NEXAVAR 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) N2-
methylpyridine -2- carboxamide 4-methylbenzenesulfonate.
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.
NEXAVAR INGREDIENTS
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.
INDICATIONS AND USAGE
Hepatocellular Carcinoma-NEXAVAR® is indicated for the treatment of patients with unresectable hepatocellular
carcinoma (HCC).
Renal Cell Carcinoma-NEXAVAR is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).
Differentiated Thyroid Carcinoma-NEXAVAR is indicated for the treatment of patients with locally recurrent or metastatic,
progressive, differentiated thyroid carcinoma (DTC) that is refractory to radioactive iodine treatment.
DOSAGE AND ADMINISTRATION
Recommended Dose for Hepatocellular Carcinoma, Renal Cell Carcinoma, and Differentiated Thyroid Carcinoma
The recommended daily dose of NEXAVAR is 400 mg (2 x 200 mg tablets) taken twice daily without food (at least 1 hour
before or 2 hours after a meal). Treatment should continue until the patient is no longer clinically benefiting from
therapy or until unacceptable toxicity occurs.
CLINICAL PHARMACOLOGY
Mechanism of Action
Sorafenib is a kinase inhibitor that decreases tumor cell proliferation in vitro.
Sorafenib was shown to inhibit 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 these kinases are thought to be
involved in tumor cell signaling, angiogenesis and apoptosis. Sorafenib inhibited tumor growth of HCC, RCC, and DTC
human tumor xenografts in immunocompromised mice. Reductions in tumor angiogenesis were seen in models of HCC
and RCC upon sorafenib treatment, and increases in tumor apoptosis were observed in models of HCC, RCC, and DTC.
Pharmacokinetics
The mean elimination half-life of sorafenib was approximately 25 to 48 hours. Multiple doses of NEXAVAR for 7 days
resulted in a 2.5- to 7-fold accumulation compared to a single dose. Steady-state plasma sorafenib concentrations were
achieved within 7 days, with a peak-to-trough ratio of mean concentrations of less than 2.
The steady-state concentrations of sorafenib following administration of 400 mg NEXAVAR twice daily were evaluated in
DTC, RCC and HCC patients. Patients with DTC have mean steady-state concentrations that are 1.8-fold higher than
patients with HCC and 2.3-fold higher than those with RCC. The reason for increased sorafenib concentrations in DTC
patients is unknown.
Absorption and Distribution: After administration of NEXAVAR tablets, the mean relative bioavailability was 38–49%
when compared to an oral solution. Following oral administration, sorafenib reached peak plasma levels in
approximately 3 hours. 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), bioavailability was reduced by 29% compared to that in the fasted
state. It is recommended that NEXAVAR be administered without food [see Dosage and Administration (2.1)].
Mean Cmax and AUC increased less than proportionally beyond oral doses of 400 mg administered twice daily. In vitro
binding of sorafenib to human plasma proteins was 99.5%.
Metabolism and Elimination: Sorafenib undergoes oxidative metabolism by hepatic CYP3A4, as well as glucuronidation
by UGT1A9. Inducers of CYP3A4 activity can decrease the systemic exposure of sorafenib [see Drug Interactions (7.1)].
Sorafenib accounted for approximately 70–85% of the circulating analytes in plasma at steady-state. Eight metabolites
of sorafenib have been identified, of which 5 have been detected in plasma. The main circulating metabolite of
sorafenib, the pyridine N-oxide that comprises approximately 9–16% of circulating analytes at steady-state, showed in
vitro potency similar to that of sorafenib.
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.
The most common side effects of NEXAVAR include (Per-Patient Incidence):
•diarrhea (frequent or loose bowel movements) (68%)
•tiredness (41%)
•infection
•hair thinning or patchy hair loss
•rash (35%)
•weight loss (49%)
•loss of appetite (30%)
•nausea (21%)
•stomach (abdominal) pain
•low blood calcium levels in people with differentiated thyroid cancer
[For Details: Dailymed.nlm.nih.gov June 15, 2014]
____________________________________________________________________________________________
FDA Messages
March 2011
Postmarketing Experience - angioedema and drug-induced hepatitis
October 2010
WARNINGS AND PRECAUTIONS
Use of Nexavar in combination with Carboplatin and Paclitaxel in Non-small Cell Lung Cancer
A randomized controlled trial in chemo-naive patients with Stage IIIB-IV Non-small Cell Lung Cancer, performed to
compare the safety and efficacy of carboplatin and paclitaxel with or without sorafenib, was stopped early because
overall survival was not improved with the addition of sorafenib. In the analysis of the subset of patients with squamous
cell carcinoma (prospectively stratified), higher mortality was observed with the addition of sorafenib compared to those
treated with carboplatin and paclitaxel alone (HR 1.81, 95% CI 1.19-2.74). No definitive cause was identified for this
finding
Neomycin - Co-administration of oral neomycin causes a decrease in sorafenib exposure
ADVERSE REACTIONS
Additional Data from Multiple Clinical Trials
Reclassification of congestive heart failure as a common adverse reaction
Addition of Stevens-Johnson Syndrome, hyperthyroidism, and interstitial lung disease-like events as uncommon
adverse reactions
____________________________________________________________________________________________
Development of Nexavar (sorafenib tosylate)
In pre-clinical models, sorafenib targeted members of two classes of kinases involved in both tumor cell proliferation
(tumor growth; An increase in the number of cells as a result of cell growth and cell division.) and tumor angiogenesis
(tumor blood supply; The formation of new blood vessels). The kinases included RAF kinase, VEGFR-2, VEGFR-3,
PDGFR-;, KIT, FLT-3 and RET. [1]
Bayer and Onyx conducted large, international, multicenter Phase III clinical studies of sorafenib (BAY 43-9006) in
patients with advanced kidney cancer, advanced primary liver cancer and metastatic melanoma. Because Sorafenib
(BAY 43-9006) is able to inhibit multiple kinases, this agent is also being evaluated in single-agent Phase II clinical trials
in lung, breast, and other cancers, along with several Phase I/II clinical trials studying the agent in combination with a
range of standard chemotherapeutics and other anticancer agents (such as carboplatin/paclitaxel, 5-Fu, docetaxel,
capecitabine, oxaliplatin, irinotecan, Gemcitabine, gefitinib, doxorubicin, DTIC and IFN. [2]
In May 2005, Bayer and Onyx reported at the annual meeting of the American Society of Clinical Oncology that
sorafenib was well tolerated and significantly delayed disease progression in an ongoing Phase III clinical trial in patients
with advanced kidney cancer. As assessed by independent radiologic review, progression-free survival was doubled to
a median value of 24 weeks in patients receiving sorafenib, compared to 12 weeks for patients receiving placebo. [2]
In July 2005, Bayer and Onyx submitted a New Drug Application (NDA) for possible approval in this indication by the U.
S. FDA. Subsequently, the NDA application had been accepted and granted priority review status by the FDA. In
September 2005, a Marketing Authorization Application was submitted to the European Medicines Agency for approval
to market sorafenib within the European Union for the same indication. [2]
SORAFENIB SIDE EFFECTS
In a few studies, Sorafenib (BAY 43-9006) appeared to be safe, well-tolerated and showed anti-tumor activities. The
toxic effects of Sorafenib (BAY 43-9006) were manageable and included hypertension, edema, diarrhea, hand and foot
syndrome, rash, and hair loss where the rash involved the scalp. [7]
In a Phase I study, 44 patients with advanced, refractory solid tumors were administered with 50 to 800 mg b.i.d of
Sorafenib (BAY 43-9006) for repeated cycles of 21 days on/7 days off. The side effects or the most frequently reported
adverse events in this study were gastrointestinal (75%), dermatologic (71%), constitutional (68%), pain (64%), or
hepatic (61%) related. Sorafenib (BAY 43-9006) was absorbed rapidly; steady-state conditions were reached within 7
days. [5]
In another study, 69 patients with advanced refractory solid tumors were administered with 50 to 800 mg b.i.d of
Sorafenib (BAY 43-9006). They found that mild to moderate diarrhea was the most common (55%) treatment-related
side effect. The maximum-tolerated dose was 400 mg bid continuous. Dose-limiting toxicities were grade 3 diarrhea and
fatigue at 800 mg bid, and grade 3 skin toxicity at 600 mg bid. [6]
PARTNERSHIP
According to Oxnyx online publication, Onyx is funding 50 percent of the development costs for sorafenib. In return,
Oxnyx has a 50/50 profit share in the United States, where they can copromote the product with Bayer. Everywhere in
the world except Japan, Oxynx share is somewhat less than 50 percent since Bayer has exclusive marketing rights. In
Japan, Bayer funds product development, and Onyx will get a royalty based on any sales there.
ABOUT RAS AND RAF
Mitogen-activated protein kinase (MAPK) signaling pathway is important in transmitting proliferative signals generated
by cell surface receptors and cytoplasmic signaling elements to the nucleus. Several important signaling elements of the
MAPK pathway, particularly Ras and Raf, are encoded by oncogenes, and as such, their structures and functions can
be modified, rendering them constitutively active.
Raf, which is an essential serine/threonine kinase constituent of the MAPK pathway and a downstream effector of the
central signal transduction mediator Ras, is activated in a wide range of human malignancies by aberrant signaling
upstream of the protein and activating mutations of the protein itself, both of which confer a proliferative advantage.
Because the MAPK pathway is dys-regulated in a notable proportion of human malignancies, many of its aberrant and
critical components represent strategic targets for therapeutic development against cancer. [3]
ABOUT VEGF AND EGF
Hypoxia-regulated genes such as vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) are
both important for tumor progression in renal cell carcinoma (RCC). Results from a Phase III clinical trial with sorafenib
show only a 2% response rate; however, a statistically significant improvement in progression-free survival was
observed. [4]
REFERENCE
[1] Bayer and Onyx Announce Access to Sorafenib (BAY 43-9006) for Individuals with Advanced Renal Cell Carcinoma,
Bayer HealthCare Press Release, May 14 2005.
[2] Products in the clinic – Sorafenib, Onyx Pharmaceuticals Online Publication, October 09. 2005.
[3] Beeram M et al, Raf: a strategic target for therapeutic development against cancer. J Clin Oncol. 2005 Sep 20;23
(27):6771-90. [4] Favaro JP and George DJ Targeted therapy in renal cell carcinoma. Expert Opin Investig Drugs. 2005
Oct;14(10):1251-8. [5] Awada A et al, Phase I safety and pharmacokinetics of BAY 43-9006 administered for 21 days
on/7 days off in patients with advanced, refractory solid tumours. Br J Cancer. 2005 May 23;92(10):1855-61. [6]
Strumberg D et al, Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth
factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol. 2005 Feb 10;23(5):
965-72. Epub 2004 Dec 21. [7] Ahmad T and Eisen T Kinase inhibition with BAY 43-9006 in renal cell carcinoma. Clin
Cancer Res. 2004 Sep 15;10(18 Pt 2):6388S-92S.
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) N2-
methylpyridine -2- carboxamide 4-methylbenzenesulfonate.
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.
NEXAVAR INGREDIENTS
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.
INDICATIONS AND USAGE
Hepatocellular Carcinoma-NEXAVAR® is indicated for the treatment of patients with unresectable hepatocellular
carcinoma (HCC).
Renal Cell Carcinoma-NEXAVAR is indicated for the treatment of patients with advanced renal cell carcinoma (RCC).
Differentiated Thyroid Carcinoma-NEXAVAR is indicated for the treatment of patients with locally recurrent or metastatic,
progressive, differentiated thyroid carcinoma (DTC) that is refractory to radioactive iodine treatment.
DOSAGE AND ADMINISTRATION
Recommended Dose for Hepatocellular Carcinoma, Renal Cell Carcinoma, and Differentiated Thyroid Carcinoma
The recommended daily dose of NEXAVAR is 400 mg (2 x 200 mg tablets) taken twice daily without food (at least 1 hour
before or 2 hours after a meal). Treatment should continue until the patient is no longer clinically benefiting from
therapy or until unacceptable toxicity occurs.
CLINICAL PHARMACOLOGY
Mechanism of Action
Sorafenib is a kinase inhibitor that decreases tumor cell proliferation in vitro.
Sorafenib was shown to inhibit 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 these kinases are thought to be
involved in tumor cell signaling, angiogenesis and apoptosis. Sorafenib inhibited tumor growth of HCC, RCC, and DTC
human tumor xenografts in immunocompromised mice. Reductions in tumor angiogenesis were seen in models of HCC
and RCC upon sorafenib treatment, and increases in tumor apoptosis were observed in models of HCC, RCC, and DTC.
Pharmacokinetics
The mean elimination half-life of sorafenib was approximately 25 to 48 hours. Multiple doses of NEXAVAR for 7 days
resulted in a 2.5- to 7-fold accumulation compared to a single dose. Steady-state plasma sorafenib concentrations were
achieved within 7 days, with a peak-to-trough ratio of mean concentrations of less than 2.
The steady-state concentrations of sorafenib following administration of 400 mg NEXAVAR twice daily were evaluated in
DTC, RCC and HCC patients. Patients with DTC have mean steady-state concentrations that are 1.8-fold higher than
patients with HCC and 2.3-fold higher than those with RCC. The reason for increased sorafenib concentrations in DTC
patients is unknown.
Absorption and Distribution: After administration of NEXAVAR tablets, the mean relative bioavailability was 38–49%
when compared to an oral solution. Following oral administration, sorafenib reached peak plasma levels in
approximately 3 hours. 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), bioavailability was reduced by 29% compared to that in the fasted
state. It is recommended that NEXAVAR be administered without food [see Dosage and Administration (2.1)].
Mean Cmax and AUC increased less than proportionally beyond oral doses of 400 mg administered twice daily. In vitro
binding of sorafenib to human plasma proteins was 99.5%.
Metabolism and Elimination: Sorafenib undergoes oxidative metabolism by hepatic CYP3A4, as well as glucuronidation
by UGT1A9. Inducers of CYP3A4 activity can decrease the systemic exposure of sorafenib [see Drug Interactions (7.1)].
Sorafenib accounted for approximately 70–85% of the circulating analytes in plasma at steady-state. Eight metabolites
of sorafenib have been identified, of which 5 have been detected in plasma. The main circulating metabolite of
sorafenib, the pyridine N-oxide that comprises approximately 9–16% of circulating analytes at steady-state, showed in
vitro potency similar to that of sorafenib.
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.
The most common side effects of NEXAVAR include (Per-Patient Incidence):
•diarrhea (frequent or loose bowel movements) (68%)
•tiredness (41%)
•infection
•hair thinning or patchy hair loss
•rash (35%)
•weight loss (49%)
•loss of appetite (30%)
•nausea (21%)
•stomach (abdominal) pain
•low blood calcium levels in people with differentiated thyroid cancer
[For Details: Dailymed.nlm.nih.gov June 15, 2014]
____________________________________________________________________________________________
FDA Messages
March 2011
Postmarketing Experience - angioedema and drug-induced hepatitis
October 2010
WARNINGS AND PRECAUTIONS
Use of Nexavar in combination with Carboplatin and Paclitaxel in Non-small Cell Lung Cancer
A randomized controlled trial in chemo-naive patients with Stage IIIB-IV Non-small Cell Lung Cancer, performed to
compare the safety and efficacy of carboplatin and paclitaxel with or without sorafenib, was stopped early because
overall survival was not improved with the addition of sorafenib. In the analysis of the subset of patients with squamous
cell carcinoma (prospectively stratified), higher mortality was observed with the addition of sorafenib compared to those
treated with carboplatin and paclitaxel alone (HR 1.81, 95% CI 1.19-2.74). No definitive cause was identified for this
finding
Neomycin - Co-administration of oral neomycin causes a decrease in sorafenib exposure
ADVERSE REACTIONS
Additional Data from Multiple Clinical Trials
Reclassification of congestive heart failure as a common adverse reaction
Addition of Stevens-Johnson Syndrome, hyperthyroidism, and interstitial lung disease-like events as uncommon
adverse reactions
____________________________________________________________________________________________
Development of Nexavar (sorafenib tosylate)
In pre-clinical models, sorafenib targeted members of two classes of kinases involved in both tumor cell proliferation
(tumor growth; An increase in the number of cells as a result of cell growth and cell division.) and tumor angiogenesis
(tumor blood supply; The formation of new blood vessels). The kinases included RAF kinase, VEGFR-2, VEGFR-3,
PDGFR-;, KIT, FLT-3 and RET. [1]
Bayer and Onyx conducted large, international, multicenter Phase III clinical studies of sorafenib (BAY 43-9006) in
patients with advanced kidney cancer, advanced primary liver cancer and metastatic melanoma. Because Sorafenib
(BAY 43-9006) is able to inhibit multiple kinases, this agent is also being evaluated in single-agent Phase II clinical trials
in lung, breast, and other cancers, along with several Phase I/II clinical trials studying the agent in combination with a
range of standard chemotherapeutics and other anticancer agents (such as carboplatin/paclitaxel, 5-Fu, docetaxel,
capecitabine, oxaliplatin, irinotecan, Gemcitabine, gefitinib, doxorubicin, DTIC and IFN. [2]
In May 2005, Bayer and Onyx reported at the annual meeting of the American Society of Clinical Oncology that
sorafenib was well tolerated and significantly delayed disease progression in an ongoing Phase III clinical trial in patients
with advanced kidney cancer. As assessed by independent radiologic review, progression-free survival was doubled to
a median value of 24 weeks in patients receiving sorafenib, compared to 12 weeks for patients receiving placebo. [2]
In July 2005, Bayer and Onyx submitted a New Drug Application (NDA) for possible approval in this indication by the U.
S. FDA. Subsequently, the NDA application had been accepted and granted priority review status by the FDA. In
September 2005, a Marketing Authorization Application was submitted to the European Medicines Agency for approval
to market sorafenib within the European Union for the same indication. [2]
SORAFENIB SIDE EFFECTS
In a few studies, Sorafenib (BAY 43-9006) appeared to be safe, well-tolerated and showed anti-tumor activities. The
toxic effects of Sorafenib (BAY 43-9006) were manageable and included hypertension, edema, diarrhea, hand and foot
syndrome, rash, and hair loss where the rash involved the scalp. [7]
In a Phase I study, 44 patients with advanced, refractory solid tumors were administered with 50 to 800 mg b.i.d of
Sorafenib (BAY 43-9006) for repeated cycles of 21 days on/7 days off. The side effects or the most frequently reported
adverse events in this study were gastrointestinal (75%), dermatologic (71%), constitutional (68%), pain (64%), or
hepatic (61%) related. Sorafenib (BAY 43-9006) was absorbed rapidly; steady-state conditions were reached within 7
days. [5]
In another study, 69 patients with advanced refractory solid tumors were administered with 50 to 800 mg b.i.d of
Sorafenib (BAY 43-9006). They found that mild to moderate diarrhea was the most common (55%) treatment-related
side effect. The maximum-tolerated dose was 400 mg bid continuous. Dose-limiting toxicities were grade 3 diarrhea and
fatigue at 800 mg bid, and grade 3 skin toxicity at 600 mg bid. [6]
PARTNERSHIP
According to Oxnyx online publication, Onyx is funding 50 percent of the development costs for sorafenib. In return,
Oxnyx has a 50/50 profit share in the United States, where they can copromote the product with Bayer. Everywhere in
the world except Japan, Oxynx share is somewhat less than 50 percent since Bayer has exclusive marketing rights. In
Japan, Bayer funds product development, and Onyx will get a royalty based on any sales there.
ABOUT RAS AND RAF
Mitogen-activated protein kinase (MAPK) signaling pathway is important in transmitting proliferative signals generated
by cell surface receptors and cytoplasmic signaling elements to the nucleus. Several important signaling elements of the
MAPK pathway, particularly Ras and Raf, are encoded by oncogenes, and as such, their structures and functions can
be modified, rendering them constitutively active.
Raf, which is an essential serine/threonine kinase constituent of the MAPK pathway and a downstream effector of the
central signal transduction mediator Ras, is activated in a wide range of human malignancies by aberrant signaling
upstream of the protein and activating mutations of the protein itself, both of which confer a proliferative advantage.
Because the MAPK pathway is dys-regulated in a notable proportion of human malignancies, many of its aberrant and
critical components represent strategic targets for therapeutic development against cancer. [3]
ABOUT VEGF AND EGF
Hypoxia-regulated genes such as vascular endothelial growth factor (VEGF) and epidermal growth factor (EGF) are
both important for tumor progression in renal cell carcinoma (RCC). Results from a Phase III clinical trial with sorafenib
show only a 2% response rate; however, a statistically significant improvement in progression-free survival was
observed. [4]
REFERENCE
[1] Bayer and Onyx Announce Access to Sorafenib (BAY 43-9006) for Individuals with Advanced Renal Cell Carcinoma,
Bayer HealthCare Press Release, May 14 2005.
[2] Products in the clinic – Sorafenib, Onyx Pharmaceuticals Online Publication, October 09. 2005.
[3] Beeram M et al, Raf: a strategic target for therapeutic development against cancer. J Clin Oncol. 2005 Sep 20;23
(27):6771-90. [4] Favaro JP and George DJ Targeted therapy in renal cell carcinoma. Expert Opin Investig Drugs. 2005
Oct;14(10):1251-8. [5] Awada A et al, Phase I safety and pharmacokinetics of BAY 43-9006 administered for 21 days
on/7 days off in patients with advanced, refractory solid tumours. Br J Cancer. 2005 May 23;92(10):1855-61. [6]
Strumberg D et al, Phase I clinical and pharmacokinetic study of the Novel Raf kinase and vascular endothelial growth
factor receptor inhibitor BAY 43-9006 in patients with advanced refractory solid tumors. J Clin Oncol. 2005 Feb 10;23(5):
965-72. Epub 2004 Dec 21. [7] Ahmad T and Eisen T Kinase inhibition with BAY 43-9006 in renal cell carcinoma. Clin
Cancer Res. 2004 Sep 15;10(18 Pt 2):6388S-92S.
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