Molecular-targeted therapy toward precision medicine for gastrointestinal cancer: Current progress and challenges

Table 3 Clinical trials of colorectal cancer classified on molecular targets

Clinical Trials gov idntifier	Agents	Type of trial	Line of treatment	Phase	Results	Comments
EGFR
NCT01862003	AZD-8931 (target EGFR/HER2/3)	Single group, open label	First	II	Completed	AZD-8931 + FOLFILI
NCT03457896	Neratinib (target EGFR/HER2/4)	Non-Randomized, open label	Third	II	Recruiting	Neratinib + trastuzumab or neratinib + cetuximab in KRAS/NRAS/BRAF/PI3CA wild-type mCRC
NCT04172597	Poziotinib (target EGFR/HER2/HER4)	Single group, open label	Second	II	Recruiting	Poziotinib in EGFR or HER2 activating mutations
MEK
NCT03428126	Trametinib	Single group, open label	Third	II	Active, not recruting	Trametinib + durvalumab in MSS mCRC
NCT03905148	PD-0325901	Non-Randomized, open label	Second	II	Recruiting	PD-0325901 + lifirafenib
NCT02788279(COTEZO IMblaze370)	Cobimetinib	Randomized, open label	Third	III	Completed	Cobimetinib + atezolizumab and atezolizumab Monotherapy vs regorafenib
Raf
NCT00869570	Sorafenib (target VEGFR/PDGFR/B-Raf/c-Kit)	Single group, open label	Neoadjuvant	I/II	Completed29241084	Sorafenib + capecitabine + radiation therapy
NCT00826540(Alliance)	Sorafenib	Single group, open label	Third	II	Completed	Sorafenib + Bevacizumab as salvage therapy
NCT01715441	Sorafenib	Randomized, open-label	Second	II	Completed	Sorafenib + irinotecan in K-Ras wild type mCRC
NCT01086267	BMS-908662	Randomized, open label	Second	I/II	Completed	BMS-908662 + Cetuximab
NCT03668431	Debrafenib	Single group, open label	Third	II	Recruiting	Debrafenib + trametinib + PDR001 in BRAF V600E mCRC
HER2
NCT03418558	Trastuzumab-emtansine	Single group, open label	Third	II	Recruiting	Trastuzumab-emtansine
NCT03384940(DESTINY-CRC01)	DS-8201a	Non-randomized, open-label	Third	II	Active, not recruting	DS-8201a in HER2 positive CRC
NCT03043313	Tucatinib	Randomized, open-label	Third	II	Recruiting	Tucatinib + trastuzumab in HER2 positive mCRC
VEGFR
NCT00387387	Pazopanib (target VEGFR/PDGFR/FGFR/c-Kit)	Non-randomized, open-label	First	I	Completed	Pazopanib + FOLFOX6 or CapeOx
NCT03170960	Cabozantinib (target MET/RET/VEGFR-2)	Non-randomized, open-label	First	I/II	Recruiting	Cabozantinib + atezolizumab
NCT03797326	Lenvatinib (target VEGFR/PDGFR/FGFR/RET)	Single group, open label	Second	II	Active, not recruiting	Lenvatinib + pembrolizumab
NCT 02549937	Surufatinib (target VEGFR1-3 /FGFR1/CSF-1α)	Non-randomized, open-label	Second	I/II	Recruiting	Surufatinib
NCT03190616	Apatinib (target VEGFR-2/c-Kit/Src)	Single group, open label	Third	II	Completed	Apatinib
NCT03271255	Apatinib (target VEGFR-2/c-Kit/Src)	Randomized, open-label	Second	II	Recruiting	Apatinib vs bevacizumab with FOLFIRI
NCT00640471	Brivanib (VEGFR-2/FGFR)	Randomized, triple blind	Second	III	Completed	Cetuximab + brivanib in K-Ras wild type mCRC
Akt
NCT01802320	MK-2206	Single group, open label	Second	II	Completed	MK-2206
mTOR
NCT03439462	ABI-009 (Nab-rapamycin)	Non-randomized, open-label	First	I/II	Recruiting	ABI009 + mFOLFOX6 + bevacizumab
MET
NCT02205398	INC280	Non-randomized, open-label	Third	I	Terminated	INC280 + cetuximab in c-MET positivemCRC
NCT02745769	Merestinib (MET/TEK/ROS1/DDR/MKNK)	Non-randomized, open-label	Third	I	Completed	Merestinib + ramucirumab
NCT002008383	Cabozantinib (target MET/RET/VEGFR-2)	Non-randomized, open-label	Second	I	Completed	Cabozantinib + panitumumab
NCT03542877	Cabozantinib (target MET/RET/VEGFR-2)	Non-randomized, open-label	Third	II	Active, not recruiting	Cabozantinib with refractory mCRC
NCT03592641	Savolitinib	Single group, open label	Second	II	Recruiting	Savolitinib in MET amplified CRC
WNT
NCT02521844	ETC-1922159	Non-randomized, open-label	First	I	Active, not recruiting	ETC-1922159
NCT02278133	WNT974	Single group, open label	Second	I/II	Completed	WNT974 + LGX818 + cetuximab in BRAF V600-mutanta mCRC
NCT03883802(Neo Fox)	Foxy-5	Randomized, open-label	Neoadjuvant	II	Recruiting	Foxy-5 in Wnt-5a low CRC
STAT
NCT02687009	Niclosamide (target STAT3)	Single group, open label	Neoadjuvant	I	Terminated	Niclosamide
NCT02983578	Danvatirsen (target STAT3)	Single group, open label	Second	II	Recruiting	Danvatirsen + durvalumab
NCT03522649	Napabucasin (target STAT3)	Randomized, open label	Second	III	Recruiting	napabucasin + FOLFIRI
NCT03647839(MODULATE)	Napabucasin (target STAT3)	Randomized, open label	Third	II	Recruiting	Nivolumab + napabucasin vs nivolumab + BNC105
Notch
NCT03422679	CB-103	Single group, open label	Second	I/II	Recruiting	CB-103 in patients with solid tumors including CRC
TGF-β
NCT04031872	LY3200882	Single group, open label	Third	I/II	Yet not recuriuting	LY3200882 + Capecitabine
PARP
NCT04166435	Olaparib	Single group, rnonrandomized, open-label	Third	II	active	Olaparib + temozolomide in patients with MGMT promoter hypermathylated CRC
BTK
NCT03332498	Ibrutinib	Single group, open label	Second	I/II	active	Ibrutinib + Pembrolizumab
ALK
NCT03792568	Crizotinib (target ALK/ROS1/MET)	Single group, open label	First	N.A.	Recruting	mCRC with ALK mutation
CDK
NCT03981614	Palbociclib	Randomized, open-label	Third	II	Recruting	Palbociclib + binimetinib in patients with KRAS and NRAS mutation

CRC: Colorectal cancer; mCRC: Metastatic colorectal cancer; PI3K: Phosphoinositide 3-kinase; AKT: Protein kinase B; also known as PKB; mTOR: Mammalian target of rapamycin; MEK: Mitogen-activated protein kinase; EGFR: Epidermal growth factor receptor; HER2/3/4: Human epidermal growth factor 2/3/4; MAPK: Mitogenactivated protein kinase; STAT3: Signal transducer and activator of transcription 3; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor; EGFR: Epidermal growth factor receptor; PDGFR: Platelet-derived growth factor receptor; FGFR: Fibroblast growth factor receptor; HGF: Hepatocyte growth factor; MET: Mesenchymal-epithelial transition factor; TEK: Tunica interna endothelial cell kinase; DDR: Discoidin domain receptor tyrosine kinase; MKNK/MAP: Kinase-interacting serine/Threonine protein kinase; FLT3: Fms-related tyrosine kinase 3; N.A.: Not applicable; MSS: Microsatellite stable; ALK: Anaplastic lymphoma kinase.