Pharmacology Update
Vandetanib Tablets (Zactima™)
By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Elliott and Chan report no financial relationship relevant to this field of study.
A tyrosine kinase inhibitor has been approved for the treatment of medullary thyroid cancer (MTC). Vandetanib is a multifunctional tyrosine kinase (TK) inhibitor that targets key signaling pathways in cancer. It was given a fast-track designation by the FDA for this indication. It is marketed by AstraZeneca as Zactima.
Indications
Vandetanib is indicated for the treatment of symptomatic or progressive MTC in patients with unresectable locally advanced or metastatic disease.1
Dosage
The recommended dose is 300 mg orally once daily. It may be taken without regard to meals.1 The dose should be reduced to 200 mg in patients with moderate-to-severe renal impairment. Dose reduction may be needed due to toxicities including QTc interval prolongation.
Vandetanib is available as 100 mg and 300 mg tablets.
Potential Advantages
Vandetanib improves progression-free survival (PFS) compared to placebo in patients with unresectable locally advanced or metastatic thyroid cancer.1
Potential Disadvantages
Vandetanib can prolong QT intervals. Torsades de pointes and sudden death have been reported in patients who have been administered this drug.1 Other serious adverse events include death associated with Stevens-Johnson syndrome and interstitial lung disease. Ischemic cerebrovascular events, hemorrhage, heart failure, and reversible posterior leukoencephalopathy syndrome have also been reported.
Comments
Vandetanib shows in vitro inhibition of various TKs including epidermal growth factor receptor, vascular endothelial cell growth factor receptors, and rearranged during transfection (RET).1,2 It has been shown to inhibit proliferation of medullary and papillary cancer cell lines.3 The efficacy of vandetanib was studied in a double-blind, placebo-controlled trial with patients with unresectable locally advanced or metastatic MTC.1 Patients were randomized to vandetanib 300 mg daily (n = 231) or placebo (n = 100). The primary outcome was improvement in PFS. Secondary endpoints include overall survival and overall objective response rate (ORR). Vandetanib showed a statistically significant improvement in PFS (event rate of 26% vs 41%, hazard ratio of 0.35, 95% confidence interval, 0.24, 0.53). The ORR (all partial responses) was in favor of vandetanib, 44% vs 1%. However, there was no significant difference in overall survival at the time of analysis. The most common adverse events were diarrhea, rash, acne, nausea, hypertension, headache, fatigue, decreased appetite, and abdominal pain.1 Due to its potential for serious adverse events (e.g., torsades de pointes, sudden death, Stevens-Johnson syndrome, interstitial lung disease), prescribing and dispensing of vandetanib are limited to prescribers and pharmacies certified with the restricted distribution program (Vandetanib REMS Program).
Clinical Implications
MTC represents up to 8% of all thyroid cancers.4 Most prevalent is the sporadic form (75%) and approximately 25% is the hereditary form. Mutations in RET proto-oncogene are found in practically all hereditary forms and about 50% of sporadic forms of MTC suggesting that targeting this signaling pathway is a rational approach.5,6 The 10-year survival is less than 50% in patients with distant metastasis. Treatment to date has consisted mainly of surgery and radiation. Vandetanib is the first drug approved for the treatment of unresectable locally advanced or metastatic disease. Vandetanib is currently being studied in numerous other cancers, including but not limited to, non-small cell lung cancer, colorectal cancer, breast cancer, and prostate cancer.
References
1. Zactima Prescribing Information. Wilmington, DE: AstraZeneca Pharmaceuticals; March 2011.
2. Herbst RS, et al. Vandetanib (ZD6474): An orally available receptor tyrosine kinase inhibitor that selectively targets pathways critical for tumor growth and angiogenesis. Expert Opin Investig Drugs 2007;16:239-249.
3. Verbeek HH, et al. The effects of four different tyrosine kinase inhibitors on medullary and papillary thyroid cancer cells. J Clin Endocrinol Metab 2011; Epub ahead of print: April 6, 2011.
4. Schlumberger M, et al. New therapeutic approaches to treat medullary thyroid carcinoma. Nat Clin Pract Endocrinol Metab 2008;4:22-32.
5. Santoro M, et al. Molecular mechanisms of RET activation in human cancer. Ann N Y Acad Sci 2002;963:116-121.
6. Ball DW. Management of medullary thyroid cancer. Minerva Endocrinol 2011;36:87-98.
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