Anti-angiogenic agents in metastatic colorectal cancer

Table 1 Bevacizumab in the first-line setting in metastatic colorectal cancer

Ref.	Regimen	PFS (mo)	P value	OS (mo)	P value
Kabbinavar et al[26]; Phase II	1Bolus 5-FU/LV ± bevacizumab	9 vs 5.2 (TTP3)	NA	21.52vs 13.8	NA
Kabbinavar et al[27]; Phase II	1Bolus 5-FU/LV + bevacizumab vs bolus 5-FU/LV + placebo	9.2 vs 5.5	0.0002	16.6 vs 12.9	0.16
Hochster et al[35]; Phase II (TREE-1)	mFOLFOX6/bFOL/CapeOX	8.7/6.9/5.9 (TTP3)	N/A4	19.2/17.9/17.2 18.2 (overall)	N/A4
Hochster et al[35]; Phase II (TREE-2)	mFOLFOX6 + bevacizumab/bFOL + bevacizumab/CapeOX + bevacizumab	9.9/8.3/10.3 (TTP3)		26.1/20.4/24.6 23.7 (overall)
Hurwitz et al[22]; Phase III	IFL + bevacizumab vs IFL + placebo	10.6 vs 6.2	< 0.001	20.3 vs 15.6	< 0.001
Stathopoulos et al[115]; Phase III	IFL ± bevacizumab	NA	NA	22 vs 25	0.1391
Saltz et al[29]; Phase III	FOLFOX/CapeOX + bevacizumab vs FOLFOX/CapeOX + placebo	9.4 vs 8	0.0023	21.3 vs 19.9	0.077

¹Roswell Park regimen: LV 500 mg/m² over 2 h and FU 500 mg/m² as a bolus midway through the LV infusion;

²Data presented is on patients who received chemotherapy plus low-dose bevacizumab;

³Time to progression;

⁴Comparison between outcomes of TREE-1 and TREE-2 is not possible as they were sequential cohorts. 5-FU: 5-Fluorouracil; LV: Leucovorin; PFS: Progression-free survival; OS: Overall survival; mFOLFOX6: Three fluoropyrimidine regimens-infusional 5FU/LV; bFOL: Bolus FU/LV; CapeOX: Capecitabine; FOLFOX: 5-FU/LV/oxaliplatin; NA: Not available; N/A: Not applicable.

Table 2 Phase III trials using bevacizumab in the second-line setting

Ref.	Regimen	PFS (mo)	P value	OS (mo)	P value
Giantonio et al[41]; (E3200)	FOLFOX4 ± bevacizumab	7.3 vs 4.7	< 0.0001	12.9 vs 10.8	0.0011
Bennouna et al[45]; (ML18147)	Chemotherapy ± bevacizumab	5.7 vs 4.1	< 0.0001	11.2 vs 9.8	0.0062
Masi et al[46]; (BEBYP)	Chemotherapy ± bevacizumab	6.8 vs 5.0	0.010	14.1 vs 15.51	0.0431

¹The lower median OS in the bevacizumab arm was due to intersection of curves; adjusted HR was 0.77 (stratified log-rank P = 0.043) and favored the bevacizumab arm. PFS: Progression-free survival; OS: Overall survival.

Table 3 Other anti-angiogenic agents

Ref.	Regimen (line of treatment)	Sample size	Objective response (%)	PFS (mo)	OS (mo)	Serious AE (grade 3-4)5
Samalin et al[73]; Phase I/II	Sorafenib/irinotecan (NEXIRI) (2nd or later line KRAS mutated)	10 (phase I)	64.9 (DCR)	3.7	8	Asthenia, diarrhea, neutropenia, HFS
		54 (phase II)
Tabernero et al[74]; Phase IIb	Sorafenib/mFOLFOX vs Placebo/mFOLFOX (1st line)	198	NA	9.1 vs 8.7	17.6 vs 18.1	Neutropenia, peripheral neuropathy, HFS
				HR, 0.88	HR, 1.13
				P = 0.46	P = 0.51
Starling et al[116]; Phase I	Sunitinib/FOLFIRI (1st line)	37	57.9	NA	NA	Febrile neutropenia neutropenia, anemia, diarrhea, mucosal inflammation, stomatitis, vomiting, lethargy, pyrexia, thrombotic events
Yoshino et al[117]; Phase I	Sunitinib/mFOLFOX6 (1st line)	12 (6 + 6)3	66.7 in each arm	NA	NA	Neutropenia, leukopenia, thrombocytopenia
Saltz et al[118]; Phase II	Sunitinib (refractory setting)	43 (prior bevacizumab)	2.4	2.2 (TTP; prior bevacizumab)	7.1	Fatigue, diarrhea, nausea, vomiting, and anorexia (most common any grade toxicities)
		41 (no prior bevacizumab)	0	2.5 (TTP; no prior bevacizumab)	10.2
Tsuji et al[75]; Phase II	Sunitinib/FOLFIRI (1st line)	71	36.61/42.32	6.71/ 7.22	NR due to early study closure	Neutropenia, leukopenia, thrombocytopenia diarrhea, nausea decreased appetite and fatigue (most common any grade)
Carrato et al[119]; Phase III	Sunitinib/FOLFIRI vs Sunitinib/placebo (1st line)	768	NA	7.8 vs 8.4 HR 1.095 one-sided stratified log-rank P = 0.807	20.3 vs 19.8 HR, 1.171 P = 0.916	Diarrhea, stomatitis/oral syndromes, fatigue, HFS, neutropenia, thrombocytopenia, anemia, febrile neutropenia
Michael et al[79]; Phase I	Vandetanib/mFOLFOX6 (1st or 2nd line)	9 (100 mg/d dose)	44.44	NA	NA	Diarrhea, nausea and lethargy (most common any grade toxicities)
		8 (300 mg/d dose)	NA	NA	NA
Saunders et al[80]; Phase I	Vandetanib/FOLFIRI	11 (100 mg/d dose)	18.18	NA	NA	Diarrhea, nausea fatigue (most common any grade toxicities; were grade 1-2)
	(1st or 2nd line)	10 (300 mg/d dose)	NA	NA	NA
Yang et al[81]; Phase II	Vandetanib/mFOLFOX6 vs Placebo/mFOLFOX6	32 (100 mg/d dose)4	NA	NA	NA	Diarrhea, nausea, thrombocytopenia, peripheral sensory neuropathy (most common any grade toxicities)
		35 (300 mg/d dose)4
Van Cutsem et al[84]; Phase III	FOLFOX 4/Vatalanib vs FOLFOX4/placebo (2nd line)	855	NA	5.6 vs 4.2	13.1 vs 11.9	Neutropenia, HTN, diarrhea, fatigue, nausea, vomiting, dizziness
				HR, 0.83	HR, 1.0
				P = 0.013	P = 0.957
Hecht et al[85]; Phase III	FOLFOX4/Vatalanib vs FOLFOX4/placebo (1st line)	1168	NA	7.7 vs 7.6	21.4 vs 20.5	Neutropenia, HTN, diarrhea, fatigue, nausea, vomiting
				HR, 0.88	HR, 1.08
				P = 0.118	P = 0.260

¹By independent review;

²Investigator initiated review;

³Six patients received sorafenib 2 wk on, 2 wk off and another 6 patients received sorafenib 4 wk on, 2 wk off;

⁴Progression events (objective/clinical progression/death) in vandetanib 100 mg arm vs placebo: 72% vs 65% (HR, 1.21; 2-sided P = 0.53); vandetanib 300 mg arm vs placebo: 77% vs 65% (HR, 1.41; 2-sided P = 0.25);

⁵In study drug containing arm. DCR: Disease control rate; NA: Not available; NR: Not reached; PFS: Progression-free survival; OS: Overall survival; mFOLFOX6: Three fluoropyrimidine regimens-infusional 5FU/LV; HFS: Hand-foot syndrome.

Table 4 Bevacizumab plus chemotherapy as conversion therapy

Ref.	Regimen	Rate ofconversion (%)	Overallresponse (%)	Median PFS (mo)	Median OS (mo)
Bertolini et al[95]; Phase II	FOLFOX6 + bevacizumab	61.9	57.1	12.9	22.5
Wong et al[97]; Phase II	CAPE-OX + bevacizumab	40	78 (95%CI: 63-89)	NA1	NA1
Nasti et al[99]; Phase II	FOLFIRI + bevacizumab	N/A	66.7 (95%CI: 49.8-80.9)	14 (95%CI: 11-24)	38 (95%CI: 28 to NA)
Klinger et al[3]; Meta-analysis/phase II	CAPE-OX/FOLFOX + bevacizumab	N/A	38 vs 10 (P < 0.001)	NA2	67 (95%CI: 8.4-125.6)2
Gruenberger et al[96]; Phase II	CAPE-OX + bevacizumab	N/A	73.2	NA	NA
Gruenberger et al[102]; Phase II	FOLFOX/FOLFOXIRI + bevacizumab	49% (FOLFOX), 61% (FOLFOXIRI)	62% (95%CI: 45-77) (FOLFOX), 81% (95%CI: 65-91) (FOLFOXIRI)	11.5 (95%CI: 9.6-13.6) (FOLFOX), 18.6 (95%CI: 12.9-22.3) (FOLFOXIRI)	32.2 (FOLFOX), not yet reached (FOLFOXIRI)
Masi et al[100]; Phase II	FOLFOXIRI + bevacizumab	26	NA	NA	NA
Loupakis et al[34]; Phase III	FOLFOX/FOLFOXIRI + bevacizumab	53.1 (FOLFOX), 65.1 (FOLFOXIRI)	12 (FOLFOX), 15 (FOLFOXIRI)	NA	NA
Saltz et al[29]; Phase III	FOLFOX/Cape-OX + bevacizumab vs FOLFOX/Cape-OX + placebo	8.4 vs 6.1	38 vs 38	9.4 vs 8	21.3 vs 19.9
		P = NA	P = 0.99	P = 0.0023	P = 0.077
Loupakis et al[98]; meta-analysis	FOLFOXIR/Cape-IRI ± bevacizumab	NA	63 vs 28	NA3	NA
			P = 0.033
Osterlund et al[101]; retrospective analysis	FOLFIRI + bevacizumab	9	42%	8.8	18.4

¹Though median PFS and OS were not specifically reported by Wong et al[97], the 12-mo PFS was 50% (95%CI: 34%-64%) and 12-mo OS was 86% (95%CI: 70%-94%);

²The OS in this study was not reported as a single parameter given its sample population. Instead, it was reported as a function of tumor regression grade, or TRG. The median OS of 67 mo cited in this table was found in those patients with lower TRGs (histologically with more fibrosis/necrosis than tumor, or major histological response). This OS decreases to 44 mo (95%CI: 14.1-73.8) in those with higher TRGs (histologically with more tumor than fibrosis/necrosis, or no histological response). Though the median PFS was not reported in this study, the 5-year PFS was 34% in lower TRGs and 9% in higher TRGs;

³Again, the PFS was reported in this study as a function of TRGs. There was a PFS benefit in those with lower TRGs compared to those with higher TRGs such that for every 10 units in the percentage of necrosis, there was a 0.83 HR reduction (95%CI: 0.7-0.99, P = 0.04). NA: Not available; N/A: Not applicable; PFS: Progression-free survival; OS: Overall survival.