Targeted therapy in advanced metastatic colorectal cancer: Current concepts and perspectives

Table 1 Effect of bevacizumab in phase III Studies in patients with metastatic colorectal cancer

Study	Treatment	Phase	Regimen	Patients (n)	Overall response	Median PFS	Median OS
						(mo)	(mo)
Hurwitz et al[5],	First-line	3	IFL + Bev	402	45%	10.6	20.3
AVF2107 trial,			vs
2004			Placebo	411	35%	6.2	15.5
					P = 0.004	P < 0.001	P < 0.001
Fuchs et al[6],	First-line	3	FOLFIRI (period 1)	144	47%	7.6	23.1
BICC-C trial,			FOLFIRI + Bev (period 2)	57	54.4%	11.2	28.0
2007
Saltz et al[10],	First-line	3	FOLFOX-4 or XELOX + Placebo	701	38%	8.0	19.9
N016966 trial,			vs
2008			FOLFOX-4 or XELOX + Bev	699	38%	9.4	21.3
						P = 0.0023	P = 0.077
Hochster et al[9],	First-line	3	mFOLFOX-6	69	41%	8.7	19.2
TREE1/2 study,			XELOX	48	27%	5.9	17.2
2008			mFOLFOX-6 + Bev	71	52%	9.9	26.1
			XELOX + Bev	72	36%	10.3	24.6
Giantonio et al[11],	Second-line	3	FOLFOX + Bev	290	22.7%	7.3	12.9
ECOG E3200,			Placebo	289	8.6%	4.7	10.8
2007						P < 0.0001	P = 0.0011
Bev beyond progression	Second-line	3	Continued use of Bev + standard	409	5.4%	5.7	11.2
Bennouna et al[12],			2nd-line CTX vs 2nd-line CTX alone	411	3.9%	4.1	9.8
ML18147 (TML),
2012					P = 0.3113	P = 0.0001	P = 0.0062

IFL: Irinotecan/bolus 5-FU/leuvovorin; Bev: Bevacizumab; PFS: Progression free survival; OS: Overall survival; CTX: Chemotherapy.

Table 2 Effect of cetuximab in phase II/III studies in patients with metastatic colorectal cancer

Study	Treatment	Phase	Regimen	Patients (n)	Overall response	Median PFS (mo)	Median OS (mo)
Cunnigham et al[22],	Refractory to irinotecan	2	Irinotecan+	218	22.90%	4.1	8.6
BOND study,			cetuximab
2004			vs
			cetuximab alone	211	10.80%	1.5	1.5
					P = 0.0074	P < 0.0001	P = 0.48
Van Cutsem et al[28],	First-line	3	FOLFIRI + cetuximab	105	36.20%	7.6	17.5
CRYSTAL trial,			vs
2009			placebo	87	40.20%	8.1	17.7
			(K-Ras mutant)		OR = 0.80	HR = 1.07	HR = 1.03
						P = 0.75
			FOLFIRI + cetuximab	172	59.30%	9.9	24.9
			vs
			placebo	176	43.20%	8.7	21.0
			(K-Ras wild-type)		OR = 1.91	HR = 0.68	HR = 0.84
					P = 0.004	P = 0.048
Bokemeyer et al[29,30],	First-line	2	FOLFOX + cetuximab	52	33%	8.6	NR
OPUS trial,			vs
2008			placebo	47	49%	5.5	NR
			(K-Ras mutant)		OR = 0.507	HR = 1.83
					P = 0.106	P = 0.0192
			FOLFOX + cetuximab	61	61%	7.7	NR
			vs
			placebo	73	37%	7.2	NR
			(K-Ras wild-type)		OR = 2.54	HR = 0.57
					P = 0.011	P = 0.016
Heinemann et al[31],	First line	3	FOLFIRI + cetuximab	297	62%	10.3	28.7
FIRE-3,			FOLFIRI + bevacizumab	295	57%	10.4	25.0
2013					OR = 1.249	HR = 1.04	HR = 0.77
					P = 0.18	P = 0.69	P = 0.017

PFS: Progression free survival; OS: Overall survival; NR: Not reported.

Table 3 Effect of panitumumab in phase III studies in patients with metastatic colorectal cancer

Study	Treatment	Phase	Regimen	Patients (n)	Overall response	Median PFS (mo)	Median OS (mo)
Van Cutsem et al[33],	Refractory to standard CTX	3	Panitumumab + BSC	231	10%
2007			vs
			BSC	232	0%	HR = 0.54	HR = 1.0
					P < 0.0001
Douillard et al[34],	First-line	3	K-Ras WT
PRIME-trial,			FOLFOX4 + panitumumab	325	55%	9.6	23.9
2010			FOLFOX4	331	48%	8.0	19.7
					OR = 1.35	HR = 0.8	HR = 0.83
					P = 0.068	P = 0.02	P = 0.072
			K-Ras MT
			FOLFOX4 + panitumumab	221	40%	7.3	15.5
			FOLFOX	219	40%	8.8	19.3
						HR = 1.29	HR = 1.24
						P = 0.02	P = 0.068
Peeters et al[35],	Second-line	3	K-Ras WT
2010			FOLFIRI + panitumumab	303	35%	5.9	14.5
			FOLFIRI	294	10%	3.9	12.5
					P = 0.001	HR = 0.73	HR = 0.85
						P = 0.004	P = 0.12
			K-Ras MT
			FOLFIRI + panitumumab	238	13%	5.0	11.8
			FOLFIRI	248	14%	4.9	11.1
						HR = 0.85	HR = 0.94
						P = 0.14
Douillard et al[36],	First-line	3	K-Ras WT/MT other Ras
Update			FOLFOX4 + panitumumab	51	NR	7.3	17.1
Prime-trial,			FOLFOX4	57	NR	8.0	18.3
2013						HR = 1.28	HR = 1.29
						P = 0.326	P = 0.305
			K-Ras + N-Ras WT
			FOLFOX4 + panitumumab	259	NR	10.1	26.0
			FOLFOX	253	NR	7.9	20.2
						HR = 0.72	HR = 0.78
						P = 0.004	P = 0.043
Schwartzberg et al[37],	First-line	2	K-Ras WT/MT other RAS				Not
PEAK-trial,			mFOLFOX6 + panitumumab	142	NR	10.9	Reached
2013			mFOLFOX6 + bevacizumab	143	NR	10.1	25.4
						HR = 0.87	HR = 0.72
						P = 0.35	P = 0.14
			K-Ras / N-RAS WT				Not
			mFOLFOX6 + panitumumab mFOLFOX6 + bevacizumab	88	NR	13.0	Reached
				82	NR	9.5	29.0
						HR = 0.65	HR = 0.61
						P = 0.03	P = 0.09

PFS: Progression free survival; OS: Overall survival; BSC: Best supportive care; CTX: Chemotherapy; WT: Wild-type; MT: Mutant; NR: Not reported.