TABLE 2.

Personalization of mCC care based on molecular markers

PREDICTORS OF RESPONSE TO EGFR INHIBITION - KRAS
Author Trial Namea	Journal	Regimen Tested	Number of Patients	Number of KRAS wt	Number of KRAS mt	Primary Endpointb		Significance
						KRAS wt	KRAS mt
De Roock et al BOND Subgroup analysis	ASCO 2007 Abstr. 4132	Irinotecan- cetuximab vs cetuximab	N=37	N=20	N=17	RR		KRAS mt p<0.01 Responders vs Nonresponders
						45.8%	1.3%
Van Cutsem et al EVEREST Subgroup analysis	ASCO 2008, Abstr. 4001	Irinotecan- cetuximab vs Same + cetuximab escalation to rash	38 39	19 28	19 11	RR		Not reported
						4/19 (21.1%) 13/28 (46.4%)	0/19 0/11
Amado et al69 Subgroup analysis	JCO, 2008	p-MAb vs BSC	208 vs 219	124 vs 119	84 vs 100	PFS		KRAS wt HR 0.59 (0.48 to0.72)
						12.3 vs 7.3	7.4 vs 7.3
Bokemeyer et al66 OPUS Phase II Subgroup analysis	JCO, 2009	FOLFOX- cetuximab vs FOLFOX	113 vs 120	61 vs 73	52 vs 47	RR		KRAS wt p= 0.011 KRAS mt p=0.106 NS
						37/61 (61%) 27/73 (37%)	17/61 (31%) 23/47 (49%)
Tol et al68 CAIRO-2 Subgroup analysis	NEJM, 2009	CapeOx- bev + cetuxmab vs CapeOx- bev	256 vs 264	158 vs 156	98 vs 108	PFS		KRAS wt p=0.3 NS KRAS mt p=0.003
						10.5 vs 10.6	8.1 vs 12.5
Hecht et al72 PACCE Subgroup analysis	JCO, 2009 ARM A	FOLFOX and bev + p-MAb vs FOLFOX and bev	336 vs 328	201 vs 203	135 vs 125	PFS		KRAS wt HR 1.36 (1.04 to 1.77) KRAS mt HR 1.25 (0.91 to 1.71)
						9.8 vs 11.5	10.4 vs 11
	ARM B	FOLFIRI and bev + p-MAb vs FOLFIRI	104 vs 97	57 vs 58	47 vs 39	PFS		KRAS wt HR 1.50 (0.82 to 2.76) KRAS mt HR 1.25 (0.65 to 2.21)
Maughan et al MRC-COIN Subgroup analysis	JCO, 2010 Abstr. 3502	FOLF OX/ CapeOX +/− cetuximab	N=1316	N=729	N=587	10  O	S 8.3	KRAS wt HR 1.50 (0.82 to 2.76) KRAS mt HR 1.25 (0.65 to 2.21)
						1 7 vs 17.9 12.5	- vs 11.9
Douillard et al PRIME Subgroup analysis	JCO, 2010 Abstr. 3528	FOLFOX+ p-MAb vs FOLFOX	N=1096	N=656	N=440	PFS		KRAS wt p= 0.02 KRAS mt p=0.019
						9.6 vs 8	7.6 vs 5.7
Van Cutsem et al CRYSTAL Subgroup analysis	GI ASCO 2010 Abstr. 281	FOLFIRI+ cetuximab vs FOLFIRI	530 vs 533	316 vs 350	214 vs 183	PFS		KRAS wt p= 0.0012 KRAS mt p=0.2661 NS
						9.9 vs 8.4	7.4 vs 7.7
De Roock et al70 Subgroup analysis	Lancet Oncol, 2010	p-MAb or cetuximab or cetuximab + chemo	N=747	448	299	OS		P<0.0001
						50 wks	32 wks
N0147 Prospective Adjuvant	2010 Abstr. 3508, CRA3507	FOLFOX+ cetuximab vs FOLFOX	902 vs 858	902 vs 858	318 vs 340	3 yr DFS		p=0.33 NS KRAS mt p=0.02
						73.3 vs 74.1	62.3 vs 70.3
PETACC-8 Prospective Adjuvant	Ongoing	FOLFOX+ cetuximab vs FOLFOX	N=>6000	-	-	3 yr DFS		First interim analysis planned 2011
PREDICTORS OF RESPONSE TO EGFR INHIBITION - OTHER
Van Cutsem et al EVEREST Subgroup analysis	GI ASCO 2007, Abstr. 237 RASH	Irinotecan- cetuximab vs Same + cetuximab escalation to rash	45 44	-	-	RR		CI 5%–27% vs 17%–48%
						13%	30%
Van Cutsem et al CRYSTAL Subgroup analysis	ASCO, 2010 Abstr. 3570 KRAS wt BRAF analysis	FOLFIRI+ cetuximab vs FOLFIRI	303 vs 322	BRAF wt 277 vs 289	BRAF mt 26 vs 33	PFS		BRAF wt p=0.0016 BRAF mt p=0.8656 NS
						10.9 vs 8.8	8 vs 5.6
De Roock et al70 Subgroup analysis	Lancet Oncol, 2010 KRAS wt BRAF analysis	p-MAb cetuximab cetuximab + chemo	N= 761	BRAF wt 725	BRAF mt 36	OS		p<0.0001
						54 wks	26 wks
De Roock et al70 Subgroup analysis	Lancet Oncol, 2010 PIK3A Exon 20 analysis	p-MAb cetuximab cetuximab + chemo cetuximab + chemo	N= 743	NRAS wt 635	NRAS mt 108 (22 exon 20 74 exon 9 12 other)	OS		p<0.0057
						51 wks	34 wks
De Roock et al70 Subgroup analysis	Lancet Oncol, 2010 KRAS wt NRAS Analysis	p-MAb cetuximab cetuximab + chemo	N= 644	NRAS wt 627	NRAS mt 17	RR		p<0.013
						38.1%	7.7%

^aRandomized Phase III trials unless otherwise specified.

^bUnits indicated in months unless otherwise indicated.

wt, wild type; mt, mutant; p-MAb, panitumumb; BSC, best supportive care; NS, not significant; bev, bevacizumab; RR, response rate; PFS, progression free survival; OS, overall survival; DFS, disease free survival.