Spotlight on bevacizumab in metastatic colorectal cancer: patient selection and perspectives

Figures & data

Figure 1 The signaling cascade of VEGF and EGFR.

Note: The red antibodies indicate the point of action of anti-VEGF and anti-EGFR therapy.

Abbreviations: VEGF, vascular endothelial growth factor; VEGF-R, vascular endothelial growth factor receptor; EGFR, epidermal growth factor receptor; PI3K, phosphoinositide 3-kinase.

Table 1 Bevacizumab as first-line therapy.

Study	Phase	Treatment arms	PFS (months)	OS (months)	P-value
Hurwitz et al^Citation11,Citation31	III	IFL/Bevacizumab	10.6	20.3	<0.001
		IFL/Placebo	6.2	15.6	NR
Fuchs et al^Citation10,Citation34	III	FOLFIRI	7.6	23.1	NR
		mIFL	5.9	17.6	NR
		CapeIRI	5.8	18.9	NR
		FOLFIRI/Bevacizumab	NR	Not reached	NR
		mIFL/Bevacizumab	NR	19.2	NR
Saltz et al^Citation36^#	III	XELOX or FOLFOX/placebo	8.0	19.9	0.077
		XELOX or FOLFOX/bevacizumab	9.4^*	21.3	NR
Hochster et al^Citation35	III	mFOLFOX6/Bevacizumab	NR	26.1	NR
		FOLFOX/Bevacizumab	NR	20.4	NR
		CapOx/Bevacizumab	NR	24.6	NR
Kabbinavar et al^Citation29	II	5-FU + LV/Bevacizumab	9.2^*	16.6	0.16
		5-FU + LV/Placebo	5.5	12.9	NR
Tebbutt et al^Citation43	III	Capecitabine	5.7	18.9	0.001
		CB	8.4	NR	NR
		CBM	8.4	16.4	NR
Masi et al^Citation38	II	FOLFOXIRI/Bevacizumab	13.1	30.9	NR
Loupakis et al^Citation39	II	FOLFIRI/Bevacizumab	9.7	25.8	0.003
		FOLFOXIRI/Bevacizumab	12.1^*	31.0	NR
Lenz et al^Citation37	II	mFOLFOX6/bev	10.1	23.9	NS
		FOLFIRI/bev	12.6	27.5	NR

Notes:

* PFS was statistically significant in this study;

# OS was not statistically significant. In this study, OS was reported with capecitabine, mitomycin, and bevacizumab. NS, both PFS and OS were not significant in this study.

Abbrevations: PFS, progression-free survival; OS, overall survival; IFL, irinotecan; 5-FU, 5-fluorouracil; LV, leucovorin; CB, capecitabine plus bevacizumab; CBM, capecitabine, bevacizumab, and mitomycin; bev, bevacizumab; NR, not reported; NS, not significant; CapeIRI, capecitabine plus irinotecan.

Table 2 Bevacizumab as maintenance therapy

Study	Treatment arms	PFS (months)	OS (months)	P-value
Diaz-Rubio et al^Citation45	Bevacizumab vs XELOX + bevacizumab	10.4 vs 9.7	20 vs 23.2	NS
Koeberle et al^Citation46	Bevacizumab vs drug holiday	4.1 vs 2.9	25.4 vs 23.8	NS
Yalcin et al^Citation47	XELOX + bevacizumab vs capecitabine + bevacizumab	8.3 vs 11	20.2 vs 23.8	0.002^*
Simkens et al^Citation48	Bevacizumab + capecitabine vs drug holiday	11.7 vs 8.5	21.6 vs 18.1	PFS: <0.0001 OS: <0.06
Bennouna et al^Citation60	^#Drug holiday vs bevacizumab vs bevacizumab + capecitabine	6.9 vs 6.1	20.2 vs 21.9	NS

Notes:

* Only PFS was significant in this study.

# In this study, there were three groups; however, analysis was done on time to progression for only bevacizumab vs bevacizumab + capecitabine.

Abbrevations: PFS, progression-free survival; OS, overall survival; NS, not significant.

Table 3 Predictive biomarkers for bevacizumab therapy

Marker	Study	Outcome	P-value
Elevated VEGF-A	Zhao et al^Citation50	Poor PFS and OS	0.0001
	Bruhn et al^Citation52	Decreased PFS	0.008
Elevated proteinuria	Uysal et al^Citation53	Decreased PFS	0.01
	Khoja et al^Citation55	Decreased OS	0.028
Hypertension	Uysal et al^Citation53	Better response	0.034
	Chen et al^Citation54	Improved PFS and OS	<0.00001
	Zhong et al	Improved PFS and OS	<0.001

Abbrevations: VEGF-A, vascular endothelial growth factor ligand A; PFS, progression-free survival; OS, overall survival.

Table 4 Anti-VEGF versus anti-EGFR therapy in first-line treatment of non-mutated RAS mCRC

			PFS (months)	P-value	OS (months)	P-value
KRAS WT	FIRE-3^17	Cetuximab + FOLFIRI	10.0	0.55	28.7	0.017
		Bevacizumab + FOLFIRI	10.3		25.0
	CALGB 80405^63	Cetuximab + FOLFOX/FOLFIRI	10.4	0.55	29.9	0.34
		Bevacizumab + FOLFOX/FOLFIRI	10.8		29.0
RAS WT	FIRE-3^17	Cetuximab + FOLFIRI	10.4	0.54	33.1	0.0059
		Bevacizumab + FOLFIRI	10.2		25.0
	CALGB 80405^63	Cetuximab + FOLFOX/FOLFIRI	11.4	0.31	32.0	0.40
		Bevacizumab + FOLFOX/FOLFIRI	11.3		31.2

Abbrevations: VEGF, vascular endothelial growth factor; EGFR, epidermal growth factor receptor; mCRC, metastatic colorectal cancer; PFS, progression-free survival; OS, overall survival; WT, wild-type.

Table 5 Anti-VEGF after progression with bevacizumab

Study	Treatment arms	Phase	PFS (months)	OS (months)	P-value
Bennouna et al^Citation60	Second-line chemotherapy (oxaliplatin or irinotecan) + bevacizumab	III	NR	11.1	0.0062
Van Cutsem et al^Citation61^*	FOLFIRI + aflibercept vs FOLFIRI + placebo	III	NR	13.5	0.0032
Tabernero et al^Citation62	FOLFIRI + ramucirumab vs FOLFIRI + placebo	III	5.7	13.3	0.0219

Note:

* Approximately 30% of patients in this study were exposed to bevacizumab in the first line.

Abbrevations: PFS, progression-free survival; OS, overall survival; NR, not reported.

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