New approaches in angiogenic targeting for colorectal cancer

Table 1 Anti-VEGF agents currently in clinical development

Agent	Targets	Phase of development
Specific anti-VEGF antibodies
Bevacizumab (Avastin)	VEGF-A	Phase III
IMC-C1121b	VEGFR-2	PhaseI-II
VEGF Trap	VEGF, PlGF, VEGF-B	Phase I
Agents that target VEGF receptors tyrosine kinase
Vatalanib (PTK787/ZK 222584)	VEGFR1, VEGFR2, VEGFR3, PDGFR-β, c-Kit	Phase III
Sorafenib (BAY 43-9006)	VEGFR-2, PDGFR-β, FLT3, c-Kit, Raf	Phase III
Sunitinib (SU11248)	VEGFR2, PDGFR-β, FLT3, c-Kit	Phase III
Semaxanib (SU5416)	VEGFR1, VEGFR2	Stopped
AZD2171	VEGFR1, VEGFR2, VEGFR3, PDGFR-β, c-Kit	PhaseI-II
CEP-7055	VEGFR1, VEGFR2, VEGFR3	PhaseI-II
CHIR258	VEGFR1, VEGFR2, FGFR1, FGFR3
CP-547632	VEGFR2	PhaseI-II
GW786034	VEGFR2	PhaseI-II
OSI-930	VEGFR, c-Kit	PhaseI-II
ZK-CDK	VEGFRs, PDGFR, CDKs	PhaseI-II
AG013736	VEGFR, PDGFR-β, c-Kit	PhaseI-II
AMG706	VEGFR1, VEGFR2, PDGFR-β, c-Kit	PhaseI-II
KRN-951	VEGFR1, VEGFR2, VEGFR3, PDGFR-β, c-Kit	PhaseI-II
BMS-582664	VEGFR2, FGFR	PhaseI-II
XL999	FGFR, VEGFRs, PDGFR, FLT3	PhaseI-II
Zactima (ZD6474)	VEGFR2, EGFR, RET	PhaseI-II
AEE788	VEGFR1, VEGFR2, EGFR	PhaseI-II
Antisense oligonucleotides
Veglin (VEGF-AS)	VEGF, VEGF-C, VEGF-D	PhaseI
Aptamer
Aplidin (Dehydrodidemnin B)	VEGF	PhaseI

CDK: Cyclin-dependent kinase; EGFR: Epidermal growth factor receptor; FGFR: Fibroblast growth factor receptor; FLT3: Fms-related tyrosine kinase 3; MMP: Matrix metalloproteinase; PDGFR: Platelet-derived growth factor receptor; PIGF: Placental growth factor; VEGF: Vascular endothelial growth factor.

Table 2 Completed trials for Bevacizumab with chemotherapy in metastatic CRC

REF	Regimen	Pts	RR (%)	P	PFS or TTP (mo)	P	OS (mo)	P
28	IFL	411	35	0.004	6.2	< 0.001	15.6	< 0.001
	IFL + BV	402	45		10.6		20.3
32	5-FU/LV	35	17	-	5.2	-	13.6	-
	5-FU/LV + BV-low	35	40	0.029	9	0.005	21.5	0.137
	5-FU/LV + BV-high	32	24	0.434	7.2	0.217	16.1	0.582
41	5-FU/LV	105	15	0.055	5.5	0.0002	12.9	0.16
	5-FU/LV + BV	104	26		9.2		16.6
43	FOLFOX	289	9	< 0.001	4.8	< 0.001	10.7	0.0018
	FOLFOX + BV	290	22		7.2		12.5
44	FOLFOX/bFOL/XELOX	147	22-43	NR	6.1-8.7	NR	18.2	NR
	FOLFOX/bFOL/XELOX + BV	213	41-53		8.3-10.3		24.4
45	FOLFOX/XELOX	701	49	0.99	8.5	< 0.001	-	-
	FOLFOX/XELOX + BV	699	47		11		-

CRC: Colorectal carcinoma; 5-FU/LV: 5-fluorouracil/leucovorin; IFL: Irinotecan/5-FU/leucovorin; FOLFOX-4: Oxaliplatin/5-FU/leucovorin; BV: Bevacizumab; Pts: Patients enrolled; REF: reference; RR: Response rate; PFS: Progression-free survival; TTP: Time to tumor progression; OS: Overall survival; NR: Not reported.

Table 3 Trials for Vatalanib with chemotherapy in metastatic CRC

REF	Regimen	Pts	RR (%)	P	PFS or TTP (mo)	P	OS (mo)	P
58	FOLFOX-4	583	46	NS	7.6	0.118	NR	-
	FOLFOX-4 + Vatalanib	585	42		7.7
59-60	FOLFOX-4	429	18	NR	4.1	0.026	11.8	0.511
	FOLFOX-4 + Vatalanib	426	19		5.5		12.1

CRC: Colorectal carcinoma; REF: Reference; Pts: Patients enrolled; FOLFOX-4: Oxaliplatin/5-FU/leucovorin; RR: Response rate; PFS: Progression-free survival; TTP: Time to tumor progression; OS: Overall survival; NS: Statistically nonsignificant; NR: Not reported.