Table 1 The multi-targeted drugs approved by FDA with their respective properties

1

Imatinib

In 2001 for malignant metastatic or unresectable GISTs

Bcr-Abl, c-KIT, PDGF

CML, GIST, Advance anaplastic thyroid cancer

Skin color change, Edema

Displacement of the drug by Glut-1,

Lysosomal sequestration

[75,76,77,78,79,80,81,82]

2

Lapatinib

In 2007 for metastatic breast cancer with overexpression of Her2

HER2, EGFR

Metastatic breast cancer

Diarrhea, rash

Glycolysis, Changes in metabolites

[15, 83,84,85,86,87,88,89,90,91,92,93,94]

3

Sorafenib

In 2005 for advanced RCC,

In 2007 for advanced unresectable HCC,

In 2013 advanced radioiodine-refractory differentiated thyroid carcinoma

Raf-1, B-Raf, c-KIT, VEGFR-1/2/3, PDGFR-β, RET, FLT3

Advanced RCC, HCC

Diarrhea, Hand-foot syndrome, Rash, Fatigue

Gene polymorphism, Intratumor genetic heterogeneity, Metabolic characterization changes

[95,96,97,98,99,100,101,102,103,104]

4

Pazopanib

In 2009 for RCC & soft tissue sarcoma

VEGFR, PDGFR,

FGFR, MAPK, Pan-RAF

RCC, Soft tissue sarcoma, NSCLC,

Breast cancer, Urothelial carcinoma, Thyroid cancer, GIST

Hypertension, Cytopenia, Proteinuria, Diarrhea, Nausea, Fatigue, QT interval

_

[103, 105,106,107,108,109,110,111,112,113,114]

5

Sunitinib

In 2006 for treating advanced RCC,

In 2011 for progressive well-differentiated pancreatic neuroendocrine

EGFR, FGFR-1, PDGFR-B, VEGFR-2

Pancreatic neuroendocrine tumors

Diarrhea, Nausea, Fatigue, Asthenia

Autophagy-flux,

Lysosomal sequestration

[115,116,117,118,119,120,121,122,123]

6

Vandetanib

In 2011 for MTC or metastatic thyroid cancer

VEGFR-2 & -3,

EGFR,

RET

MTC

Diarrhea,

Hypertension,

QTc prolongation,

Fatigue

Genetic alternation, Epigenetic modifications

[124,125,126,127,128,129,130]

7

Axitinib

In 2012 for RCC

VEGFR-1, -2 and -3

RCC, head and neck squamous cell carcinoma

Hypertension, Fatigue,

Diarrhea

_

[131,132,133,134,135,136,137]

8

Cabozantinib

In 2016 for RCC,

In 2019 for HCC,

In 2021 for thyroid cancer

c-MET, VEGFR2, RET, FLT3, KIT, AXL

Liver cancer

Hypertension, fatigue,

Diarrhea

Resistance of tumor cells with low CMET levels to c-MET inhibitors

[138,139,140,141,142,143,144,145,146]

9

Regorafenib

In 2017 for advanced HCC, metastatic colorectal cancer, GISTs treatment

KIT, FGFR, PDGFR, VEGFR, RET, STAT3, AXL signaling

HCC, Metastatic Colorectal cancer, GISTs

Hand-foot skin

reaction,

Hypertension, Fatigue

Topoisomerase IIα high expression

[147,148,149,150,151,152,153]

10

Lorlatinib

First in 2018 for treatment of ALK positive metastatic NSCLC,

In 2021 for patient with metastatic ALK positive NSCLC

ALK, ROS1

Anaplastic lymphoma kinase (ALK) and ROS1 positive NSCLC

Hypercholesterolemia, Hypertriglyceridemia, Edema, Weight gain,

Peripheral neuropathy

ALK rearrangement in NSCLC

[154,155,156,157,158]

11

Lenvatinib

In 2018 for treatment of RCC, HCC and radioactive iodine-refractory differentiated thyroid cancer

VEGFR-1, -2 and -3

Endometrial cancer,

Adenoid cystic,

Medullary and anaplastic thyroid carcinomas, RCC, HCC

Hypertension, Fatigue,

Weight loss, Diarrhea,

Nausea

Increased activation of EGFR and insulin-like growth factor 1 receptor (IGF1R)/insulin receptor (INSR)

[159,160,161,162,163,164,165,166,167]

12

Entrectinib

In 2019 for treatment of NTRK positive solid tumors

TRK A,B, & C, ROS1 and ALK

Primary and metastatic CNS tumors, NTRK positive solid tumors

Fatigue, Paresthesia,

Dysgeusia, Myalgia, Nausea

NTRK1 mutation with resistance to TRK inhibitor

[168,169,170,171,172,173,174]