Comparative Efficacy and Safety of Neoadjuvant Immunotherapy with Chemotherapy versus Chemotherapy Alone in Non-Small Cell Lung Cancer: A Propensity Score and Inverse Probability Treatment Weighting Analysis

Figures & data

Figure 1 Flow chart of study design.

Abbreviations: NSCLC, non-small cell lung cancer; NCT, neoadjuvant chemotherapy; NICT, neoadjuvant immunotherapy combined with chemotherapy; PSM, propensity score matching.

Table 1 Baseline Characteristics Before and After PSM and IPTW

Variable	Before PSM				After PSM				IPTW
	NCT (n = 130)	NICT (n = 176)	P value	SMD	NCT (n = 116)	NICT (n = 116)	P value	SMD	NCT (n = 302)	NICT (n = 309)	P value	SMD
Age (%)			0.795	0.044			1.000	<0.001			0.976	0.004
<60	46 (35.4)	66 (37.5)			42 (36.2)	42 (36.2)			110 (36.4)	112 (36.2)
≥60	84 (64.6)	110 (62.5)			74 (63.8)	74 (63.8)			192 (63.6)	197 (63.8)
Sex (%)			0.355	0.125			1.000	0.023			0.898	0.016
Male	108 (83.1)	154 (87.5)			96 (82.8)	95 (81.9)			253 (83.8)	257 (83.2)
Female	22 (16.9)	22 (12.5)			20 (17.2)	21 (18.1)			49 (16.2)	52 (16.8)
Smoking (%)			0.225	0.154			0.687	0.071			0.810	0.029
No	54 (41.5)	60 (34.1)			44 (37.9)	48 (41.4)			112 (37.1)	119 (38.5)
Yes	76 (58.5)	116 (65.9)			72 (62.1)	68 (58.6)			190 (62.9)	190 (61.5)
Alcohol (%)			0.630	0.071			0.453	0.118			0.907	0.014
No	95 (73.1)	123 (69.9)			83 (71.6)	89 (76.7)			217 (71.9)	224 (72.5)
Yes	35 (26.9)	53 (30.1)			33 (28.4)	27 (23.3)			85 (28.1)	85 (27.5)
Comorbidity (%)			0.284	0.138			0.894	0.035			0.879	0.019
No	74 (56.9)	112 (63.6)			66 (56.9)	68 (58.6)			181 (59.9)	188 (60.8)
Yes	56 (43.1)	64 (36.4)			50 (43.1)	48 (41.4)			121 (40.1)	121 (39.2)
KPS (%)			0.154	0.179			0.679	0.073			0.872	0.019
=80	47 (36.2)	49 (27.8)			38 (32.8)	42 (36.2)			95 (31.5)	100 (32.4)
>80	83 (63.8)	127 (72.2)			78 (67.2)	74 (63.8)			207 (68.5)	209 (67.6)
Family history (%)			0.010	0.314			0.394	0.135			0.893	0.017
No	101 (77.7)	157 (89.2)			92 (79.3)	98 (84.5)			254 (84.1)	258 (83.5)
Yes	29 (22.3)	19 (10.8)			24 (20.7)	18 (15.5)			48 (15.9)	51 (16.5)
FEV 1% (%)			0.306	0.143			0.286	0.176			0.737	0.041
≤70	10 (7.7)	21 (11.9)			10 (8.6)	5 (4.3)			30 (9.9)	27 (8.7)
>70	120 (92.3)	155 (88.1)			106 (91.4)	111 (95.7)			272 (90.1)	282 (91.3)
Tracheoscopy (%)			0.660	0.064			1.000	0.017			0.816	0.029
No	64 (49.2)	81 (46.0)			56 (48.3)	57 (49.1)			147 (48.7)	146 (47.2)
Yes	66 (50.8)	95 (54.0)			60 (51.7)	59 (50.9)			155 (51.3)	163 (52.8)
PET-CT (%)			0.179	0.171			0.776	0.056			0.720	0.044
No	91 (70.0)	109 (61.9)			79 (68.1)	82 (70.7)			198 (65.6)	209 (67.6)
Yes	39 (30.0)	67 (38.1)			37 (31.9)	34 (29.3)			104 (34.4)	100 (32.4)
T (%)			0.376	0.205			0.493	0.205			0.515	0.186
1	13 (10.0)	12 (6.8)			12 (10.3)	9 (7.8)			28 (9.3)	22 (7.1)
2	77 (59.2)	95 (54.0)			69 (59.5)	62 (53.4)			180 (59.6)	164 (53.1)
3	22 (16.9)	34 (19.3)			21 (18.1)	24 (20.7)			48 (15.9)	63 (20.4)
4	18 (13.8)	35 (19.9)			14 (12.1)	21 (18.1)			46 (15.2)	60 (19.4)
N (%)			0.129	0.196			0.132	0.221			0.060	0.235
N0	19 (14.6)	39 (22.2)			17 (14.7)	27 (23.3)			42 (13.9)	71 (23.0)
N+	111 (85.4)	137 (77.8)			99 (85.3)	89 (76.7)			260 (86.1)	238 (77.0)
TNM (%)			0.152	0.223			0.828	0.081			0.978	0.025
I	5 (3.8)	3 (1.7)			4 (3.4)	3 (2.6)			8 (2.6)	7 (2.3)
II	39 (30.0)	40 (22.7)			35 (30.2)	32 (27.6)			81 (26.8)	84 (27.2)
III	86 (66.2)	133 (75.6)			77 (66.4)	81 (69.8)			213 (70.5)	218 (70.6)
Pathology (%)			< 0.001	0.689			< 0.001	0.58			< 0.001	0.664
Squamous carcinoma	55 (42.3)	131 (74.4)			50 (43.1)	82 (70.7)			129 (42.7)	228 (73.8)
Adenocarcinoma	75 (57.7)	45 (25.6)			66 (56.9)	34 (29.3)			173 (57.3)	81 (26.2)
Neoadjuvant cycle (%)			1.000	0.002			1	< 0.001			0.801	0.028
<2	3 (2.3)	4 (2.3)			2 (1.7)	2 (1.7)			6 (2.0)	5 (1.6)
≥2	127 (97.7)	172 (97.7)			114 (98.3)	114 (98.3)			296 (98.0)	304 (98.4)
Chemotherapy regimen (%)			< 0.001	0.689			< 0.001	0.580			< 0.001	0.664
Paclitaxel plus platinum	55 (42.3)	131 (74.4)			50 (43.1)	82 (70.7)			129 (42.7)	228 (73.8)
Pemetrexed plus platinum	75 (57.7)	45 (25.6)			66 (56.9)	34 (29.3)			173 (57.3)	81 (26.2)
Adjuvant therapy (%)			0.095	0.213			0.020	0.331			0.062	0.234
No	22 (16.9)	45 (25.6)			19 (16.4)	35 (30.2)			52 (17.2)	83 (26.9)
Yes	108±83.1	131 (74.4)			97 (83.6)	81 (69.8)			250 (82.8)	226 (73.1)

Abbreviations: PSM, propensity score matching; IPTW, inverse probability of treatment weighting; NCT, neoadjuvant chemotherapy; NICT, neoadjuvant immunotherapy combined with chemotherapy; SMD, standardized mean difference; Comorbidity, including hypertension, diabetes mellitus, chronic obstructive pulmonary disease, coronary atherosclerotic heart disease; KPS, Karnofsky Performance Status; FEV 1%, forced expiratory volume in one second/forced vital capacity;

Figure 2 Histogram for propensity scores.

Abbreviations: NCT, neoadjuvant chemotherapy; NICT, neoadjuvant immunotherapy combined with chemotherapy.

Table 2 Comparative Analysis of Pathological Outcomes Between NCT and NICT Before and After PSM and IPTW

Variable	Before PSM			After PSM			IPTW
	NCT (n = 130)	NICT (n = 176)	P value	NCT (n = 116)	NICT (n = 116)	P value	NCT (n = 302)	NICT (n = 309)	P value
R0 resection (%)			1.000			1.000			0.904
No	4 (3.1)	5 (2.8)		4 (3.4)	3 (2.6)		9 (3.0)	10 (3.2)
Yes	126 (96.9)	171 (97.2)		112 (96.6)	113 (97.4)		293 (97.0)	299 (96.8)
pCR (%)			< 0.001			< 0.001			< 0.001
pCR	4 (3.1)	78 (44.3)		3 (2.6)	52 (44.8)		7 (2.3)	135 (43.7)
Non-pCR	126 (96.9)	98 (55.7)		113 (97.4)	64 (55.2)		295 (97.7)	174 (56.3)
MPR (%)			< 0.001			< 0.001			< 0.001
MPR	29 (22.3)	116 (65.9)		24 (20.7)	77 (66.4)		68 (22.5)	209 (67.6)
Non-MPR	101 (77.7)	60 (34.1)		92 (79.3)	39 (33.6)		234 (77.5)	100 (32.4)
Primary lesion Complete pathological remission (%)			< 0.001			< 0.001			< 0.001
No	126 (96.9)	98 (55.7)		113 (97.4)	64 (55.2)		295 (97.7)	175 (56.6)
Yes	4 (3.1)	78 (44.3)		3 (2.6)	52 (44.8)		7 (2.3)	134 (43.4)
Lymph nodes Complete pathological remission (%)			< 0.001			< 0.001			< 0.001
No	66 (50.8)	46 (26.1)		60 (51.7)	28 (24.1)		160 (53.0)	77 (24.9)
Yes	64 (49.2)	130 (73.9)		56 (48.3)	88 (75.9)		142 (47.0)	232 (75.1)
Neural invasion (%)			0.415			0.245			0.048
No	127 (97.7)	175 (99.4)		113 (97.4)	116 (100.0)		295 (97.7)	308 (99.7)
Yes	3 (2.3)	1 (0.6)		3 (2.6)	0 (0.0)		7 (2.3)	1 (0.3)
LVSI (%)			0.238			0.593			0.146
No	118 (90.8)	167 (94.9)		107 (92.2)	110 (94.8)		274 (90.7)	294 (95.1)
Yes	12 (9.2)	9 (5.1)		9 (7.8)	6 (5.2)		28 (9.3)	15 (4.9)

Abbreviations: PSM, propensity score matching; IPTW, inverse probability of treatment weighting; NCT, neoadjuvant chemotherapy; NICT, neoadjuvant immunotherapy combined with chemotherapy; pCR, pathological complete remission; MPR, major pathological remission; LVSI, lymphovascular invasion.

Table 3 Comparative Analysis of Surgical Information Between NCT and NICT Before and After PSM and IPTW

Variable	Before PSM			After PSM			IPTW
	NCT (n = 130)	NICT (n = 176)	P value	NCT (n = 116)	NICT (n = 116)	P value	NCT (n = 302)	NICT (n = 309)	P value
Surgical approach (%)			0.367			0.511			0.352
Thoracotomy	64 (49.2)	97 (55.1)		56 (48.3)	62 (53.4)		148 (49.0)	169 (54.7)
VATS	66 (50.8)	79 (44.9)		60 (51.7)	54 (46.6)		154 (51.0)	140 (45.3)
Surgical excision method (%)			0.503			0.578			0.941
Lung lobectomy	111 (85.4)	156 (88.6)		97 (83.6)	101 (87.1)		261 (86.4)	268 (86.7)
Non-lobectomy	19 (14.6)	20 (11.4)		19 (16.4)	15 (12.9)		41 (13.6)	41 (13.3)
Length of stay in hospital (day)	18.2±5.6	16.3±5.9	0.015	18.5±5.8	16.5±6.4	0.048	18.1±5.7	16.4±6.1	0.044
Intraoperative bleeding (mL)	112.8±76.5	128.6±134.1	0.229	111.8±79.7	140.7±161.8	0.086	112.2±71.4	129.3±141.3	0.185
Length of surgery (min)	138.0±38.6	123.1±36.3	0.001	137.8±39.1	122.4±37.6	0.003	139.1±39.7	122.8±36.8	0.001
Surgical interval (day)	35.5±9.4	37.3±11.5	0.149	35.9±9.3	37.2±12.0	0.373	35.3±9.17	37.4±11.2	0.079
30d death (%)			0.879			1.000			0.308
No	129 (99.2)	176 (100.0)		115 (99.1)	116 (100.0)		298 (98.7)	309 (100.0)
Yes	1 (0.8)	0 (0.0)		1 (0.9)	0 (0.0)		4 (1.3)	0 (0.0)
90d death (%)			0.879			1.000			0.308
No	129 (99.2)	176 (100.0)		115 (99.1)	116 (100.0)		298 (98.7)	309 (100.0)
Yes	1 (0.8)	0 (0.0)		1 (0.9)	0 (0.0)		4(1.3)	0 (0.0)
Postoperative complications (%)			0.317			0.182			0.144
No	118 (90.8)	153 (86.9)		105 (90.5)	102 (87.9)		271 (89.8)	272 (88.0)
Pneumonia	2 (1.5)	6 (3.4)		3 (2.6)	4 (3.4)		9 (3.0)	12 (3.9)
Chylothorax	0 (0.0)	3 (1.7)		0 (0.0)	2 (1.7)		0 (0.0)	5 (1.6)
Hydropneumothorax	4 (3.1)	9 (5.1)		4 (3.4)	6 (5.2)		11 (3.6)	12 (3.9)
Others	6 (4.6)	5 (2.8)		4 (3.4)	2 (1.7)		11 (3.6)	8 (2.6)

Abbreviations: PSM, propensity score matching; IPTW, inverse probability of treatment weighting; NCT, neoadjuvant chemotherapy; NICT, neoadjuvant immunotherapy combined with chemotherapy; VATS, video-assisted thoracoscopic surgery.

Table 4 Failure Modes After Surgery

Failure mode	Before PSM			After PSM			IPTW
	NCT (n = 130)	NICT (n = 176)	P value	NCT (n = 116)	NICT (n = 116)	P value	NCT (n = 302)	NICT (n = 309)	P value
DM	42 (32.3)	11 (6.2)	< 0.001	38 (32.8)	7 (6.0)	< 0.001	103 (34.1)	21 (6.8)	< 0.001
LRR	4 (3.1)	5 (2.8)	1.000	4 (3.4)	2 (1.7)	0.679	9 (3.0)	6 (1.9)	0.532

Abbreviations: PSM, propensity score matching; IPTW, inverse probability of treatment weighting; NCT, neoadjuvant chemotherapy; NICT, neoadjuvant immunotherapy combined with chemotherapy; LRR, local regional recurrence; DM, distant metastasis.

Figure 3 Kaplan-Meier survival analysis of DFS (A) and OS (B) between NCT and NICT before PSM; Kaplan-Meier survival analysis of DFS (C) and OS (D) between NCT and NICT after PSM.

Abbreviations: PSM, propensity score matching; DFS, disease-free survival; OS, overall survival; NCT, neoadjuvant chemotherapy; NICT, neoadjuvant immunotherapy combined with chemotherapy.

Figure 4 Kaplan-Meier survival analysis of DFS (A) and OS (B) between pCR and Non-pCR before PSM; Kaplan-Meier survival analysis of DFS (C) and OS (D) between pCR and Non-pCR after PSM.

Abbreviations: PSM, propensity score matching; DFS, disease-free survival; OS, overall survival; pCR, pathological complete remission.

Figure 5 Kaplan-Meier survival analysis of DFS (A) and OS (B) between MPR and Non-MPR before PSM; Kaplan-Meier survival analysis of DFS (C) and OS (D) between MPR and Non-MPR after PSM.

Abbreviations: PSM, propensity score matching; DFS, disease-free survival; OS, overall survival; MPR, major pathological remission.

Figure 6 Kaplan-Meier survival analysis of DFS (A) and OS (B) between NCT and NICT before inverse probability of treatment weighting; Kaplan-Meier survival analysis of DFS (C) and OS (D) between NCT and NICT after inverse probability of treatment weighting.

Abbreviations: DFS, disease-free survival; OS, overall survival; NCT, neoadjuvant chemotherapy; NICT, neoadjuvant immunotherapy combined with chemotherapy.

Figure 7 Kaplan-Meier survival analysis of DFS (A) and OS (B) between pCR and Non-pCR before inverse probability of treatment weighting; Kaplan-Meier survival analysis of DFS (C) and OS (D) between pCR and Non-pCR after inverse probability of treatment weighting.

Abbreviations: DFS, disease-free survival; OS, overall survival; pCR, pathological complete remission.

Figure 8 Kaplan-Meier survival analysis of DFS (A) and OS (B) between MPR and Non-MPR before inverse probability of treatment weighting; Kaplan-Meier survival analysis of DFS (C) and OS (D) between MPR and Non-MPR after inverse probability of treatment weighting.

Abbreviations: DFS, disease-free survival; OS, overall survival; MPR, major pathological remission.

Table 5 Logistical Regression Analysis for Predictors of pCR

Variables	Univariate Analysis		Multivariate Analysis
	OR(95% CI)	P value	OR(95% CI)	P value
Neoadjuvant therapy
NCT	Reference		Reference
NICT	25.071(8.871, 70.855)	<0.001	19.033(6.615, 54.761)	<0.001
Age (<60)	0.703(0.419, 1.180)	0.182
Sex (Male)	1.771(0.786, 3.989)	0.168
Smoking history (Yes)	1.202(0.707, 2.042)	0.496
Alcohol history (No)	0.807(0.455, 1.430)	0.462
Comorbidity (No)	0.859(0.509, 1.449)	0.569
KPS
>80	1.103(0.642, 1.894)	0.723
=80	Reference
Family history (No)	0.585(0.270, 1.268)	0.174
FEV 1% (>70)	1.286(0.532, 3.108)	0.577
Clinical T stage
1	Reference
2	1.262(0.475, 3.347)	0.641
3	1.267(0.428, 3.751)	0.670
4	0.829(0.267, 2.575)	0.746
Clinical N stage
N0	Reference
N+	1.167(0.620, 2.197)	0.631
Clinical TNM stage
I	Reference
II	1.158(0.217, 6.177)	0.864
III	1.081(0.212, 5.506)	0.926
Pathology
Adenocarcinoma	Reference		Reference
Squamous carcinoma	3.255(1.795, 5.901)	<0.001	1.895(0.965, 3.720)	0.063
Surgical approach
Thoracotomy	Reference
VATS	0.944(0.569, 1.568)	0.825
Postoperative complications (Yes)	1.291(0.602, 2.770)	0.512

Abbreviations: pCR, pathological complete remission; OR, odds ratio; 95% CI, 95% confidence interval; NCT, neoadjuvant chemotherapy; NICT, neoadjuvant immunotherapy combined with chemotherapy; Comorbidity, including hypertension, diabetes mellitus, chronic obstructive pulmonary disease, coronary atherosclerotic heart disease; KPS, Karnofsky Performance Status; FEV 1%, forced expiratory volume in one second/forced vital capacity; VATS, video-assisted thoracoscopic surgery.

Table 6 Cox Regression Analysis for Predictors of OS and DFS

Variables	OS Univariate Analysis		OS Multivariate Analysis		DFS Univariate Analysis		DFS Multivariate Analysis
	HR(95% CI)	P	HR(95% CI)	P	HR(95% CI)	P	HR(95% CI)	P
Neoadjuvant therapy
NCT	Reference		Reference		Reference		Reference
NICT	0.239(0.115, 0.500)	<0.001	0.381(0.166, 0.877)	0.023	0.346(0.215, 0.557)	<0.001	0.651(0.387, 1.095)	0.106
Age (<60)	0.549(0.313, 0.962)	0.036	0.644(0.354, 1.170)	0.148	0.758(0.491, 1.168)	0.209
Sex (Male)	0.805(0.377, 1.719)	0.575			0.832(0.460, 1.504)	0.542
Smoking (No)	0.834(0.475, 1.464)	0.528			0.749(0.488, 1.151)	0.188
Alcohol (Yes)	1.314(0.719, 2.399)	0.374			1.170(0.734, 1.864)	0.510
Comorbidity (Yes)	0.908(0.510, 1.617)	0.744			1.042(0.674, 1.610)	0.854
KPS
>80	0.776(0.431, 1.395)	0.396			0.942(0.603, 1.472)	0.794
=80	Reference				Reference
Family history (Yes)	1.191(0.606, 2.341)	0.611			1.026(0.593, 1.774)	0.928
FEV 1% (>70)	0.936(0.370, 2.369)	0.888			0.852(0.439, 1.652)	0.635
Clinical T stage
1	Reference				Reference
2	0.439(0.177, 1.091)	0.076			0.599(0.279, 1.284)	0.188
3	0.599(0.213, 1.684)	0.331			0.932(0.405, 2.148)	0.869
4	0.838(0.317, 2.212)	0.721			0.965(0.421, 2.211)	0.933
Clinical N stage
N0	0.729(0.327, 1.624)	0.439			0.685(0.372, 1.263)	0.226
N+	Reference				Reference
Clinical TNM stage
I	Reference				Reference
II	1.565(0.203, 12.062)	0.668			3.277(0.441, 24.350)	0.246
III	1.520(0.208, 11.115)	0.680			2.995(0.415, 21.644)	0.277
Pathology
Adenocarcinoma	Reference		Reference		Reference		Reference
Squamous carcinoma	0.447(0.251, 0.795)	0.006	0.870(0.457, 1.659)	0.673	0.386(0.249, 0.598)	<0.001	0.674(0.418, 1.088)	0.106
Surgical approach
Thoracotomy	Reference		Reference		Reference
VATS	0.529(0.284, 0.986)	0.045	0.564(0.299, 1.066)	0.078	1.161(0.753, 1.789)	0.499
Surgical excise method
Lung lobectomy	Reference				Reference
Non-lobectomy	1.419(0.707, 2.851)	0.325			0.695(0.358, 1.347)	0.281
Postoperative complications (Yes)	1.327(0.524, 3.362)	0.550			1.272(0.634, 2.552)	0.498
LVSI (Yes)	3.057(1.368, 6.833)	0.006	1.876(0.809, 4.354)	0.143	3.366(1.820, 6.224)	<0.001	1.539(0.814, 2.910)	0.185
MPR (No)	6.862(2.919, 16.129)	<0.001	4.279(1.581, 11.581)	0.004	8.826(4.554, 17.108)	<0.001	7.462(3.385, 9.450)	<0.001
R0 resection (Yes)	0.889(0.215, 3.671)	0.870			0.736(0.269, 2.014)	0.551
Primary lesion Complete pathological remission (Yes)	0.219(0.068, 0.706)	0.011	1.375(0.334, 5.652)	0.659	0.250(0.115, 0.543)	<0.001	1.961(0.750, 5.127)	0.170
Lymph Nodes Complete pathological remission (Yes)	0.416(0.233, 0.742)	0.003	0.716(0.381, 1.347)	0.301	0.330(0.212, 0.513)	<0.001	0.546(0.334, 0.891)	0.016
Adjuvant therapy (Yes)	1.325(0.620, 2.830)	0.468			2.159(1.115, 4.182)	0.023	1.505(0.765, 2.958)	0.236
Length of surgery	1.003(0.996, 1.010)	0.399			1.001(0.996, 1.006)	0.710
Surgical interval	0.999(0.968, 1.031)	0.965			0.987(0.963, 1.012)	0.318
Number of lymph nodes removed	0.989(0.953, 1.027)	0.568			1.001(0.973, 1.029)	0.971

Abbreviations: OS, overall survival; DFS, disease-free survival; HR, hazard ratio; 95% CI, 95% confidence interval; NCT, neoadjuvant chemotherapy; NICT, neoadjuvant immunotherapy combined with chemotherapy; Comorbidity, including hypertension, diabetes mellitus, chronic obstructive pulmonary disease, coronary atherosclerotic heart disease; KPS, Karnofsky Performance Status; FEV 1%,forced expiratory volume in one second/forced vital capacity; VATS, video-assisted thoracoscopic surgery; LVSI, lymphovascular invasion; MPR, major pathological remission.