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 1, February 2019, pages 55-61

Gustave Roussy Immune Score Is a Prognostic Factor for Chemotherapy-Naive Pulmonary Adenocarcinoma With Wild-Type Epidermal Growth Factor Receptor

Figure 1. Kaplan-Meier curves of overall survival (OS) according to GRIm-Score. (a) Wild-type EGFR adenocarcinoma. (b) NSCLC with activated EGFR mutation. (c) Squamous cell carcinoma.

Figure 2. Kaplan-Meier curves of progression-free survival (PFS) according to GRIm-Score. (a) Wild-type EGFR adenocarcinoma. (b) NSCLC with activated EGFR mutation. (c) Squamous cell carcinoma.

**Table 1.** Baseline Characteristics of Wild-Type EGFR Adenocarcinoma
	All	Low	High	P
CI: confidence interval; DCR: disease control rate; ECOG-PS: Eastern Cooperative Oncology Group performance status; IQR: interquartile range; LDH: lactate dehydrogenase; NA: not assessed; NLR: neutrophil-to-lymphocyte ratio; ORR: overall response rate; ULN: upper limit of normal. ^aFisher’s exact test; ^bMann-Whitney U test.
N	185	139	46
Backgrounds
Sex (N), men/women	128/57	94/45	34/12	0.47^a
Age (years), median (IQR)	68 (62 - 74)	67 (62 - 73)	69 (62.3 - 75)	0.56^b
Smoking status (N), non/former or current smokers	31/154	25/114	6/40	0.50^a
PD-L1 status (N), ≥ 50%/1-49%/< 1%/NA	7/9/8/161	6/7/6/120	1/2/2/41	0.97^a
ECOG-PS (N), 0 - 1/≥ 2	143/42	120/19	23/23	< 0.01^a
Stage (N), IIIB/IV/recurrence	34/139/12	31/98/10	3/41/2	0.03^a
Metastatic sites (N), ≥ 2	93/92	78/61	15/31	< 0.01^a
First-line chemotherapy
Regimen (N)
Single/combination	7/178	6/133	1/45	0.68^a
Pemetrexed-containing	93/92	64/75	29/17	0.06^a
Bevacizumab-containing	37/148	32/107	5/41	0.09^a
Efficacy
ORR (%) (95% CI)	38.4 (31.3 - 45.8)	45.3 (36.9 - 54.0)	17.4 (7.8 - 31.4)	< 0.01^a
DCR (%) (95% CI)	71.9 (64.8 - 78.2)	78.4 (70.6 - 84.9)	52.2 (36.9 - 67.1)	< 0.01^a
Second and further line
Second-line (N)	113	96	17	< 0.01^a
Immuno-checkpoint inhibitor (N)	28	25	3	0.09^a
Laboratory data
NLR
Median (IQR)	3.3 (2.2 - 4.9)	2.8 (2.1 - 3.9)	6.5 (4.3 - 8.7)	< 0.01^b
> 6 (N)	34	7	27	< 0.01^a
LDH (U/L)
Median (IQR)	203 (170 - 257)	189 (164.5 - 220.5)	284.5 (239.3 - 440)	< 0.01^b
> ULN (N)	73	33	40	< 0.01^a
Albumin (g/dL)
Median (IQR)	3.7 (3.3 - 3.9)	3.8 (3.6 - 4.1)	3.1 (2.7 - 3.3)	< 0.01^b
< 3.5 g/dL (N)	60	19	41	< 0.01^a

Table 1. Baseline Characteristics of Wild-Type EGFR Adenocarcinoma

All

Low

High

CI: confidence interval; DCR: disease control rate; ECOG-PS: Eastern Cooperative Oncology Group performance status; IQR: interquartile range; LDH: lactate dehydrogenase; NA: not assessed; NLR: neutrophil-to-lymphocyte ratio; ORR: overall response rate; ULN: upper limit of normal. ^aFisher’s exact test; ^bMann-Whitney U test.

185

139

Backgrounds

Sex (N), men/women

128/57

94/45

34/12

0.47^a

Age (years), median (IQR)

68 (62 - 74)

67 (62 - 73)

69 (62.3 - 75)

0.56^b

Smoking status (N), non/former or current smokers

31/154

25/114

6/40

0.50^a

PD-L1 status (N), ≥ 50%/1-49%/< 1%/NA

7/9/8/161

6/7/6/120

1/2/2/41

0.97^a

ECOG-PS (N), 0 - 1/≥ 2

143/42

120/19

23/23

< 0.01^a

Stage (N), IIIB/IV/recurrence

34/139/12

31/98/10

3/41/2

0.03^a

Metastatic sites (N), ≥ 2

93/92

78/61

15/31

< 0.01^a

First-line chemotherapy

Regimen (N)

Single/combination

7/178

6/133

1/45

0.68^a

Pemetrexed-containing

93/92

64/75

29/17

0.06^a

Bevacizumab-containing

37/148

32/107

5/41

0.09^a

Efficacy

ORR (%) (95% CI)

38.4 (31.3 - 45.8)

45.3 (36.9 - 54.0)

17.4 (7.8 - 31.4)

< 0.01^a

DCR (%) (95% CI)

71.9 (64.8 - 78.2)

78.4 (70.6 - 84.9)

52.2 (36.9 - 67.1)

< 0.01^a

Second and further line

Second-line (N)

113

< 0.01^a

Immuno-checkpoint inhibitor (N)

0.09^a

Laboratory data

NLR

Median (IQR)

3.3 (2.2 - 4.9)

2.8 (2.1 - 3.9)

6.5 (4.3 - 8.7)

< 0.01^b

> 6 (N)

< 0.01^a

LDH (U/L)

Median (IQR)

203 (170 - 257)

189 (164.5 - 220.5)

284.5 (239.3 - 440)

< 0.01^b

> ULN (N)

< 0.01^a

Albumin (g/dL)

Median (IQR)

3.7 (3.3 - 3.9)

3.8 (3.6 - 4.1)

3.1 (2.7 - 3.3)

< 0.01^b

< 3.5 g/dL (N)

< 0.01^a

**Table 2.** Baseline Characteristics of NSCLC With Active EGFR Mutation
	All	Low	High	P
CI: confidence interval; DCR: disease control rate; EGFR: epidermal growth factor receptor; ECOG-PS: Eastern Cooperative Oncology Group performance status; Ex: exon; IQR: interquartile range; LDH: lactate dehydrogenase; NA: not assessed; NLR: neutrophil-to-lymphocyte ratio; ORR: overall response rate; TKI: tyrosine kinase inhibitor; ULN: upper limit of normal. ^aFisher’s exact test; ^bMann-Whitney U test.
N	140	119	21
Backgrounds
Sex (N), men/women	55/85	46/73	9/12	0.81^a
Age (years), median (IQR)	73 (65 - 78)	73 (65 - 77)	74 (61 - 78)	0.82^b
Smoking status (N), non/former or current smokers	69/71	60/59	9/12	0.64^a
EGFR mutation status (N), ex19el/ex21 point/minor or compound	69/62/9	59/51/9	10/11/ 0	0.52^a
PD-L1 status (N), ≥ 50%/1-49%/< 1%/NA	3/7/8/122	3/6/8/102	0/1/0/20	0.83^a
ECOG-PS (N), 0 - 1/≥ 2	101/39	96/23	5/16	< 0.01^a
Stage (N), III/IV/recurrence	10/96/34	10/75/34	0/21/0
Metastatic sites (N), ≥ 2	99	82	17	0.31^a
EGFR-TKI
Regimen (N), gefitinib/erlotinib/afatinib	83/41/16	72/33/14	11/8/2	0.61^a
Line (N), first/second or further	108/32	90/29	18/3	0.41^a
Efficacy
ORR (%) (95% CI)	64.3 (55.8 - 72.2)	68.9 (59.8 - 77.1)	38.1 (18.1 - 61.6)	0.01^a
DCR (%) (95% CI)	82.9 (75.6 - 88.7)	87.4 (80.1 - 92.8)	57.1 (34.0 - 78.2)	< 0.01^a
Post-EGFR-TKI therapy
Further-line (N)	69	57	12	0.48^a
Osimeritinib (N)	28	22	6	0.37^a
Immuno-checkpoint inhibitor (N)	6	5	1	1.00^a
Laboratory data
NLR
Median (IQR)	2.77 (1.93 - 4.28)	2.52 (1.87 - 3.42)	5.72 (3.46 - 6.93)	< 0.01^b
> 6 (N)	14	4	10	< 0.01^a
LDH
Median (IQR)	199.5 (176 - 240)	193 (174 - 224)	251 (234 - 379)	< 0.01^b
> ULN	49	30	19	< 0.01^a
Albumin (g/dL)
Median (IQR)	3.8 (3.3 - 4.1)	3.9 (3.6 - 4.2)	3.0 (2.7 - 3.2)	< 0.01^b
< 3.5 g/dL (N)	40	20	20	< 0.01^a

Table 2. Baseline Characteristics of NSCLC With Active EGFR Mutation

All

Low

High

CI: confidence interval; DCR: disease control rate; EGFR: epidermal growth factor receptor; ECOG-PS: Eastern Cooperative Oncology Group performance status; Ex: exon; IQR: interquartile range; LDH: lactate dehydrogenase; NA: not assessed; NLR: neutrophil-to-lymphocyte ratio; ORR: overall response rate; TKI: tyrosine kinase inhibitor; ULN: upper limit of normal. ^aFisher’s exact test; ^bMann-Whitney U test.

140

119

Backgrounds

Sex (N), men/women

55/85

46/73

9/12

0.81^a

Age (years), median (IQR)

73 (65 - 78)

73 (65 - 77)

74 (61 - 78)

0.82^b

Smoking status (N), non/former or current smokers

69/71

60/59

9/12

0.64^a

EGFR mutation status (N), ex19el/ex21 point/minor or compound

69/62/9

59/51/9

10/11/ 0

0.52^a

PD-L1 status (N), ≥ 50%/1-49%/< 1%/NA

3/7/8/122

3/6/8/102

0/1/0/20

0.83^a

ECOG-PS (N), 0 - 1/≥ 2

101/39

96/23

5/16

< 0.01^a

Stage (N), III/IV/recurrence

10/96/34

10/75/34

0/21/0

Metastatic sites (N), ≥ 2

0.31^a

EGFR-TKI

Regimen (N), gefitinib/erlotinib/afatinib

83/41/16

72/33/14

11/8/2

0.61^a

Line (N), first/second or further

108/32

90/29

18/3

0.41^a

Efficacy

ORR (%) (95% CI)

64.3 (55.8 - 72.2)

68.9 (59.8 - 77.1)

38.1 (18.1 - 61.6)

0.01^a

DCR (%) (95% CI)

82.9 (75.6 - 88.7)

87.4 (80.1 - 92.8)

57.1 (34.0 - 78.2)

< 0.01^a

Post-EGFR-TKI therapy

Further-line (N)

0.48^a

Osimeritinib (N)

0.37^a

Immuno-checkpoint inhibitor (N)

1.00^a

Laboratory data

NLR

Median (IQR)

2.77 (1.93 - 4.28)

2.52 (1.87 - 3.42)

5.72 (3.46 - 6.93)

< 0.01^b

> 6 (N)

< 0.01^a

LDH

Median (IQR)

199.5 (176 - 240)

193 (174 - 224)

251 (234 - 379)

< 0.01^b

> ULN

< 0.01^a

Albumin (g/dL)

Median (IQR)

3.8 (3.3 - 4.1)

3.9 (3.6 - 4.2)

3.0 (2.7 - 3.2)

< 0.01^b

< 3.5 g/dL (N)

< 0.01^a

**Table 3.** Baseline Characteristics of Squamous Cell Carcinoma
	All	Low	High	P
CI: confidence interval; DCR: disease control rate; ECOG-PS: Eastern Cooperative Oncology Group performance status; IQR: interquartile range; LDH: lactate dehydrogenase; NA: not assessed; NLR: neutrophil-to-lymphocyte ratio; nab-PTX: nanoparticle albumin-bound paclitaxel; ORR: overall response rate; PTX: paclitaxel; ULN: upper limit of normal. ^aFisher’s exact test; ^bMann-Whitney U test.
N	115	88	27
Backgrounds
Sex (N), men/women	90/25	71/17	19/8	0.29^a
Age (years), median (IQR)	71 (66 - 75.5)	72 (66 - 76)	70 (64.5 - 74)	0.21^b
Smoking status (N), non/former or current smokers	8/107	7/81	1/26	0.68^a
PD-L1 status (N), ≥ 50%/1-49%/< 1%/NA	1/3/5/106	1/0/4/83	0/3/1/23	0.02^a
ECOG-PS (N), 0 - 1/≥ 2	86/29	69/19	17/10	0.13^a
Stage (N), IIIB/IV/recurrence	42/59/14	33/41/14	9/18/0	0.04^a
Metastatic sites (N), ≥ 2	34	28	6	0.47^a
First-line chemotherapy
Regimen (N)
Single/combination	11/104	9/79	2/25	1.00^a
PTX or nab-PTX	76	56	20	0.36^a
Efficacy
ORR (%) (95% CI)	42.6 (33.4 - 52.2)	44.3 (33.7 - 55.3)	37.0 (19.4 - 57.6)	0.66^a
DCR (%) (95% CI)	65.2 (55.8 - 73.9)	64.8 (53.9 - 74.7)	66.7 (46.0 - 83.5)	1.00^a
Second and further line
Second-line (N)	71	60	11	0.01^a
Immuno-checkpoint inhibitor (N)	11	6	5	0.13^a
Laboratory data
NLR
Median (IQR)	3.52 (2.46 - 5.40)	2.97 (2.29 - 4.03)	7.49 (5.39 - 8.65)	< 0.01^b
> 6 (N)	22	3	19	< 0.01^a
LDH
Median (IQR)	197 (168.5 - 230.5)	195.5 (167.5 - 221)	224 (173 - 278.5)	0.07^b
> ULN	31	18	13	< 0.01^a
Albumin (g/dL)
Median (IQR)	3.5 (3.2 - 3.9)	3.7 (3.4 - 3.9)	3.1 (2.75 - 3.3)	< 0.01^b
< 3.5 g/dL (N)	56	30	26	< 0.01^a

Table 3. Baseline Characteristics of Squamous Cell Carcinoma

All

Low

High

CI: confidence interval; DCR: disease control rate; ECOG-PS: Eastern Cooperative Oncology Group performance status; IQR: interquartile range; LDH: lactate dehydrogenase; NA: not assessed; NLR: neutrophil-to-lymphocyte ratio; nab-PTX: nanoparticle albumin-bound paclitaxel; ORR: overall response rate; PTX: paclitaxel; ULN: upper limit of normal. ^aFisher’s exact test; ^bMann-Whitney U test.

115

Backgrounds

Sex (N), men/women

90/25

71/17

19/8

0.29^a

Age (years), median (IQR)

71 (66 - 75.5)

72 (66 - 76)

70 (64.5 - 74)

0.21^b

Smoking status (N), non/former or current smokers

8/107

7/81

1/26

0.68^a

PD-L1 status (N), ≥ 50%/1-49%/< 1%/NA

1/3/5/106

1/0/4/83

0/3/1/23

0.02^a

ECOG-PS (N), 0 - 1/≥ 2

86/29

69/19

17/10

0.13^a

Stage (N), IIIB/IV/recurrence

42/59/14

33/41/14

9/18/0

0.04^a

Metastatic sites (N), ≥ 2

0.47^a

First-line chemotherapy

Regimen (N)

Single/combination

11/104

9/79

2/25

1.00^a

PTX or nab-PTX

0.36^a

Efficacy

ORR (%) (95% CI)

42.6 (33.4 - 52.2)

44.3 (33.7 - 55.3)

37.0 (19.4 - 57.6)

0.66^a

DCR (%) (95% CI)

65.2 (55.8 - 73.9)

64.8 (53.9 - 74.7)

66.7 (46.0 - 83.5)

1.00^a

Second and further line

Second-line (N)

0.01^a

Immuno-checkpoint inhibitor (N)

0.13^a

Laboratory data

NLR

Median (IQR)

3.52 (2.46 - 5.40)

2.97 (2.29 - 4.03)

7.49 (5.39 - 8.65)

< 0.01^b

> 6 (N)

< 0.01^a

LDH

Median (IQR)

197 (168.5 - 230.5)

195.5 (167.5 - 221)

224 (173 - 278.5)

0.07^b

> ULN

< 0.01^a

Albumin (g/dL)

Median (IQR)

3.5 (3.2 - 3.9)

3.7 (3.4 - 3.9)

3.1 (2.75 - 3.3)

< 0.01^b

< 3.5 g/dL (N)

< 0.01^a

**Table 4.** Multivariate Analysis of Overall Survival
Variable	Ad, EGFR mt (-)	P	NSCLC, EGFR mt (+)	P	SQ	P
Ad: adenocarcinoma; CI: confidence interval; ECOG-PS: Eastern Cooperative Oncology Group performance status; EGFR: epidermal growth factor receptor; HR: hazard ratio; LIPI: lung immune prognostic index; nab-PTX: nanoparticle albumin-bound paclitaxel; NSCLC: non-small cell carcinoma; SQ: squamous cell carcinoma; TKI: tyrosine kinase inhibitor.
Age, years
< 70	1 (Reference)		1 (Reference)		1 (Reference)
≥ 70	1.31 (0.93 - 1.84)	0.12	1.62 (0.98 - 2.69)	0.06	0.95 (0.59 - 1.51)	0.81
Smoking history
Non-smoker	1 (Reference)		1 (Reference)		1 (Reference)
Smoker	1.48 (0.92 - 2.37)	0.11	1.19 (0.72 - 1.99)	0.50	2.06 (0.63 - 6.74)	0.23
No. of metastatic sites
< 2	1 (Reference)		1 (Reference)		1 (Reference)
≥ 2	0.83 (0.59 - 1.18)	0.31	2.03 (1.13 - 3.66)	0.02	1.51 (0.94 - 2.42)	0.09
ECOG-PS
0 or 1	1 (Reference)		1 (Reference)		1 (Reference)
≥ 2	3.10 (2.04 - 4.70)	< 0.01	3.24 (1.73 - 6.06)	< 0.01	3.01 (1.80 - 5.04)	< 0.01
Line of EGFR-TKI
First-line			1 (Reference)
Second or later line			1.59 (0.91 - 2.78)	0.10
GRIm-Score
Low	1 (Reference)		1 (Reference)		1 (Reference)
High	2.20 (1.47 - 3.31)	< 0.01	1.95 (0.94 - 4.04)	0.07	0.94 (0.54 - 1.65)	0.84

Table 4. Multivariate Analysis of Overall Survival

Variable

Ad, EGFR mt (-)

NSCLC, EGFR mt (+)

HR (95% CI)

Ad: adenocarcinoma; CI: confidence interval; ECOG-PS: Eastern Cooperative Oncology Group performance status; EGFR: epidermal growth factor receptor; HR: hazard ratio; LIPI: lung immune prognostic index; nab-PTX: nanoparticle albumin-bound paclitaxel; NSCLC: non-small cell carcinoma; SQ: squamous cell carcinoma; TKI: tyrosine kinase inhibitor.

Age, years

< 70

1 (Reference)

≥ 70

1.31 (0.93 - 1.84)

0.12

1.62 (0.98 - 2.69)

0.06

0.95 (0.59 - 1.51)

0.81

Smoking history

Non-smoker

1 (Reference)

Smoker

1.48 (0.92 - 2.37)

0.11

1.19 (0.72 - 1.99)

0.50

2.06 (0.63 - 6.74)

0.23

No. of metastatic sites

< 2

1 (Reference)

≥ 2

0.83 (0.59 - 1.18)

0.31

2.03 (1.13 - 3.66)

0.02

1.51 (0.94 - 2.42)

0.09

ECOG-PS

0 or 1

1 (Reference)

≥ 2

3.10 (2.04 - 4.70)

< 0.01

3.24 (1.73 - 6.06)

< 0.01

3.01 (1.80 - 5.04)

< 0.01

Line of EGFR-TKI

First-line

1 (Reference)

Second or later line

1.59 (0.91 - 2.78)

0.10

GRIm-Score

Low

1 (Reference)

High

2.20 (1.47 - 3.31)

< 0.01

1.95 (0.94 - 4.04)

0.07

0.94 (0.54 - 1.65)

0.84

**Table 5.** Multivariate Analysis of Progression-Free Survival
Variable	Ad, EGFR mt (-)	P	NSCLC, EGFR mt (+)	P	SQ	P
Ad: adenocarcinoma; CI: confidence interval; ECOG-PS: Eastern Cooperative Oncology Group performance status; EGFR: epidermal growth factor receptor; HR: hazard ratio; LIPI: lung immune prognostic index; nab-PTX: nanoparticle albumin-bound paclitaxel; NSCLC: non-small cell carcinoma; SQ: squamous cell carcinoma; TKI: tyrosine kinase inhibitor.
Age, years
< 70	1 (Reference)		1 (Reference)		1 (Reference)
≥ 70	1.06 (0.77 - 1.47)	0.72	1.07 (0.72 - 1.61)	0.73	1.16 (0.74 - 1.83)	0.52
Smoking history
Non-smoker	1 (Reference)		1 (Reference)		1 (Reference)
Smoker	1.02 (0.66 - 1.56)	0.94	1.06 (0.72 - 1.56)	0.78	1.17 (0.52 - 2.62)	0.71
No. of metastatic sites
< 2	1 (Reference)		1.41 (0.90 - 2.19)	0.13	1 (Reference)
≥ 2	1.01 (0.74 - 1.39)	0.95			1.24 (0.78 - 1.98)	0.36
ECOG-PS
0 or 1	1 (Reference)		1 (Reference)		1 (Reference)
≥ 2	1.95 (1.31 - 2.90)	< 0.01	1.63 (0.99 - 2.71)	0.057	1.57 (0.92 - 2.69)	0.10
Bevacizumab-containing
Yes	1 (Reference)
No	1.38 (0.93 - 2.05)	0.12
Line of EGFR-TKI
First-line			1 (Reference)
Second or later line			1.58 (0.99 - 2.52)	0.054
PTX or nab-PTX-containing
Yes					1 (Reference)
No					1.30 (0.83 - 2.04)	0.25
GRIm-Score
Low	1 (Reference)		1 (Reference)		1 (Reference)
High	1.25 (0.85 - 1.82)	0.25	1.89 (1.00 - 3.55)	0.049	1.10 (0.66 - 1.83)	0.71

Table 5. Multivariate Analysis of Progression-Free Survival

Variable

Ad, EGFR mt (-)

NSCLC, EGFR mt (+)

HR (95% CI)

Age, years

< 70

1 (Reference)

≥ 70

1.06 (0.77 - 1.47)

0.72

1.07 (0.72 - 1.61)

0.73

1.16 (0.74 - 1.83)

0.52

Smoking history

Non-smoker

1 (Reference)

Smoker

1.02 (0.66 - 1.56)

0.94

1.06 (0.72 - 1.56)

0.78

1.17 (0.52 - 2.62)

0.71

No. of metastatic sites

< 2

1 (Reference)

1.41 (0.90 - 2.19)

0.13

1 (Reference)

≥ 2

1.01 (0.74 - 1.39)

0.95

1.24 (0.78 - 1.98)

0.36

ECOG-PS

0 or 1

1 (Reference)

≥ 2

1.95 (1.31 - 2.90)

< 0.01

1.63 (0.99 - 2.71)

0.057

1.57 (0.92 - 2.69)

0.10

Bevacizumab-containing

Yes

1 (Reference)

1.38 (0.93 - 2.05)

0.12

Line of EGFR-TKI

First-line

1 (Reference)

Second or later line

1.58 (0.99 - 2.52)

0.054

PTX or nab-PTX-containing

Yes

1 (Reference)

1.30 (0.83 - 2.04)

0.25

GRIm-Score

Low

1 (Reference)

High

1.25 (0.85 - 1.82)

0.25

1.89 (1.00 - 3.55)

0.049

1.10 (0.66 - 1.83)

0.71