Targeted therapy combined with immunotherapy vs trifluridine/tipiracil with bevacizumab as late-line therapy in metastatic colorectal cancer

Table 1 Demographic and clinical characteristics of the patients at baseline, n (%)

Characteristics	Levels	n
Age	≤ 60	51 (40.2)
	> 60	76 (59.8)
Gender	Male	80 (63.0)
	Female	47 (37.0)
ECOG	0-1	110 (86.6)
	2	17 (13.4)
Primary tumor location	Right colon	31 (24.4)
	Left colon and rectum	96 (75.6)
Primary tumor surgery	No	8 (6.3)
	Yes	119 (93.7)
Number of metastatic organs	1	28 (22.0)
	≥ 2	99 (78.0)
Liver metastasis	No	48 (37.8)
	Yes	79 (62.2)
Lung metastasis	No	47 (37.0)
	Yes	80 (63.0)
RAS	Wild-type	34 (26.8)
	KRAS mutation	62 (48.8)
	NRAS mutation	7 (5.5)
	Unknown	24 (18.9)
Treatment regimen	Targeted drug + PD-1	88 (69.3)
	TAS-102 + bevacizumab	39 (30.7)
BRAF	Wild-type	91 (71.7)
	Mutation	6 (4.7)
	Unknown	30 (23.6)
Prior fluorouracil	No	78 (61.4)
	Yes	49 (38.6)
Prior oxaliplatin	No	19 (15.0)
	Yes	108 (85.0)
Prior irinotecan	No	19 (15.0)
	Yes	108 (85.0)
Prior capecitabine	No	26 (20.5)
	Yes	101 (79.5)
Prior raltitrexed	No	86 (67.7)
	Yes	41 (32.3)
Prior bevacizumab	No	18 (14.2)
	Yes	109 (85.8)
Prior cetuximab	No	95 (74.8)
	Yes	32 (25.2)
Treatment line	3 Line	69 (54.3)
	> 3 Line	58 (45.7)

ECOG: Eastern Cooperative Oncology Group; PD-1: Programmed cell death 1; TAS-102: Trifluridine/tipiracil.

Table 2 Univariate and multivariate Cox analysis of the effect of prognostic factors in the original cohort (progression-free survival), n (%)

Dependent: Survival (PFS/30, status PFS)		All	HR (univariable)	HR (multivariable)
Gender	Male	80 (63.0)
	Female	47 (37.0)	1.11 (0.74-1.66, P = 0.619)
Age	≤ 60	51 (40.2)
	> 60	76 (59.8)	0.87 (0.58-1.31, P = 0.514)
ECOG	0-1	110 (86.6)
	2	17 (13.4)	0.54 (0.28-1.01, P = 0.055)	0.56 (0.30-1.07, P = 0.079)
Number of metastatic organs	1	28 (22.0)
	≥ 2	99 (78.0)	2.22 (1.34-3.68, P = 0.002)	2.14 (1.28-3.57, P = 0.004)
Primary tumor location	Right colon	31 (24.4)
	Left colon and rectum	96 (75.6)	0.94 (0.59-1.49, P = 0.800)
Liver metastasis	No	48 (37.8)
	Yes	79 (62.2)	1.39 (0.91-2.11, P = 0.126)
Lung metastasis	No	47 (37.0)
	Yes	80 (63.0)	1.01 (0.67-1.52, P = 0.966)
RAS	Wild-type	34 (26.8)
	Mutation	69 (54.3)	1.02 (0.65-1.59, P = 0.932)
	Unknown	24 (18.9)	0.63 (0.33-1.20, P = 0.159)
Treatment regimen	Targeted drug + PD-1	88 (69.3)
	TAS102 + bevacizumab	39 (30.7)	1.43 (0.94-2.18, P = 0.094)	1.23 (0.80-1.88, P = 0.348)

n = 127, events = 100, likelihood ratio test = 16 on 3 (P = 0.001). HR: Hazard ratio; ECOG: Eastern Cooperative Oncology Group; PD-1: Programmed cell death 1; PFS: Progression-free survival; TAS-102: Trifluridine/tipiracil.

Table 3 Comparison of short-term efficacy between two groups after propensity score matching (ratio = 4)

Group	Number	PR	SD	PD	ORR (%)	DCR (%)
1TP	55	3	29	23	5.45	58.19
2TB	30	1	16	13	3.33	56.67
χ2 value			0	0.1803		0.1803
P value		13	1	0.6711	13	0.6711

¹Received targeted therapy combined with anti-programmed cell death 1 immunotherapy.

²Received trifluridine/tipiracil combined with bevacizumab.

³Fisher’s exact test.

PR: Partial response; SD: Stable disease; PD: Progressive disease; ORR: Objective response rate; DCR: Disease control rate.

Table 4 Propensity score-adjusted multivariable Cox regression analysis of prognostic factors associated with progression-free survival in the original cohort, mean ± SD/n (%)

Dependent: Survival (PFS/30, status PFS)		All	HR (multivariable)
Gender	Male	80 (63.0)
	Female	47 (37.0)	0.99 (0.62-1.58, P = 0.969)
Age	≤ 60	51 (40.2)
	> 60	76 (59.8)	0.95 (0.62-1.47, P = 0.834)
ECOG	0-1	110 (86.6)
	2	17 (13.4)	0.51 (0.26-1.00, P = 0.051)
Number of metastatic organs	1	28 (22.0)
	≥ 2	99 (78.0)	2.40 (1.31-4.41, P = 0.005)
Primary tumor location	Right colon	31 (24.4)
	Left colon and rectum	96 (75.6)	1.23 (0.72-2.10, P = 0.450)
Liver metastasis	No	48 (37.8)
	Yes	79 (62.2)	0.91 (0.56-1.49, P = 0.721)
Lung metastasis	No	47 (37.0)
	Yes	80 (63.0)	0.99 (0.64-1.56, P = 0.982)
RAS	Wild-type	34 (26.8)
	Mutation	69 (54.3)	0.81 (0.50-1.34, P = 0.415)
	Unknown	24 (18.9)	0.67 (0.34-1.29, P = 0.228)
Treatment regimen	Targeted drug + PD-1	88 (69.3)
	TAS-102 + bevacizumab	39 (30.7)	1.26 (0.76-2.10, P = 0.367)
PS		0.3 ± 0.2	0.85 (0.23-3.18, P = 0.805)

n = 127, events = 100, likelihood ratio test = 19.13 on 11 (P = 0.059). HR: Hazard ratio; ECOG: Eastern Cooperative Oncology Group; PD-1: Programmed cell death 1; PFS: Progression-free survival; TAS-102: Trifluridine/tipiracil; PS: Propensity score.

Table 5 Treatment-emergent adverse events in the 85 patients of the matched dataset, n (%)

Toxicities	TP group			TB group			P value for grade 1-2	P value for grade 3-4
	Grade 0	Grade 1-2	Grade 3-4	Grade 0	Grade 1-2	Grade 3-4
	n = 55			n = 30
Anemia	37 (67.3)	17 (30.9)	1 (1.8)	21 (70.0)	7 (23.3)	2 (6.7)	0.62461	0.28332
Neutropenia	41 (74.5)	9 (16.4)	5 (9.1)	17 (56.7)	5 (16.7)	8 (26.7)	12	0.055132
Leukocytopenia	33 (60.0)	18 (32.7)	4 (7.3)	18 (60.0)	11 (36.7)	1 (3.3)	0.89921	0.65212
Thrombocytopenia	40 (72.7)	15 (27.3)	0 (0)	17 (56.7)	12 (40.0)	1 (3.3)	0.33671	0.35292
Proteinuria	39 (70.9)	16 (29.1)	0 (0)	23 (76.7)	7 (23.3)	0 (0)	0.75231	12
Aspartate transaminase increased	36 (65.5)	18 (32.7)	1 (1.8)	23 (76.7)	6 (20.0)	1 (3.3)	0.32041	12
Alanine transaminase increased	41 (74.5)	14 (25.5)	0 (0)	20 (66.7)	8 (26.7)	2 (6.7)	11	0.35292
Alkaline phosphatase increased	40 (72.7)	13 (23.6)	2 (3.6)	21 (70.0)	9 (30.0)	0 (0)	0.70321	0.53782
Blood bilirubin increased	39 (70.9)	16 (29.1)	0 (0)	24 (80.0)	5 (16.7)	1 (3.3)	0.31441	0.35292
Triglycerides increased	36 (65.5)	17 (30.9)	2 (3.6)	24 (80.0)	4 (13.3)	2 (6.7)	0.11332	0.61132
Nausea	40 (72.7)	15 (27.3)	0 (0)	23 (76.7)	6 (20.0)	1 (3.3)	0.63141	12
Vomiting	49 (89.1)	6 (10.9)	0 (0)	21 (70.0)	8 (26.7)	1 (3.3)	0.11741	0.35292
Fatigue	42 (76.4)	13 (23.6)	0 (0)	20 (66.7)	9 (30.0)	1 (3.3)	0.70321	0.35292
Fever	49 (89.1)	6 (10.9)	0 (0)	26 (86.7)	4 (13.3)	0 (0)	0.73671	12
Diarrhea	47 (85.5)	8 (14.5)	0 (0)	25 (83.4)	4 (13.3)	1 (3.3)	11	0.35292
Hypertension	48 (87.3)	6 (10.9)	1 (1.8)	24 (80.0)	3 (10.0)	3 (10.0)	12	0.12382

¹P values were calculated by χ² test.

²P values were calculated by Fisher’s exact test.

TP: Targeted therapy combined with anti-programmed cell death 1 immunotherapy; TB: Bevacizumab.