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Cancer Drug Information

  • Updated: 11/26/2013

FDA Approval for Sorafenib Tosylate

Brand name(s): Nexavar®

Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions, and contraindications.

Thyroid Cancer

On November 22, 2013, the Food and Drug Administration (FDA) approved sorafenib tosylate (Nexavar® tablets, made by Bayer Healthcare Pharmaceuticals Inc. and comarketed by Onyx.) for the treatment of locally recurrent or metastatic, progressive differentiated thyroid carcinoma (DTC) refractory to radioactive iodine treatment. Sorafenib was previously approved for treatment of renal cell carcinoma (2005) and hepatocellular carcinoma (2007).

The current approval was based on the results of a multicenter double-blind placebo-controlled trial conducted in 417 patients with locally recurrent or metastatic, progressive DTC refractory to radioactive iodine treatment.  Patients had papillary (57 percent), follicular (25 percent), and poorly differentiated (10 percent) carcinomas. Ninety-six percent of patients had metastases (pulmonary, 86 percent; lymph nodes, 51 percent; and bone, 27 percent).

Approximately half of the patients were male, the median age was 63 years, 68 percent had no uptake of radioactive iodine (RAI), and 34 percent had received a cumulative dose of at least 600 mCi of RAI. The median cumulative RAI activity administered prior to study entry was 400 mCi.

Patients were randomly assigned (1:1) to receive sorafenib tosylate 400 mg orally twice daily or matching placebo. The trial demonstrated an improvement in progression-free survival (PFS), as assessed by blinded independent radiological review. The median PFS was 10.8 months for patients who received sorafenib tosylate and 5.8 months for patients who received placebo [HR 0.59 (95 percent CI: 0.46, 0.76, p<0.001)]. The overall response rates were 12 percent for patients who received sorafenib tosylate versus 1 percent for patients who received placebo. No complete responses were observed. Following investigator-determined disease progression, 157 (75 percent) patients randomly assigned to receive the placebo crossed over to open-label sorafenib tosylate. In an analysis performed after 33% of the patients had died, overall survival was not statistically significantly different in patients who received sorafenib tosylate compared with patients who received placebo [HR 0.88 (95 percent CI: 0.63, 1.24, p=0.47)]. 

Sixty-six percent of patients receiving sorafenib tosylate had dose interruptions for adverse reactions; 64 percent had dose reductions. Treatment discontinuation for adverse reactions was reported in 14 percent of patients who received sorafenib tosylate and 1.4 percent of patients who received placebo.

The most common (greater than or equal to 10 percent) adverse reactions included hand-foot skin reaction, diarrhea, alopecia, weight loss, hypertension, rash, decreased appetite, stomatitis, nausea, pruritus, and abdominal pain. Other significant adverse reactions reported include squamous cell carcinoma of the skin (3 percent) and hypocalcemia (36 percent).

In this population with adequate thyroid suppression [99 percent with baseline thyroid stimulating hormone (TSH) levels less than 0.5 mU/L], elevation of TSH levels above 0.5 mU/L were observed in 41 percent of sorafenib tosylate-treated patients compared with 16 percent of patients receiving placebo. The median time to loss of adequate thyroid suppression was 4.6 months in the sorafenib tosylate-treated group (range, 1 to 22 months). An increase in thyroid replacement medication was necessary to re-acquire thyroid suppression. Inadequate TSH suppression may promote thyroid cancer, and, therefore, TSH levels should be monitored monthly and thyroid replacement therapy adjusted. 

The recommended dose and schedule for sorafenib tosylate is 400 mg (two 200 mg tablets) taken twice daily without food (at least 1 hour before or 2 hours after a meal).

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Liver Cancer

On November 16, 2007, the FDA approved sorafenib tosylate (Nexavar® tablets, made by Bayer Pharmaceuticals Corp.), a small molecule Raf kinase and VEGF receptor kinase inhibitor, for the treatment of patients with unresectable hepatocellular carcinoma (HCC), a type of liver cancer.

The current approval was based on the results of an international, multicenter, randomized, double-blind, placebo-controlled trial in patients with unresectable, biopsy-proven hepatocellular carcinoma. Overall survival was the primary efficacy endpoint. A total of 602 patients were randomized; 299 to sorafenib 400 mg twice daily and 303 to matching placebo.

Demographics and baseline disease characteristics were similar between the sorafenib and placebo groups. Prior treatments included surgical resections (20 percent), locoregional therapies (including radiofrequency ablation, percutaneous ethanol injection and transarterial chemoembolization in 40 percent), radiotherapy (5 percent), and systemic therapy (4 percent).

The trial was stopped following a pre-specified second interim analysis for survival disclosing a statistically significant advantage for sorafenib [median 10.7 vs. 7.9 months; HR: 0.69 (95 percent CI: 0.55, 0.87), p= 0.00058]. The final analysis of time-to-tumor progression (TTP) by independent radiologic review was based on data from an earlier time point and demonstrated a statistically significant improvement in TTP in the sorafenib arm [median 5.5 vs. 2.8 months; HR: 0.58 (95 percent CI: 0.45, 0.74), p=0.000007].

The most common adverse reactions (≥20 percent) considered related to sorafenib were fatigue, weight loss, rash/ desquamation, hand-foot skin reaction, alopecia, diarrhea, anorexia, nausea and abdominal pain. Diarrhea was reported in 55 percent of sorafenib patients (grade 3 in 10 percent). Hand-foot syndrome (21 percent overall; grade 3 in 8 percent) and rash (19 percent overall; grade 3 in 1 percent) were the most common dermatologic adverse reactions to sorafenib.

Cardiac ischemia or infarction was reported in 2.7 percent of sorafenib patients (1.3 percent placebo). Treatment-emergent hypertension was reported in 9 percent of sorafenib patients (4 percent placebo). Grade 3 hypertension was reported in 4 percent of sorafenib patients (1 percent placebo). Elevated serum lipase occurred in 40 percent of sorafenib patients (37 percent placebo), and hypophosphatemia occurred in 35 percent of sorafenib patients (11 percent placebo).

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Kidney Cancer

On December 20, 2005, the FDA granted approval for sorafenib for the treatment of patients with advanced renal cell carcinoma (RCC), a type of kidney cancer.

This indication is based on the demonstration of improved progression-free survival (PFS) in a large, multinational, randomized double-blind, placebo-controlled phase III study and a supportive phase II study. Overall survival results from the phase III study are preliminary at this time.

The sorafenib tosylate phase III study was conducted in patients with advanced (unresectable or metastatic) renal cell carcinoma who had received one prior systemic treatment. Eligibility also included ECOG performance status (PS) 0 or 1, and MSKCC (Memorial Sloan Kettering Cancer Center) RCC prognostic risk category of low or intermediate.

Patients with brain metastases, MSKCC high risk score, or advanced cardiac conditions were not eligible. Study endpoints included overall survival, progression-free survival, and response rate.

Among 769 patients randomized, the median age was 59 years and 70 percent were male; there were approximately equal patient numbers in each arm for each category of PS and MSKCC prognostic risk category. Baseline patient and disease characteristics were well balanced. Regarding prior therapies, 93 percent had prior nephrectomies; 99 percent had received prior systemic therapies, including interleukin-2 (44 percent) and an interferon (68 percent).

PFS (time from randomization to progression or death from any cause), progression and response rate were determined by independent blinded radiologic review. The median PFS was 167 days in the sorafenib tosylate group versus 84 days in the placebo control group (HR 0.44, 95 percent CI for HR: 0.35 - 0.55), logrank p < 0.000001). Results were similar regardless of MSKCC prognostic risk category, ECOG PS, age, or prior therapy.

Time-to-progression was similarly improved. Tumor response was determined by independent radiological review according to RECIST criteria. Overall, of 672 patients who were evaluable for response, seven (2 percent) sorafenib tosylate patients and no (0 percent) placebo patients had confirmed partial responses.

Sorafenib tosylate toxicities (based on an updated phase III study database of 902 patients) included reversible skin rashes in 40 percent and hand-foot skin reaction in 30 percent. Diarrhea was reported in 43 percent, treatment-emergent hypertension in 17 percent, and sensory neuropathic changes in 13 percent.

Alopecia, oral mucositis, and hemorrhage also were reported more commonly on the sorafenib tosylate arm. The incidence of treatment-emergent cardiac ischemia/infarction events was higher in the sorafenib tosylate group (2.9 percent) compared with the placebo group (0.4 percent). Grade 3 and 4 adverse events were unusual; only hand-foot skin reaction occurred at 5 percent or greater frequency in the sorafenib tosylate arm.

Laboratory findings included asymptomatic hypophosphatemia in 45 percent versus 12 percent and serum lipase elevations in 41 percent versus 30 percent of sorafenib tosylate versus placebo patients, respectively. Grade 4 pancreatitis was reported in two sorafenib tosylate patients, although both patients subsequently resumed sorafenib tosylate, one at full dose.

Physicians should be aware of the importance of frequent blood pressure monitoring and management, especially during the first six weeks after starting sorafenib tosylate, and the unusual laboratory alterations on sorafenib tosylate therapy.

The recommended dose is 400 mg (two 200 mg tablets) twice daily taken either one hour before or two hours after meals. Adverse events were accommodated by temporary dose interruptions or reductions to 400 mg once daily or 400 mg every other day.

Sorafenib tosylate metabolism is principally hepatic via CYP3A4 and UGT1A9 pathways. Sorafenib tosylate is an inhibitor of UGT1A1.

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This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.

The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.