08

0.73-1.59

0.71

-

-

-

Radiotherapy, yes vs. no0.91

0.61-1.35

0.63

-

-

-Line, 3rd vs. 2nd

1.61

1.05-2.45

0.029

5.50

1.71-17.7

0.0042

PS at week 25, 1 vs. 0

2.05

1.08-3.69

0.028

1.550.55-4.41

0.41

PS at week 25, >2 vs. 0

22.1

9.54-51.0<0.0001

56.6

3.36-954.0

0.0051(Continued)

Association Between OS from Week 25 andPatient Characteristics / Clinical Data at Week 25
Cox proportional hazard model

Univariate

Multivariate

HR

95%CI

p

HR

95%CI

p

Lymphocyte, /μL

0.16

0.087-0.28<0.0001

0.50

0.17-1.35

0.17

Alb, g/U/L

0.94

0.91-0.98

0.00160.97

0.92-1.02

0.20

ALT, U/L

1.005

1.001-1.008

0.054

1.002

0.998-1.007

0.29

Cr, mg/dL

1.007

1.003-1.011

0.00021.006

0.997-1.014

0.19

LDH, U/L

1.26

1.17-1.36<0.0001

1.07

0.84-1.37

0.59

CRP, mg/dL

0.150.020-1.18

0.072

-

-

-

RECIST, CR/PR vs.SD/PD/NE

0.24

0.14-0.41<0.0001---

RECIST, CR/PR/SD vs. PD/NE

0.30

0.20-0.44<0.0001

0.19

0.066-0.55

0.0023(Continued)

Association Between OS from Week 25 andPatient Characteristics / Clinical Data at Week 25
Cox proportional hazard model

Univariate

Multivariate

HR95%CI

p

HR

95%CI

p

QOL MO, yes vs. no1.99

1.55-2.55<0.0001

1.29

0.61-2.75

0.50

QOL SC

2.74

1.92-3.92<0.00011.18

0.40-3.43

0.77

QOL UA

1.93

1.54-2.42<0.0001

0.48

0.14-1.59

0.23

QOL PD

2.12

1.71-2.64<0.0001

2.85

1.31-6.23

0.0086QOL AD

1.88

1.41-2.51<0.0001

2.65

1.67-5.15

0.0039QOL, health

0.98

0.96-0.99

0.0003

1.03

0.99-1.08

0.13

Imunne-related Adverse Events (irAE) of Nivolumab
Grade 3

Grade 4

n%

n%

Any21

8.6

10.4

Pulmonary toxicity

114.5

10.4

Diarrhea

52.100Rash4

1.600

Thyroid dysfunction

31.200Type 1 diabetes

10.4

00Others

197.820.8

irAE
Anyの数値を確認

Association Between Pulmonary Toxicity andPatient Characteristics / Clinical Data at Baseline
Univariate

Multivariate

OR

95%CI

p*

OR

95%CI

p*

Gender, female vs male

0.33

0.19-2.35

0.52

-

--

Age

0.99

0.95-1.04

0.71

-

--

BMI

1.16

1.00-1.35

0.049

1.22

1.04-1.43

0.017

PS, 1 vs. 0

1.14

0.42-3.10

0.95

-

-

-

Smoking, yes vs. no2.84

0.37-22.0

0.32---Co-morbidity, yes vs. no3.74

1.43-9.77

0.007

4.63

1.70-12.61

0.003

Line, 3rd vs. 2nd

0.86

0.30-2.47

0.78

-

-

-

Lymphocyte, /μL

1.65

0.69-3.93

0.26

-

-

-

LDH, U/L

0.99

0.88-1.10

0.79

-

-

-

CRP, mg/dL

0.560.06-5.04

0.61

-

-

-

Conclusions
Male gender, high lymphocyte count and low serum creatinine at week 9 may beclinical predictors for nivolumab efficacy in patients with advanced or recurrent
NSCLC.

Body mass index and co-morbidity such as interstitial lung disease, chronic
obstructive pulmonary disease and liver disease at baseline were independently
associated with pulmonary toxicity by nivolumab.

In addition, patient reported outcomes may be independent prognostic factors.

Construction of a prediction model using these factors as candidates will beconsidered in the future.