World J Oncol

World Journal of Oncology, ISSN 1920-4531 print, 1920-454X online, Open Access

Article copyright, the authors; Journal compilation copyright, World J Oncol and Elmer Press Inc

Journal website http://www.wjon.org

Original Article

Volume 10, Number 6, December 2019, pages 187-198

Low Body Mass Index Is an Independent Prognostic Factor in Patients With Non-Small Cell Lung Cancer Treated With Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor

Figure 1. Representative cross-sectional CT images obtained at the third lumber vertebra. Two female patients had similar BMI and age, but different PMI, IMAC and VSR. The areas of bilateral psoas muscles, visceral fat, subcutaneous fat, multifidus muscle and subcutaneous four small circles were identified by green, red, blue, yellow and orange. CT: computed tomography; BMI: body mass index; PMI: psoas muscle index; IMAC: intramuscular adipose tissue content; VSR: visceral-to-subcutaneous adipose tissue area ratio.

Figure 2. Kaplan-Meier curves of overall survival according to BMI (a), PMI (b), IMAC (c) and VSR (d). BMI: body mass index; PMI: psoas muscle index; IMAC: intramuscular adipose tissue content; VSR: visceral-to-subcutaneous adipose tissue area ratio.

Figure 3. Kaplan-Meier curves of progression-free survival according to BMI (a), PMI (b), IMAC (c) and VSR (d). BMI: body mass index; PMI: psoas muscle index; IMAC: intramuscular adipose tissue content; VSR: visceral-to-subcutaneous adipose tissue area ratio.

**Table 1.** Baseline Characteristics According to Body Mass Index
	BMI	P
^aFisher’s exact test. ^bMann-Whitney U test. BMI: body mass index; CI: confidence interval; CR: complete response; CS: current smoker; DCR: disease control rate; ECOG-PS: Eastern Cooperative Oncology Group performance status; EGFR: epidermal growth factor receptor; Ex: ex-smoker; ICI: immune-checkpoint inhibitors; IQR: interquartile range; NE: not evaluated; NLR: neutrophil-to-lymphocyte ratio; NS: non-smoker; ORR: overall response rate; PD: progressive disease; PR: partial response; SD: stable disease; TKI: tyrosine kinase inhibitor.
N	134	33
Backgrounds
Sex (N)
Male/female	50/84	13/20	0.84^a
Age (years)
Median (IQR)	72 (63.3 - 77.0)	74 (67.8 - 78.3)	0.21^b
< 75/≥ 75 years (N)	82/52	18/15	0.55^a
Smoking status
NS/Ex, CS	69/65	16/17	0.85^a
EGFR mutation
Ex19del/others	67/67	13/20	0.33^a
ECOG-PS
0-1/2/3-4	103/25/6	22/6/5	0.10^a
Extra-pulmonary metastases
Yes/no	72/62	20/13	0.56^a
Metastatic sites
< 3/≥ 3	68/66	8/25	< 0.01^a
BMI
Median (IQR)	23.2 (21.1 - 24.8)	17.7 (16.4 - 18.1)	< 0.01^b
Treatment (N)
Regimen
Gefitinib/erlotinib/afatinib	15/31/88	2/11/20	0.44^a
Line
First/Second or later	95/39	24/9	1.00^a
Post-TKI treatment
Osimertinib	21	3	0.42^a
ICI therapy	13	1	0.31^a
TKI efficacy
CR/PR/SD/PD/NE	6/82/26/15/5	1/16/5/5/6
ORR (%) (95% CI)	65.7 (57.0 - 73.7)	51.5 (33.5 - 69.2)	0.16^a
DCR (%) (95% CI)	85.1 (77.9 - 90.6)	66.7 (48.2 - 82.0)	0.02^a
Laboratory data
NLR
Median (IQR)	2.51 (1.78 - 4.27)	2.98 (2.20 - 3.98)	0.23^b
≤ 5/> 5 (N)	112/22	28/5	1.00^a

Table 1. Baseline Characteristics According to Body Mass Index

BMI

≥ 18.5

< 18.5

^aFisher’s exact test. ^bMann-Whitney U test. BMI: body mass index; CI: confidence interval; CR: complete response; CS: current smoker; DCR: disease control rate; ECOG-PS: Eastern Cooperative Oncology Group performance status; EGFR: epidermal growth factor receptor; Ex: ex-smoker; ICI: immune-checkpoint inhibitors; IQR: interquartile range; NE: not evaluated; NLR: neutrophil-to-lymphocyte ratio; NS: non-smoker; ORR: overall response rate; PD: progressive disease; PR: partial response; SD: stable disease; TKI: tyrosine kinase inhibitor.

134

Backgrounds

Sex (N)

Male/female

50/84

13/20

0.84^a

Age (years)

Median (IQR)

72 (63.3 - 77.0)

74 (67.8 - 78.3)

0.21^b

< 75/≥ 75 years (N)

82/52

18/15

0.55^a

Smoking status

NS/Ex, CS

69/65

16/17

0.85^a

EGFR mutation

Ex19del/others

67/67

13/20

0.33^a

ECOG-PS

0-1/2/3-4

103/25/6

22/6/5

0.10^a

Extra-pulmonary metastases

Yes/no

72/62

20/13

0.56^a

Metastatic sites

< 3/≥ 3

68/66

8/25

< 0.01^a

BMI

Median (IQR)

23.2 (21.1 - 24.8)

17.7 (16.4 - 18.1)

< 0.01^b

Treatment (N)

Regimen

Gefitinib/erlotinib/afatinib

15/31/88

2/11/20

0.44^a

Line

First/Second or later

95/39

24/9

1.00^a

Post-TKI treatment

Osimertinib

0.42^a

ICI therapy

0.31^a

TKI efficacy

CR/PR/SD/PD/NE

6/82/26/15/5

1/16/5/5/6

ORR (%) (95% CI)

65.7 (57.0 - 73.7)

51.5 (33.5 - 69.2)

0.16^a

DCR (%) (95% CI)

85.1 (77.9 - 90.6)

66.7 (48.2 - 82.0)

0.02^a

Laboratory data

NLR

Median (IQR)

2.51 (1.78 - 4.27)

2.98 (2.20 - 3.98)

0.23^b

≤ 5/> 5 (N)

112/22

28/5

1.00^a

**Table 2.** Baseline Characteristics According to Psoas Muscle Index
	PMI	P
^aFisher’s exact test. ^bMann-Whitney U test. BMI: body mass index; CI: confidence interval; CR: complete response; CS: current smoker; DCR: disease control rate; ECOG-PS: Eastern Cooperative Oncology Group performance status; EGFR: epidermal growth factor receptor; Ex: ex-smoker; ICI: immune-checkpoint inhibitors; IQR: interquartile range; NE: not evaluated; NLR: neutrophil-to-lymphocyte ratio; NS: non-smoker; ORR: overall response rate; PD: progressive disease; PMI: psoas muscle index; PR: partial response; SD: stable disease; TKI: tyrosine kinase inhibitor.
N	102	65
Backgrounds
Sex (N)
Male/female	43/59	20/45	0.15^a
Age (years)
Median (IQR)	74 (66 - 79)	71 (60 - 76)	0.03^b
< 75/≥ 75 years (N)	58/44	42/23	0.34^a
Smoking status
NS/Ex, CS	49/53	36/29	0.43^a
EGFR mutation
Ex19del/others	45/57	35/30	0.27^a
ECOG-PS
0-1/2/3-4	71/23/8	54/8/3	0.16^a
Extra-pulmonary metastases
Yes/no	60/42	32/33	0.27^a
Metastatic sites
< 3/≥ 3	46/56	30/35	1.00^a
BMI
Median (IQR)	21.2 (18.3 - 23.4)	23.7 (21.0 - 25.6)	< 0.01^b
PMI
Median (IQR)	3.53 (2.91 - 4.45)	5.01 (4.58 - 6.75)	< 0.01^b
Treatment (N)
Regimen
Gefitinib/erlotinib/afatinib	65/28/9	43/14/8	0.59^a
Line
First/second or later	74/28	45/20	0.73^a
Post-TKI treatment
Osimertinib	10	14	0.04^a
ICI therapy	6	8	0.16^a
TKI efficacy
CR/PR/SD/PD/NE	4/55/19/14/10	3/43/12/6/1
ORR (%) (95% CI)	57.8 (47.7 - 67.6)	70.8 (58.2 - 81.4)	0.10^a
DCR (%) (95% CI)	76.5 (67.0 - 84.3)	89.2 (79.1 - 95.6)	0.04^a
Laboratory data
NLR
Median (IQR)	2.83 (1.94 - 4.57)	2.50 (1.61 - 3.54)	0.10^b
≤ 5/> 5 (N)	82/20	58/7	0.20^a

Table 2. Baseline Characteristics According to Psoas Muscle Index

PMI

Low

High

^aFisher’s exact test. ^bMann-Whitney U test. BMI: body mass index; CI: confidence interval; CR: complete response; CS: current smoker; DCR: disease control rate; ECOG-PS: Eastern Cooperative Oncology Group performance status; EGFR: epidermal growth factor receptor; Ex: ex-smoker; ICI: immune-checkpoint inhibitors; IQR: interquartile range; NE: not evaluated; NLR: neutrophil-to-lymphocyte ratio; NS: non-smoker; ORR: overall response rate; PD: progressive disease; PMI: psoas muscle index; PR: partial response; SD: stable disease; TKI: tyrosine kinase inhibitor.

102

Backgrounds

Sex (N)

Male/female

43/59

20/45

0.15^a

Age (years)

Median (IQR)

74 (66 - 79)

71 (60 - 76)

0.03^b

< 75/≥ 75 years (N)

58/44

42/23

0.34^a

Smoking status

NS/Ex, CS

49/53

36/29

0.43^a

EGFR mutation

Ex19del/others

45/57

35/30

0.27^a

ECOG-PS

0-1/2/3-4

71/23/8

54/8/3

0.16^a

Extra-pulmonary metastases

Yes/no

60/42

32/33

0.27^a

Metastatic sites

< 3/≥ 3

46/56

30/35

1.00^a

BMI

Median (IQR)

21.2 (18.3 - 23.4)

23.7 (21.0 - 25.6)

< 0.01^b

PMI

Median (IQR)

3.53 (2.91 - 4.45)

5.01 (4.58 - 6.75)

< 0.01^b

Treatment (N)

Regimen

Gefitinib/erlotinib/afatinib

65/28/9

43/14/8

0.59^a

Line

First/second or later

74/28

45/20

0.73^a

Post-TKI treatment

Osimertinib

0.04^a

ICI therapy

0.16^a

TKI efficacy

CR/PR/SD/PD/NE

4/55/19/14/10

3/43/12/6/1

ORR (%) (95% CI)

57.8 (47.7 - 67.6)

70.8 (58.2 - 81.4)

0.10^a

DCR (%) (95% CI)

76.5 (67.0 - 84.3)

89.2 (79.1 - 95.6)

0.04^a

Laboratory data

NLR

Median (IQR)

2.83 (1.94 - 4.57)

2.50 (1.61 - 3.54)

0.10^b

≤ 5/> 5 (N)

82/20

58/7

0.20^a

**Table 3.** Baseline Characteristics According to Intramuscular Adipose Tissue Content
	IMAC	P
^aFisher’s exact test. ^bMann-Whitney U test. BMI: body mass index; CI: confidence interval; CR: complete response; CS: current smoker; DCR: disease control rate; ECOG-PS: Eastern Cooperative Oncology Group performance status; EGFR: epidermal growth factor receptor; Ex: ex-smoker; ICI: immune-checkpoint inhibitors; IMAC: intramuscular adipose tissue content; IQR: interquartile range; NE: not evaluated; NLR: neutrophil-to-lymphocyte ratio; NS: non-smoker; ORR: overall response rate; PD: progressive disease; PR: partial response; SD: stable disease; TKI: tyrosine kinase inhibitor.
N	148	19
Backgrounds
Sex (N)
Male/female	91/57	13/6	0.62^a
Age (years)
Median (IQR)	72 (64 - 77)	76 (69.5 - 81)	0.04^b
< 75/≥ 75 years (N)	91/57	9/10	0.32^a
Smoking status
NS/Ex, CS	77/71	8/11	0.47^a
EGFR mutation
Ex19del/others	70/78	10/9	0.81^a
ECOG-PS
0-1/2/3-4	114/24/10	11/7/1	0.10^a
Extra-pulmonary metastases
Yes/no	80/68	12/7	0.63^a
Metastatic sites
< 3/≥ 3	70/78	6/13	0.23^a
BMI
Median (IQR)	20.1 (19.1 - 24.4)	22.3 (20.1 - 24.4)	0.68^a
IMAC
Median (IQR)	-0.52 (-0.63, -0.43)	-0.16 (-0.23, -0.10)	< 0.01^b
Treatment (N)
Regimen
Gefitinib/erlotinib/afatinib	97/35/16	11/7/1	0.45^a
Line
First/second or later	106/42	13/6	0.79^a
Post-TKI treatment
Osimertinib	23	1	0.32^a
ICI therapy	14	0	0.37^a
TKI efficacy
CR/PR/SD/PD/NE	33/81/24/8/2	3/8/7/1
ORR (%) (95% CI)	77.0 (69.4 - 83.5)	57.9 (33.5 - 79.7)	0.09^a
DCR (%) (95% CI)	93.2 (87.9 - 96.7)	94.7 (74.0 - 99.9)	1.00^a
Laboratory data
NLR
Median (IQR)	2.67 (1.79 - 3.93)	2.95 (2.05 - 4.92)	0.42^b
≤ 5/> 5 (N)	126/22	14/5	0.20^a

Table 3. Baseline Characteristics According to Intramuscular Adipose Tissue Content

IMAC

Low

High

^aFisher’s exact test. ^bMann-Whitney U test. BMI: body mass index; CI: confidence interval; CR: complete response; CS: current smoker; DCR: disease control rate; ECOG-PS: Eastern Cooperative Oncology Group performance status; EGFR: epidermal growth factor receptor; Ex: ex-smoker; ICI: immune-checkpoint inhibitors; IMAC: intramuscular adipose tissue content; IQR: interquartile range; NE: not evaluated; NLR: neutrophil-to-lymphocyte ratio; NS: non-smoker; ORR: overall response rate; PD: progressive disease; PR: partial response; SD: stable disease; TKI: tyrosine kinase inhibitor.

148

Backgrounds

Sex (N)

Male/female

91/57

13/6

0.62^a

Age (years)

Median (IQR)

72 (64 - 77)

76 (69.5 - 81)

0.04^b

< 75/≥ 75 years (N)

91/57

9/10

0.32^a

Smoking status

NS/Ex, CS

77/71

8/11

0.47^a

EGFR mutation

Ex19del/others

70/78

10/9

0.81^a

ECOG-PS

0-1/2/3-4

114/24/10

11/7/1

0.10^a

Extra-pulmonary metastases

Yes/no

80/68

12/7

0.63^a

Metastatic sites

< 3/≥ 3

70/78

6/13

0.23^a

BMI

Median (IQR)

20.1 (19.1 - 24.4)

22.3 (20.1 - 24.4)

0.68^a

IMAC

Median (IQR)

-0.52 (-0.63, -0.43)

-0.16 (-0.23, -0.10)

< 0.01^b

Treatment (N)

Regimen

Gefitinib/erlotinib/afatinib

97/35/16

11/7/1

0.45^a

Line

First/second or later

106/42

13/6

0.79^a

Post-TKI treatment

Osimertinib

0.32^a

ICI therapy

0.37^a

TKI efficacy

CR/PR/SD/PD/NE

33/81/24/8/2

3/8/7/1

ORR (%) (95% CI)

77.0 (69.4 - 83.5)

57.9 (33.5 - 79.7)

0.09^a

DCR (%) (95% CI)

93.2 (87.9 - 96.7)

94.7 (74.0 - 99.9)

1.00^a

Laboratory data

NLR

Median (IQR)

2.67 (1.79 - 3.93)

2.95 (2.05 - 4.92)

0.42^b

≤ 5/> 5 (N)

126/22

14/5

0.20^a

**Table 4.** Baseline Characteristics According to Visceral-to-Subcutaneous Adipose Tissue Area Ratio
	VSR	P
^aFisher’s exact test. ^bMann-Whitney U test. BMI: body mass index; CI: confidence interval; CR: complete response; CS: current smoker; DCR: disease control rate; ECOG-PS: Eastern Cooperative Oncology Group performance status; EGFR: epidermal growth factor receptor; Ex: ex-smoker; ICI: immune-checkpoint inhibitors; IQR: interquartile range; NE: not evaluated; NLR: neutrophil-to-lymphocyte ratio; NS: non-smoker; ORR: overall response rate; PD: progressive disease; PR: partial response; SD: stable disease; TKI: tyrosine kinase inhibitor; VSR: visceral-to-subcutaneous adipose tissue area ratio.
N	128	39
Backgrounds
Sex (N)
Male/female	44/84	19/20	0.13^a
Age (years)
Median (IQR)	71 (64 - 76)	77 (70.5 - 80.5)	< 0.01^b
< 75/≥ 75 years (N)	83/45	17/22	0.02^a
Smoking status
NS/Ex, CS	65/63	20/19	1.00^a
EGFR mutation
Ex19del/others	62/66	18/21	0.86^a
ECOG-PS
0-1/2/3-4	97/23/8	28/8/3	0.81^a
Extra-pulmonary metastases
Yes/no	69/59	23/16	0.71^a
Metastatic sites
< 3/≥ 3	54/74	22/17	0.14^a
BMI
Median (IQR)	21.6 (19.1 - 24.1)	23.4 (19.7 - 25.6)	0.16^b
VSR
Median (IQR)	0.41 (0.23 - 0.74)	1.45 (1.26 - 1.93)	< 0.01^b
Treatment (N)
Regimen
Gefitinib/erlotinib/afatinib	82/31/15	26/11/2	0.54^a
Line
First/second or later	91/37	28/11	1.00^a
Post-TKI treatment
Osimertinib	20	4	0.60^a
ICI therapy	12	2	0.52^a
TKI efficacy
CR/PR/SD/PD/NE	4/79/23/15/7	3/19/8/5/4
ORR (%) (95% CI)	64.8 (55.9 - 73.1)	56.4 (39.6 - 72.2)	0.35^a
DCR (%) (95% CI)	82.8 (75.1 - 88.9)	76.9 (60.7 - 88.9)	0.48^a
Laboratory data
NLR
Median (IQR)	2.60 (1.79 - 4.16)	2.84 (2.02 - 4.23)	0.53^b
≤ 5/> 5 (N)	105/23	35/4	0.33^a

Table 4. Baseline Characteristics According to Visceral-to-Subcutaneous Adipose Tissue Area Ratio

VSR

Low

High

128

Backgrounds

Sex (N)

Male/female

44/84

19/20

0.13^a

Age (years)

Median (IQR)

71 (64 - 76)

77 (70.5 - 80.5)

< 0.01^b

< 75/≥ 75 years (N)

83/45

17/22

0.02^a

Smoking status

NS/Ex, CS

65/63

20/19

1.00^a

EGFR mutation

Ex19del/others

62/66

18/21

0.86^a

ECOG-PS

0-1/2/3-4

97/23/8

28/8/3

0.81^a

Extra-pulmonary metastases

Yes/no

69/59

23/16

0.71^a

Metastatic sites

< 3/≥ 3

54/74

22/17

0.14^a

BMI

Median (IQR)

21.6 (19.1 - 24.1)

23.4 (19.7 - 25.6)

0.16^b

VSR

Median (IQR)

0.41 (0.23 - 0.74)

1.45 (1.26 - 1.93)

< 0.01^b

Treatment (N)

Regimen

Gefitinib/erlotinib/afatinib

82/31/15

26/11/2

0.54^a

Line

First/second or later

91/37

28/11

1.00^a

Post-TKI treatment

Osimertinib

0.60^a

ICI therapy

0.52^a

TKI efficacy

CR/PR/SD/PD/NE

4/79/23/15/7

3/19/8/5/4

ORR (%) (95% CI)

64.8 (55.9 - 73.1)

56.4 (39.6 - 72.2)

0.35^a

DCR (%) (95% CI)

82.8 (75.1 - 88.9)

76.9 (60.7 - 88.9)

0.48^a

Laboratory data

NLR

Median (IQR)

2.60 (1.79 - 4.16)

2.84 (2.02 - 4.23)

0.53^b

≤ 5/> 5 (N)

105/23

35/4

0.33^a

**Table 5.** Adjusted Hazard Ratios of Markers of Sarcopenia and Visceral Obesity by Age, Neutrophil to Lymphocyte Ratio, ECOG-PS, EGFR Mutation Type, Regimen Line and Extra-Pulmonary Metastases
Variables	OS	PFS
Multivariate adjustment for age (< 75 vs. ≥ 75 years), neutrophil to lymphocyte ratio (< 5 vs. ≥ 5), ECOG-PS (0 - 1 vs. 2 - 4), EGFR mutation type (exon 19 deletion vs. others), regimen line (first-line vs. second or later line) and extra-pulmonary metastases (yes vs. no). BMI: body mass index; CI: confidence interval; ECOG-PS: Eastern Cooperative Oncology Group performance status; EGFR: epidermal growth factor receptor; HR: hazard ratio; IMAC: intramuscular adipose tissue content; OS: overall survival; PFS: progression-free survival; PMI: psoas muscle index; VSR: visceral-to-subcutaneous adipose tissue area ratio.
BMI (kg/m²)
≥ 18.5	1 (Reference)		1(Reference)
< 18.5	1.70 (1.03 - 2.81)	0.04	1.72 (1.11 - 2.67)	0.02
PMI (cm²/m²)
High	1 (Reference)		1(Reference)
Low	1.10 (0.73 - 1.64)	0.65	1.10 (0.76 - 1.58)	0.61
IMAC
Low	1 (Reference)		1(Reference)
High	1.25 (0.66 - 2.37)	0.49	0.98 (0.56 - 1.71)	0.94
VSR
Low	1 (Reference)		1(Reference)
High	1.20 (0.76 - 1.91)	0.44	1.01 (0.66 - 1.54)	0.98

Table 5. Adjusted Hazard Ratios of Markers of Sarcopenia and Visceral Obesity by Age, Neutrophil to Lymphocyte Ratio, ECOG-PS, EGFR Mutation Type, Regimen Line and Extra-Pulmonary Metastases

Variables

PFS

HR (95% CI)

Multivariate adjustment for age (< 75 vs. ≥ 75 years), neutrophil to lymphocyte ratio (< 5 vs. ≥ 5), ECOG-PS (0 - 1 vs. 2 - 4), EGFR mutation type (exon 19 deletion vs. others), regimen line (first-line vs. second or later line) and extra-pulmonary metastases (yes vs. no). BMI: body mass index; CI: confidence interval; ECOG-PS: Eastern Cooperative Oncology Group performance status; EGFR: epidermal growth factor receptor; HR: hazard ratio; IMAC: intramuscular adipose tissue content; OS: overall survival; PFS: progression-free survival; PMI: psoas muscle index; VSR: visceral-to-subcutaneous adipose tissue area ratio.

BMI (kg/m²)

≥ 18.5

1 (Reference)

1(Reference)

< 18.5

1.70 (1.03 - 2.81)

0.04

1.72 (1.11 - 2.67)

0.02

PMI (cm²/m²)

High

1 (Reference)

1(Reference)

Low

1.10 (0.73 - 1.64)

0.65

1.10 (0.76 - 1.58)

0.61

IMAC

Low

1 (Reference)

1(Reference)

High

1.25 (0.66 - 2.37)

0.49

0.98 (0.56 - 1.71)

0.94

VSR

Low

1 (Reference)

1(Reference)

High

1.20 (0.76 - 1.91)

0.44

1.01 (0.66 - 1.54)

0.98

**Table 6.** Multivariate Cox Proportional Hazard Analyses, When Extra-Pulmonary Metastases Was Replaced by Numbers of Metastatic Sites as an Explanatory Variable
Variables	OS	PFS
BMI: body mass index; CI: confidence interval; ECOG-PS: Eastern Cooperative Oncology Group performance status; EGFR: epidermal growth factor receptor; HR: hazard ratio; NLR: neutrophil-to-lymphocyte ratio; OS: overall survival; PFS: progression-free survival.
Age
< 75 years	1 (Reference)		1(Reference)
≥ 75 years	1.08 (0.72 - 1.64)	0.71	0.86 (0.59 - 1.24)	0.42
NLR
< 5	1 (Reference)		1(Reference)
≥ 5	0.95 (0.55 - 1.63)	0.85	0.79 (0.50 - 1.26)	0.33
ECOG-PS
0 - 1	1 (Reference)		1(Reference)
2 - 4	2.86 (1.80 - 4.54)	< 0.01	2.09 (1.39 - 3.13)	< 0.01
EGFR mutation
Exon 19 del	1 (Reference)		1 (Reference)
Others	1.29 (0.86 - 1.93)	0.22	1.28 (0.90 - 1.82)	0.17
Regimen line
First-line	1 (Reference)		1 (Reference)
Second or later	1.72 (1.12 - 2.65)	0.01	1.46 (1.00 - 2.12)	0.049
Metastatic sites
< 3	1 (Reference)		1 (Reference)
≥ 3	1.96 (1.28 - 3.00)	< 0.01	2.11 (1.46 - 3.05)	< 0.01
BMI (kg/m²)
≥ 18.5	1 (Reference)		1(Reference)
< 18.5	1.48 (0.89 - 2.46)	0.13	1.36 (0.87 - 2.13)	0.18

Table 6. Multivariate Cox Proportional Hazard Analyses, When Extra-Pulmonary Metastases Was Replaced by Numbers of Metastatic Sites as an Explanatory Variable

Variables

PFS

HR (95% CI)

BMI: body mass index; CI: confidence interval; ECOG-PS: Eastern Cooperative Oncology Group performance status; EGFR: epidermal growth factor receptor; HR: hazard ratio; NLR: neutrophil-to-lymphocyte ratio; OS: overall survival; PFS: progression-free survival.

Age

< 75 years

1 (Reference)

1(Reference)

≥ 75 years

1.08 (0.72 - 1.64)

0.71

0.86 (0.59 - 1.24)

0.42

NLR

< 5

1 (Reference)

1(Reference)

≥ 5

0.95 (0.55 - 1.63)

0.85

0.79 (0.50 - 1.26)

0.33

ECOG-PS

0 - 1

1 (Reference)

1(Reference)

2 - 4

2.86 (1.80 - 4.54)

< 0.01

2.09 (1.39 - 3.13)

< 0.01

EGFR mutation

Exon 19 del

1 (Reference)

Others

1.29 (0.86 - 1.93)

0.22

1.28 (0.90 - 1.82)

0.17

Regimen line

First-line

1 (Reference)

Second or later

1.72 (1.12 - 2.65)

0.01

1.46 (1.00 - 2.12)

0.049

Metastatic sites

< 3

1 (Reference)

≥ 3

1.96 (1.28 - 3.00)

< 0.01

2.11 (1.46 - 3.05)

< 0.01

BMI (kg/m²)

≥ 18.5

1 (Reference)

1(Reference)

< 18.5

1.48 (0.89 - 2.46)

0.13

1.36 (0.87 - 2.13)

0.18