In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
New Indication
On November 22, 2013, sorafenib (Nexavar) was approved for the treatment of locally recurrent or metastatic, progressive, differentiated thyroid carcinoma refractory to radioactive iodine treatment.1,2 Sorafenib was previously approved for treatment of renal cell carcinoma (2005) and hepatocellular carcinoma (2007).
The current approval is based on the finding of significantly increased progression-free survival with sorafenib vs placebo in a phase III multicenter, double-blind trial in which 417 patients were randomly assigned to receive sorafenib at 400 mg twice daily orally (n = 207) or placebo (n = 209).2 Overall, 52% of patients were female, median age was 63 years (61% ≥ 60 years), 60% were white, 62% had Eastern Cooperative Oncology Group performance status of 0, and 99% had undergone thyroidectomy.
Histologic diagnoses included papillary carcinoma in 57%, follicular carcinoma in 25%, and poorly differentiated carcinoma in 10%. Metastases were present in 96% of patients, with sites including lungs in 86%, lymph nodes in 51%, and bone in 27%.
The median cumulative radioactive iodine activity administered prior to study entry was 400 mCi. Radioactive iodine refractoriness was indicated by target lesion with no iodine uptake on radioactive iodine scan in 68%, tumors with iodine uptake and progression after radioactive iodine treatment within 16 months of enrollment in 12%, tumors with iodine uptake and multiple radioactive iodine treatments with the last treatment greater than 16 months prior to enrollment and disease progression after each of two radioactive iodine treatments within 16 months of each other in 7%, and cumulative radioactive iodine dose ≥ 600 mCi in 34%.
Median progression-free survival was 10.8 months in the sorafenib group and 5.8 months in the placebo group (hazard ratio [HR] = 0.59, P < .001). Objective response occurred in 24% vs 0.5% of patients, and median response duration was 10.2 months in the sorafenib group. After progression, 75% of the placebo group crossed over to sorafenib treatment and 30% of the sorafenib group received open-label sorafenib. Median overall survival was not reached in the sorafenib group and was 36.5 months in the placebo group (HR = 0.88, P = .47).
How It Works
Sorafenib inhibits multiple intracellular (c-CRAF, BRAF, and mutant BRAF) and cell surface kinases (KIT, FLT-3, RET, RET/PTC, VEGFR-1, VEGFR-2, VEGFR-3, and PDGFR-ß), several of which are thought to be involved in tumor cell signaling, angiogenesis, and apoptosis. The drug results in decreased tumor cell proliferation in vitro, inhibits tumor growth of hepatocellular carcinoma, renal cell carcinoma, and differentiated thyroid carcinoma xenografts in immunocompromised mice, reduces tumor angiogenesis in models of hepatocellular carcinoma and renal cell carcinoma, and increases tumor apoptosis in models of hepatocellular carcinoma, renal cell carcinoma, and differentiated thyroid carcinoma.
How It Is Given
The recommended daily dose of sorafenib is 400 mg taken twice daily without food. Treatment should continue until loss of clinical benefit or unacceptable toxicity.
Interruption of treatment is recommended in patients undergoing major surgical procedures, and interruption or discontinuation may be required for cardiac ischemia or infarction, hemorrhage requiring medical intervention, severe or persistent hypertension despite adequate antihypertensive therapy, gastrointestinal perforation, QTc prolongation, or severe drug-induced liver injury.
When dose reductions are required, doses are reduced sequentially to 400 mg and 200 mg doses 12 hours apart, 200 mg twice daily, and 200 mg once daily. The product labeling provides specific recommendations for dose reductions for dermatologic toxicities. Concomitant use of strong CYP3A4 inducers (eg, rifampin, carbamazepine) should be avoided.
Safety Profile
In the phase III trial, adverse events resulted in dose interruptions in 66% and dose reductions in 64% of sorafenib recipients and in treatment discontinuation in 14% of sorafenib recipients and 1% of placebo recipients. The most common adverse events of any grade in sorafenib-treated patients were palmar-plantar erythrodysesthesia syndrome (69% vs 8% with placebo), diarrhea (68% vs 15%), alopecia (67% vs 8%), weight loss (49% vs 14%), hypertension (41% vs 12%), fatigue (41% vs 20%), rash (35% vs 7%), and decreased appetite (30% vs 5%).
Grade 3 adverse events occurred in 53% of sorafenib patients and 23% of placebo patients and grade 4 adverse events occurred in 12% and 7%; the most common grade 3 or 4 adverse events were palmar-plantar erythrodysesthesia syndrome (19% vs 0%), hypertension (10% vs 2%), diarrhea (6% vs 1%), weight loss (6% vs 1%), rash (5% vs 0%), and fatigue (5% vs 1%). Squamous cell carcinoma of the skin occurred in 3% of sorafenib patients.
Alanine aminotransferase and aspartate aminotransferase elevations were observed in 59% and 54% of sorafenib patients and in 24% and 15% of placebo patients, with grade 3 or higher elevations observed in 4% and 2% of sorafenib patients and in no placebo patients. Hypocalcemia (which was more common and severe in differentiated thyroid carcinoma patients than in renal cell carcinoma or hepatocellular carcinoma patients) occurred in 36% of sorafenib recipients and 11% of placebo recipients, with grade 3 or higher events occurring in 10% and 3%.
Other laboratory abnormalities that have occurred in > 10% of sorafenib-treated patients in trials in differentiated thyroid carcinoma, renal cell carcinoma, and hepatocellular carcinoma include leukopenia, lymphopenia, hypokalemia, hyponatremia, and hypothyroidism.
Thyroid suppression to thyroid-stimulating hormone (TSH) levels < 0.5 mU/L was present in 99% of patients at baseline. TSH elevations to > 0.5 mU/L were observed in 41% of sorafenib-treated patients and 16% of patients receiving placebo, with a median time to loss of adequate thyroid suppression of 4.6 months in the sorafenib group (range, 1–22 months). An increase in thyroid replacement medication was necessary to regain thyroid suppression.
The sorafenib label includes warning/precautions for cardiac ischemia or infarction, bleeding, hypertension, dermatologic toxicities, gastrointestinal perforation, QT prolongation, drug-induced hepatitis, impairment of TSH suppression, and embryo-fetal toxicity.
Blood pressure should be monitored weekly during the first 6 weeks of treatment and periodically thereafter. ECGs and electrolytes should be monitored in patients at increased risk of ventricular arrhythmias. Liver function tests should be regularly monitored. Inadequate TSH suppression may promote thyroid cancer; TSH levels should be monitored monthly and thyroid replacement therapy adjusted.
Sorafenib in combination with carboplatin and paclitaxel is contraindicated in patients with squamous cell lung cancer. ■
References
1. U.S. Food and Drug Administration: Sorafenib (Nexavar). Available at http://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm376547.htm.
2. NEXAVAR® (sorafenib) tablets prescribing information. Bayer HealthCare Pharmaceuticals Inc, November 2013. Available at http://labeling.bayerhealthcare.com/html/products/pi/Nexavar_PI.pdf.
Report Adverse Events
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
