Sorafenib (Nexavar)

Targets multiple classes of kinases involved in tumor cell proliferation and angiogenesis.

Oral agent which targets tumor cell and tumor vasculature.

Inhibits RAF kinase, VEGFR-2, VEGFR-3, PDGFR-B KIT, RET and FLT-3 receptor tyrosine kinases.

Sorafenib is an oral multi-kinase inhibitor that targets Raf serine/threonine kinases, vascular endothelial growth factor receptor and the platelet derived growth factor receptors.

Approved for advanced renal cell carcinoma, unresectable hepatocellular carcinoma and radioactive iodine refractory thyroid cancer.

Has clinical activity in thyroid cancer, melanoma, and soft tissue sarcoma.

Highly down to 99% blasts and proteins, mainly to albumin.

Targets pathways of VEGF and TGF-α.

Maybe associated with cardiac ischemia or infarction.

The most common 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%) and hypocalcemia (36%).

Gastrointestinal perforation reported in less than 1% of patients.

Squamous cell cancers of the skin and Stevens Johnson syndrome has been reported.

Increases risk of bleeding.

Gastrointestinal perforation associated in less than 1% of treated patients.

Hand-foot skin reactions and rash are common.

Toxicities may cause treatment reduction in 6 35% of patients, and termination of treatment in approximately 10% of patients.

Elevations of serum lipase and reductions in serum phosphate may be seen.

Increased toxicity with compounds metabolized by UGT1A9 pathway and include irinotecan, docetaxel, 5 FU, and CYPB6, CYP2C8 and CYP3A4 inducers.

Significantly prolongs progression free survival, 24 weeks, compared to placebo, 12 weeks, in advanced renal cell carcinoma.

A majority of patients treated for renal cell cancer show tumor shrinkage.

In a phase II study 30% of heavily pretreated patients for renal cell cancer had a greater than 25% regression of disease.

Phase II studies suggest most responses occur in patients with clear cell renal cancer.

TARGET study with sorafenib doubled the median progression free survival from 2.8 months with placebo to 5.5 months with this drug in patients with advanced RCC with a 56% reduction in the risk of progression of disease (Treatment Approaches in Renal cancer Global Evaluation Trial, Escudier B et al).

TARGET study sorafenib associated with 78% stable disease and 2% partial response, compared to 55% and 0%, respectively for placebo, and a median survival of 17.8 months compared with 15.2 in the placebo arm in advanced renal cell carcinoma.

Primary toxicities diarrhea and skin rash.

Hand-foot syndrome common reaction.

Can be associated with elevated serum lipase levels and reductions in serum phosphate levels.

May be associated with squamous cell cancer of the skin along with other BRAF inhibitors.

Metabolized primarily in the liver, undergoing oxidative metabolism.

Caution when utilized with compounds metabolized by UGT149 pathway (CPT-11), doxorubicin, docetaxel, fluorouracil, and substrates of CYP2B6, CYP2C8 and CYP3A4 inducers.

Mainly eliminated in the feces.

Terminal half-life ranges from 25-38 hours and undergoes enterohepatic circulation.

Increased risk of myocardial infarction and arterial thrombotic events.

Can exacerbate muscle loss, consistent with the role of kinases in regulating muscle mass.

Muscle loss with the use of this agent may relate to asthenia, fatigue and physical disability (Antoun S).

Hypertension reported in 9.4% of patients compared to 4.3% of placebo treated patients in a hepatocellular cancer study.

Uncommon adverse reactions include: keratoanthomas, squamous cell carcinoma of the skin and Stevens-Johnson syndrome.

Blood pressure should be monitored weekly for the first 6 weeks and periodically thereafter.

Approximately 5% of patients on 800 mg/day have grade3/4 hypertension.

With Temozolomide with has a 39% partial response in chemotherapy naïve melanoma patients.

Did not restore temozolomide sensitivity in patients who failed prior treatment for melanoma.

With Temozolomide, patients experienced lymphopenia, hand-foot syndrome, rash and nausea.

Approved for use in unresectable hepatocellular carcinoma.

First and presently (2011) only systemic drug to extend survival in unresectable hepatocellular carcinoma.

400 mg bid in a phase 2 trial of 137 patients with inoperable hepatocellular carcinoma associated with a median time to progression and median overall survival of 4.2 months and 9.2 months, respectively.

Not effective in an adjuvant setting in hepatocellular carcinoma following resection or ablation.

SHARP trial, phase 3 trial Sorafenib HCC Assessment Randomized Protocol compared sorafenib 400 mg bid to placebo in 602 patients with unresectable hepatocellular disease without prior treatment: median overall survival 10.7 months for sorafenib and 7.9 months for placebo, 71% of patients with stable disease 2.3% had a partial response (LLovet JM et al).

SHARP trial sorafenib doubled time to progressive disease 5.5 months vs. 2.3 months with placebo.

SHARP trial: 1 year survival 44% with sorafenib vs 33% with placebo.

For hepatoma overall survival time with doxorubicin 13.7months and 6.5 months for doxorubicin plus placebo (Abou-Alfa GK et al).

In a placebo controlled phase 2 trial utilizing sorafenib in combination with capecitabine, significantly extended progression free survival in patients with advanced breast cancer.

The combination of sorafenib and capecitabine had a 74% improvement in progression free survival in advanced breast cancer compared to capecitabine alone, 6.4 vs. 4.1 months (Baselga).

Contraindicated in squamous cell lung cacer in combination with paclitaxel and carboplatin.

Approved for the treatment of locally recurrent or metastatic, progressive, differentiated thyroid carcinoma (DTC) refractory to radioactive iodine treatment based on a study: The median PFS was 10.8 and 5.8 months for the sorafenib and placebo arms, respectively, and the overall response rates were 12% versus 1% for the sorafenib and placebo arms, respectively.

In a double-blind, placebo controlled phase 2 trial of 417 patients treated with radioactive iodine refractory thyroid cancer, locally advanced or metastatic differentiated thyroid cancer given sorafenib 400 mg b.i.d. or placebo:median progression free survival was 10.8 months and 5.8 months for placebo.

Among patients with progressive, refractory, or symptomatic desmoid tumors, sorafenib significantly prolonged progression free survival and induced durable responses: The progression free survival rate was 81% at two years vs, 36% in the placebo group (Gounder MM).

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