Rationally designed treatment for metastatic colorectal cancer: Current drug development strategies

Table 1 Completed trials of approved targeted treatments

Drug	Target	Study	Phase patients	Outcome
Bevacizumab	VEGF-A	Bevacizumab in combination with Oxaliplatin-based chemotherapy as first-line therapy in metastatic CRC.	Phase III	Median OS 21.3 mo Bev/chemo arm vs 19.9 mo chemo alone
			n = 1401	(HR = 0.89, 97.5%CI: 0.76-1.03, P = 0.077)
Cetuximab	EGFR	Cetuximab combined with FOLFIRI vs FOLFIRI alone as first line in mCRC.	Phase III n = 599	Median OS for KRAS WT patients: 23.5 mo (97.5%CI: 21.2-26.3) in Cetux/FOLFIRI arm vs 20 mo (97.5%CI: 17.4-21.7) in FOLFIRI alone
Panitumumab	EGFR	Panitumumab with FOLFOX vs FOLFOX alone in first line aCRC	Phase III n = 656	Median OS (KRAS wt) 23.8 mo (97.5%CI: 20.0–27.7) with panitum/FOLFOX vs 19.4 mo (97.5%CI: 17.4-22.6) with FOLFOX alone
Ziv-aflibercept	VEGFA	Addition of Aflibercept to FOLFIRI in patient with mCRC previously treated with Oxaliplatin-based chemotherapy (including patients who received Bevacizumab)	Phase III	Median OS 13.5 mo (97.5%CI: 12.5-14.9) with Aflibercept/FOLFIRI vs 12 mo (97.5%CI: 11-13) with FOLFIRI alone
	VEGFB		n = 1226
	PIGF
Regorafenib	VEGFR -1, -2, -3	Regorafenib monotherapy for previously treated metastatic colorectal cancer vs best supportive care (CORRECT)	Phase III	Median OS 6.5 mo with Regorafenib vs 5 mo for best supportive care (HR = 0.77, 97.5%CI: 0.64-0.94, P = 0.0052)
	TIE2		n = 760
	KIT, RET, RAF1, BRAF, and BRAFV600E
	PDGFR and FGFR

VEGF: Vascular-endothelial growth factor; EGFR: Epidermal growth factor receptor; FGFR: Fibroblast growth factor receptor; PDGFR: Platelet-derived growth factor receptor; mCRC: Metastatic colorectal cancer; OS: Overall survival.

Table 2 On-going clinical trials with novel targeted therapeutics

Drug	Target	Study	Phase	Objective
			Patients (est.)	(primary, secondary)
Vemurafenib plus	BRAF/EGFR	A Pilot Study of Vemurafenib and Panitumumab Combination Therapy in Patients With BRAF V600E Mutated Metastatic Colorectal Cancer	I/II	ORR
Panitumumab			n = 15	PFS/OS
Vemurafenib, Cetuximab plus	BRAF/EGFR plus chemotherapy	A Phase I Trial of Vemurafenib in Combination With Cetuximab and Irinotecan in Patients With BRAF V600 Mutant Advanced Solid Malignancies	I	MTD
Irinotecan			n = 63
Dabrafenib, Trametinib panitumumab	BRAF/MEK and EGFR	An Open-Label, Three-Part, Phase I/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of the MEK Inhibitor GSK1120212, BRAF Inhibitor GSK2118436 and the Anti-EGFR antibody Panitumumab in Combination in Subjects With BRAF-mutation V600E or V600K Positive Colorectal Cancer	I/II	DLTs
			n = 200	Pharmacokinenics
				RR
LGX818	BRAF	A phase I, multicentre, open label, dose-escalation study of oral LGX818 in adult patients advanced colorectal cancer BRAF mutated	I	DLT
			n = 126	Tumour response
LGX818	BRAF	A Phase Ib/II Multi-center, Open-label, Dose Escalation Study of LGX818 and Cetuximab or LGX818, BYL719, and Cetuximab in Patients With BRAF Mutant Metastatic Colorectal Cancer	I/II	DLT
BYL719	PI3K		n = 124	PFS
Cetuximab	EGFR
CEP-32496	BRAF	An open-Label, Phase 1/2, Single-Agent Study of CEP-32496 in Patients With Advanced Solid Tumors in Phase 1 and in Patients With Advanced Melanoma and Metastatic Colorectal Cancer With BRAF Mutation in Phase 2	I/IIn = 154	ORRPFS
BKM120	PI3K	Phase I Trial of Irinotecan and BKM120 in Previously Treated Advanced Colorectal Cancer	I	MTD
Irinotecan	plus chemotherapy		n = 30	Pharmacokinetics
BKM120	PI3K	Phase I/II Study of the P13Kinase Inhibitor BKM120 Given in Combination With Panitumumab in Patients With Metastatic or Advanced RAS-Wild Type Colorectal Cancer	I/II	MTD
			n = 40	Antitumour activity
Panitumumab	EGFR		Translational research
GSK- 2636771	PI3K-beta	A Phase I/IIa, First Time in Human, Open-label Dose-escalation Study of GSK2636771 in Subjects With Advanced Solid Tumors With PTEN Deficiency	I/II	MTD
			n = 150	Pharmacokinetics
				Efficacy
BKM120	PI3K	A Phase Ib, Open-label, Multi-center, Dose-escalation and Expansion Study of an Orally Administered Combination of BKM120 Plus MEK162 in Adult Patients With Selected Advanced Solid Tumors	I	Rate of DLTs
MEK162	MEK		n = 88	ORR and PFS
MK-2206	Akt	A Phase 2 Study of MK-2206 in Previously Treated Metastatic Colorectal Cancer Patients Enriched for PTEN Loss and PIK3CA Mutation	II	ORR
			n = 54	Biomarker validation
MK-2206	Akt	Pilot Study of the Combination of MK-2206, an AKT Inhibitor, and AZD6244, a MEK Inhibitor, in Patients With Advanced Colorectal Carcinoma	II	Evaluate reduction of pAKT, pERK and Ki-67
Selumetinib	MEK		n = 38
Everolimus	mTOR	Phase I/Randomized Phase II Study of Second Line Therapy With Irinotecan and Cetuximab With or Without RAD001, an Oral mTOR Inhibitor for Patients With Metastatic Colorectal Cancer	I/II	MTD
Irinotecan	EGFR		n = 41	ORR
Cetuximab	plus chemotherapy
SAR245408 (XL147)	mTOR	A Phase 1 Dose Escalation Study of Combination Therapy With Oral SAR245408 (XL147) and Oral MSC1936369B in Patients With Locally Advanced or Metastatic Solid Tumors	I	MTD
MSC 1936369B	MEK		n = 170	Pharmacokinetics
Onartuzumab	c-MET	Randomized, Double-Blind, Phase II Study of FOLFOX/Bevacizumab With Onartuzumab (MetMAb) vs Placebo as First-Line Treatment for Patients With Metastatic Colorectal Ca	II	PFS
Bevacizumab	VEGF-A		n = 196	Response rate
FOLFOX	plus chemotherapy
Trastuzumab	HER2	A Phase II multi-center 2-sequential cohorts trial, designed to assess the objective response rate of the anti HER2 monoclonal antibody trastuzumab, used in combination with either the small molecule tyrosine kinase inhibitor lapatinib (Cohort A) or the monoclonal antibody pertuzumab (Cohort B), in advanced disease CRC patients harbouring an amplified HER2 tumor	II	ORR
Pertuzumab	EGFR		n = 54	PFS
Lapatinib
Olaparib	PARP	Phase II, Open-Label, Multicenter Trial to Assess the Efficacy and Safety of the PARP Inhibitor, Olaparib, Alone in Previously-Treated Patients With Stage IV, Measurable Colorectal Cancer, Stratified by MSI Status	II	Tumour response
			n = 33
ABT-888	PARP	A Phase I Study of ABT-888 in Combination With Oxaliplatin and Capecitabine in Advanced Solid Tumors	I	MTD/DLTs
Oxaliplatin			n = 36	Pharmacokinetics
Capecitabine				Tumour response
Brivanib Alaninate	VEGFR	A phase II Study of second-line irinotecan plus brivanib, a dual tyrosine inhibitor of VEGFR and FGFR, in metastatic colorectal cancer patients enriched for elevated levels of plasma FGF following progression on bevacizumab-based treatment	II	PFS
Irinotecan	FGFR plus chemotherapy		n = 60

VEGF: Vascular-endothelial growth factor; EGFR: Epidermal growth factor receptor; FGFR: Fibroblast growth factor receptor; PDGFR: Platelet-derived growth factor receptor; mCRC: Metastatic colorectal cancer; ORR: Objective response rate; MTD: Maximum tolerated dose; DLTs: Dose limiting toxicities; RR: Response rate; OS: Overall survival; PFS: Progression free survival.