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Hepatocellular carcinoma: Nexavar significantly prolongs overall survival

Sorafenib ( Nexavar ) tablets has significantly extended overall survival in patients with hepatocellular carcinoma ( HCC ), or primary liver cancer versus those taking placebo by 44% ( HR=0.69; p-value=0.0006 ).

The Phase 3, placebo-controlled Sorafenib HCC Assessment Randomized Protocol ( SHARP ) Trial evaluated 602 liver cancer patients who had no prior systemic therapy.

The primary objective of the study was to compare overall survival in patients administered Sorafenib versus those administered placebo.

Median overall survival was 10.7 months in Sorafenib-treated patients compared to 7.9 months in those taking placebo.

The SHARP trial was halted in February 2007 when an independent data monitoring committee determined in a pre-scheduled analysis that the overall survival endpoint had been met.

There were no significant differences in serious adverse event rates between the Sorafenib and placebo-treated groups, with the most commonly observed serious adverse events in patients receiving Sorafenib being diarrhea and hand-foot-skin reaction.

Hepatocellular carcinoma is the most common form of liver cancer and is responsible for about 90 percent of the primary malignant liver tumors in adults.
It is the fifth most common cancer in the world3 and the third leading cause of cancer-related deaths globally.
Over 600,000 new cases of HCC are diagnosed globally each year ( 19,000 in the United States and 32,000 in the European Union ), and in 2002 approximately 600,000 people ( about 13,000 Americans and 57,000 Europeans ) died of HCC.
Although overall cancer incidence and mortality are decreasing in the United States, both the incidence and mortality of liver cancer are increasing.

In preclinical studies, Sorafenib has been shown to target members of two classes of kinases known to be involved in both cell proliferation and angiogenesis – two important processes that enable cancer growth. These kinases included Raf kinase, VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-B, KIT, FLT-3 and RET. Preclinical models have also demonstrated that the Raf/MEK/ERK pathway has a role in hepatocellular carcinoma ; therefore blocking signaling through Raf-1 may offer therapeutic benefits in HCC.

Nexavar is currently approved in more than 50 countries, including the United States and those in the European Union, for the treatment of patients with advanced kidney cancer. In Europe, Nexavar is approved for the treatment of patients with advanced renal cell carcinoma ( RCC ) who have failed prior Interferon-alpha or interleukin-2 based therapy or are considered unsuitable for such therapy.

Nexavar is also being evaluated by the companies, international study groups, government agencies and/or individual investigators as a single agent or combination treatment in a wide range of other cancers, including adjuvant therapy for kidney cancer, metastatic melanoma, breast cancer and non-small cell lung cancer ( NSCLC ).
The Phase 3 ESCAPE ( Evaluation of Sorafenib, Carboplatin, and Paclitaxel efficacy in NSCLC ) trial recently completed enrollment of more than 900 previously untreated patients with NSCLC of all histologies.

Based on the currently approved package insert of Nexavar for the treatment of patients with advanced kidney cancer, hypertension may occur early in the course of therapy and blood pressure should be monitored weekly during the first six weeks of therapy and treated as needed. Incidence of bleeding regardless of causality was 15% for Nexavar versus 8% for placebo and the incidence of treatment-emergent cardiac ischemia/infarction was 2.9% for Nexavar versus 0.4% for placebo.
Most common treatment-emergent adverse events with Nexavar were diarrhea, rash/desquamation, fatigue, hand-foot skin reaction, alopecia, and nausea. Grade 3/4 adverse events were 38% for Nexavar versus 28% for placebo. Women of child-bearing potential should be advised to avoid becoming pregnant and advised against breast-feeding. In cases of any severe or persistent side effects, temporary treatment interruption, dose modification or permanent discontinuation should be considered.

Source: American Society of Clinical Oncology ( ASCO ) – Annual Meeting, 2007