Sorafenib

Sorafenib is a prescription drug used in treatment of hepatocellular carcinoma and renal cell carcinoma. It works by inhibiting a class of signal-transducing enzymes called kinases that activate other proteins by phosphorylation (i.e., addition of a phosphate group). Sorafenib has therefore been describedas an oral multikinase inhibitor of the vascular endothelial growth factor (VEGF))receptor,platelet derived growth factor (PDGF) receptor and Raf gene. It is marketed by Onyx Pharmaceuticals and Bayer as Nexavar, and was approved for use in the US in December 2005.

Since kinase molecules are important in several types of cancer, drugs that inhibit kinases have proven useful in cancer therapy. Other kinase inhibitors used in cancer therapy include vandetanib (Zactima) and imatinib (Gleevec).

Uses

Sorafenib is used specifically for the treatment of patients with:

• unresectable hepatocellular carcinoma (HCC) (liver cancer that cannot be surgically removed)
• advanced renal cell carcinoma (RCC) (advanced kidney cancer)

How Sorafenib is Taken

Sorafenib is supplied in 200 mg oral tablets. The recommended dose is 400 mg taken twice daily without food.

How Sorafenib Works

Sorafenib inhibits several different kinases, including:

• CRAF
• BRAF
• KIT
• FLT-3
• RET
• VEGFR-1
• VEGFR-2
• VEGFR-3
• PDGFR-β

Several of the above kinases are involved in tumor cell signaling, new blood vessel growth, and cell death. By inhibiting these kinases, sorafenib has been shown to inhibit tumor growth in human hepatocellular carcinoma and renal cell carcinoma.

How the Body Affects Sorafenib

Sorafenib reaches peak circulating levels in approximately 3 hours post-dosing. It is metabolized primarily in the liver enzymes CYP3A4 and UGT1A9. 77% of the original dose in the form of metabolites is excreted in the feces, and 19% in the urine.

Side Effects

The most common side effects (occurring in >10% of treated patients) attributable to Nexavar use are:

• Hypertension
• Fatigue
• Weight loss
• Rash/desquamation (skin shedding)
• Hand-foot skin reaction
• Alopecia (hair loss)
• Pruritus (itching)
• Dry skin
• Diarrhea
• Nausea
• Anorexia (loss of appetite)
• Vomiting
• Constipation
• Bleeding
• Neuropathy-sensory
• Pain, abdomen
• Pain, joint
• Headache
• Dyspnea

Risks and Precautions

Sorafenib may cause birth defects. Women are not to get pregnant during treatment and for at least 2 weeks after stopping treatment.

Drug Interactions

The following drugs have been shown to interact with sorafenib use:

• UGT1A1 and UGT1A9 substrates
• Docetaxel
• Doxorubicin
• Fluorouracil
• CYP2B6 and CYP2C8 Substrates
• CYP3A4 Inducers

Effectiveness

In hepatocellular carcinoma (HCC)

One study found that sorafenib significantly improved overall survival compared with placebo.^[1]

A more recent phase 3 multicenter study (the SHARP trial)of 602 patients with advanced hepatocellualr carcinoma reported that patients randomized to sorafenib had improved survival compared to placebo ^[2]

References

1. ↑ Abou-Alfa GK, Schwartz L, Ricci S, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006 Sep 10;24(26):4293-300. Abstract Full Text PDF
2. ↑ Llovet JP, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc J, et al. Sorafenib in advanced hepatocelualr carcinoma. N Engl J Med 2008;359:378-90 All patients had advanced hepatocellular carcinoma who were either not candidates for other forms of treatment or who had progressed on lco-regional therapy.One year survival for the sorafenib group was 10.7 months versus 7.9 months in the placebo groupThe most common side effects with sorafenib were diarrhea, weight loss, skin rashes (especailly hands and feet) adn low phosphate levels.

   In renal cell carcinoma (RCC)

   One study demonstrated that patients who received treatment with interleukin-2 or interferon, those who received sorafenib had 167 days before the tumor progressed as compared to only 84 days in patients who received placebo.<ref>Kane RC, Farrell AT, Saber H, et al. Sorafenib for the treatment of advanced renal cell carcinoma. ''Clin Cancer Res''. 2006 Dec 15;12(24):7271-8. [http://pubmed.gov/17189398 Abstract] [http://clincancerres.aacrjournals.org/cgi/content/full/12/24/7271 Full Text] [http://clincancerres.aacrjournals.org/cgi/reprint/12/24/7271 PDF]</li></ol></ref>

2. Llovet JP, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc J, et al. Sorafenib in advanced hepatocelualr carcinoma. N Engl J Med 2008;359:378-90

External Links

• CenterWatch
• FDA: Patient Information Sheet
• Drugs.com

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