Pharmacology Update

Sorafenib Tablets(Nexavar®)

By William T. Elliott, MD, FACP, andJames Chan, PharmD, PhD; Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationship to this field of study.

Sorafenib has been approved by the FDA forthe treatment of inoperable hepatocellular cancer. It is an oral multikinase inhibitor that was previously approved for advanced renal cell carcinoma. It is manufactured by Bayer HealthCare AG in Germany and marketed by Bayer Pharmaceuticals Corporation as Nexavar.

Indications

Sorafenib is indicated for the treatment of patients with unresectable hepatocellular carcinoma (HCC) and patients with advanced renal cell carcinoma.1

Dosage

The recommended dose is 400 mg (2 x 200 mg) taken orally twice daily. It should be taken at least one hour before or 2 hours after meals.1

Sorafenib is available as 200 mg tablets.

Potential Advantages

Sorafenib treatment has shown a median survival advantage of about 3 months compared to placebo in patients with limited therapeutic options.1

Potential Disadvantages

Common adverse events (20%) include fatigue, weight loss, rash/desquamation, hand-foot skin reaction, alopecia, diarrhea, anorexia, nausea, and abdominal pain. Common laboratory abnormalities include elevated lipase, amylase, lymphopenia and anemia. Serious dermatological toxicity may require interruption or discontinuation of therapy.1 Other adverse events include hypertension and less likely, hemorrhage, cardiac ischemia, myocardial infarction, and gastrointestinal perforation.1 Strong CYP3A4 inducers can decrease the levels of sorafenib. Sorafenib increases the level of docetaxel and drug metabolized by UGT1A1 (eg, irinotecan). Caution use be exercised with coadministration with doxorubicin, 5-fluorouracil, CYP2C8 and CYP2B6 substrates.1

Comments

The efficacy of sorafenib has been shown in the Multinational Sorafenib HCC Assessment Randomization Protocol (SHARP) trial. This phase III trial included 602 patients with unresectable HCC who were randomized to sorafenib 400 mg daily (n = 299) or matched placebo group (n = 303).1,2 These patients had biopsy proven HCC, mainly Stage III or IV (90%), Eastern Cooperative Oncology Group performance status from 0-2, Child-Pugh Class A, measurable disease, and no prior therapy. The median survival times were 10.7 months for sorafenib compared to 7.9 months for placebo (hazard ratio, 0.69; 95% CI, 0.55-0.87). The median times to disease progression were 5.5 months for sorafenib compared to 2.8 months for placebo (hazard ratio (95% CI) 0.58 (0.45-0.74). Additionally, 2.3% vs 0.7% had partial response, 71% vs 67% had stable disease and 18% vs 24% had progressive disease. These frequencies did not reach statistical difference (p = 0.06). No complete response was observed. The drug also did not appear to improve quality of life.3 The cost is approximately $4600.

Clinical Implications

Hepatocellular carcinoma is on the rise in the United States and Western Europe.4 Unresectable and metastic disease carries a poor prognosis and survival is measured in months. The estimated number of new cases in the US per year is 18,500 with 16,000 deaths.5 While sorafenib showed statistical improvement in survival compared to placebo, and the drug is touted as the new reference standard for therapy of HCC, the benefit is modest at less than 3 months improved survival.

References

1. Nexavar Product Information. Bayer Pharmaceutical Corporation. November 2007.

2. Zhu AX. Cancer. Nov 26, 2007 (Epub)

3. Hampton T. JAMA. 2007;298:273-275.

4. El-Serag HB, Mason AC. N Engl J Med. 1999;340:745-750.

5. American Cancer Society. Cancer Facts and Figures 2007. Atlanta, Ga. American Cancer Society 2007.