Existing anti-angiogenic therapeutic strategies for patients with metastatic colorectal cancer progressing following first-line bevacizumab-based therapy

Table 1 Food and Drug Administration-approved antiangiogenic drugs for the treatment of metastatic colorectal cancer

Agent	Class	Target	Indication	Approved for	Recommended dose
Bevacizumab	Humanized Moab	VEGF-A	First- and second-line	Use in combination with oxaliplatin and irinotecan-based chemotherapy	5 mg/kg or 10 mg/kg i.v. every 2 wk
Aflibercept	Fully human Moab	VEGF-A, -B, and PIGF	Second-line	Use in combination with FOLFIRI	4 mg/kg i.v. every 2 wk
Ramucirumab	Fully human Moab	The extracellular domain of VEGFR-2	Second-line	Use in combination with FOLFIRI	8 mg/kg i.v. every 2 wk
Regorafenib	Oral multikinase inhibitor	VEGFR-1, -2, and -3 (in addition to RET, KIT, PDGFR, and FGFR	Beyond second-line	Single-use	160 mg once daily, days 1-21 of 28-d cycle

Moab: Monoclonal antibody; VEGF: Vascular endothelial growth factor; VEGFR: vascular endothelial growth factor receptor; PIFG: Placental growth factor; PDGF: Platelet derived growth factor; FGFR: Fibroblast growth factor; FOLFIRI: 5-fluorouracil, leucovorin, irinotecan.

Table 2 Randomized clinical studies comparing the efficacy of second-line chemotherapy plus antiangiogenic agent with chemotherapy alone (or plus placebo) in metastatic colorectal cancer

Study	Type of study	The proportion of patients who received prior BEV	Treatment arms (No. of patients)	ORR (%)	mPFS (mo)	HR	mOS (mo)	HR
BRiTE[16]	Observational cohort	100%	CT + BEV (642)	NA	19.2	0.49	31.8	0.48
			CT alone (531)	NA	9.5		19.9
			No treatment (253)	NA	3.6	2.05	12.6
ARIES[17]	Observational cohort	100%	CT + BEV (438)	NA	14.4	0.84	NA
			CT alone (667)	NA	10.6		NA
Cartwright et al[18]	Observational cohort	100%	CT+ BEV (267)	NA	14.6	0.74	27.9	0.76
			CT alone (306)	NA	10.1		21.4
ML18147[19]	Phase 3	100%	FOLFOX/FOLFIRI + BEV (409)	5	5.7	0.68	11.2	0.81
			FOLFOX/FOLFIRI + placebo (411)	4	4.1		9.8
BEBYP[20]	Phase 3	100%	FOLFOX/FOLFIRI + BEV (92)	21	6.8	0.70	15.5	0.77
			FOLFOX/FOLFIRI + placebo (92)	17	5.0		14.4
VELOUR[27]	Phase 3	30%	FOLFIRI + Aflibercept (612)	19.8	6.9	0.76	13.5	0.82
			FOLFIRI + placebo (614)	11.1	4.7		12.0
RAISE[37]	Phase 3	100%	FOLFIRI + Ramucirumab (536)	13.4	5.7	0.79	13.3	0.84
			FOLFIRI + placebo (536)	12.5	4.5		11.7

BEV: Bevacizumab; mPFS: Median progression-free survival; mOS: Median overall-survival; HR: Hazard ratio; CT: Chemotherapy; NA: Not available; FOLFOX: 5-FU, leucovorin, oxaliplatin; FOLFIRI: 5-FU, leucovorin, irinotecan.