Mechanisms of resistance to anti-epidermal growth factor receptor inhibitors in metastatic colorectal cancer

Table 1 On-going clinical trials to overcome resistance to anti-epidermal growth factor receptor

Target	Drug	Study	ClinicalTrials.gov	Phase
			Identifier
EGFR	Afatinib	Afatinib and cetuximab combo vs cetuximab alone in treatment of patients with refractory KRAS WT mCRC	NCT01919879	Phase II
	Cetuximab
EGFR	Sym004	Sym004 vs investigator's choice (best supportive care, capecitabine, 5-FU) in subjects with mCRC and acquired resistance to anti-EGFR moAbs	NCT02083653	Phase II
EGFR, HER2, HER4	Neratinib	Neratinib and cetuximab in KRAS/NRAS/BRAF/PIK3CA WT mCRC patients resistant to cetuximab	NCT01960023	Phase I/II
	Cetuximab
EGFR	Cetuximab	Cetuximab plus irinotecan as rechallenge 3rd-line treatment of KRAS, NRAS and BRAF WT irinotecan-pretreated mCRC patients progressing after an initial response to a 1st-line cetuximab-containing therapy and a standard 2nd-line	NCT02296203	Phase II
	Irinotecan
EGFR	Panitumumab	FOLFIRI plus panitumumab in extended RAS WT and BRAF WT mCRC with acquired resistance to prior cetuximab (or Panitumumab) plus irinotecan-based therapy and who failed at least one subsequent non-anti-EGFR containing regimen	NCT02508077	Phase II
	FOLFIRI
ERBB2	Pertuzumab	Pertuzumab and lapatinib in KRAS exon 2 WT and HER2-positive mCRC refractory to standard of care (including cetuximab or panitumumab)	-	Phase II
	Trastuzumab
MET	Cetuximab INC280	INC280 in combination with cetuximab in c-MET positive mCRC and HNSCC Patients who have progressed after anti-EGFR moAbs therapy	NCT02205398	Phase
				Ib
MET	Cabozantinib	Cabozantinib with panitumumab in subjects with KRAS WT refractory mCRC		Phase II
	Panitumumab
BRAF/EGFR	Vemurafenib	Irinotecan and cetuximab with or without vemurafenib in BRAF mutant mCRC patients	NCT02164916	Phase II
	Cetuximab
	Irinotecan
BRAF/PI3K/EGFR	LGX818 BYL719	LGX818 and cetuximab or LGX818, BYL719, and cetuximab in BRAF mutant mCRC patients	NCT01719380	Phase I/II
	Cetuximab
BRAF/MEK/EGFR	Trametinib	Trametinib and dabrafenib administered in combination with panitumumab in BRAF-V600E positive mCRC patients with secondary resistance to prior anti-EGFR therapy	NCT01750918	Phase I/II
	Dabrafenib
	Panitumumab
PI3K-mTOR	Panitumumab	Second line therapy with panitumumab, irinotecan and everolimus in KRAS WT mCRC patients	NCT01139138	Phase
	Everolimus			Ib/II
	Irinotecan
PI3K/MEK	BKM120	BKM120 plus MEK162 in adult patients with selected advanced solid tumors	NCT01363232	Phase
	MEK162			Ib
Immune evasion	Pembrolizumab	Pembrolizumab plus cetuximab for KRAS-NRAS-BRAF WT mCRC patients	NCT02318901	Phase I/II
	Cetuximab

EGFR: Epidermal growth factor receptor; mCRC: Metastatic colorectal cancer; WT: Wild type; mAb: Monoclonal antibody; FOLFIRI: Fluorouracil, leucovorin, and irinotecan; PI3K: Phosphoinositide kinase-3; mTOR: Mammalian target of rapamycin.