TREATMENTS

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The Angiogenesis Foundation seeks to improve patients outcomes in disease treatment and prevention on a global level, by democratizing the transfer and use of expert medical knowledge.

Through research, education, and advocacy — with patients, physicians, researchers, industry, payers, and government — we enable patients to gain access to safe and effective treatments coming from the angiogenesis field for cancer, blinding diseases, wounds, and many other serious diseases.

In the U.S., there are currently thirteen approved anti-cancer therapies with recognized antiangiogenic properties in oncology. These agents, which interrupt critical cell signaling pathways involved in tumor angiogenesis and growth, comprise three primary categories:

1) monoclonal antibodies directed against specific proangiogenic growth factors and/or their receptors; and
2) small molecule tyrosine kinase inhibitors (TKIs) of multiple proangiogenic growth factor receptors;
3) inhibitors of mTOR (mammalian target of rapamycin).

In addition, at least two other approved angiogenic agents may indirectly inhibit angiogenesis through mechanisms that are not completely understood. Finally, in the field of dermatology, there are several agents used for neoplasms of the skin.

AntiAngiogenesisBloodVessel



Monoclonal Antibody Therapies
One monoclonal antibody therapy is approved to treat several tumor types: bevacizumab (Avastin).

Bevacizumab (Avastin®)
Description
Genentech
A humanized monoclonal antibody that binds biologically active forms of vascular endothelial growth factor (VEGF) and prevents its interaction with VEGF receptors (VEGFR-1 and VEGFR-2), thereby inhibiting endothelial cell proliferation and angiogenesis.

Approved Indications
Metastatic colorectal cancer (mCRC), non-small cell lung cancer (NSCLC), advanced breast cancer (Europe), glioblastoma, metastatic renal cell cancer (RCC), advanced ovarian cancer (Europe).
  • In combination with 5-FU-based chemotherapy as first-line and second-line treatment of mCRC.
  • In combination with carboplatin and paclitaxel as first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous NSCLC.
  • In combination with paclitaxel as first-line treatment in patients with locally recurrent or metastatic breast cancer (Europe only).
  • Second-line treatment of patients with glioblastoma following temozolomide failure.
  • In combination with interferon-alfa as first-line treatment of RCC.
  • In combination with chemotherapy as first-line treatment in patients with newly diagnosed, advanced ovarian cancer (Europe only).
  • In combination with paclitaxel plus cisplatin or topotecan as a treatment for patients with persistent, recurrent, or metastatic cervical cancer.
 
 

Ramucirumab (Cyramza®)
Description
Eli Lilly
A fully human monoclonal antibody (IgG1) developed for the treatment of solid tumors. It is directed against the vascular endothelial growth factor receptor 2 (VEGFR2). By binding to VEGFR2 it works as a receptor antagonist blocking the binding of vascular endothelial growth factor (VEGF) to VEGFR2. VEGFR2 is known to mediate the majority of the downstream effects of VEGF in angiogenesis.

Approved Indications
Advanced or metastatic gastric or gastroesophageal junction adenocarinoma, metastatic non-small cell lung cancer, and metastatic colorectal cancer.
  • As a single agent or in combination with paclitaxel as a treatment for people with advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose cancer has progressed on or after prior fluoropyrimidine- or platinum-containing chemotherapy.
  • In combination with docetaxel as a treatment for people with metastatic non-small cell lung cancer whose cancer has progressed on or after platinum-based chemotherapy.
  • Treatment with FOLFIRI as a therapy for people with metastatic colorectal cancer whose cancer has progressed on or after therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine.
 
 
 
 
Small Molecule Tyrosine Kinase Inhibitors (TKIs)
Seven TKIs with antiangiogenic activity are currently approved as anticancer therapies: axitinib (Inlyta), cabozantinib (Cometriq), pazopanib (Votrient), regorafenib (Stivarga), sorafenib (Nexavar), sunitinib (Sutent), and vandetanib (Caprelsa).

Axitinib (Inlyta®)
Description
Pfizer
Oral multikinase inhibitor that targets VEGFR-1, -2, -3.

Approved Indications
Advanced renal cell carcinoma after failure of one prior systemic therapy.
 

Cabozantinib (Cometriq®)
Description
Exelixis
Small molecule tyrosine kinase inhibitor of c-Met and VEGFR2.

Approved Indications
Progressive, metastatic medullary thyroid cancer.
 

Lenvatinib (Lenvima®)
Description
Eisai
A multikinase inhibitor of FGF, VEGF, PDGFR-alpha, RET, and KIT.

Approved Indications
Progressive, differentiated thyroid cancer whose disease progressed despite receiving radioactive iodine therapy
 

Pazopanib (Votrient®)
Description
GlaxoSmithKline
Small molecule TK inhibitor of VEGF, PDGFR and c-kit

Approved Indications
Advanced renal cell carcinoma.
 

Regorafenib (Stivarga®)
Description
Bayer
Oral multikinase inhibitor that targets VEGFR-1, -2, -3, TIE2, PDGFR, and FGFR, KIT, RET, RAF, BRAF, and BRAFV600E.

Approved Indications
Advanced metastatic colorectal cancer (mCRC) that has progressed or has recurred after multiple treatments.
 

Sorafenib (Nexavar®)
Description
Bayer
Onyx
Small molecule TK inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-ß, and Raf-1.

Approved Indications
Advanced renal cell carcinoma, advanced hepatocellular carcinoma, thyroid carcinoma.
  • Treatment of advanced renal cell carcinoma.
  • Treatment of unresectable hepatocellular carcinoma.
  • Treatment of locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) refractory to radioactive iodine.
 

Sunitinib (Sutent®)
Description
Pfizer
Small molecule TK inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR- ß, and RET.

Approved Indications
Advanced renal cell carcinoma, GIST, pancreatic neuroendocrine tumors
  • Treatment of gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate.
  • Progressive neuroendocrine cancerous tumors located in the pancreas that cannot be removed by surgery or that have spread to other parts of the body (metastatic).
 

Vandetanib (Caprelsa®)
Description
AstraZeneca
Small molecule TK inhibitor of VEGFR and EGFR

Approved Indications
Medullary Thyroid Cancer
  • Late-stage (metastatic) medullary thyroid cancer in adult patients who are ineligible for surgery.
 
 
 
Inhibitors of mTOR
Two mTOR inhibitors, temsirolimus (Torisel) and everolimus (Afinitor), are currently approved as anti-cancer therapy.

Temsirolimus (Torisel®)
Description
Wyeth
A small molecule inhibitor of mTOR (mammalian target of rapamycin), part of the PI3 kinase/AKT pathway involved in tumor cell proliferation and angiogenesis.

Approved Indications
Advanced renal cell carcinoma, Relapsed or refractory mantle cell lymphoma/Non-Hodgkins Lymphoma (European Union).
 

Everolimus (Afinitor®)
Description
Novartis
A small molecule inhibitor of mTOR (mammalian target of rapamycin), part of the PI3 kinase/AKT pathway involved in tumor cell proliferation and angiogenesis.

Approved Indications
Advanced renal cell carcinoma, pancreatic neuroendocrine tumors, subependymal giant cell astrocytoma (SEGA).
  • After failure of treatment with sunitinib or sorafenib.
  • Treatment of progressive neuroendocrine tumors of pancreatic origin (PNET) in patients with unresectable, locally advanced, or metastatic disease.
  • Patients with subependymal giant cell astrocytoma (SEGA) who require therapeutic intervention but are not candidates for curative surgical resection.
  • In combination with exemestane to treat certain postmenopausal women with advanced hormone-receptor positive, HER2-negative breast cancer.
 
 
 
Fusion Protein

Ziv-Aflibercept (ZALTRAP®)
Description
Regeneron / Sanofi
A recombinant fusion protein that consists of VEGF-binding portions from the extracellular domains of human VEGF receptors 1 and 2 fused to the Fc portion of the human IgG1 immunoglobulin.

Approved Indications
In combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) for the treatment of patients with metastatic colorectal cancer that is resistant to or has progressed following treatment with an oxaliplatin‑containing regimen.
 
 
 
Other Antiangiogenic Agents

Interferon alfa (Intron® A and Roferon®)
Description
Roche
Schering
Pharmacologic version of an endogenous cytokine with antiangiogenic activity.

Approved Indications
Hairy Cell Leukemia, Malignant Melanoma, Follicular Lymphoma, AIDS-Related Kaposi's Sarcoma.
 

Lenalidomide (Revlimid®)
Description
 
Celgene
Possesses immunomodulatory, anti-inflammatory, and antiangiogenic properties, although the precise mechanisms of action are not fully understood.

Approved Indications
Myelodisplastic Syndrome associated with 5q deletion, Multiple myeloma.
  • Treatment of multiple myeloma in combination with dexamethasone in patients who have received at least one prior therapy.
 

Thalidomide (Thalomid®)
Description
 
Celgene
Possesses immunomodulatory, anti-inflammatory, and antiangiogenic properties, although the precise mechanisms of action are not fully understood.

Approved Indications
Multiple myeloma.
  • Administered in combination with dexamethasone in patients with newly diagnosed multiple myeloma.
 

TAS-102 (Lonsurf®)
Description
 
Taiho
A combination of two active pharmaceutical ingredients: trifluridine, a nucleoside analog, and tipiracil hydrochloride, a thymidine phosphorylase inhibitor.

Approved Indications
Third- or fourth-line treatment in metastatic colorectal cancer which has already received both conventional chemotherapy and biologic therapy.
 

rhEndostatin (Endostar/Endu-available only in China)
Description
 
Simcere
Endogenous angiogenesis inhibitor; recombinant protein; blocks VEGF-induced tyrosine phosphorylation of KDR-Flk-1 in endothelial cells, and down regulates MMP-2/9.

Approved Indications
Non-small cell lung cancer (NSCLC).
 
 


Additionally, in the field of dermatology, a number of FDA-approved agents have antiangiogenic properties:
  • Alitretinoin (Panretin® 0.1% gel, Ligand) is a topical retinoid indicated for the treatment of AIDS-related Kaposi's sarcoma (KS). Retinoids, derivates of vitamin A, are antiangiogenic via downregulation of VEGF.

  • Imiquimod (Aldara® 5% cream, Zyclara 3.75% cream, Medicis) is a Toll-Like Receptor 7 agonist which is an immune response modifier that exerts antiangiogenic activity through local upregulation of interferons and interleukins, downregulation of FGF-2 and MMP-9, and induction of endothelial apoptosis. Imiquimod is indicated for both benign neoplasms (genital warts) and for malignant skin cancers (actinic keratosis and basal cell carcinoma).

  • Polyphenon E (Veregen® 15% ointment, Bradley/MediGene) is a defined composition of polyphenolic kunecatechins extracted from green tea leaves. The major green tea catechins, epigallocatechin-3 (EGCG), inhibits VEGF expression. Polyphenon E topical ointment indicated for genital warts.

  • Vismodegib (Eviredge, Genentech) is a cyclopamine-competitive antagonist of the smoothened receptor (SMO) which is part of the hedgehog signaling pathway.  Vismodegib is indicated for patients with basal cell carcinoma (BCC) which has metastasized to other parts of the body, relapsed after surgery, or cannot be treated with surgery or radiation.

  • Sonidegib (Odomzo, Novartis) is a Hedgehog signaling pathway inhibitor (via smoothened antagonism) indicated for locally advanced basal cell carcinoma that has recurred following surgery or radiation therapy, or who are not candidates for surgery or radiation therapy.