Earlier today, the U.S. Food and Drug Administration (FDA) announced that the agency has approved axitinib (Inlyta?, Pfizer Inc) to treat patients with advanced or metastatic renal cell carcinoma (mRCC) who have not responded to another drug for this type of cancer. Axitinib helps keep the cancer from progressing.

Axitinib is a small molecule tyrosine kinase inhibitor which inhibits multiple targets, including VEGFR-1, VEGFR-2, VEGFR-3, platelet derived growth factor receptor (PDGFR), and cKIT (CD117). It has been shown to significantly inhibit growth of breast cancer in xenograft models[1] and has been successful in trials with renal cell carcinoma (RCC)[2] and several other tumor types.[3]

Renal cell carcinoma is a type of kidney cancer that starts in the lining of very small tubes in the kidney. Axitinib, dosed as a that patients take twice a day, works by blocking certain proteins called kinases that play a role in tumor growth and cancer progression.

More treatment options for RCC
Statistical data shows that in 2011 more than 60,000 new cases of renal cell carcinoma were diagnosed in the United States. [4,5] Approximately 20% of patients will ultimately present with metastatic disease and those who present with local or locally advanced disease, approximately 30% of patients will relapse. [6] As a result, approximately 13,000 Americans will die of this disease annually.[4,5]

Clinical trials
In 2010, a Phase III trial for previously treated metastatic renal cell carcinoma (mRCC) showed significantly extended progression-free survival when compared to sorafenib. Based on the results of the Phase III trial comparing axitinib and sorafenib, the Oncologic Drugs Advisory Committee (ODAC) voted unanimously to recommend the approval of axitinib for the second-line treatment of patients with advanced renal cell carcinoma.

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Multiple drugs approved
The market for kidney cancer drugs has grown over the last few years. “This is the seventh drug that has been approved for the treatment of metastatic or advanced kidney cell cancer since 2005,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Collectively, this unprecedented level of drug development within this time period has significantly altered the treatment paradigm of metastatic kidney cancer, and offers patients multiple treatment options.”

Recently approved drugs for the treatment of kidney cancer include sorafenib (2005), sunitinib (2006), temsirolimus (2007), everolimus (2009), bevacizumab (2009) and pazopanib (2009).

Drug evaluation
The safety and effectiveness of axitinib were evaluated in a single randomized, open-label, multi-center clinical study of 723 patients whose disease had progressed on or after treatment with one prior systemic therapy. The study was designed to measure progression-free survival, the time a patient lived without the cancer progressing. Results showed a median progression-free survival of 6.7 months compared to 4.7 months with a standard treatment (sorafenib).

Common side effects
The most common side effects observed in greater than 20% of patients in the clinical study were diarrhea, high blood pressure (hypertension), fatigue, decreased appetite, nausea, loss of voice (dysphonia), hand-foot syndrome (palmar-plantar erythrodysesthesia), weight loss, vomiting, weakness (asthenia) and constipation.

Based on the study results, patients with high blood pressure should have their BP well-controlled before taking axitinib. Some patients who took axitinib experienced bleeding problems, which in some cases were fatal. Patients with untreated brain tumors or gastrointestinal bleeding should not take axitinib.

For more information:
– FDA: Office of Hematology and Oncology Products
– FDA: Approved Drugs: Questions and Answers
– FDA: Oncologic Drugs Advisory Committee Meeting (axitinib)

[1] Wilmes LJ, Pallavicini MG, Fleming LM, Gibbs J, Wang D, Li KL, Partridge SC, et al.AG-013736, a novel inhibitor of VEGF receptor tyrosine kinases, inhibits breast cancer growth and decreases vascular permeability as detected by dynamic contrast-enhanced magnetic resonance imaging.Magn Reson Imaging 25(3):319-27
[2] Rini B, Rixe O, Bukowski R, Michaelson MD, Wilding G, Hudes G, Bolte O,et al.AG-013736, a multi-target tyrosine kinase receptor inhibitor, demonstrates anti-tumor activity in a Phase 2 study of cytokine-refractory, metastatic renal cell cancer (RCC). ASCO Proceedings Abstract 4509
[3] Rugo HS, Herbst RS, Liu G, Park JW, Kies MS, Steinfeldt HM, Pithavala YK, et al. Phase Itrial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results. J Clin Oncol. 23(24):5474-83
[4] Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011 Jul-Aug;61(4):212-36. Epub 2011 Jun 17.<BR>[5] SEER 2011(NCI)<BR>
[6] Cohen HT and McGovern FJ. Renal-cell carcinoma. N Engl J Med 2005;353:2477-90

Also read:
– Pfizer?s Phase III Trial in mRCC Turns Up Positive Results. GEN News Highlights: November 19, 2010
– Positive Phase III Trial Results Reported For Axitinib (AG013736) In Patients With Previously-Treated Metastatic Renal Cell Carcinoma (mRCC). Onco’Zine: November 20, 2010.
– Axitinib Shows Significantly Extended Progression-free Survival in mRCC. Onco’Zine: June 1, 2011.
ODAC Unanimously Supports Axitinib for Renal Cell Carcinoma. OncLive: December 7, 2011.

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