Nexavar (sorafenib) - 3 indications

Scroll down for more information on each indication:

• for the treatment of advanced renal cell carcinoma; approved December 2005
• for the treatment of unresectable hepatocellular carcinoma; approved November 2007
• for the treatment of locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) refractory to radioactive iodine treatment; approved November 2013

General Information

Nexavar (sorafenib) is a multikinase inhibitor targeting a number of serine/threonine and receptor tyrosine kinases. Inhibition of these systems inhibits division and growth of tumor cells, and potentiates cellular apoptosis.

Nexavar is specifically indicated for the treatment of:

advanced renal cell carcinoma

unresectable hepatocellular carcinoma

locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) refractory to radioactive iodine treatment;

Nexavar is supplied as a orally available tablet; each tablet contains 200 mg of the drug. Recommended dosage is 400 mg (two tablets) twice daily. As necessary, dose may be reduced to 400 mg once daily or once every other day to manage treatment-related toxicity.

Mechanism of Action

Nexavar is a multikinase inhibitor, with disruptive activity at intracellular CRAF, BRAF and mutant BRAF receptors, and extracellular KIT, FLT-3, VEGFR-2, VEGFR-3 and PDGFR-B receptors. These kinases are involved in multiple systems of angiogenesis and intracellular signalling, and their disruption is thought to inhibit tumor growth.

Side Effects

Adverse events associated with the use of Nexavar may include, but are not limited to, the following:

• Diarrhea
• Rash/Desquamation
• Fatigue
• Anemia
• Hand/Foot Skin Reaction
• Alopecia
• Nausea
• Pruritus
• Anorexia
• Hemorrhage
• Sensory Neuropathy

In addition, the dermatologic adverse events, including erythmia, often required dose adujustment when they were grade 2 or higher. Recurrent grade 3 reactions (3 or more instances), including moist desquamation, ulceration, blistering and severe discomfort, may require termination of treatment. Patients are advised to monitor such reactions closely in cooperation with their doctors.

Indication 1 - for the treatment of advanced renal cell carcinoma

approved December 2005

Clinical Trial Results

Approval of Nexavar was supported by both a Phase II and a Phase III clinical trial.

Phase II Study
Nexavar was investigated in a randomized, controlled study designed to investigate the efficacy of the drug; the trial's primary endpoint was the percentage of patients remaining on-treatment and progression free after 24 weeks. 202 RCC patients received 12 weeks of open label Necavar therapy; following radiological assessment of tumor state, patients experiencing >25% reduction in tumor size continued open label treatment (n=79), and patients with <25% response were randomized to receive the drug or placebo through week 24. Among this subject of patients, Nexavar was seen to significantly increase both the percentage of patients maintianing progression-free survival (PFS) at week 24 (50% vs. 18%; p=0.0077) and the duration of PFS (163 vs. 41 days; p=0.0001), compared to placebo.

Phase III study
Nexavar was also studied in an international, multi-center, randomized, double-blind, placebo-controlled phase III trial, which enrolled 769 RCC patients. Subjects received 400 mg of the drug or placebo twice daily, until evidence of PFS was observed. Trial data demonstrated significant efficacy in prolonging PFS, compared to placebo (167 days vs. 84 days). This corresponded to an estimated hazard ratio (risk of disease progression for Nexavar compared to placebo) of 0.44. Subpopulation analyses indicated comparable efficacy across several tumor demographics, including patients who had not previously received therapy with interferon or IL-2 (PFS: 172 days vs. 85 days). Secondary analysis of tumor response indicated that 2% of patients receiving Nexavar (n=7) experienced partial disease response (>50% reduction in tumor size); no patients receiving placebo experienced this response. Interim overall survival data yielded a risk of death hazard ratio of 0.72 (Nexavar vs. placebo), which did not meet statistical significance.

Indication 2- for the treatment of unresectable hepatocellular carcinoma

approved November 2007

Clinical Trial Results

The SHARP (HCC) study was an international, multicenter, randomized, double blind, placebo-controlled trial in patients with unresectable hepatocellular carcinoma. Overall survival was the primary endpoint. A total of 602 patients were randomized; 299 to NEXAVAR 400 mg twice daily and 303 to matching placebo. All 602 randomized subjects were included in the ITT population for the efficacy analyses. The trial was stopped for efficacy following a pre-specified second interim analysis for survival showing a statistically significant advantage for NEXAVAR over placebo for overall survival. This advantage was consistent across all subsets analyzed.

Indication 3- for the treatment of locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) refractory to radioactive iodine treatment

approved November 2013

Clinical Trial Results

The safety and effectiveness of NEXAVAR was evaluated in a multicenter, randomized (1:1), double blind, placebo-controlled trial (DECISION; NCT00984282) conducted in 417 patients with locally recurrent or metastatic, progressive differentiated thyroid carcinoma (DTC) refractory to radioactive iodine (RAI) treatment. All patients were required to have actively progressing disease defined as progression within 14 months of enrollment. The major efficacy outcome measure was progression-free survival (PFS) as determined by a blinded, independent radiological review using a modified Response Evaluation Criteria in Solid Tumors v. 1.0 (RECIST). RECIST was modified by inclusion of clinical progression of bone lesions based on the need for external beam radiation (4.4% of progression events). Additional efficacy outcomes measures included overall survival (OS), tumor response rate, and duration of response. Patients were randomized to receive NEXAVAR 400 mg twice daily (n=207) or placebo (n=210). A statistically significant prolongation of PFS was demonstrated for NEXAVAR-treated patients compared to those receiving placebo (Figure 3); no statistically significant difference was seen in the final overall survival (OS) analysis. Crossover to open label NEXAVAR occurred in 161 (77%) patients randomized to placebo after investigator-determined disease progression.