Efficacy comparison of fruquintinib, regorafenib monotherapy or plus programmed death-1 inhibitors for microsatellite stable metastatic colorectal cancer

Table 1 Programmed death-1 inhibitors in the fruquintinib plus programmed death-1 inhibitor and regorafenib plus programmed death-1 inhibitor group, n (%)

PD-1 inhibitors	FP	RP
Camrelizumab	28 (29.5)	53 (65.5)
Sintilimab	45 (47.4)	18 (22.2)
Tislelizumab	9 (9.5)	1 (1.2)
Nivolumab	1 (1.0)	7 (8.6)
Toripalimab	10 (10.5)	2 (2.5)
Pembrolizumab	2 (2.1)	0 (0.0)

PD-1: Programmed death-1; RP: Regorafenib plus programmed death-1 inhibitor; FP: Fruquintinib plus programmed death-1 inhibitor.

Table 2 Baseline characteristics, n (%)

Characteristic	Total	F	R	FP	RP	P value
Patients	313	70	67	95	81
Median age (range)	55 (21-88)	55 (29-88)	57 (29-79)	54 (22-81)	54 (21-83)
Age group						0.895
< 65 yr	251 (80.2)	54 (77.1)	55 (82.1)	77 (81.1)	65 (80.2)
≥ 65 yr	62 (19.8)	16 (22.9)	12 (17.9)	18 (18.9)	16 (19.8)
Sex						0.476
Male	171 (54.6)	37 (52.9)	32 (47.8)	57 (60.0)	45 (55.6)
Female	142 (45.4)	33 (47.1)	35 (52.2)	38 (40.0)	36 (44.4)
ECOG						0.189
0-1	281 (89.8)	59 (84.3)	60 (89.6)	85 (89.5)	77 (95.1)
2	32 (10.2)	11 (15.7)	7 (10.4)	10 (10.5)	4 (4.9)
Primary tumor location						0.335
Left	238 (76.0)	51 (72.9)	56 (83.6)	73 (76.8)	58 (71.6)
Right	75 (24.0)	19 (27.1)	11 (16.4)	22 (23.2)	23 (28.4)
Status of the primary tumor						0.289
Resected	248 (79.2)	53 (75.7)	53 (79.1)	72 (75.8)	70 (86.4)
Unresected	65 (20.8)	17 (24.3)	14 (20.9)	23 (24.2)	11 (13.6)
RAS mutation status1						0.934
Wild-type	98 (31.3)	23 (32.9)	22 (32.8)	30 (31.6)	23 (28.4)
Mutation	144 (46.0)	30 (42.9)	35 (52.2)	42 (44.2)	37 (45.7)
Unknown	71 (22.7)	17 (24.2)	10 (15.0)	23 (24.2)	21 (25.9)
BRAF mutation status1						0.233
Wild-type	222 (70.9)	50 (71.4)	55 (82.1)	65 (68.4)	52 (64.2)
Mutation	20 (6.4)	3 (4.3)	2 (3.0)	7 (7.4)	8 (9.9)
Unknown	71 (22.7)	17 (24.3)	10 (14.9)	23 (24.2)	21 (25.9)
Site of metastases
Liver	178 (56.9)	40 (57.1)	35 (52.2)	53 (55.8)	50 (61.7)	0.703
Lung	174 (55.6)	43 (61.4)	40 (59.7)	45 (47.4)	46 (56.8)	0.254
Number of metastatic sites						0.060
< 3	206 (65.8)	48 (68.6)	50 (74.6)	64 (67.4)	44 (54.3)
≥ 3	107 (34.2)	22 (31.4)	17 (25.4)	31 (32.6)	37 (45.7)
Prior treatment lines
2	188 (60.1)	40 (57.1)	40 (59.7)	53 (55.8)	55 (67.9)	0.384
> 2	125 (39.9)	30 (42.9)	27 (40.3)	42 (44.2)	26 (32.1)
Previous treatment agents
Fluoropyrimidine	313 (100.0)	70 (100.0)	67 (100.0)	95 (100.0)	81 (100.0)	> 0.999
Irinotecan	280 (89.5)	61 (87.1)	61 (91.0)	82 (86.3)	76 (93.8)	0.360
Oxaliplatin	297 (94.9)	68 (97.1)	62 (92.5)	88 (92.6)	79 (97.5)	0.304
Anti-VEGF antibody	270 (86.3)	65 (92.9)	52 (77.6)	83 (87.4)	70 (86.4)	0.075
Anti-EGFR antibody	56 (17.9)	10 (14.3)	15 (22.4)	15 (15.8)	16 (19.8)	0.569

¹Patients with unknown status of KRAS and BRAF V600E were not included in the analysis.

R: Regorafenib; RP: Regorafenib plus programmed death-1 inhibitor; F: Fruquintinib; FP: Fruquintinib plus programmed death-1 inhibitor; ECOG: Eastern cooperative oncology group.

Table 3 efficacy comparisons in patients treated with regorafenib, regorafenib plus programmed death-1 inhibitors, fruquintinib, and fruquintinib plus programmed death-1 inhibitors regimens

Efficacy	F	R	FP	RP	P(F vs FP)	P(R vs RP)	P(F vs R)	P(FP vs RP)
ORR	4.3%	6.0%	11.6%	4.9%	0.097	> 0.999	0.714	0.116
DCR	60.0%	61.2%	74.7%	70.4%	0.044a	0.240	0.886	0.517
6-month PFS, month	27.8%	27.8%	47.1%	22.0%	0.014a	0.521	0.862	0.001a
1-yr OS	61.3%	60.4%	62.2%	53.9%	0.922	0.259	0.945	0.157
3-yr OS	26.6%	29.7%	10.0%	12.9%	0.849	0.066	0.754	0.120
PFS, month	3.5	3.6	4.9	3.0	0.057	0.534	0.747	0.030a
OS, month	14.6	15.7	16.7	14.1	0.849	0.080	0.754	0.120

^aP < 0.05, and the difference is statistically significant.

F: Fruquintinib; R: Regorafenib; FP: Fruquintinib plus programmed death-1 inhibitors; RP: Regorafenib plus programmed death-1 inhibitors; ORR: Objective response rate; DCR: Disease control rate; PFS: Progression-free survival; OS: Overall survival.

Table 4 Clinical response of metastatic colorectal cancer patients

Response	Total (n = 313)		F (n = 70)		R (n = 67)		FP (n = 95)		RP (n = 81)
	n	%	n	%	n	%	n	%	n	%
PR	22	7.0	3	4.3	4	6.0	11	11.6	4	4.9
SD	189	60.4	39	55.7	37	55.2	60	63.1	53	65.5
PD	102	32.6	28	40.0	26	38.8	24	25.3	24	29.6
ORR	22	7.0	3	4.3	4	6.0	11	11.6	4	4.9
DCR	211	67.4	42	60.0	41	61.2	71	74.7	57	70.4

PR: Partial response; SD: Stable disease; PD: Progressive disease; ORR: Objective response rate; DCR: Disease control rate; F: Fruquintinib; R: Regorafenib; FP: Fruquintinib plus programmed death-1 inhibitors; RP: Regorafenib plus programmed death-1 inhibitors.

Table 5 Univariate and multivariate analyses of risk factors for progression-free survival and overall survival

All patients	Progression-free survival						Overall survival
	Univariate analysis			Multivariate analysis			Univariate analysis			Multivariate analysis
	HR	95%CI	P value	HR	95%CI	P value	HR	95%CI	P value	HR	95%CI	P value
Age (< 65/≥ 65 yr)	0.764	0.533-1.095	0.143				1.054	0.713-1.558	0.791
Sex (female/male)	0.713	0.552-0.923	0.010	0.587	0.447-0.771	< 0.001a	0.755	0.556-1.024	0.071
Primary tumor location (left/right)	1.123	0.826-1.527	0.460				1.162	0.815-1.657	0.407
Baseline ECOG (0/1)	1.434	0.931-2.207	0.102				1.426	0.893-2.278	0.137
RAS mutation status (wild/mutant)	1.058	0.886-1.262	0.536				1.001	0.808-1.240	0.992
BRAF mutation status (wild/mutant)	1.034	0.888-1.204	0.664				1.127	0.946-1.342	0.180
Status of primary tumor (unresected/resected)	0.728	0.529-1.002	0.051	0.815	0.583-1.141	0.233	0.696	0.478-1.012	0.058	0.882	0.591-1.318	0.540
Liver metastasis (no/yes)	1.591	1.221-2.071	0.001a	1.796	1.353-2.383	< 0.001a	1.843	1.344-2.527	< 0.001a	1.645	1.184-2.285	0.003a
Lung metastasis (no/yes)	0.994	0.766-1.290	0.963				0.729	0.538-0.988	0.042a	0.705	0.511-0.973	0.033a
Number of metastatic sites (</≥ 3)	1.350	1.035-1.762	0.027a	1.181	0.893-1.562	0.244	1.726	1.267-2.350	0.001a	1.714	1.235-2.378	0.001a
Prior treatment lines (2/> 2)	1.270	0.976-1.653	0.075				1.094	0.800-1.494	0.575
Irinotecan (no/yes)	1.833	1.157-2.905	0.010a	1.625	0.976-2.707	0.062	1.586	0.900-2.794	0.111
Oxaliplatin (no/yes)	0.656	0.388-1.108	0.115				0.859	0.438-1.683	0.657
Prior treatment with VEGF (no/yes)	1.640	1.122-2.398	0.011a	1.747	1.133-2.692	0.011a	1.617	1.018-2.568	0.042a	1.709	1.068-2.734	0.026a
Prior treatment with EGFR (no/yes)	1.281	0.921-1.781	0.141				1.264	0.866-1.844	0.225
Regimen (The F group as the reference)
R	0.928	0.632-1.363	0.702				0.917	0.564-1.491	0.727
Regimen (the R group as the reference)
RP	1.145	0.787-1.666	0.479				1.474	0.966-2.250	0.072	1.517	0.744-1.801	0.518
Regimen (the FP group as the reference)
F	1.400	0.979-2.001	0.065	1.399	0.974-2.010	0.070	1.012	0.640-1.600	0.959
RP	1.487	1.052-2.103	0.025a	1.470	1.030-2.097	0.034a	1.369	0.920-2.035	0.121

^aP < 0.05, and the difference is statistically significant.

F: Fruquintinib; R: Regorafenib; FP: Fruquintinib plus programmed death-1 inhibitors; RP: Regorafenib plus programmed death-1 inhibitors; HR: Hazard ratio; ECOG: Eastern cooperative oncology group.

Table 6 Treatment-related adverse events, n (%)

Adverse events	All				Grade ≥ 3
	F	R	FP	RP	F	R	FP	RP
Hand-foot skin reaction	9 (12.9)	18 (26.9)	14 (14.7)	26 (32.1)	2 (2.9)	5 (7.5)	1 (1.1)	3 (3.7)
Hypertension	14 (20.0)	8 (11.9)	27 (28.4)	11 (13.6)	5 (7.1)	2 (3.0)	5 (5.3)	1 (1.2)
Fatigue	2 (2.9)	3 (4.5)	5 (5.3)	10 (12.3)	1 (1.4)	0 (0.0)	0 (0.0)	0 (0.0)
Bleeding	2 (2.9)	2 (3.0)	1 (1.1)	3 (3.7)	1 (1.4)	2 (3.0)	0 (0.0)	1 (1.2)
Weight loss	1 (1.4)	3 (4.5)	5 (5.3)	1 (1.2)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Fever	7 (10.0)	4 (6.0)	8 (8.4)	13 (16.0)	2 (2.9)	1 (1.5)	1 (1.1)	1 (1.2)
Oral mucositis	5 (7.1)	3 (4.5)	4 (4.2)	4 (4.9)	0 (0.0)	0 (0.0)	0 (0.0)	1 (1.2)
Hoarseness	2 (2.9)	1 (1.5)	3 (3.2)	2 (2.5)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Hematuria	9 (12.9)	6 (9.0)	15 (15.8)	12 (14.8)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Proteinuria	10 (14.3)	9 (13.4)	21 (22.1)	10 (12.3)	1 (1.4)	0 (0.0)	2 (2.1)	0 (0.0)
Diarrhea	6 (8.6)	9 (13.4)	10 (10.5)	10 (12.3)	0 (0.0)	1 (1.5)	0 (0.0)	1 (1.2)
Constipation	5 (7.1)	7 (10.4)	12 (12.6)	8 (9.9)	1 (1.4)	1 (1.5)	0 (0.0)	0 (0.0)
Nausea/Vomiting	14 (20.0)	15 (22.4)	27 (28.4)	21 (25.9)	1 (1.4)	3 (4.5)	1 (1.1)	1 (1.2)
Hyperthyroidism	2 (2.9)	1 (1.5)	6 (6.3)	3 (3.7)	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)
Hypothyroidism	3 (4.3)	0 (0.0)	25 (26.3)	13 (16.0)	0 (0.0)	0 (0.0)	2 (2.1)	0 (0.0)
ALT/AST elevation	14 (20.0)	19 (28.4)	19 (20.0)	28 (34.6)	2 (2.9)	5 (7.5)	4 (4.2)	8 (9.9)
Myocardial enzyme elevation	2 (2.9)	3 (4.5)	12 (12.6)	14 (17.3)	0 (0.0)	0 (0.0)	0 (0.0)	1 (1.2)

ALT: Alanine transaminase; AST: Aspartate transaminase; F: Fruquintinib; R: Regorafenib; FP: Fruquintinib plus programmed death-1 inhibitors; RP: Regorafenib plus programmed death-1 inhibitors.