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

Table 1 Clinic al trials of esophageal cancer classified on molecular targets

Signaling	Agents	Type of trial	Line of treatment	Phase	Results	Comments
EGFR
NCT00100945	Gefitinib	Single group, open-label	Second	II	Completed	Gefitinib
NCT01249352	Nimotuzumab	Randmized, open-label	First	II/III	Completed	Chemoradiation + nimotuzumab
NCT02591784	Nimotuzumab	Single group, open-label	First	II	Completed	Radiotherapy+ nimotuzumab
NCT01855854	Icotinib	Single group, open-label	Second	II	Completed	Icotinib in EGFR-positive EC
NCT02353936	Afatinib (target EGFR/HER2)	Single group, open-label	Second	II	Active, not-recruiting	Afatinib
NCT01522768	Afatinib (target EGFR/HER2)	Single group, open-label	Second	II	Active, not-recruiting	Afatinib ± paclitaxel
NCT01608022	Dacomitib	Single group, open-label	Third	II	Completed	Dacomitib
NCT03817567	SCT200	Single group, open-label	Third	I/II	Recruiting	SCT200
NCT03770988	Poziotinib (target EGFR/HER2/HER4)	Single group, open-label	Third	II	Not yet recruiting	Poziotinib
RAF
NCT00917462	Sorafenib (target VEGFR2/PDGFR/RET/RAF1)	Single group, open-label	Third	II	Completed26275293	Sorafenib
HER2
NCT01608022	Vizimpro	Single group, open-label	First	II	Completed	Vizimpro
NCT02120911	Pertuzumab	Single group, open-label	First	I/II	Completed	Chemoradation + Ttastumab + pertuzumab
FGFR
NCT03292250	Nintedanib	Non-randmized, open-label	Second	II	Recruiting	Nintedanib
NCT02699606	Erdafitinib	Single group, open label	Second	II	Recruiting	Erdafitinib
VEGFR
NCT02773524	Regorafenib	Randomized, triple	Third	III	Recruiting	Regorafenib
NCT03762534	Ramucirumab	Randomized, open label	Second	II	Recruiting	Ramucirumab + paclitaxel
NCT03542422	Apatinib (target VEGFR2/c-Kit/Src)	Single group, open label	First	II	Not yet recruiting	Apatinib
NCT03787251	Apatinib	Randomized, open label	Second	II	Not yet recruiting	Apatinib + chemotherapeutic drug
NCT04063638	Anlotinib (target VEGFR/FGFR/PDGFR)	Single group, open label	First	II	Recruiting	Anlotinib
PI3K
NCT03544905	CYH33	Single group, open label	Second	I	Recruting	CYH33
NCT03292250	BYL719	Non-randmized, open-label	Second	II	Recruting	BYL719
mTOR
NCT01490749	Everolimus	Single group, open label	First	I	Completed	Everolimus + FXELOX followed by radiation
PARP
NCT03995017	Rucaparib	Non-randomized, open label	Second	I/II	Recruting	Rucaparib + Ramucirumab
NCT03829345	Olaparib	Single group, open-label	Third	II	Recruting	Olaparib
ALK
NCT03917043	APG-2449 (target ALK/FAK/ROS1)	Sequential Assignment	Second	I	Recruting	APG-2449
Hedgehog
NCT02138929	Sonidegib	Single group, open label	Third	I	Active, not recruiting	Sonidegib + everolimus
DKK1
NCT02013154	DKN-01	Non-randomized, open label	Third	I	Active, not recruiting	DKN-01 + paclitaxel or pembrolizumab + chemotherapy
SHP2
NCT04000529	TNO155	Non-randomized, open label	Third	I	Recuruiting	TNO155 + spartalizumab + ribociclib
Cadherin
NCT02375958	PCA062 (target P-cadherin)	Single group, open label	Third	I	Completed	PCA062 in p-cadherin positive tumors

EC: Esophageal 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; PDGFR: Platelet-derived growth factor receptor; FGFR: Eibroblast 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; DKK1: Dickkopf-1; ALK: Anaplastic lymphoma kinase; PARP: Poly (ADP-ribose) polymerases.

Table 2 Clinic al trials for gastric cancer classified on molecular targets

Clinical Trials gov idntifier	Agents	Type of trial	Line of treatment	Phase	Results	Comments
EGFR
NCT01813253	Nimotuzumab	Randomized, open label	Second	III	Terminated	Nimotuzumab + irinotecan
NCT02370849	Nimotuzumab	Randomized, open label	First	II	Completed	Nimotuzumab + cisplatin + S-1
NCT03130790	Varlitinib	Randomized, double	First	II/III	Active, not recruiting	Varlitinib; mFOLFOX6
NCT01743365	Afatinib	Nonr-andomized, open-label	First	II	Completed	Afatinib ± 5-FU/cisplatin
NCT02501603	Afatinib	Single group, open label	Second	II	Recruiting	Afatinib + paclitaxel
NCT01746771	Poziotinib (target EGFR/HER2/HER4)	Single group, open label	First	I/II	Completed	Poziotinib + Paclitaxel + Trastuzumab in HER2-positive GC
HER2(3)
NCT01152853	Vizimpro	Single group, open label	Second	II	Completed	Vizimpro
NCT01602406	LJM716	Single group, open label	Second	I	Completed	LJM716 + Trastuzumab
NCT03329690(DESTINY-Gastric01)	DS-8201a	Randomized, open label	Third	II	Active, not recuruiting	DS-8201a + physician’s choice treatment
NCT03619681	KN026	Single group, open label	N.A.	I	Recruiting	KN026 in HER2-positive GC
NCT02689284	Margetuximab	Single group, open-label	Third	I/II	Active, not-recruiting	Margetuximab + pembrolizumab
FGFR
NCT04071184	Alofanib	Single group, open label	Third	I	Recruiting	Alofanib
NCT02699606	Erdafitinib	Single group, open label	Second	II	Recruiting	Erdafitinib
NCT03694522	Bemarituzumab (FPA144)	Randomized, double blinded	First	II	Active, not recuiting	Bemarituzumab + mFOLFOX6
NCT04149691	CPL304110	Single group, open label	Third	I	Recruiting	CPL304110
VEGFR
NCT03817411	Telatinib (target VEGFR/PDGFα/c-Kit)	Randomized, quadruple	First	II	Recruting	Telatinib + capecitabine/oxaliplatin
NCT01238055	Sunitinib (target VEGFR/PDGFR)	Randomized, open label	Second	II	Completed	Sunitinib + docetaxel
NCT01719549	Dovitinib (target FLT3/c-Kit/ FGFR1/3/VEGFR1/2/3/PDGFR/CFS-1R)	Single group, open label	Third	II	Completed	Dovitinib as a salvage chemotherapy
NCT01921673	Dovitinib	Single group, open label	Second	I/II	Completed	Dovitinib + docetaxel
NCT04286711	Apatinib (target VEGFR2/c-Kit/Src)	Single group, open label	Second	I/II	Not yet recruiting	Apatinib + Camrelizumab + Albumin-paclitaxel
NCT03286244	Vorolanib (target VEGFR/PDGFR/CSF1R)	Single group, open label	Second	I	Recruiting	Vorolanib + paclitaxel
NCT01716546	Pazopanib (target VEGFR/PDGFR/FGFR/c-Kit)	Single group, open label	First	I/II	Terminated	Pazopanib + DCF
NCT03609359	Lenvatinib (target VEGFR2/3)	Single group, open label	N.A.	II	Active, not recruiting	Lenvatinib + pembrolizumab
NCT03941873	Sitravatinib (target VEGFR1/2/3, Axl, MER, KIT, FLT3, DDR2, RET)	Nonr-andomized, open-label	Third	I/II	Recruiting	Sitravatinib + Tislelizumab
AKT
NCT02451956	AZD5363	Single group, open label	Second	II	Completed	AZD5363 + paclitaxel in PIK3CA mutation or/and amplification GC
NCT02240212	Afuresertib	Non-Randomized, open-label	Second	I	Completed	Afuresertib + paclitaxel
PI3KCA
NCT01613950	Alpelisib	Single group, open label	Second/third	I	Completed	Alpelisib + AUY922 in GC mutated PI3KCA
MET
NCT02096666	AMG337	Single group, open label	Third	I/II	Completed	AMG337
NCT03542877	Cabozantinib (target MET/RET/VEGFR-2)	Single group, open label	Third	I	Recruiting	Cabozantinib + durvalumab
TGF-β
NCT03724851	Vactosertib (target TGFBR1/ALK4/5)	Single group, open label	Second	I/II	Recuriuting	Vactosertib + pembrolizumab
PARP
NCT01063517(Study 39)	Olaparib	Multicenter, randomized, double	Second	II	Active, not recruiting	Olaparib + paclitaxel vs paclitaxel
NCT01924533(GOLD)	Olaparib	Multicenter, randomized, double	Second	III	Active, not recruiting	Olaparib + paclitaxel vs placebo + paclitaxel
NCT03008278	Olaparib	Randomized, open-label	First	I/II	Recruiting	Olaparib + ramucirumab
NCT03427814	Pamiparib	Randomized, double	Second	II	Active, not recruiting	Pamiparib
NCT04178460	Niraparib	Single group, open label	Second	I	Recruiting	Niraparib + MGDO013
NCT03995017	Rucaparib	Non-randomized, open-label	Third	I/II	Recruiting	Rucaparib + ramucirumab + nivolumab
STAT
NCT02178956	Napabucasin	Randomized, quadruple	Second	III	Completed	Napabucasin + paclitaxel
ALK
NCT02435108	Crizotinib (target ALK/ROS1/MET)	Single group, open label	Third	II	Completed	Crizotinib for c-MET positive GC
NCT03698825	Vactosertib (target ALK4/5)	Single group, open label	Thurd	I/II	Recruiting	Vactosertib+paclitaxel
CDK
NCT03480256	SHR6390 (target CDK 4/6)	Sequential Assigment, open label	Second	I	Recruiting	SHR6390 + pyrotinib in HRE2 positive GC
NCT03311334	Alvocidib (target CDK9)	Non-randomized, open-label	Third	I/II	Recruiting	Alvocidib+nivolumab or pembrolizumab
HSP90
NCT01402401	Luminespib	Single group, open label	Second	II	Terminated	Luminespib + trastuzumab
Hedgehog
NCT03052478	Vismodegib	Single group, open label	Second	II	Active, not recruiting	Vismodegib
NCT04007744	Sonidegib	Single group, open label	Second	I	Recruiting	Sonidegib + pembrolizumab
DKK1
NCT04363801(DisTinGuish)	DKN-01	Non-randomized, open label	First or Second	II	Not yet recruiting	DKN-01 + ttsleizumab + chemotherapy
CLDN18.2
NCT03528629	Zolbetuximab	Non-randomized, open label	Third	I	Completed	Zolbetuximab
NCT03504397	Zolbetuximab	Randomized, double	First	III	Recruiting	Zolbetuxima + mFOLFOX6
NCT03653507	Zolbetuximab	Randomized, double	First	III	Recruiting	Zolbetuximab + CAPOX in CLDN-positive, HER2-negative GC
NCT01671774	IMAB362	Non-randomized, open label	First	I	Completed	IMAB362 + zoledronicacid + interleukin-2

GC: Gastric 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, MEK: Mitogen-activated protein kinase; N.A.: Not applicable; MSS: Microsatellite stable; HDAC: Histone deacetylases; CLDN: Claudin.

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.