Promising development of BAY 43-9006, a novel Raf Kinase and Vascular Endothelial Growth Factor Receptor Inhibitor, for the treatment of renal and other advanced Refractory Solid Tumors.

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Promising development of BAY 43-9006, a novel Raf Kinase and Vascular Endothelial Growth Factor Receptor Inhibitor, for the treatment of renal and other advanced Refractory Solid Tumors.

The therapeutic and commercial importance of angiogenesis inhibitors was advanced with last year's US and European approvals of Genentech/Roche's Avastin (bevacizumab). Peak sales are forecast to reach between $845.3 million and $1.7 billion (see Colorectal Cancer - Avastin and Erbitux Pave The Way For Pipeline Targeted Therapies). BAY 43-9006 targets tumor growth directly as well as by blocking angiogenesis. This phase III candidate is the first compound to block both the RAS signaling pathway to inhibit cell proliferation and the VEGFR-2/PDGFR-beta signaling cascades to inhibit tumor angiogenesis.

The therapeutic and commercial importance of angiogenesis inhibitors was advanced with last year's US and European approvals of Genentech/Roche's Avastin (bevacizumab). Peak sales are forecast to reach between $845.3 million and $1.7 billion (see Colorectal Cancer - Avastin and Erbitux Pave The Way For Pipeline Targeted Therapies). Our alert service DailyUpdates-Oncology has recently featured AstraZeneca's phase II candidate ZD6474, an antiangiogenic VEGF-2 tyrosine kinase Inhibitor. The J Clin Oncol article featured here presents clinical data from a phase I study of BAY 43-9006 (sorafenib), which like ZD6474 inhibits VEGF-2 tyrosine kinase Inhibitor, but which in addition reduces cell proliferation. BAY 43-9006 is being advanced through collaboration between Bayer and Onyx Pharmaceuticals.

Mutations in the RAS gene occur in approximately 20% of all human cancers, including 90% of pancreatic cancer, 50% of colon cancer and 30% of non-small cell lung cancer. VEGFR-2 and PDGFR-beta are receptors of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), which play key roles in angiogenesis. BAY 43-9006 is the first compound to target both the RAS signaling pathway (through the inhibition of RAF kinase, a specific enzyme in the RAS pathway) to inhibit cell proliferation and the VEGFR-2/PDGFR-beta signaling cascades to inhibit tumor angiogenesis.

BAY 43-9006 represents an exciting new avenue for development of a new class of therapeutics.

The highlighted journal article reports that BAY 43-9006 when administered as a single agent to patients with a variety of solid tumors was well tolerated and appeared to provide some clinical benefits. Mild to moderate diarrhea was the most common (55%) treatment-related adverse event. The maximum-tolerated dose was 400 mg bid. Dose-limiting toxicities were grade 3 diarrhea and fatigue at 800 mg bid, and grade 3 skin toxicity at 600 mg bid. Of the 45 patients treated, 1 with hepatocellular carcinoma had a partial response and 25 had stable disease, 5 of whom displayed stable disease for longer than 12 months.

Since the completion of this phase I study, the development of BAY 43-9006 has progressed rapidly. A phase II study reported that 70% of patients with advanced kidney cancer, the lead indication for BAY 43-9006, experienced tumor shrinkage or disease stabilization after 12 weeks. Time to tumor was over 5 months for the entire study population (ie including those patients who received placebo) comparing favorably with 2-3 months for control groups in other studies with similar patient populations. Renal cell carcinoma is a niche cancer that accounts for only 2-3% of all solid tumors in the major pharmaceutical markets however treatments are weekly effective and prognosis poor. Approximately 30,000 patients are diagnosed with the disease each year in the US and 12,000 patients die from it annually. The market is currently dominated by the cytokines. Indeed interleukin-2 is the only FDA-approved therapy used to treat renal cell carcinoma in the US . Patients who fail IL-2 therapy have a median survival of only six months and furthermore IL-2 produces a response in only 15-20% of patients. Treatment is also associated with serious side-effects. As described in our feature Renal Cell Carcinoma - A Gateway for Angiogenesis Inhibitors? the development of angiogenesis inhibitors for the treatment of this cancer is attracting considerable attention.

BAY 43-9006 is currently being evaluated in an international, multicenter Phase III clinical study in patients with advanced kidney cancer. In addition BAY 43-9006 is also being evaluated in single agent phase II clinical trials in breast, lung, and other cancers, along with several Phase I/II clinical trials studying the agent in combination with a range of standard chemotherapeutics. At the 2004 ASCO meeting, investigators reported encouraging interim data, including durable partial responses, from a Phase I/II clinical study of BAY 43-9006 administered in combination with the chemotherapeutics carboplatin and paclitaxel in patients with advanced malignant melanoma. Of the 35 study participants, 83% of those treated with the combination therapy were observed by the investigator to have either a partial response or stable disease.

Entry date Sunday, March 06, 2005

J Clin Oncol. 2004 Dec 21; [Epub ahead of print]

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