Genomic diversity of colorectal cancer: Changing landscape and emerging targets

Table 1 Ongoing combination targeted therapy trials for colorectal cancer

Agent(s)	Class of agent	Phase	Trial number1	Misc
MEK162 + Panitumumab	MEK tyrosine kinase inhibitor, anti-EGFR mAb	Ib/II	NCT01927341	mCRC with mutant or wild-type RAS tumors
Dabrafenib + Trametinib + Panitumumab + 5-Fluorouracil	BRAF tyrosine kinase inhibitor, MEK tyrosine kinase inhibitor, anti-EGFR mAb	I/II	NCT01750918	BRAF-V600E mutant + and in pts with secondary resistance to anti-EGFR mAb
LGX818 + Cetuximab ± BYL719	BRAF tyrosine kinase inhibitor, anti-EGFR mAb, PI3K tyrosine kinase inhibitor	I/II	NCT01719380	BRAF mutant mCRC
Irinotecan + Cetuximab ± Vemurafenib	anti-EGFR mAb, BRAF tyrosine kinase inhibitor	II	NCT02164916	BRAF mutant mCRC
Neratinib + Cetuximab	HER-2 tyrosine kinase inhibitor, anti-EGFR mAb	I/II	NCT01960023	KRAS, NRAS, BRAF, PIK3CA wild type

¹Utilizing the NCT number, clinical trial information can be obtained at https://clinicaltrials.gov. mAb: Monoclonal antibody; mCRC: Metastatic colorectal cancer; EGFR: Epidermal growth factor receptor; PIK3CA: Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha; BRAF: v-Raf murine sarcoma viral oncogene homolog B.

Table 2 Tumor genomic variants and potential targeted therapies of interest

Gene	Agents of Interest	Mechanism of action	Phase	Trial number1	Comment
FGFR (FGFR1, FGFR2, FGFR3, FGFR4)	Ponatinib	Multi-kinase small molecule inhibitor	II	NCT02272998
	BGJ398	Pan FGFR small molecule inhibitor	I	NCT01928459
RET	Cabozantinib	Multi-kinase small molecule inhibitor	I	NCT02008383	Cabozantinib + panitumumab
	Vandetanib	Multi-kinase small molecule inhibitor	I	NCT01582191
	Apatinib	Multi-kinase small molecule inhibitor
	Ponatinib	Multi-kinase small molecule inhibitor	II	NCT02272998
	RXDX-105	RET and BRAF small molecule inhibtor	I	NCT01877811
	Sunitinib	Multi-kinase small molecule inhibitor
	Sorafenib	Multi-kinase small molecule inhibitor	I	NCT01531361
HER-2	AZD8931	Small molecule inhibitor of EGFR, HER-2, HER-3	I/II	NCT01862003	AZD8931 + FOLFIRI
	Neratinib	Small molecule inhibitor of EGFR, HER-2, HER-3	II	NCT01953926
	HER-2 vaccine	B cell peptide vaccine	I	NCT01376505
	T-DM1	Antibody-drug conjugate of traztuzumab and DM1	II	HERACLES-RESCUE	At the time of traztumab failure
	Pertuzumab	Anti HER-2 monoclonal antibody	II	HERACLES	Pertuzumab + trastuzumab
	Lapatinib	Anti HER-2 small molecule inhibitor	II	HERACLES	Lapatinib + trastuzumab
c-MET (MET, HGFR)	Crizotinib	Multi-kinase small molecule inhibitor		NCT02510001	Crizotinib + PD-0325901
	Tivantinib	c-MET inhibitor		NCT01892527	Tivantinib + cetuximab
	Cabozantinib	c-MET and VEGFR2 inhibitor
	INC280	Small molecule inhibitor of c-MET	II	NCT2205398	INC280 + cetuximab
	AMG102	HGF inhibitor
	AV299	HGF inhibitor

¹Utilizing the NCT number, clinical trial information can be obtained at https://clinicaltrials.gov. FGFR: Fibroblast growth factor receptor; EGFR: Epidermal growth factor receptor; BRAF: v-Raf murine sarcoma viral oncogene homolog B; HER-2: Human growth factor receptor 2; HGFR: Hepatocyte growth factor receptor; TDM-1: Ado-trastuzumab emtansine; VEGFR: Vascular endothelial growth factor receptor.

Table 3 Current ongoing immune therapy trials for colorectal cancer

Agent	Class of agent	Phase	Trial number1	Comment
MK-3475	Anti-PD-1 mAb	II	NCT01876511	MSI-high tumors
MEDI4736	Anti-PD-L1 mAb	I/II	NCT01693562
Nivolumab ± ipiliumumab	Anti-PD-1 mAb/anti-CTLA-4 mAb	I/II	NCT02060188	Recurrent and metastatic CRC
MK-3475 + mFOLFOX6	Anti-PD-1 mAb	II	NCT02375672
Tremelimumab + MEDI4736	Anti-CTLA-4 mAb + anti-PD-L1 mAb	I	NCT01975831

¹Utilizing the NCT number, clinical trial information can be obtained at https://clinicaltrials.gov. mAb: Monoclonal antibody; CRC: Colorectal cancer; MSI: Microsatellite instability; CTLA: Cytotoxic T associated lymphocyte protein; PD-1: Program cell death protein 1; PD-L1: Programmed cell death protein ligand 1; FOLFOX: Combination of 5-Flurouracil, folinic acid and oxaliplatin chemotherapy regimen.