Effect of PD-1 inhibitor on exhaled nitric oxide and pulmonary function in non-small cell lung cancer patients with and without COPD

Figures & data

Table 1 Clinical characteristics of 95 patients with NSCLC

	ALL cases (n=95)	COPD (n=41)	non-COPD (n=54)
Age, yr	69 (65–74*)	69 (67–73*)	69 (63–75*)
Sex
Male	74 (77.9%)	38 (92.7%)	36 (66.7%)
Female	21 (22.1%)	3 (7.3%)	18 (33.3%)
Observation	56 (51–58*)	56 (51–58*)	56 (51–58*)
Smoking status
Never smoker	17 (17.9%)	0 (%)	17 (31.5%)
Former smoker	69 (72.6%)	36 (87.8%)	33 (61.1%)
Current smoker	9 (9.5%)	5 (12.2%)	4 (7.4%)
Comorbidity
COPD	41 (43.2%)	-	-
Hypertension	23 (24.2%)	8 (19.5%)	15 (27.8%)
Cardiovascular disease	9 (9.5%)	4 (9.8)	5 (9.3%)
Cerebrovascular disease	7 (7.4%)	3 (7.3%)	4 (7.4%)
Digestive ulcer	6 (6.3%)	2 (4.9%)	4 (7.4%)
Bronchial asthma	3 (3.2)	2 (4.9%)	1 (1.9%)
GOLD stage, I/II/III/IV	11 (26.8%)/ 21 (51.2%)/ 7 (17.1%)/ 2 (4.9%)
Performance status at enrollment
0	63 (66.3%)	26 (63.4%)	37 (68.5%)
1	31 (32.6%)	15 (36.6%)	16 (29.6%)
2	1 (1.1%)	0 (0%)	1 (1.9%)
Stage
IIIA	6 (6.3%)	4 (9.8%)	2 (3.7%)
IIIB	15 (15.8%)	9 (22.0%)	6 (11.1%)
IV	69 (72.6%)	25 (61.0%)	44 (81.5%)
Recurrent	5 (5.3%)	3 (7.3%)	2 (3.7%)
Histology
Adenocarcinoma	57 (60.0%)	24 (58.5%)	33 (61.1%)
Squarmaous cell carcinoma	36 (37.9%)	17 (41.5%)	19 (35.2%)
Other	2 (2.1%)	0 (0%)	2 (3.7%)
PD-L1 expression
≥50%	8 (8.4%)	3 (7.3%)	5 (9.3%)
≥5% and <50%	15 (15.8%)	6 (14.6%)	9 (16.7%)
≥1% and <5%	9 (9.5%)	4 (9.8%)	5 (9.3%)
<1%	37 (38.9%)	14 (34.1%)	23 (42.6%)
Not examined	26 (27.4%)	14 (34.1%)	12 (22.2%)
EGFR mutation status
Wild type	73 (76.8%)	29 (70.7%)	44 (81.5%)
Positive mutation	6 (6.3%)	2 (4.9%)	4 (7.4%)
Not examined	16 (16.8%)	10 (24.4%)	6 (11.1%)
ALK fusion gene
Negative	73 (76.8%)	29 (70.7%)	44 (81.5%)
Positive	0 (0%)	0 (0%)	0 (0%)
Not examined	22 (23.2%)	12 (29.3%)	10 (18.5%)
Number of prior systematic regimens
1	43 (45.3%)	20 (48.8%)	23 (42.6%)
2	25 (26.3%)	12 (29.3%)	13 (24.1%)
3	10 (10.5%)	2 (4.9%)	8 (14.8%)
≥4	17 (17.9%)	7 (17.1%)	10 (18.5%)
Efficacy of 4Cy treatment of nivolumab
PR	29 (30.5%)	16 (39.0%)	13 (24.1%)
SD	30 (31.6%)	14 (34.1%)	16 (29.6%)
PD	36 (37.9%)	11 (26.8%)	25 (46.3%)

Note: *Median and interquartile range.

Abbreviations: COPD, chronic obstructive pulmonary disease; PD-L1, programmed death ligand 1; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; PR, partial response; SD, stable disease; PD, progressive disease.

Table 2 Peripheral blood analyses before and after 4 cycles of nivolumab therapy in NSCLC patients with or without combined COPD

	All cases (n=95)			COPD cases (n=41)			non-COPD cases (n=54)
	Baseline	After	p-value	Baseline	After	p-value	Baseline	After	p-value
WBC (/mm^3)	6368 (3745)	6248 (2146)	0.7207	5882 (1722)	5990 (1680)	0.5528	6781 (4757)	6448 (2445)	0.9283
Neut (/mm^3)	4446 (3324)	4236 (1941)	0.1199	3947 (1370)	4003 (1495)	0.6168	4861 (4255)	4416 (2223)	0.7188
Neut (%)	68.0 (9.7)	66.1 (11.8)	0.9342	66.6 (10.5)	65.5 (10.9)	0.4018	69.1 (9.1)	66.5 (12.5)	0.1749
Ly (/mm^3)	1208 (555)	1296 (659)	0.1634	1237 (520)	1277 (593)	0.6628	1190 (589)	1311 (711)	0.2709
Ly (%)	20.3 (8.1)	22.1 (10.5)	0.2376	21.7 (8.5)	22.6 (10.1)	0.4701	19.1 (7.6)	21.8 (10.8)	0.1901
Eo (/mm^3)	171 (214)	229 (164)	0.0010	208 (289)	233 (161)	0.1116	142 (129)	226 (168)	0.0010
Eo (%)	2.8 (2.4)	3.8 (2.5)	0.0005	3.2 (2.9)	3.9 (2.6)	0.1307	2.4 (1.9)	3.6 (2.5)	0.0018
Ba (/mm^3)	39 (46)	38^26	0.1590	35 (28)	34 (24)	0.9813	43 (56)	41 (27)	0.1836
Ba (%)	0.61 (0.52)	0.63 (0.38)	0.2826	0.60 (0.43)	0.58 (0.37)	0.6708	0.62 (0.59)	0.68 (0.39)	0.0429
Mo (/mm^3)	463 (247)	466 (254)	0.7007	434 (200)	444 (183)	0.5550	488 (278)	483 (298)	0.4805
Mo (%)	7.6 (3.4)	7.8 (4.4)	0.8240	7.6 (3.2)	7.5 (2.3)	0.9258	7.7 (3.6)	8.1 (5.6)	0.7431
IgE (IU/L) (n75)	179.8 (253.0)	187.9 (236.8)	0.1889	185.6 (205.6)	217.4 (224.5)	0.1335	174.1 (294.7)	159.1 (247.9)	0.7007
CRP (mg/dl)	1.67 (3.04)	1.30 (1.59)	0.1424	1.32 (2.08)	1.07 (1.95)	0.2182	1.95 (3.63)	1.48 (3.00	0.3856
ESR (mm) (n75)	48.4 (29.2)	42.2 (25.9)	0.0365	45.6 (30.4)	38.3 (23.1)	0.1918	50.9 (28.3)	45.6 (27.9)	0.1182
ESR (mm) (n58)	70.8 (29.2)	65.1 (27.2)	0.2159	68.3 (30.9)	62.4 (23.6)	0.2343	73.1 (28.1)	67.4 (30.2)	0.5396

Table 3 Pulmonary function tests before and after 4 cycles of nivolumab therapy in NSCLC patients with or without combined COPD

	All cases (n=90)			COPD cases (n=40)			non-COPD cases (n=50)
	Baseline	After	p-value	Baseline	After	p-value	Baseline	After	p-value
FVC (L)	2.79 (0.73)	2.80 (0.74)	0.4446	2.89 (0.84)	2.98 (0.80)	0.0451	2.70 (0.63)	2.66 (0.66)	0.4665
FVC (% pred)	87.2 (21.5)	87.6 (21.1)	0.4639	86.8 (22.7)	89.1 (20.9)	0.0635	87.6 (20.7)	86.4 (21.4)	0.4696
FEV1.0 (L)	1.95 (0.54)	1.96 (0.54)	0.4942	1.77 (0.58)	1.84 (0.59)	0.0350	2.09 (0.46)	2.05 (0.48)	0.2753
FEV1.0 (% pred)	87.5 (21.9)	87.9 (21.6)	0.4665	69.4 (21.1)	71.2 (19.9)	0.0993	87.3 (22.0)	86.0 (24.3)	0.3097
FEV1.0/FVC %	70.2 (11.5)	70.8 (12.2)	0.6057	60.6 (8.6)	62.2 (11.0)	0.2004	77.9 (6.9)	77.7 (8.1)	0.6028
SpO2 (%)	96.9 (1.7)	96.6 (1.7)	0.2433	96.3 (2.2)	96.4 (1.7)	0.6215	97.2 (1.2)	96.7 (1.6)	0.0861
mMRC	0.9 (1.0)	0.9 (1.0)	0.8602	1.2 (1.1)	0.9 (1.0)	0.0918	0.7 (0.9)	0.8 (1.1)	0.1934
CAT	8.3 (6.6)	8.2 (7.1)	0.7304	9.8 (7.4)	8.7 (7.0)	0.3005	7.2 (5.5)	7.8 (7.2)	0.5747
	All cases (n=57)			COPD cases (n=26)			non-COPD cases (n=31)
FRC (L)	3.01 (0.81)	2.99 (0.81)	0.7317	3.27 (0.85)	3.30 (0.94)	0.9631	2.78 (0.70)	2.73 (0.59)	0.5595
FRC (% pred)	94.4 (25.5)	93.3 (25.7)	0.6040	91.0 (24.6)	90.5 (24.8)	0.7501	97.2 (26.4)	95.7 (26.5)	0.6461
RV (L)	1.96 (0.55)	1.91 (0.62)	0.2403	2.12 (0.54)	2.14 (0.73)	0.8940	1.83 (0.53)	1.72 (0.41)	0.1559
RV (% pred)	116.6 (29.6)	113.2 (34.4)	0.1219	124.8 (29.1)	125.4 (41.4)	0.6348	109.7 (28.6)	102.9 (23.4)	0.1156
TLC (L)	4.87 (1.15)	4.83 (1.13)	0.7192	5.20 (1.29)	5.28 (1.29)	0.4265	4.60 (0.98)	4.45 (0.81)	0.2184
TLC (% pred)	97.6 (20.2)	96.5 (20.1)	0.4425	98.4 (22.4)	99.3 (22.4)	0.8564	96.9 (18.4)	94.1 (18.0)	0.1962
RV/TLC (%)	40.3 (6.8)	39.7 (8.2)	0.3541	41.1 (6.2)	40.5 (8.2)	0.4578	39.6 (7.3)	39.1 (8.4)	0.5422
%DLCO	76.8 (27.5)	77.5 (23.6)	0.5046	69.8 (26.7)	72.4 (24.7)	0.2221	82.7 (27.2)	81.8 (22.0)	0.7942

Abbreviations: FVC, forced vital capacity; FEV₁, forced expiratory volume in 1.0 second; FRC, functional residual capacity; RV, residual volume; TLC, total lung capacity; DLCO, diffusing capacity of the lung for carbon monoxide; VA, alveolar volume; mMRC, modified Medical Research Council; CAT, COPD assessment test.

Table 4 Adverse events during the nivolumab therapy

	All cases (n=95)	COPD (n=41)	non-COPD (n=54)
Haematologic toxicity
Leucopenia	2 (0)*	1 (0)	1 (0)
Neutropenia	2 (0)	-	2 (0)
Anemia	10 (0)	3 (0)	7 (0)
Thrombocytopenia	2 (0)	–	2 (0)
Non-haematologic toxicity
ALT/AST increased	4 (2)	1 (1)	3 (1)
Bilirubin increased	1 (0)	-	1 (0)
Creatinie increased	4 (0)	1 (0)	3 (0)
Nausea/Appetite loss	5 (1)	–	5 (1)
Constipation	2 (0)	–	2 (0)
Diarrhea	7 (4)	3 (2)	4 (2)
Fatigue	8 (0)	3 (0)	5 (0)
Dysgeusia	1 (0)	1 (0)	-
Rash acneiform	4 (1)	2 (0)	2 (1)
Dry skin	3 (0)	1 (0)	2 (0)
Pneumonitis	6 (0)	3 (0)	3 (0)
Lung infection	4 (3)	2 (2)	2 (1)
Haemoptysis	1 (0)	–	1 (0)
Thromboembolic events	1 (0)	–	1 (0)
Hyperglycemia	1 (1)	–	1 (1)
Immune-rerated Adverse Events
Myositis	1 (1)	–	1 (1)
Type I Diabets Mellitus, Hyperglycemia	1 (1)	–	1 (1)
Hyperthyroidism	1 (1)	1 (1)	–
Hypothyroidism	3 (1)	3 (1)	–
Adrenal insufficiency	1 (0)	1 (0)	–

Note: *Any (Grade ≥ III).

Figure 1 Study profile.

Figure 2 FeNO levels before and after four cycles of nivolumab treatment. (A) FeNO levels before (filled circle) and after (unfilled circle) 4 cycles of nivolumab treatment. (B) Differences in FeNO levels before and after 4 cycles of nivolumab.

Figure 3 FeNO levels before and after four cycles of nivolumab treatment in patients with or without comorbid COPD. (A) FeNO levels before (filled circle) and after (unfilled circle) 4 cycles of nivolumab treatment in COPD and non-COPD patients. (B) Differences in FeNO levels before and after 4 cycles of nivolumab in COPD and non-COPD patients.