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Brand name(s): Nexavar®

• Approved for liver cancer
• Approved for kidney cancer

Full prescribing information ³ is available, including clinical trial information, safety, dosing, drug-drug interactions and contraindications.

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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On December 20, 2005, the U.S. Food and Drug Administration 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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Glossary Terms

The lack or loss of hair from areas of the body where hair is usually found. Alopecia can be a side effect of some cancer treatments.

A procedure in which the blood supply to the tumor is blocked surgically or mechanically and anticancer drugs are administered directly into the tumor. This permits a higher concentration of drug to be in contact with the tumor for a longer period of time.

In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works.

In clinical trials, an event or outcome that can be measured objectively to determine whether the intervention being studied is beneficial. The endpoints of a clinical trial are usually included in the study objectives. Some examples of endpoints are survival, improvements in quality of life, relief of symptoms, and disappearance of the tumor.

In medicine, loss of blood from damaged blood vessels. A hemorrhage may be internal or external, and usually involves a lot of bleeding in a short time.

A blood pressure of 140/90 or higher. Hypertension usually has no symptoms. It can harm the arteries and cause an increase in the risk of stroke, heart attack, kidney failure, and blindness. Also called high blood pressure.

A biological response modifier (a substance that can improve the body's natural response to infections and other diseases). Interferons interfere with the division of cancer cells and can slow tumor growth. There are several types of interferons, including interferon-alpha, -beta, and -gamma. The body normally produces these substances. They are also made in the laboratory to treat cancer and other diseases.

One of a group of related proteins made by leukocytes (white blood cells) and other cells in the body. Interleukin-2 is made by a type of T lymphocyte. It increases the growth and activity of other T lymphocytes and B lymphocytes, and affects the development of the immune system. Aldesleukin (interleukin-2 made in the laboratory) is being used as a biological response modifier to boost the immune system in cancer therapy. Interleukin-2 is a type of cytokine. Also called IL-2.

A statistics term. The middle value in a set of measurements.

The spread of cancer from one part of the body to another. A tumor formed by cells that have spread is called a “metastatic tumor” or a “metastasis.” The metastatic tumor contains cells that are like those in the original (primary) tumor. The plural form of metastasis is metastases (meh-TAS-tuh-SEEZ).

A complication of some cancer therapies in which the lining of the digestive system becomes inflamed. Often seen as sores in the mouth.

Inflammation of the pancreas. Chronic pancreatitis may cause diabetes and problems with digestion. Pain is the primary symptom.

An injection of ethanol (alcohol) through the skin directly into a tumor to kill cancer cells. Ultrasound or a CT scan is used to guide the needle into the tumor. Also called alcohol ablation, ethanol ablation, and PEI.

A measure of how well a patient is able to perform ordinary tasks and carry out daily activities.

A study to test whether a new treatment has an anticancer effect (for example, whether it shrinks a tumor or improves blood test results) and whether it works against a certain type of cancer.

A study to compare the results of people taking a new treatment with the results of people taking the standard treatment (for example, which group has better survival rates or fewer side effects). In most cases, studies move into phase III only after a treatment seems to work in phases I and II. Phase III trials may include hundreds of people.

An inactive substance or treatment that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.

The length of time during and after treatment in which a patient is living with a disease that does not get worse. Progression-free survival may be used in a clinical study or trial to help find out how well a new treatment works. Also called PFS.

A procedure that uses radio waves to heat and destroy abnormal cells. The radio waves travel through electrodes (small devices that carry electricity). Radiofrequency ablation may be used to treat cancer and other conditions.

The percentage of patients whose cancer shrinks or disappears after treatment.

A drug used to treat advanced kidney cancer and a type of liver cancer that cannot be removed by surgery. It is also being studied in the treatment of other types of cancer. Sorafenib stops cells from dividing and may prevent the growth of new blood vessels that tumors need to grow. It is a type of kinase inhibitor and a type of antiangiogenesis agent. Also called BAY 43-9006, Nexavar, and sorafenib tosylate.

Describes a mathematical measure of difference between groups. The difference is said to be statistically significant if it is greater than what might be expected to happen by chance alone. Also called significant.

Unable to be removed with surgery.

A substance that blocks an enzyme needed to form blood vessels. Also called vascular endothelial growth factor receptor tyrosine kinase inhibitor.