Nexavar (Sorafenib) - Description and Clinical Pharmacology

DESCRIPTION

NEXAVAR, a kinase inhibitor, is the tosylate salt of sorafenib.

Sorafenib tosylate has the chemical name 4-(4-{3-[4-Chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy) N ²-methylpyridine-2-carboxamide 4-methylbenzenesulfonate and its structural formula is:

Sorafenib tosylate is a white to yellowish or brownish solid with a molecular formula of C₂₁H₁₆ClF₃N₄O₃ x C₇H₈O₃S and a molecular weight of 637.0 g/mole. Sorafenib tosylate is practically insoluble in aqueous media, slightly soluble in ethanol and soluble in PEG 400.

Each red, round NEXAVAR film-coated tablet contains sorafenib tosylate (274 mg) equivalent to 200 mg of sorafenib and the following inactive ingredients: croscarmellose sodium, microcrystalline cellulose, hypromellose, sodium lauryl sulphate, magnesium stearate, polyethylene glycol, titanium dioxide and ferric oxide red.

CLINICAL PHARMACOLOGY

Mechanism Of Action

Sorafenib is a kinase inhibitor that decreases tumor cell proliferation in vitro. Sorafenib was shown to inhibit multiple intracellular (CRAF, BRAF and mutant BRAF) and cell surface kinases (KIT, FLT-3, RET, VEGFR-1, VEGFR-2, VEGFR-3, and PDGFR-ß). Several of these kinases are thought to be involved in tumor cell signaling, angiogenesis, and apoptosis. Sorafenib inhibited tumor growth and angiogenesis of human hepatocellular carcinoma and renal cell carcinoma, and several other human tumor xenografts in immunocompromised mice.

Pharmacokinetics

After administration of NEXAVAR tablets, the mean relative bioavailability is 38-49% when compared to an oral solution. The mean elimination half-life of sorafenib is approximately 25-48 hours. Multiple dosing of NEXAVAR for 7 days resulted in a 2.5- to 7-fold accumulation compared to single dose administration. Steady-state plasma sorafenib concentrations are achieved within 7 days, with a peak-to-trough ratio of mean concentrations of less than 2.

Absorption and Distribution

Following oral administration, sorafenib reaches peak plasma levels in approximately 3 hours. When given with a moderate-fat meal (30% fat; 700 calories), bioavailability was similar to that in the fasted state. With a high-fat meal (50% fat; 900 calories), sorafenib bioavailability was reduced by 29% compared to administration in the fasted state. It is recommended that NEXAVAR be administered without food [see DOSAGE AND ADMINISTRATION (2) ].

Mean C_max and AUC increased less than proportionally beyond doses of 400 mg administered orally twice daily.

In vitro binding of sorafenib to human plasma proteins is 99.5%.

Metabolism and Elimination

Sorafenib is metabolized primarily in the liver, undergoing oxidative metabolism, mediated by CYP3A4, as well as glucuronidation mediated by UGT1A9.

Sorafenib accounts for approximately 70-85% of the circulating analytes in plasma at steady-state. Eight metabolites of sorafenib have been identified, of which five have been detected in plasma. The main circulating metabolite of sorafenib in plasma, the pyridine N -oxide, shows in vitro potency similar to that of sorafenib. This metabolite comprises approximately 9-16% of circulating analytes at steady-state.

Following oral administration of a 100 mg dose of a solution formulation of sorafenib, 96% of the dose was recovered within 14 days, with 77% of the dose excreted in feces, and 19% of the dose excreted in urine as glucuronidated metabolites. Unchanged sorafenib, accounting for 51% of the dose, was found in feces but not in urine.

Special Populations

Age

Analyses of demographic data suggest that no dose adjustments are necessary for age.

Gender

Analyses of demographic data suggest that no dose adjustments are necessary for gender.

Race

A study of the pharmacokinetics of sorafenib indicated that the mean AUC of sorafenib in Asians (N=78) was 30% lower than in Caucasians (N=40).

Pediatric

There are no pharmacokinetic data in pediatric patients.

Hepatic Impairment

Sorafenib is cleared primarily by the liver.

Comparison of data across studies suggests that in HCC patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment, 400 mg doses of sorafenib appear to be associated with AUC values that were 23 to 65% lower than those of other subjects without hepatic impairment. The AUC of sorafenib is similar between HCC patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment. The pharmacokinetics of sorafenib have not been studied in patients with severe (Child-Pugh C) hepatic impairment  [see Warnings and Precautions and Use in Specific Populations (8.6)].

Renal Impairment

In a study of drug disposition after a single oral dose of radiolabeled sorafenib to healthy subjects, 19% of the administered dose of sorafenib was excreted in urine.

In a clinical pharmacology study, the pharmacokinetics of sorafenib were evaluated following administration of a single 400 mg dose to subjects with normal renal function, and in subjects with mild (CrCl > 50-80 ml/min), moderate (CrCl 30-50 ml/min), or severe (CrCl < 30 ml/min) renal impairment, not undergoing dialysis. There was no relationship observed between sorafenib exposure and renal function. No dosage adjustment is necessary based on mild, moderate or severe renal impairment not undergoing dialysis. Monitoring of fluid balance and electrolytes in patients with renal dysfunction is advised [see Use in Specific Populations].

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity studies have not been performed with sorafenib.

Sorafenib was clastogenic when tested in an in vitro mammalian cell assay (Chinese hamster ovary) in the presence of metabolic activation. Sorafenib was not mutagenic in the in vitro Ames bacterial cell assay or clastogenic in an in vivo mouse micronucleus assay. One intermediate in the manufacturing process, which is also present in the final drug substance (<0.15%), was positive for mutagenesis in an in vitro bacterial cell assay (Ames test) when tested independently.

No specific studies with sorafenib have been conducted in animals to evaluate the effect on fertility. However, results from the repeat-dose toxicity studies suggest there is a potential for sorafenib to impair reproductive function and fertility. Multiple adverse effects were observed in male and female reproductive organs, with the rat being more susceptible than mice or dogs. Typical changes in rats consisted of testicular atrophy or degeneration, degeneration of epididymis, prostate, and seminal vesicles, central necrosis of the corpora lutea and arrested follicular development. Sorafenib-related effects on the reproductive organs of rats were manifested at daily oral doses ≥30 mg/m² (approximately 0.5 times the AUC in cancer patients at the recommended human dose). Dogs showed tubular degeneration in the testes at 600 mg/m²/day (approximately 0.3 times the AUC at the recommended human dose) and oligospermia at 1200 mg/m²/day of sorafenib.

Adequate contraception should be used during therapy and for at least 2 weeks after completing therapy.

CLINICAL STUDIES

The clinical safety and efficacy of NEXAVAR have been studied in patients with hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC).

Hepatocellular Carcinoma

The HCC Study was a Phase 3, 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.

Demographics and baseline disease characteristics were similar between the NEXAVAR and placebo groups with regard to age, gender, race, performance status, etiology (including hepatitis B, hepatitis C and alcoholic liver disease), TNM stage (stage I: <1% vs. <1%; stage II: 10.4% vs. 8.3%; stage III: 37.8% vs. 43.6%; stage IV: 50.8% vs. 46.9%), absence of both macroscopic vascular invasion and extrahepatic tumor spread (30.1% vs. 30.0%), and Barcelona Clinic Liver Cancer stage (stage B: 18.1% vs. 16.8%; stage C: 81.6% vs. 83.2%; stage D: <1% vs. 0%). Liver impairment by Child-Pugh score was comparable between the NEXAVAR and placebo groups

(Class A: 95% vs. 98%; B: 5% vs. 2%). Only one patient with Child-Pugh class C was entered. Prior treatments included surgical resection procedures (19.1% vs. 20.5%), locoregional therapies (including radiofrequency ablation, percutaneous ethanol injection and transarterial chemoembolization; 38.8% vs. 40.6%), radiotherapy (4.3% vs. 5.0%) and systemic therapy (3.0% vs. 5.0%).

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 (HR: 0.69, p= 0.00058) (see Table 4 and Figure 1).  This advantage was consistent across all subsets analyzed.  

Final analysis of time to tumor progression (TTP) based on data from an earlier time point (by independent radiologic review) also was significantly longer in the NEXAVAR arm (HR: 0.58, p=0.000007) (see Table 4).

Table 4: Efficacy Results from HCC Study

CI=Confidence interval
Efficacy Parameter	NEXAVAR (N=299)	Placebo (N=303)	Hazard Ratio 1 (95% CI)	P-value (log-rank test 2)
Overall Survival Median, months (95% CI) No. of events	10.7 (9.4, 13.3) 143	7.9 (6.8, 9.1) 178	0.69 (0.55, 0.87)	0.00058
Time to Progression 3 Median, months (95% CI) No. of events	5.5 (4.1, 6.9) 107	2.8 (2.7, 3.9) 156	0.58 (0.45, 0.74)	0.000007

Renal Cell Carcinoma

The safety and efficacy of NEXAVAR in the treatment of advanced renal cell carcinoma (RCC) were studied in the following two randomized controlled clinical trials.

RCC Study 1 was a Phase 3, international, multicenter, randomized, double blind, placebo-controlled trial in patients with advanced renal cell carcinoma who had received one prior systemic therapy. Primary study endpoints included overall survival and progression-free survival (PFS). Tumor response rate was a secondary endpoint. The PFS analysis included 769 patients stratified by MSKCC (Memorial Sloan Kettering Cancer Center)

prognostic risk category (low or intermediate) and country and randomized to NEXAVAR 400 mg twice daily

(N=384) or to placebo (N=385).

Table 5 summarizes the demographic and disease characteristics of the study population analyzed. Baseline demographics and disease characteristics were well balanced for both treatment groups. The median time from initial diagnosis of RCC to randomization was 1.6 and 1.9 years for the NEXAVAR and placebo groups, respectively.

Table 5: Demographic and Disease Characteristics - RCC Study 1">

Renal Cell Carcinoma

The safety and efficacy of NEXAVAR in the treatment of advanced renal cell carcinoma (RCC) were studied in the following two randomized controlled clinical trials.

RCC Study 1 was a Phase 3, international, multicenter, randomized, double blind, placebo-controlled trial in patients with advanced renal cell carcinoma who had received one prior systemic therapy. Primary study endpoints included overall survival and progression-free survival (PFS). Tumor response rate was a secondary endpoint. The PFS analysis included 769 patients stratified by MSKCC (Memorial Sloan Kettering Cancer Center)

prognostic risk category (low or intermediate) and country and randomized to NEXAVAR 400 mg twice daily

(N=384) or to placebo (N=385).

Table 5 summarizes the demographic and disease characteristics of the study population analyzed. Baseline demographics and disease characteristics were well balanced for both treatment groups. The median time from initial diagnosis of RCC to randomization was 1.6 and 1.9 years for the NEXAVAR and placebo groups, respectively.

Table 5: Demographic and Disease Characteristics - RCC Study 1

NOTE: HR is from Cox regression model with the following covariates: MSKCC prognostic risk category and country. P-value is from two-sided Log-Rank test stratified by MSKCC prognostic risk category and country.

The median PFS for patients randomized to NEXAVAR was 167 days compared to 84 days for patients randomized to placebo. The estimated hazard ratio (risk of progression with NEXAVAR compared to placebo) was 0.44 (95% CI: 0.35, 0.55).

A series of patient subsets were examined in exploratory univariate analyses of PFS. The subsets included age

above or below 65 years, ECOG PS 0 or 1, MSKCC prognostic risk category, whether the prior therapy was for

progressive metastatic disease or for an earlier disease setting, and time from diagnosis of less than or greater than 1.5 years. The effect of NEXAVAR on PFS was consistent across these subsets, including patients with no prior IL-2 or interferon therapy (N=137; 65 patients receiving NEXAVAR and 72 placebo), for whom the median PFS was 172 days on NEXAVAR compared to 85 days on placebo.

Tumor response was determined by independent radiologic review according to RECIST criteria. Overall, of 672 patients who were evaluable for response, 7 (2%) NEXAVAR patients and 0 (0%) placebo patients had a confirmed partial response. Thus the gain in PFS in NEXAVAR-treated patients primarily reflects the stable disease population.

At the time of a planned interim survival analysis, based on 220 deaths, overall survival was longer for NEXAVAR than placebo with a hazard ratio (NEXAVAR over placebo) of 0.72. This analysis did not meet the prespecified criteria for statistical significance. Additional analyses are planned as the survival data mature.

RCC Study 2 was a Phase 2 randomized discontinuation trial in patients with metastatic malignancies, including RCC. The primary endpoint was the percentage of randomized patients remaining progression-free at 24 weeks. All patients received NEXAVAR for the first 12 weeks. Radiologic assessment was repeated at week 12. Patients with <25% change in bi-dimensional tumor measurements from baseline were randomized to NEXAVAR or placebo for a further 12 weeks. Patients who were randomized to placebo were permitted to cross over to open-label NEXAVAR upon progression. Patients with tumor shrinkage ≥25% continued NEXAVAR, whereas patients with tumor growth ≥25% discontinued treatment.

Two hundred and two patients with advanced RCC were enrolled into RCC Study 2, including patients who had received no prior therapy and patients with tumor histology other than clear cell carcinoma. After the initial 12 weeks of NEXAVAR therapy, 79 RCC patients continued on open-label NEXAVAR, and 65 patients were randomized to NEXAVAR or placebo. After an additional 12 weeks, at week 24, for the 65 randomized patients, the progression-free rate was significantly higher in patients randomized to NEXAVAR (16/32, 50%) than in patients randomized to placebo (6/33, 18%) (p=0.0077). Progression-free survival was significantly longer in the NEXAVAR group (163 days) than in the placebo group (41 days) (p=0.0001, HR=0.29).

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