Table 1.

Anti-angiogenic drugs approved by FDA for clinical treatment

Drugs	Targets	Indications	Companies	Adverse effects
Monoclonal antibodies
Bevacizumab (Avastin®)	VEGF-A	CRC in 2004, NSCLC in 2006, RCC in 2009, GBM in 2009, CC in 2014	Genentech/Roche	Arterial or venous, back pain, dry skin, exfoliative dermatitis gastrointestinal perforation, headache, hemorrhage, hypertension, lacrimation disorder, poor wound healing, proteinuria, rhinitis, and taste alteration, thrombosis
Ranibizumab (Lucentis®, RG-6321)	VEGF-A	wAMD in 2006, DME in 2015, DR in 2017, Myopic choroidal neovascularization in 2017	Genentech/Roche	Conjunctival hemorrhage, endophthalmitis, eye infection, eye pain, floaters, increased intraocular pressure, rhegmatogenous retinal detachment, and retinal hemorrhage
Ramucirumab (Cyramza®)	VEGFR-2	NSCLC in 2014, Advanced GC in 2014, GEJ adenocarcinoma in 2014, metastatic CRC in 2015	Genentech and Eli Lilly	Abdominal pain, thrombocytopenia, anorexia, arthralgia, constipation, cough, diarrhea, dyspnea, epistaxis, fatigue, headache, hypertension, leucopenia, nausea, neutropenia, peripheral edema, proteinuria, upper respiratory tract infection, and vomiting
Olaratumab (Lartruvo®)	PDGFR-α	STS in 2016	ImClone/Eli Lilly	Appetite, abdominal pain, alopecia, diarrhea, decreased fatigue, headache, neuropathy, musculoskeletal pain, mucositis, nausea, and vomiting
Bevacizumab-awwb (Mvasi®)	VEGF	CRC, NSCLC, RCC, GBM, and CC in 2017	Amgen	Altered taste, arterial and venous thromboembolic events, bleeding, dry skin, epistaxis, exfoliative dermatitis, headache, hypertension, hypertension, infusion-related reactions, lacrimation disorders, ovarian failure, perforation or fistula, post-reversible encephalopathy syndrome, proteinuria, proteinuria, and rhinitis
Oligonucleotide aptamers
Pegaptanib (Macugen®)	VEGF-A165	wAMD in 2004	Eyetech/Pfizer	Endophthalmitis and retinal detachment
Recombinant fusion proteins
Aflibercept (Eylea®)	VEGF-A, VEGF-B, PlGF	wAMD in 2011 CRC in 2012 DME in 2015 DR in 2019	Regeneron	Cataracts, conjunctival hemorrhage, decreased vision, eye pain, floaters, increased intraocular pressure, and vitreous detachment
ziv-Aflibercept (Zaltrap®)	VEGF-A, VEGF-B, PlGF	CRC in 2012	Sanofi and Regeneron	Abdominal pain, bleeding, decreased appetite, decreased ejection fraction, diarrhea, dyspnea, epigastric pain, fatigue, fatigue, gastrointestinal perforation, headache, heart failure, hypertension, impaired wound healing, infection, leukopenia, nephrotic syndrome, neutropenia, osteonecrosis of the lower jaw, proteinuria, severe diarrhea, stomatitis, thrombocytopenia, and weight loss
mTOR inhibitors
Temsirolimus (Torisel®)	mTOR	RCC in 2007	Wyeth	Acute renal failure, asthenia, edema, elevated aspartate aminotransferases, hyperlipidemia, hypersensitivity, interstitial pneumonia, intestinal perforation, lymphopenia, mucositis, nausea, rash, thrombocytopenia
Everolimus (RAD001, Afinitor®)	mTOR	RCC in 2009 SEGA in 2010 pNET in 2011 HER2- BC	Novartis	Canker sores, increased heart rate, paronychia, rash, swollen and painful gums, tiredness, and tongue ulcers
Immunomodulatory agents
Thalidomide (Thalomid®)	VEGF-A, TNF, NF-κB	MM in 2006	Celgene	Abdominal pain, constipation, dizziness, drowsiness, dry oral mucosa, facial puffiness, nausea, rash, teratogenic, and tiredness
Lenalidomide (Revlimid®)	VEGF-A, TNF, NF-κB	MM in 2006 MCL in 2013	Celgene	Anemia, diarrhea, fatigue, headache, loss of appetite, low back pain, neo-malignant neoplasms, neutropenia, rash, renal insufficiency, thrombocytopenia, and thrombotic complications
Tyrosine kinase inhibitors
Sorafenib (Nexavar®, BAY-439006)	VEGFR-1/-2/-3, c-Kit, Flt-3, PDGFR-β, Raf, Ret	RCC in 2005 HCC in 2007 DTC in 2013 TC in 2014	Bayer and Onyx/Amgen	Abdominal pain, alopecia, decreased appetite, diarrhea, fatigue, hand-foot skin reaction, hypertension, nausea, rash, and weight loss
Sunitinib (Sutent®, SU11248)	VEGFR-1/-2/-3, Flt-3, c-Kit, Ret, PDGFR-α/-β, CSF-1R	RCC in 2006 GIST in 2006 pNET in 2011	Sugen/Pfizer	Abdominal pain, anorexia, asthenia, diarrhea, dysgeusia, dyspepsia, fatigue, hypertension, mucositis, nausea, skin discoloration, stomatitis, and thrombocytopenia
Pazopanib (Votrient®, GW-786034)	VEGFR-1/-2/3, c-Kit, PDGFR-α/-β,	RCC in 2009 STS in 2012	GlaxoSmithKline	Anorexia, diarrhea, fatigue, fatigue, hair color changes, nausea, vomiting, and weight loss
Vandetanib (Caprelsa®, ZD6474)	VEGFR-2, VEGFR-3, EGFR, Ret	MTC in 2011	AstraZeneca	Diarrhea, headache, rash, hypertension, nausea, and QTc prolongation
Regorafenib (Stivarga®)	VEGFR-1/-2/-3, c-Kit, PDGFR-β, Ret, Raf-1, bRaf, FGFR-1, Tie-2	CRC in 2012 GIST in 2013 HCC in 2017	Bayer	Anorexia, diarrhea, fatigue, hand-foot skin reaction, hypertension, and oral mucositis
Axitinib (Inlyta®, AG013736)	VEGFR-1/-2/3, c-Kit, PDGFR-α, PDGFR-β	RCC in 2012	Pfizer	Asthenia, constipation, decreased appetite, diarrhea, dysphonia, fatigue, hand-foot syndrome, hypertension, nausea, vomiting, and weight decreased
Ponatinib (Iclusig®)	VEGFRs, PDGFRs, EPHs, FGFRs, ABL, Src, Ret, LYN, LCK, c-Kit, HCK, FYN, FRK, c-FMS, FGR, BLK	CML in 2012 Ph+ AML in 2012	Ariad/Takeda	Abdominal pain, arthralgia, dermatitis, dry skin, fatigue, increased lipase, nausea, rash, and thrombocytopenia
Cabozantinib (Cometriq®, BMS-907351)	VEGFR-2, c-Met, c-Kit, Ret, Flt-3, Tie-2, AXL, RON	MTC in 2013 RCC in 2016 HCC in 2019	Exelixis	Abdominal pain, constipation, decreased appetite, decreased weight, diarrhea, dysgeusia, fatigue, hair color changes, hypertension, nausea, oral pain, palmar-plantar erythrodysesthesia syndrome, and stomatitis
Apatinib (Aitan®)	VEGFR-2, Src, c-Kit	GC in 2014	Hengrui Medicine	Fatigue, gastrointestinal bleeding, granulocytopenia, hand-foot syndrome, hoarseness, hypertension, leukopenia, proteinuria, and thrombocytopenia
Nintedanib (Ofev®, BIBF1120)	VEGFRs, FGFRs, PDGFRs, Flt-3, LCK, LYN, Src	NSCLC in 2015	Boehringer and Ingelheim	Bleeding, decreased appetite, diarrhea, electrolyte imbalance, mucositis, nausea, neutropenia, peripheral neuropathy, rash, and vomiting
Lenvatinib (Lenvima®, E7080)	VEGFRs, PDGFRs, Ret, c-Kit, FGFRs	DTC and TC in 2015 RCC in 2016 HCC in 2018 Endometrial Carcinoma in 2019	Eisai	Abdominal pain, arthralgia, decreased appetite, decreased weight, diarrhea, dysphonia, fatigue, headache, hypertension, myalgia, nausea, proteinuria, stomatitis, and vomiting

ALL acute lymphoblastic leukemia, BC breast cancer, BTC biliary tract cancer, CC cervical cancer, CML chronic myeloid leukemia, CRC colorectal cancer, CSF colony-stimulating factor, DME diabetic macular edema, DR diabetic retinopathy, DTC differentiated thyroid cancer, EC esophageal cancer, GEJ gastroesophageal junction, GBM glioblastoma, GC gastric cancer, GIST gastrointestinal stromal tumor, HCC hepatocellular carcinoma, HER2 human epidermal growth factor receptor 2, HNSCC head and neck squamous cell carcinoma, MCL mantle cell lymphoma, MM multiple myeloma, MTC medullary thyroid cancer, mTOR mammalian target of rapamycin, NSCLC non-small cell lung cancer, Ph+ AML Philadelphia chromosome-positive acute myeloid leukemia, pNET pancreas neuroendocrine tumor, RCC renal cell carcinoma, SEGA subependymal giant cell astrocytoma, STS soft tissue sarcoma, TC thyroid cancer, TNBC triple-negative breast cancer, wAMD wet age-related macular degeneration