Critical appraisal of bevacizumab in the treatment of metastatic colorectal cancer

Figures & data

Table 1 Response rate, progression-free survival, and overall survival of bevacizumab in first-line treatment of metastatic colorectal cancer

Author	Phase study	Treatment	Population	Median OS (months)	HR, P value	Median PFS (months)	HR, P value	RR (%)	OR, P value
Bevacizumab with fluoropyrimidines plus irinotecan
Hurwitz et al^Citation13	III	IFL-placebo	411	15.6		6.2		34.8
		IFL-BV	402	20.3	0.66,	10.6	0.54,	44.8	P = 0.004
		5-FU-FA-BV	110	18.3	P < 0.001	8.8	P < 0.001	40
Stathopoulos et al^Citation32	III	IFL-Placebo	108	25.0	P = 0.1391	NR	NR	35.2	NR
		IFL-BV	114	22.0		NR		36.8
Fuchs et al^Citation33	III	FOLFIRI-BV	57	28.0	P = 0.007	11.2	P = 0.28	57.9	NR
		mIFL-BV	60	19.8		8.3		53.3
Sobrero et al^Citation34	IV	FOLFIRI-BV	209	22.2	NR	11.1	NR	53.1	NR
Kopetz et al^Citation35	II	FOLFIRI-BV	43	31.3	NR	12.8	NR	65	NR
Bevacizumab with fluoropyrimidines plus oxaliplatin
Saltz et al^Citation15	III	XELOX-FOLFOX4-placebo	701	19.9	0.89,	8.0	0.83,	49	0.90,
		XELOX-FOLFOX4-BV	699	21.3	P = 0.0769	9.4	P = 0.0023	47	P = 0.31
Hochster et al^Citation37	III	FOLFOX-BV	71	26.1	NR	NR	NR	52	NR
		bFOL-BV	70	20.4				39
		CapeOx-BV	72	24.6				46
Bevacizumab with fluoropyrimidines alone
Kabbinavar et al^Citation11	II	5-FU-FA	36	13.8		NR	NR	17	NR
		5-FU-FA-BV (5 mg/g)	35	21.5	0.63			40
		5-FU-FA-BV (10 mg/kg)	33	16.1	1.17			24
		5-FU-FA-placebo	105	12.9	0.79,	5.5	0.50,	15	P = 0.0552
Kabbinavar et al^Citation12	II	5-FU-FA-BV	104	16.6	P = 0.159	9.2	P = 0.0002	26
Tebbutt et al^Citation38	III	Capecitabine	156	18.9	0.875,	5.7	0.63,	30.3	P = 0.16
		Capecitabine-BV	157	18.9	P = 0.314	8.5	P < 0.001	38.1	P = 0.006
		Capecitabine-BV-mitomycin	158	16.4	0.942,	8.4	0.59,	45.9
					P = 0.642		P < 0.001

Abbreviations: OS, overall survival; PFS, progression-free survival; RR, response rate; HR, hazard ratio; OR, odds ratio; IFL, bolus 5-fluorouracil-folinic acid-irinotecan; BV, bevacizumab; 5-FU, 5-fluorouracil; FA, folinic acid; FOLFIRI, infusional 5-fluorouracil-bolus folinic acid-irinotecan; mIFL, modified bolus 5-fluorouracil-irinotecan; FOLFOX4, infusional 5-fluorouracil-bolus folinic acid-oxaliplatin; XELOX, capecitabine-oxaliplatin; bFOL, bolus 5-fluorouracil-oxaliplatin; CapeOx, capecitabine-oxaliplatin; NR, not reported.

Table 2 Response rate, progression-free survival, and overall survival of bevacizumab in second-line and later-line treatment of metastatic colorectal cancer

Author	Phase study	Treatment line	Treatment	Population	Median OS (months)	HR, P value	Median PFS (months)	HR, P value	RR (%)	OR, P value
Giantonio et al^Citation14	III	II	FOLFOX4	291	12.9	0.75,	7.3	0.61,	22.7	P < 0.001
			FOLFOX4-BV	289	10.8	P = 0.0011	4.7	P < 0.0001	8.6
			BV	243	10.2		2.7		3.3
Yildiz et al^Citation41	Retrospective	II	BV + irinotecan-based therapy	40	14	NR	6	NR	20	NR
Horita et al^Citation42	II	II	FOLFIRI-BV	25	21.4	NR	11.6	NR	32	NR
Morikawi et al^Citation40	Cohort	II	FOLFIRI-BV	115	21.6	NR	8.3	NR	25	NR
			FOLFOX4-BV	45	16.5		7.8		29
Bennouna et al^Citation44	II	II	BV + irinotecan-based or oxaliplatin-based therapy	53	19.3	NR	6.5	NR	32	NR
Chen et al^Citation45	II	III	BV-5-FU-FA	100	9.1	NR	3.7	NR	4	NR
Park et al^Citation46	Retrospective	II or later-line	BV-FOLFIRI or FOLFOX4	40	14	NR	6.3	NR	7.5	NR
Lievre et al^Citation47	Retrospective	II or later-line	BV + FOLFIRI or FOLFOX4	31	18.4	NR	9.7	NR	32.2	NR
Kwon et al^Citation49	Retrospective	III	BV-FOLFIRI	14	10.9	NR	3.9	NR	28.5	NR
Kang et al^Citation48	Retrospective	III or later-line	BV-FOLFIRI or FOLFOX4	42	0.5	NR	5.3	NR	9.5	NR

Abbreviations: OS, overall survival; PFS, progression-free survival; RR, response rate; HR, hazard ratio; OR, odds ratio; BV, bevacizumab; 5-FU, 5-fluorouracil; FA, folinic acid; FOLFIRI, infusional 5-fluorouracil-bolus folinic acidirinotecan; FOLFOX4, infusional 5-fluorouracil-bolus folinic acid-oxaliplatin; NR, not reported.

Table 3 Response and resectability of liver metastatic disease treated with neoadjuvant bevacizumab + chemotherapy

Author	Phase Study	Liver metastases	Treatment	Population	RR (%)	Surgery R0 (%)	Curative intent rate (%)
Van Cutsem et al^Citation50	IV	No operable	BV-FOLFIRI	704	NR	11.7	14.3
			BV-FOLFOX		NR	15.4	20.3
Gruenberger et al^Citation16	II	Operable	BV-XELOX	56	73.2	92.85	92.85
Bouganim et al^Citation51	Retrospective	Operable	BV-oxaliplatin BV-irinotecan	60	80	NR	100
Blazer et al^Citation52	Retrospective	No operable	BV-FOLFIRI-XELIRI	305	40.7	89.83	8.85
			BV-FOLFOX-XELOX		62.9	NR
Masi et al^Citation53	II	No operable	BV-FOLFOXIRI	30	NR	43	NR
Wong et al^Citation54	II	No operable	BV-CAPOX	45	78	6.52	17.7

Abbreviations: RR, response rate; BV, bevacizumab; FOLFIRI, infusional 5-fluorouracil-bolus folinic acid-irinotecan; FOLFOX, infusional 5-fluorouracil-bolus folinic acidoxaliplatin; XELOX, capecitabine-oxaliplatin; CAPOX, capecitabine-oxaliplatin; NR, not reported.

Table 4 Overall survival, progression-free survival, and response rate of bevacizumab continued beyond first progression and in maintenance treatment

Author	Phase study	Treatment	Overall	Median OS (months)	HR, P value	Median PFS (months)	HR, P value	RR (%)	OR, P value
Grothey et al^Citation59,*	Prospective	Post progression treatment without BV	531	19.9	0.49,	NR	NR	NR	NR
		Post progression treatment with BV	642	31.8	P < 0.001	NR		NR
Andre et al^Citation60,*	III	II line CT until PD	411	9.8	0.81,	4.1	0.68,	3.9	P = 3113
		II line CT + BV until PD	409	11.2	P = 0.0062	5.7	P < 0.0001	5.4
Grothey et al^Citation62,§	III	Conventional L-OHP	139	NR	NR	7.3	NR	NR	NR
		Intermittent L-OHP + BV		NR		12		NR
Diaz-Rubio et al^Citation63,§		III XELOX + BV →	239	23.3	1.05,	10.4	1.10,	47%	0.95
		XELOX + BV XELOX + BV → BV	241	20.0	P = 0.65	9.7	P = 0.38	49%
Tournigand et al^Citation64,§	III	BV + erlotinib	222	NR	NR	5.76	0.73,	NR	NR
		BV	226	NR		4.67	P = 0.0050	NR
Johnsonn et al^Citation65,§	III	BV + erlotinib	249	NR	NR	5.9	0.81,	NR	NR
		BV		NR		4.2	P = 0.24	NR

Notes:

* BV continued beyond first progression;

§ BV used as maintenance treatment.

Abbreviations: OR, odds ratio; OS, overall survival; PFS, progression-free survival; BV, bevacizumab; CT, chemotherapy; HR, hazard ratio; L-OHP, oxaliplatin; XELOX, capecitabine-oxaliplatin; NR, not reported; PD, progression disease; RR, response rate.

Table 5 Response rate, overall survival, and progression-free survival: comparability of results between wild-type KRAS versus mutated KRAS groups and wild-type BRAF versus mutated BRAF groups

Author	Treatment	Population	RR (%)	OR, P value	Median OS (months)	HR, P value	Median PFS (months)	HR, P value
Hurwitz et al^Citation71	IFL-placebo wt-Kras	67	37.3	P = 0.006	17.6	0.58,	7.4	0.44,
	IFL-BV wt-Kras	85	60	P = 0.86	27.7	P = 0.04;	13.5	P < 0.0001;
	IFL-placebo mut-Kras	34	41.2		13.6	0.69,	5.5	0.41,
	IFL-BV mut-Kras	44	44		19.9	P = 0.26	9.3	P = 0.0008
Price et al^Citation72	Cape wt-Kras	315	27.1	P = 0.02	20	NR	5.9	NR
	Cape mut-Kras		48.5		22.8		6.2
	CB wt-Kras		41		19.8	NR	8.8	NR
	CB mut-Kras		24.2		17.6		8.2
	CBM wt-Kras		44.7		21.4	NR	6	NR
	CBM mut-Kras		45.8		6.3		2.5
	Cape wt-Braf	315	35.5	P = 0.91	20.8	NR	9.1	NR
	Cape mut-Braf		25		9.2		5.5
	CB wt-Braf		35.6
	CB mut-Braf		42.9
	CBM wt-Braf		48.2
	CBM mut-Braf		27.8
Tol et al^Citation73	Cape-L-OHP-BVwt-Kras	156	50	P = 0.16	22.4	P = 0.82	10.6	P = 0.80
	Cape-L-OHP-BV mut-Kras	108	59.2	P = 0.03	24.9	P = 0.06	12.5	P = 0.04
	Cape-L-OHP-BV-C wt-Kras	158	61.4		21.8		10.5
	Cape-L-OHP-BV-C mut-Kras	98	45.9		17.2		8.1
Hecht et al^Citation74	L-OHP-CT-BV wt-Kras	203	56	NR	24.5	HR, 1.89;	11.5	HR, 1.36;
	L-OHP-CT-BV-P wt-Kras	201	50		20.7		9.8
	L-OHP-CT-BV mut-Kras	125	44	NR	19.3	HR, 1.02	11	HR, 1.25
	L-OHP-CT-BV-P mut-Kras	135	47		19.3		10.4
	CPT-11-CT-BV wt-Kras	58	48	NR	19.8	HR, 1.28 to NR;	12.5	HR, 1.50;
	CPT-11-CT-BV-P wt-Kras	57	54		NR	HR, 2.14	10
	CPT-11-CT-BV mut-Kras	39	38	NR	20.5		11.9	HR, 1.19
	CPT-11-CT-BV-P mut-Kras	47	30		17.8		8.3
Van Cutsem et al^Citation61	II line CT wt-Kras	316	NR	NR	11.1	HR, 0.69	4.5	HR, 0.61
	II line CT + BV wt-Kras	300	NR		15.4	P = 0.0052;	6.4	P < 0.0001;
	II line CT mut-Kras		NR	NR	10	HR, 0.91	4.1	HR, 0.70
	II line CT + BV mut-Kras		NR		10.4	P = 0.4969	5.5	P = 0.0027

Note: All studies are Phase III.

Abbreviations: OS, overall survival; PFS, progression-free survival; RR, response rate; HR, hazard ratio; OR, odds ratio; IFL, bolus 5-fluorouracil-folinic acid-irinotecan; BV, bevacizumab; Cape, capecitabine; CB, capecitabine, bevacizumab; CBM, capecitabine, bevacizumab, mitomycin; wt, wild-type; mut, mutated; vs, versus; L-OHP, oxaliplatin; C, cetuximab; CPT-11, irinotecan; L-OHP-CT, oxaliplatin-based chemotherapy; CPT-11-CT, irinotecan-based chemotherapy; P, panitumumab; NR, not reported.

Table 6 Bevacizumab and anti-epithelial growth factor receptor monoclonal antibodies

Author	Phase study	Treatment	Population	Median OS (months)	HR, P value	Median PFS (months)	HR, P value	RR (%)	OR, P value
Saltz et al^Citation77	II	CPT-11-BV-Cmab	43	14.5	NR	7.3	NR	37	NR
		BV-Cmab	40	11.4		4.9		20
Tol et al^Citation73	III	Cape-L-OHP-BV	368	20.3	P = 0.16	10.7	P = 0.01	50	P = 0.49
		Cape-L-OHP-BC-Cmab	368	19.4		9.4		52.7
Hecht et al^Citation74	IIIB	L-OHP-CT-BV	410	24.5	HR, 1.43	11.4	HR, 1.06	48	NR
		L-OHP-CT-BV-Pmab	413	19.4		10		46
		CPT-11-CT-BV	115	20.5	HR, 1.42	11.7	HR, 1.19	46	NR
		CPT-11-CT-BV-Pmab	115	20.7		10.1		49

Abbreviations: OS, overall survival; PFS, progression-free survival; RR, response rate; HR, hazard ratio; OR, odds ratio; BV, bevacizumab; Cmab, catuximab; Pmab, panitumumab; Cape, capecitabine; L-OHP, oxaliplatin; CPT-11, irinotecan; L-OHP-CT, oxaliplatin-based chemotherapy; CPT-11-CT, CPT-11-based chemotherapy; NR, not reported.

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