Evaluation of efficacy and safety of targeted therapy and immune checkpoint inhibitors in metastatic colorectal cancer

Table 1 Comparison of covariate balance in the study population before and after propensity score matching and inverse probability of treatment weighting analysis, n (%)

Variables	Original				1:1 PSM				IPW
	TT, n = 68	TT + ICI, n = 31	P value	SMD	TT, n = 24	TT + ICI, n = 24	P value	SMD	TT, n = 981	TT + ICI, n = 731	P value	SMD
Age			0.95	0.09			0.24	0.23			0.95	0.04
mean ± SD	61.8 ± 9.3	61.0 ± 9.6			62.0 ± 10.4	63.9 ± 7.86			61.9 ± 9.0	61.5 ± 9.3
Median (range)	62 (40-90)	64 (42-74)			62 (57-65)	65 (60-70)			63 (56-68)	64 (57-69)
Age groups (year)			0.86	0.09			0.36	0.39			0.86	0.03
> 60	41 (60.3)	20 (64.5)			14 (58.3)	18 (75.0)			62 (63.3)	47 (64.4)
≤ 60	27 (39.7)	11 (35.5)			10 (41.7)	6 (25.0)			36 (36.7)	26 (35.6)
Gender			0.47	0.21			1	0.09			0.47	0.05
Male	37 (54.4)	20 (64.5)			15 (62.5)	14 (58.7)			55 (56.1)	42 (58.3)
Female	31 (45.6)	11 (35.5)			9 (37.5)	10 (41.7)			43 (43.9)	30 (41.7)
Primary site			1	0.03			0.77	0.17			1	0.01
Rectal cancer	34 (50.5)	16 (51.6)			15 (62.5)	13 (54.2)			50 (51.0)	37 (50.7)
Colon cancer	34 (50.0)	15 (48.4)			9 (37.5)	11 (45.8)			48 (49.0)	36 (49.3)
Radical surgery			0.40	0.22			1	0.09			0.4	0.09
Yes	55 (80.9)	22 (71.0)			18 (73.1)	17 (70.8)			77 (77.8)	54 (74.0)
No	13 (19.1)	9 (29.0)			6 (26.9)	7 (29.2)			22 (22.2)	19 (26.0)
Treatment line			0.76	0.14			1	0.00			0.76	0.03
Third-line	56 (82.4)	27 (87.1)			21 (87.5)	21 (87.5)			82 (83.7)	62 (84.9)
Fourth-line	12 (17.6)	4 (12.9)			3 (12.5)	3 (12.5)			16 (16.3)	11 (15.1)
Targeted agents			0.87	0.03			1	0.00			1	0.06
Fruquintinib	60 (88.2)	27 (87.1)			22 (91.7)	22 (91.7)			86 (87.8)	65 (89.0)
Regorafenib	8 (11.8)	4 (12.9)			2 (8.3)	2 (8.3)			12 (12.2)	8 (11.0)
Treating hospital			0.27	0.35			1	0.00			0.27	0.09
NCUST-AH	9 (13.2)	4 (12.9)			3 (12.5)	3 (12.5)			13 (13.3)	10 (13.9)
TSPH	33 (48.5)	10 (32.3)			7 (29.2)	7 (29.2)			42 (42.9)	27 (37.5)
QPH	26 (38.2)	17 (54.8)			14 (58.3)	14 (58.3)			43 (43.9)	35 (48.6)
Metastatic status			0.51	0.54			0.97	0.30			0.53	0.30
LM	10 (14.7)	5 (16.1)			6 (25.0)	8 (33.3)			5 (15.3)	13 (18.1)
LuM	26 (8.3)	8 (25.8)			2 (8.3)	3 (12.5)			13 (33.7)	20 (27.8)
PM	3 (4.4)	2 (6.5)			2 (8.3)	2 (8.3)			5 (5.1)	4 (5.6)
LM + LuM	13 (19.1)	5 (16.1)			6 (25.0)	5 (20.8)			19 (19.4)	14 (19.4)
LuM + PM	2 (2.9)	1 (3.2)			1 (4.2)	1 (4.2)			3 (3.1)	3 (4.2)
LM + PM	3 (4.4)	0 (0)			0 (0)	0 (0)			3 (3.1)	0 (0)
OM	11 (16.2)	10 (32.2)			7 (29.2)	5 (20.8)			20 (20.4)	18 (25.0)
CEA level (ng/mL)			0.01	1.48			1	0.10			0.01	0.51
≤ 5	13 (19.1)	11 (35.5)			6 (25.0)	5 (20.8)			16 (16.3)	15 (20.8)
5 < CEA ≤ 25	21 (30.9)	3 (9.7)			1 (4.2)	1 (4.2)			21 (21.4)	3 (4.2)
> 25	34 (50.0)	17 (54.8)			17 (70.8)	18 (75.0)			61 (62.2)	54 (75.0)

¹The sample size indicated here represents the "pseudo-sample size" generated by applying the inverse probability of treatment weighting to the total population.

PSM: Propensity score matching; IPW: Inverse probability weighting; TT: Targeted therapy; ICI: Immune checkpoint inhibitor; NCUST-AH: North China University of Science and Technology Affiliated Hospital; TSPH: Tangshan People’s Hospital; QPH: Qinhuangdao People’s Hospital; LM: Liver metastasis; LuM: Lung metastasis; PM: Peritoneal metastasis; OM: Other metastases; CEA: Carcinoembryonic antigen.

Table 2 Assessment of treatment efficacy in patients with metastatic colorectal cancer receiving targeted therapy alone and combined targeted plus immunotherapy, n (%)

Best overall response	TT (n = 68)	TT + ICI (n = 31)	χ2	P value
CR	0	0	0	1
PR	10 (14.7)	5 (16.1)	-1	1
SD	33 (48.5)	15 (48.4)	0	0.990
PD	25 (36.8)	11 (35.5)	0.015	0.902
ORR	10 (14.7)	5 (16.1)	-1	1
DCR	43 (63.2)	21 (67.7)	0.189	0.664

¹Fisher's exact probability method.

TT: Targeted therapy; ICI: Immune checkpoint inhibitor; CR: Complete response; PR: Partial response; SD: Stable disease; PD: Progressive disease; ORR: Objective response rate; DCR: Disease control rate.

Table 3 Univariate and multivariate survival analyses of patients treated with targeted therapy and combined targeted-immunotherapy

Variable	PFS months (95%CI)	Univariate P value	HR	95%CI	Multivariate P value
Age groups (year)		0.819			0.677
> 60	3.7 (3.11-4.29)		1.05	0.68-1.61
≤ 60	4.7 (3.98-5.43)		0.95	0.62-1.46
Gender		0.471			0.623
Female	3.7 (2.85-4.55)		1.17	0.76-1.80
Male	4.2 (2.99-5.41)		0.85	0.56-1.31
Radical surgery		0.591			0.829
Yes	4.3 (3.04-5.56)		0.87	0.52-1.44
No	3.5 (3.13-3.87)		1.15	0.69-1.91
Treatment line		0.254			0.125
Third-line	3.8 (3.01-4.59)		1.40	0.79-2.48
Fourth-line	5.4 (2.75-7.85)		0.72	0.40-1.27
Treatment plan		0.003			0.000
TT	3.4 (2.83-3.97)		2.07	1.28-3.32
TT + ICI	6.0 (4.26-7.75)		0.48	0.30-0.78
Primary site		0.006			0.000
Rectal cancer	4.8 (3.79-5.81)		0.55	0.36-0.84
Colon cancer	3.4 (2.95-3.85)		1.81	1.19-2.75
Metastatic status					0.005
LM	5.0 (4.50-5.51)	0.511	0.82	0.45-1.48
LuM	3.4 (2.07-4.73)	0.825	0.95	0.61-1.49
PM	4.3 (3.01-5.59)	0.999	1.00	0.40-2.47
LM + LuM	3.5 (2.11-4.89)	0.322	1.31	0.77-2.25
LuM + PM	1.3 (0.18-2,42)	0.303	1.84	0.58-5.90
LM + PM	3.7 (2.71-4.69)	0.000	18.67	5.21-66.97
OM	4.0 (3.20-4.80)	0.299	0.75	0.44-1.28
CEA level					0.894
≤ 5	4.7 (2.74-6.66)	0.459	0.81	0.46-1.42
5 < CEA ≤ 25	4.0 (2.65-5.35)	0.828	1.06	0.65-1.72
> 25	3.7 (3.02-4.39)	0.679	1.09	0.71-1.67
Gene mutation status
KRAS mutation	3.5 (2.84-4.16)	0.400	0.80	0.47-1.35	0.216
NRAS mutation	3.2 (1.40-5.00)	0.715	0.84	0.33-2.12	0.835
dMMR	3.3 (2.82-3.78)	0.564	0.66	0.16-2.70	0.394

PFS: Progression-free survival; TT: Targeted therapy; ICI: Immune checkpoint inhibitor; HR: Hazard ratio; 95%CI: 95% confidence interval; LM: Liver metastasis; LuM: Lung metastasis; PM: Peritoneal metastasis; OM: Other metastases; CEA: Carcinoembryonic antigen; dMMR: Deficient mismatch repair.

Table 4 Comparison of adverse reaction rates in patients with metastatic colorectal cancer in the targeted and target-exempted groups, n (%)

	All grades		χ2	P value	Grade 3-4
	TT	TT + ICI			TT	TT + ICI
Hypertension	14 (20.6)	5 (16.1)	0.06	0.805	2 (2.9)	0 (0.0)
Proteinuria	9 (13.2)	3 (9.7)	-1	0.748	0 (0.0)	0 (0.0)
Rash	5 (7.4)	3 (9.7)	-1	0.703	0 (0.0)	0 (0.0)
Abnormal myocardial enzymes	3 (4.4)	3 (9.7)	-1	0.374	0 (0.0)	0 (0.0)
Liver function impairment	13 (19.1)	4 (12.9)	0.22	0.636	0 (0.0)	0 (0.0)
Occult blood positive	4 (5.9)	3 (9.7)	-1	0.674	0 (0.0)	0 (0.0)
Hand-foot skin reaction	8 (11.8)	2 (6.5)	-1	0.499	0 (0.0)	0 (0.0)
Dysphonia	3 (4.4)	5 (16.1)	-	0.104	0 (0.0)	0 (0.0)
Fatigue	24 (35.3)	10 (32.3)	0.00	0.947	1 (1.5)	0 (0.0)
Decreased appetite	12 (17.6)	3 (9.7)	-1	0.378	0 (0.0)	0 (0.0)
Bilirubin level elevated	9 (13.2)	2 (6.5)	-1	0.494	0 (0.0)	0 (0.0)
Hypothyroidism	2 (2.9)	0 (0.0)	-1	1.000	0 (0.0)	0 (0.0)
Platelet count decreased	5 (7.4)	3 (9.7)	-1	0.703	1 (1.5)	0 (0.0)
Diarrhea	9 (13.2)	3 (9.7)	-1	0.748	0 (0.0)	0 (0.0)

¹Fisher's exact probability method.

TT: Targeted therapy; ICI: Immune checkpoint inhibitor.