Targeting metastatic colorectal cancer – present and emerging treatment options

Figures & data

Table 1 Selected Phase III trials employing targeted biologic therapies with or without chemotherapy in metastatic colorectal cancer

Trial	Biologic ± chemotherapy	Sample size	Endpoints	P-value
Price et al^Citation17 ASPECCT	Cetuximab vs panitumumab in refractory mCRC	N=999	OS: 10.0 vs 10.4 mos PFS: 4.4 vs 4.1 mos ORR: 19.8% vs 22%	P=0.0007
Ye et al^Citation18	Chemotherapy (mFOLFOX6 or FOLFIRI) ± cetuximab in first-line mCRC therapy	N=138	R0 resection rate for liver mets: 25.7% vs 7.4%	P<0.01
			ORR: 57.1% vs 29.4% OS: 30.9 vs 21.0 mos	P<0.01 P=0.013
Heinemann et al^Citation19 FIRE-3 (AIO KRK-0306)	FOLFIRI + cetuximab vs FOLFIRI + bevacizumab in first-line mCRC therapy	N=508	ORR: 62% vs 58% PFS: 10.0 vs 10.3 mos OS: 28.7 vs 25 mos	P=0.183 P=0.547 P=0.017
Bennouna et al^Citation32 ML18147	Second-line chemotherapy ± bevacizumab	N=820	OS: 11.2 vs 9.8 mos	P=0.0062
Falcone et al^Citation36 TRIBE	FOLFOXIRI + bevacizumab vs FOLFIRI + bevacizumab	N=508	PFS: 12.2 vs 9.7 mos ORR: 65% vs 53% R0 resection rate: 15% vs 12% OS: 31.0 vs 25.8 mos	P=0.0012 P=0.006 P=0.327 P=0.054
Punt et al^Citation39 CAIRO-3	CAPOX-B followed by maintenance capecitabine + bevacizumab or observation	N=558	PFS1: 8.5 vs 4.1 mos PFS2: 11.5 vs 10.5 mos TTP2: 18.7 vs 14.1 mos OS: 21.7 vs 18.0 mos	P<0.0001 P=0.03 P<0.0001 P=0.16
Johnsson et al^Citation40 Nordic ACT	First-line doublet chemotherapy + bevacizumab, followed by bevacizumab ± erlotinib	N=249	PFS: 5.7 vs 4.2 mos OS: 21.5 vs 22.8 mos	P=0.19 P=0.51
Van Cutsem et al^Citation42 VELOUR	FOLFIRI + aflibercept vs FOLFIRI + placebo in previously oxaliplatin-treated mCRC	N=1,226	OS: 13.50 vs 12.06 mos ORR: 19.8% vs 11.1% PFS: 6.90 vs 4.67 mos	P=0.0032 P=0.0001 P<0.0001
Grothey et al^Citation45 CORRECT	Regorafenib vs placebo in refractory mCRC	N=1,513	OS: 6.4 vs 5.0 mos PFS: 1.9 vs 1.7 mos ORR: 1.0% vs 0.4%	P=0.0052 P<0.0001 P=0.19

Abbreviations: mCRC, metastatic colorectal cancer; mets, metastases; mos, months; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PFS1, PFS at first progression; PFS2, PFS at second progression; TTP2, time to second progression; FOLFOX, chemotherapy regimen involving drugs folinic acid, fluorouracil, and oxaliplatin; FOLFIRI, chemotherapy regimen involving drugs folinic acid, fluorouracil, and irinotecan; FOLFOXIRI, chemotherapy regimen involving folinic acid, fluorouracil, oxaliplatin and irinotecan; CAPOX-B, chemotherapy regimen involving capecitabine, oxaliplatin and bevacizumab.

Table 2 Summary of approved targeted therapies for metastatic colorectal cancer

Drug	Class	Method of administration	Target(s)	Pathway(s)
Cetuximab (Erbitux^®)	Monoclonal antibody (IgG1 chimeric)	Intravenous	EGFR	PI3K/Akt, MAPK
Panitumumab (Vectibix^®)	Monoclonal antibody (fully human)	Intravenous	EGFR	PI3K/Akt, MAPK
Bevacizumab (Avastin^®)	Monoclonal antibody	Intravenous	VEGF-A	Angiogenesis
Aflibercept (Zaltrap^®)	Recombinant fusion protein	Intravenous	VEGF-A, VEGF-B, PlGF-1, PlGF-2	Angiogenesis
Regorafenib (Stivarga^®)	Tyrosine kinase inhibitor	Oral	VEGFR1, VEGFR2, VEGFR3, PDGFR-β, FGFR1, TIE2, KIT, RET, BRAF	Angiogenesis, oncogenesis, tumor microenvironment

Notes: Manufacturers are as follows: Erbitux: Bristol-Myers Squibb, New York, NY, USA; Vectibix: Amgen Inc., Thousand Oaks, CA, USA; Avastin: Genentech, Inc., South San Francisco, CA, USA; Zaltrap: Sanofi-Aventis, Bridgewater, NJ, USA; Stivarga: Bayer AG, Leverkusen, Germany.

Abbreviations: EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; Ig, immunoglobulin; MAPK, mitogen-activated protein kinase; PDGFR, platelet-derived growth factor receptor; PI3K, phosphatidylinositide 3-kinase; PlGF, placental growth factor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

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