Baseline Serum Cholesterol Levels Predict the Response of Patients with Advanced Non-Small Cell Lung Cancer to Immune Checkpoint Inhibitor-Based Treatment

Figures & data

Table 1 Baseline Characteristics of Patients (n=169)

Characteristics	All	Hypocholesterolemia	Hypercholesterolemia	P-value
Age(years)				0.748
<60	69 (40.83%)	30 (42.25%)	39 (39.80%)
≥60	100 (59.17%)	41 (57.75%)	59 (60.20%)
Gender				0.129
Male	136 (80.47%)	61 (85.92%)	75 (76.53%)
Female	33 (19.53%)	10 (14.08%)	23 (23.47%)
BMI (kg/m^2)				0.013*
<25	118(69.82%)	54(76.06%)	65(66.33%)
≥25	51(30.18%)	17(23.94%)	33(33.67%)
Smoking history				0.618
Not heavy (No/light)	68 (40.24%)	27 (38.03%)	41 (41.84%)
Heavy	101 (59.76%)	44 (61.97%)	57 (58.16%)
Stage				0.043*
III(IIIB/IIIC)	33 (19.53%)	19 (26.76%)	14 (14.29%)
IV	136 (80.47%)	52 (73.24%)	84 (85.71%)
Histology				0.129
Squamous carcinoma	48 (28.40%)	26 (36.62%)	22 (22.45%)
Adeno	111 (65.68%)	41 (57.75%)	70 (71.43%)
Other	10 (5.92%)	4 (5.63%)	6 (6.12%)
ECOG score				0.059
0–1	159 (94.08%)	67 (94.37%)	92 (93.88%)
2–3	10 (5.92%)	4 (5.63%)	6 (6.12%)
PD-L1 expression				0.731
Unknown	63(37.28%)	28 (39.44%)	35 (35.71%)
Negative	21(12.43%)	11 (15.49%)	10 (10.20%)
Low (1–49%)	37 (21.89%)	10 (14.08%)	27 (27.55%)
High (≥50%)	48 (28.40%)	22 (30.99%)	26 (26.53%)
Treatment line of Immunotherapy				0.593
First	51(30.18%)	23 (32.39%)	28 (28.57%)
Non-first	118(69.82%)	48 (67.61%)	70 (71.43%)
Treatment regime				0.456
Monotherapy	80(47.34%)	36 (50.70%)	44 (44.90%)
ICIs+ chemotherapy	89(52.66%)	35 (49.30%)	54 (55.10%)
Statin therapy				0.250
No	113(66.86%)	44 (61.97%)	69 (70.41%)
Yes	56(33.14%)	27 (38.03%)	29 (29.59%)
Baseline TG (mmol/L)				0.094
<1.76	127(75.15%)	58 (81.69%)	69 (70.41%)
≥1.76	42(24.85%)	13 (18.31%)	29 (29.59%)
Baseline LDL cholesterol(mmol/L)				0.887
<3.37	130(76.92%)	55 (77.46%)	75 (76.53%)
≥3.37	39(33.14%)	16 (22.54%)	23 (23.47%)
Baseline HDL cholesterol(mmol/L)				0.508
≥1.04	129(76.33%)	56 (78.87%)	73 (74.49%)
<1.04	40(23.67%)	15 (21.13%)	25 (25.51%)
Response
PR	43 (25.44%)	10 (14.08%)	33 (33.67%)	0.004*
SD	54 (31.95%)	20 (28.17%)	34 (34.69%)	0.369
PD	72 (42.61%)	41 (57.75%)	31 (31.63%)	<0.001*
ORR	43 (25.44%)	10 (14.08%)	33 (33.67%)	0.004*
DCR	97(57.40%)	30 (42.25%)	67 (68.37%)	0.001*

Note: *p<0.05.

Abbreviations: BMI, body mass index; ECOG score, Eastern Cooperative Oncology Group score; PD-L1, programmed cell death-1 ligand-1; ICIs, immune checkpoint inhibitors; TG, triglyceridemia; LDL, low-density lipoprotein; HDL, high-density lipoprotein; PR, partial response; SD, stable disease; PD, progression disease.

Table 2 Baseline Characteristics of Patients in Unknown/No/Low PD-L1 Group (n=121)

Characteristics	All	Hypocholesterolemia	Hypercholesterolemia	P-value
Age(years)				0.820
<60	43(35.54%)	18 (36.73%)	25 (34.72%)
≥60	78(64.46%)	31 (63.27%)	47 (65.28%)
Gender				0.061
Male	99(58.58%)	44 (89.80%)	55 (76.39%)
Female	22(41.42%)	5 (10.20%)	17 (23.61%)
BMI (kg/m^2)				0.027*
<25	92(76.03%)	39(79.59%)	53(73.61%)
≥25	29(23.97%)	10(20.41%)	19(26.39%)
Smoking history				0.832
Not heavy (No/light)	48(39.67%)	20 (40.82%)	28 (38.89%)
Heavy	73(60.33%)	29 (59.18%)	44 (61.11%)
Stage				0.373
III(IIIB/IIIC)	18(14.88%)	9 (18.37%)	9 (12.50%)
IV	103(85.12%)	40 (81.63%)	63 (87.50%)
Histology				0.096
Squamous carcinoma	34(28.10%)	19 (38.78%)	15 (20.83%)
Adeno	79(65.29%)	27 (55.10%)	52 (72.22%)
Other	8(6.61%)	3 (6.12%)	5 (6.94%)
ECOG score				0.340
0–1	116(95.87%)	48 (97.96%)	68 (94.44%)
2–3	5(4.13%)	1 (2.04%)	4 (5.56%)
Statin therapy				0.520
No	83(68.60%)	32 (65.31%)	51 (70.83%)
Yes	38(31.40%)	17 (34.69%)	21 (29.17%)
Treatment line of Immunotherapy				0.736
First	35(28.93%)	15 (30.61%)	20 (27.78%)
Non-first	86(71.07%)	34 (69.39%)	52 (72.22%)
Treatment regime				0.358
Monotherapy	34(28.10%)	16 (32.65%)	18 (25.00%)
ICIs+ chemotherapy	87(71.90%)	33 (67.35%)	54 (75.00%)
Baseline TG (mmol/L)				0.041*
<1.76	95(78.51%)	43 (87.76%)	52 (72.22%)
≥1.76	26(21.49%)	6 (12.24%)	20 (27.78%)
Baseline LDL cholesterol(mmol/L)				0.491
<3.37	95(78.51%)	40 (81.63%)	55 (76.39%)
≥3.37	26(21.49%)	9 (18.37%)	17 (23.61%)
Baseline HDL cholesterol(mmol/L)				0.678
≥1.04	94(77.69%)	39 (79.59%)	55 (76.39%)
<1.04	27(22.31%)	10 (20.41%)	17 (23.61%)
Response
PR	25(20.66%)	3 (6.12%)	22 (30.56%)	0.001*
SD	36(29.75%)	13 (26.53%)	23 (31.94%)	0.523
PD	60(49.59%)	33 (67.35%)	27 (37.50%)	0.001*
ORR	25(20.66%)	3 (6.12%)	22 (30.56%)	<0.001*
DCR	61(50.41%)	16 (32.65%)	45 (62.50%)	0.002*

Note: *p<0.05.

Abbreviations: BMI, body mass index; ECOG score, Eastern Cooperative Oncology Group score; PD-L1, programmed cell death-1 ligand-1; ICIs, immune checkpoint inhibitors; TG, triglyceridemia; LDL, low-density lipoprotein; HDL, high-density lipoprotein; PR, partial response; SD, stable disease; PD, progression disease.

Table 3 Baseline Characteristics of Patients in High PD-L1 Group (n=48)

Characteristics	All	Hypocholesterolemia	Hypercholesterolemia	P-value
Age(years)				0.961
<60	26 (54.17%)	12 (54.55%)	14 (53.85%)
≥60	22 (45.83%)	10 (45.45%)	12 (46.15%)
Gender				0.977
Male	37 (77.08%)	17 (77.27%)	20 (76.92%)
Female	11 (22.92%)	5 (22.73%)	6 (23.08%)
BMI (kg/m^2)				0.202
<25	26(54.17%)	14(63.64%)	12(46.15%)
≥25	22(45.83%)	8(36.36%)	14(53.85%)
Smoking history				0.203
Not heavy (No/light)	20 (41.67%)	7 (31.82%)	13 (50.00%)
Heavy	28 (58.33%)	15 (68.18%)	13 (50.00%)
Stage				0.051
III(IIIB/IIIC)	15 (31.25%)	10 (45.45%)	5 (19.23%)
IV	33 (68.75%)	12 (54.55%)	21 (80.77%)
Histology				0.920
Squamous carcinoma	14 (29.17%)	7 (31.82%)	7 (26.92%)
Adeno	32 (66.67%)	14 (63.64%)	18 (69.23%)
Other	2 (4.17%)	1 (4.55%)	1 (3.85%)
ECOG score				0.050*
0–1	43 (89.58%)	19 (86.36%)	24 (92.31%)
2–3	5 (10.42%)	3 (13.64%)	2 (7.69%)
Statin therapy				0.295
No	30 (62.5%)	12 (54.55%)	18 (69.23%)
Yes	18 (37.5%)	10 (45.45%)	8 (30.77%)
Treatment line of Immunotherapy				0.682
First	16 (33.33%)	8 (36.36%)	8 (30.77%)
Non-first	32 (66.67%)	14 (63.64%)	18 (69.23%)
Treatment regime				0.116
Monotherapy	46 (95.83%)	20 (90.91%)	26 (100.00%)
ICIs+ chemotherapy	2 (4.17%)	2 (9.09%)	0 (0.00%)
Baseline TG (mmol/L)				0.838
<1.76	32 (66.67%)	15 (68.18%)	17 (65.38%)
≥1.76	16 (33.33%)	7 (31.82%)	9 (34.62%)
Baseline LDL cholesterol(mmol/L)				0.497
<3.37	35 (72.92%)	15 (68.18%)	20 (76.92%)
≥3.37	13 (27.08%)	7 (31.82%)	6 (23.08%)
Baseline HDL cholesterol(mmol/L)				0.532
≥1.04	35 (72.92%)	17 (77.27%)	18 (69.23%)
<1.04	13 (27.08%)	5 (22.73%)	8 (30.77%)
Response
PR	18 (37.50%)	7 (31.82%)	11 (42.31%)	0.454
SD	18 (37.50%)	7 (31.82%)	11 (42.31%)	0.454
PD	12 (25.00%)	8 (36.36%)	4 (15.38%)	0.094
ORR	18 (37.50%)	7 (31.82%)	11 (42.31%)	0.454
DCR	36(75.00%)	14(63.64%)	22 (84.62%)	0.094

Note: *p<0.05.

Abbreviations: BMI, body mass index; ECOG score, Eastern Cooperative Oncology Group score; PD-L1, programmed cell death-1 ligand-1; ICIs, immune checkpoint inhibitors; TG, triglyceridemia; LDL, low-density lipoprotein; HDL, high-density lipoprotein; PR, partial response; SD, stable disease; PD, progression disease.

Figure 1 Response comparison of patients with hypercholesterolemia or hypocholesterolemia based on the ICI-based treatment.

Notes: ORR comparison of patients with different level of serum cholesterol. (A) total population included to study (n=169); (B) patients with unknown/no/low PD-L1 expression (n=121); (C) patients with high PD-L1 expression (n=48).

Figure 2 Survival analysis of patients with hypercholesterolemia or hypocholesterolemia based on the ICI-based treatment.

Notes: PFS and OS comparison of patients with different level of serum cholesterol; (A) PFS in total population (n=169, mPFS:4.4m VS 7.9m, P<0.001); (B) OS in total population (n=169, mOS:8.0m VS 11.0m, P<0.001); (C) PFS in population of unknown/no/low PD-L1 expression (n=121, mPFS:3.7m VS 7.5m, P<0.001); (D) OS in population of unknown/no/low PD-L1 expression (n=121, mPFS:7.2m VS 10.0m, P<0.001); (E) PFS in population of high PD-L1 expression (n=48, mPFS:4.9m VS 8.9m, P<0.001); (F) OS in population of PD-L1 expression (n=48, mPFS:9.9m VS 13.9m, P<0.001). PFS, progression-free survival; OS overall survival.

Table 4 Univariate and Multivariate Analyses of Clinical Parameters of PFS in Overall Patients

Factors	Univariate Analysis			Multivariate Analysis
	HR	95% CI	P-value	HR	95% CI	P-value
Age(years)
<60/≥60	6.226	2.978–13.016	0.000*	1.068	1.036–1.102	0.000*
Gender
Male/Female	0.845	0.454–1.574	0.595
BMI (kg/m2)
<25/≥25	0.704	4.620–7.380	0.000*	0.902	0.803–1.014	0.084
Smoking history
Not heavy (No/light)/Heavy	1.147	0.703–1.871	0.584
Stage
III (IIIB, IIIC)/IV	2.998	1.207–7.447	0.018*	2.360	0.793–7.029	0.123
Histology
Squamous carcinoma/Adeno	0.824	0.483–1.408	0.479
Squamous carcinoma/Other	0.779	0.264–2.296	0.650
ECOG score
0–1/2–3	0.781	0.283–2.150	0.632
PD-L1 expression
Not high (unknown/no/low)/high	0.394	0.214–0.726	0.003*	0.763	0.613–0.951	0.016*
Statin therapy
No/Yes	0.370	0.199–0.691	0.002*	0.448	0.234–0.859	0.016*
Treatment line of Immunotherapy
First/Non-first	1.021	0.602–1.732	0.938	0.838	0.468–1.500	0.551
Treatment regime
Monotherapy/ICIs+ chemotherapy	1.011	0.631–1.620	0.964
Baseline TC (mmol/L)
<5.18/≥5.18	0.268	0.161–0.447	0.000*	0.231	0.135–0.395	0.000*
Baseline TG (mmol/L)
<1.76/≥1.76	0.630	0.349–1.137	0.125	0.890	0.404–1.961	0.773
Baseline LDL cholesterol(mmol/L)
<3.37/≥3.37	0.786	0.443–1.397	0.412
Baseline HDL cholesterol(mmol/L)
≥1.04/<1.04	0.568	0.304–1.059	0.075	2.146	0.812–5.673	0.124

Note: *p<0.05.

Abbreviations: BMI, body mass index; ECOG score, Eastern Cooperative Oncology Group score; PD-L1, programmed cell death-1 ligand-1; ICIs, immune checkpoint inhibitors; TC, total cholesterolemia; TG, triglyceridemia; LDL, low-density lipoprotein; HDL, high-density lipoprotein; PR, partial response; SD, stable disease; PD, progression disease.

Table 5 Univariate and Multivariate Analyses of Clinical Parameters of OS in Overall Patients

Factors	Univariate Analysis			Multivariate Analysis
	HR	95% CI	P-value	HR	95% CI	P-value
Age(years)
<60/≥60	1.055	0.655–1.698	0.827
Gender
Male/Female	1.313	0.872–1.977	0.193	1.191	0.699–2.030	0.520
BMI (kg/m2)
<25/≥25	0.368	8.980–10.420	0.019*	0.990	0.904–1.085	0.837
Smoking history
Not heavy (No/light)/Heavy	0.876	0.540–1.420	0.591
Stage
III(IIIB/IIIC)/IV	1.660	1.166–2.3627	0.005*	1.300	0.724–2.336	0.380
Histology
Squamous carcinoma/Adeno	0.650	0.422–1.002	0.050*	1.606	0.605–4.264	0.342
Squamous carcinoma/Other	0.646	0.250–1.666	0.366
ECOG score
0–1/2–3	1.526	0.736–3.164	0.256
PD-L1 expression
Not high (unknown/no/low)/high	0.450	0.285–0.711	0.000*	0.786	0.650–0.950	0.013*
Statin therapy
No/Yes	1.0123	0.661–1.550	0.955
Treatment line of Immunotherapy
First/Non-first	1.040	0.663–1.630	0.865
Treatment regime
Monotherapy/ICIs+ chemotherapy	1.478	0.985–2.217	0.050*	1.535	0.963–2.446	0.072
Baseline TC (mmol/L)
<5.18/≥5.18	0.295	0.190–0.458	0.000*	0.235	0.147–0.377	0.000*
Baseline TG (mmol/L)
<1.76/≥1.76	0.599	0.369–0.972	0.038*	0.909	0.494–1.674	0.760
Baseline LDL cholesterol(mmol/L)
<3.37/≥3.37	0.629	0.377–1.050	0.076	0.882	0.540–1.442	0.616
Baseline HDL cholesterol(mmol/L)
≥1.04/<1.04	0.764	0.471–1.240	0.275

Note: *p<0.05.

Abbreviations: BMI, body mass index; ECOG score, Eastern Cooperative Oncology Group score; PD-L1, programmed cell death-1 ligand-1; ICIs, immune checkpoint inhibitors; TC, total cholesterolemia; TG, triglyceridemia; LDL, low-density lipoprotein; HDL, high-density lipoprotein; PR, partial response; SD, stable disease; PD, progression disease.

Table 6 Univariate and Multivariate Analyses of Clinical Parameters of Objective Response in Overall Patients

Factors	Univariate Analysis			Multivariate Analysis
	HR	95% CI	P-value	HR	95% CI	P-value
Age(years)
<60/≥60	1.121	0.054–0.271	0.000*	0.169	0.057–0.501	0.001*
Gender
Male/Female	0.615	0.270–1.404	0.249
BMI (kg/m2)
<25/≥25	9.792	4.460–21.498	0.000*	8.766	2.954–21.015	0.000*
Smoking history
Not heavy (No/light)/Heavy	0.549	0.273–1.105	0.093	0.665	0.230–1.924	0.452
Stage
III(IIIB/IIIC)/IV	0.158	0.070–2.3627	0.000*	0.130	0.034–0.497	0.003*
Histology
Squamous carcinoma/Adeno	1.647	0.310–8.748	0.558
Squamous carcinoma/Other	1.286	0.257–6.426	0.760
ECOG score
0–1/2–3	0.310	0.038–2.517	0.273
PD-L1 expression
Not high (unknown/no/low)/high	2.304	1.109–4.788	0.025*	0.989	0.322–3.035	0.984
Statin therapy
No/Yes	4.894	2.344–10.217	0.000*	3.834	1.209–16.162	0.023*
Treatment line of Immunotherapy
First/Non-first	0.565	0.273–1.169	0.124	0.839	0.267–2.643	0.765
Treatment regime
Monotherapy/ICIs+ chemotherapy	0.923	0.461–1.844	0.820
Baseline TC (mmol/L)
<5.18/≥5.18	3.097	1.407–6.817	0.005*	11.503	2.898–45.663	0.001*
Baseline TG (mmol/L)
<1.76/≥1.76	2.279	1.072–4.844	0.032*	1.944	0.551–6.862	0.301
Baseline LDL cholesterol(mmol/L)
<3.37/≥3.37	1.014	0.446–2.302	0.974
Baseline HDL cholesterol(mmol/L)
≥1.04/<1.04	2.928	1.369–2.263	0.006*	3.949	1.187–13.134	0.025*

Note: *p<0.05.

Abbreviations: BMI, body mass index; ECOG score, Eastern Cooperative Oncology Group score; PD-L1, programmed cell death-1 ligand-1; ICIs, immune checkpoint inhibitors; TC, total cholesterolemia; TG, triglyceridemia; LDL, low-density lipoprotein; HDL, high-density lipoprotein; PR, partial response; SD, stable disease; PD, progression disease.

Figure 3 Predictive value of serum cholesterol and PD-L1 expression in advanced NSCLC patients based on the ICI-based treatment.

Notes: ROC curves of the total population for serum cholesterol and PD-L1 expression. The AUC for serum cholesterol was 0.706 (p<0.001) distinguishing patients with disease control from the total population (n=169); The AUC for PD-L1 expression was 0.643 (p=0.001) distinguishing patients with disease control from the total population (n=169).