Role of cetuximab in first-line treatment of metastatic colorectal cancer

Table 1 Clinical trials of cetuximab in combination with irinotecan-based chemotherapy

Clinical trial	Type of study	KRAS analysis	Treatment	Response rate	R0 resection rate	PFS (mo)	OS (mo)
Folprecht et al[37]	Phase I/II	No	Cetuximab-Irinotecan/5FU/FA1	67%	19%	9.9	33
Raoul et al[38]	Phase I/II	No	Cetuximab-FOLFIRI	48%	19.20%	8.6	22.4
CRYSTAL, Van Cutsem et al[6,20]	Phase III	Yes	Cetuximab-FOLFIRI vs FOLFIRI	57.3% vs 39.7% (OR = 2.069, P < 0.001)2	5.1% vs 2% (OR = 2.65, P = 0.0265)2	9.9 vs 8.4 (HR = 0.696, P = 0.0012)2	23.5 vs 20 (HR = 0.796, P = 0.0093)2
FIRE-3, Heinemann et al[41]	Phase III	Yes	Cetuximab-FOLFIRI vs Bevacizumab-FOLFIRI	62 vs 57 (OR = 1.18, P = 0.183)		10 vs 10.3 (HR = 1.06, P = 0.547)	28.7 vs 25 (HR = 0.77, P = 0.017)

¹AIO group regimen of irinotecan, folinic acid and infusional 5FU;

²Results in wild-type KRAS population. PFS: Progression-free survival; OS: Overall survival; FA: Folinic acid; 5FU: 5-fluorouracil; FOLFIRI: Regimen of irinotecan, infusional fluorouracil and leucovorin; AIO: Arbeitgemeinschaft internistische onkologie; CRYSTAL: CRYSTAL trial (cetuximab combined with irinotecan in first-line therapy for metastatic colorectal cancer); FIRE-3: AIO KRK-0306 trial; KRAS: v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog.

Table 2 Clinical trials of cetuximab in combination with oxaliplatin-based chemotherapy

Clinical trial	Type of study	KRAS analysis	Treatment	Response rate (%)	R0 resection rate (%)	PFS (mo)	OS (mo)
Arnold et al[48]	Phase Ib/II	No	Cetuximab-FUFOX1	57%	4%	8.1	28.2
Tabernero et al[49]	Phase II	No	Cetuximab-FOLFOX4	72%	21%	12.3	30
OPUS, Bokemeyer et al[7,21]	Phase II	Yes	Cetuximab-FOLFOX4 vs FOLFOX4	57% vs 34% (OR = 2.551, P = 0.0027)2	12% vs 3% (P = 0.0242)2	8.3 vs 7.2 (HR = 0.567, P = 0.0064)2	22.8 vs 18.5 (HR = 0.855, P = 0.39)2
COIN, Maughan et al[23]	Phase III	Yes	Cetuximab-mFOLFOX6/XELOX vs mFOLFOX6/XELOX	64% vs 57% (OR = 1.35, P = 0.049)2	15% vs 13 % (P = 0.74)2	8.6 vs 8.6 (HR = 0.96, P = 0.60)2	17 vs 17.9 (HR = 1.04, P = 0.67)2
NORDIC VII, Tveit et al[50]	Phase III	Yes	Cetuximab-Nordic FLOX vs Nordic FLOX3	46% vs 47% (OR = 0.96, P = 0.89)2	13.4% vs 14.4%2	7.9 vs 8.7 (HR = 1.07, P = 0.66)2	20.1 vs 22 (HR = 1.14, P = 0.48)2

¹FUFOX: AIO group weekly regimen of oxaliplatin, folinic acid and infusional 5FU;

²Results in wild-type KRAS population;

³Nordic FLOX: Biweekly regimen of oxaliplatin, bolus 5FU and folinic acid. KRAS: v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; PFS: Progression-free survival; OS: Overall survival; 5FU: 5-fluorouracil; XELOX: Capecitabine plus oxaliplatin.

Table 3 Clinical trials of neoadjuvant cetuximab in the treatment of liver metastases

Clinical trial	Type of study	KRAS analysis	Treatment	Response rate	R0 resection rate	PFS (mo)	OS (mo)
CELIM, Folprecht et al[67,68]	Phase II	Yes	Cetuximab-FOLFOX6 vs cetuximab-FOLFIRI	68% vs 57% (OR = 1.62, P = 0.23)	38% vs 30%	11.2 vs 10.5 (HR = 1.15, NS)	35.7 vs 29.0 (HR = 1.09, NS)
			Wild-type KRAS vs mutated KRAS	70% vs 41% (OR = 3.42, P = 0.008)	33% vs 30%	11.9 vs 9.9 (HR = 1.31, NS)	36.1 vs 27.4 (HR = 1.48, NS)
Ye et al[70]	Phase IV	Yes	Cetuximab-mFOLFOX6/FOLFIRI vs mFOLFOX6/FOLFIRI	57.1% vs 29.4% (P < 0.01)	25.7% vs 7.4% (P < 0.01)	10.2 vs 5.8 (HR = 0.6, P = 0.004)	30.9 vs 21 (HR = 0.54, P = 0.013)
			Cetuximab-mFOLFOX6 vs Cetuximab-FOLFIRI	52.8% vs 59.1% (P = 0.31)		10.1 vs 9.1 (P = 0.28)	34.8 vs 23.1 (P = 0.24)
POCHER, Garufi et al[73]	Phase II	Yes	Cetuximab-Chrono-IFLO1	79.1	60	14	37
Saridaki et al[75]	Phase II	Yes	Cetuximab-FOLFIRINOX	70	372 623	10.2	30.3

¹Chronomodulated infusion of irinotecan, 5FU, leucovorin and oxaliplatin;

²R0 resection rate in overall population;

³R0 resection rate in the subgroup of patients with metastatic disease limited to the liver. KRAS: v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; PFS: Progression-free survival; OS: Overall survival; NS: Not significant; 5FU: 5-fluorouracil; FOLFIRI: Regimen of irinotecan, infusional fluorouracil and leucovorin.