Antiangiogenic agents

February 5, 2007

FDA-Approved Drugs: bevacizumab (Avastin), sorafenib (Nexavar), sunitinib (Sutent) Investigational Drugs: vatalanib (PTK787, Novartis), AMG 706 (Amgen), GW-786034 (GlaxoSmithKline), ZD6474 (AstraZeneca)

ABSTRACT: FDA-Approved Drugs: bevacizumab (Avastin), sorafenib (Nexavar), sunitinib (Sutent) Investigational Drugs: vatalanib (PTK787, Novartis), AMG 706 (Amgen), GW-786034 (GlaxoSmithKline), ZD6474 (AstraZeneca)

Mechanism of Action

Antiangiogenesis agents block tumor cell signals to develop new blood vessels. Tumors cannot grow beyond 1-2 mm (diffusion distance of oxygen) without new blood vessels to supply nutrients and remove waste products. These signals can be blocked before they reach the endothelial cells (eg, bevacizumab, a monoclonal antibody that binds to vascular endothelial growth factor [VEGF]). Signals can be blocked inside the endothelial cell membrane by tyrosine kinase inhibitors (TKIs), stopping the message to make more endothelial cells, as with sorafenib and sunitinib. These TKIs are multitargeted and block other pathways that indirectly contribute to angiogenesis.

Metabolism

Bevacizumab has a terminal half-life of approximately 20 days. Sorafenib and sunitinib have a half-life of about 25-60 hours. The bioavailability of sorafenib is reduced by 29% when taken with high-fat meals, so it should be taken on an empty stomach.

Indications

Bevacizumab is indicated for the treatment of patients with (1) metastatic cancer of the colon or rectum, as first or second line, in combination with IV fluorouracil (5-FU)-based chemotherapy, and (2) unresectable, locally advanced, recurrent or metastatic nonsquamous, non-small-cell lung cancer, as first line in combination with paclitaxel and carboplatin. Sorafenib and sunitinib are indicated for the treatment of patients with advanced renal cell cancer; sunitinib is also indicated for the treatment of patients with gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate (Gleevec).

Patient Education

Teach patients about class-related side effects such as (1) risk for developing hypertension and need for blood pressure monitoring; (2) bleeding from the nose (epistaxis) or more rarely gastrointestinal (GI) bleeding; (3) delayed wound healing. Rarely, GI perforation may occur. Patients should be instructed to report severe abdominal pain, with or without constipation and nausea/vomiting. Teach patients about drug-specific side effects.

Interactions

Sorafenib and sunitinib are metabolized by the P450 microenzyme system so any agents that increase (induce) the metabolism of the drugs may reduce serum concentration (St. John's wort, rifampin, phenytoin, phenobarbital, dexamethasone); if the drug must be coadministered with any of these other agents, the sorafenib or sunitinib dose may need to be increased. Sunitinib metabolism may be inhibited by certain drugs like ketoconazole, requiring a dose reduction. Use caution if sorafenib is combined with chemotherapy such as doxorubicin or irinotecan (Camptosar), as the chemotherapy serum concentrations are increased (21% and 26% to 42%, respectively, and the active metabolite of irinotecan SN-38, by 67% to 120%).

Special Considerations

Drug should be held for severe hypertension that does not respond to antihypertensive medications. If patient develops proteinuria, congestive heart failure, or changes in neurosensory status, drug should be stopped and the patient evaluated further.

Contraindications/Precautions

Drug should not be given to pregnant women; mothers should not breastfeed while receiving the drug. Some patients with squamous cell non-small-cell lung cancer have experienced fatal hemorrhage with bevacizumab. Arterial thrombotic events occur rarely, and patients at risk are those aged ≥ 65 years old with atherosclerotic heart disease or previous thrombotic events.

Adverse Reactions by System (vary with drug)

CV: Reduced left ventricular ejection fraction, arterial blood clots, reversible posterior leukoencephalopathy

EENT: Dry mouth

GI: Diarrhea, nausea, mucositis, dyspepsia, altered taste, constipation, loss of appetite, GI perforation

GU: Erectile dysfunction, nephritic syndrome

Hematologic: Bleeding, hemorrhage, leukopenia, anemia, neutropenia, thrombocytopenia

Metabolic: Increased serum lipase and amylase, hypophosphatemia, hyperuricemia,

Musculoskeletal: Arthralgias, myalgias

Neurological: Headache, peripheral neuropathy,

Skin: Rash, hand-foot syndrome, skin discoloration, blister formation, hair thinning, acne, flushing

Other: Hypothyroidism