Therapeutic activity of Bayer's BAY 43-9006 in renal cell carcinoma

Renal cell carcinoma (RCC) is a niche cancer that accounts for 2-3% of all solid tumors in the major pharmaceutical markets. Approximately 30,000 patients are diagnosed with the disease each year in the and 12,000 patients die of the disease annually. The market is currently dominated by the cytokines, but there is significant interest among physicians in the potential of anti-angiogenics, particularly so since renal cell carcinomas are known to be well vascularized. Bayer's BAY 43-9006 is a broad spectrum kinase inhibitor that blocks components of the angiogenesis pathway and also signal transduction mechanis involved in cellular proliferation. BAY 43-9006 has recently been shown to have therapeutic activity in a phase II study of renal cell carcinoma patients.

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DailyUpdates 5th October, 2004: Renal cell carcinoma is a niche cancer that accounts for 2-3% of all solid tumors in the major pharmaceutical markets. Approximately 30,000 patients are diagnosed with the disease each year in the while RCC accounts for 12,000 deaths annually. The market is currently dominated by the cytokines. Indeed interleukin-2 (IL-2) is the only FDA-approved therapy used to treat renal cell carcinoma in the . Patients with RCC 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 (for an evaluation of RCC therapeutics click here).

The FDA's fast track program is designed to facilitate development and expedite review of new drugs or biologicals that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs. Treatments of renal cell carcinoma are therefore likely to gain fast-track status with the FDA

The approval of the first inhibitor of angiogenesis, Avastin has accelerated research activity in this field. There is especial interest among physicians in the potential of anti-angiogenics for the treatment of renal cell carcinomas which are known to be well vascularized. For example LeadDiscovery's most recent edition of TherapeuticAdvances highlights 's FK-866, a novel antitumor agent in phase I trial, which inhibits the production of VEGF. FK-866 reduces angiogenesis in experimental models of renal cell carcinoma and at higher doses reduced primary tumor volume by 40% and the number of metastases was reduced by 57% (click here an editorial on this data).

VEGF is one of the principal growth factors that drives angiogenesis. This growth factor acts on endothelial cells binding to endothelial tyrosine kinase receptors including Flt-1 (VEGFR-1) and KDR/flk-1 (VEGFR-2). Activation of VEGF receptors promotes endothelial cell growth, mitogenesis, and tube formation. A third receptor, VEGFR-3 which binds VEGFC but not VEGF has been implicated in lymphogenesis, another key step in tumor progression.

BAY 43-9006 (Sorafenib) is a novel bi-aryl urea developed by Bayer and which inhibits a broad spectrum of kinases including VEGFR-2 and VEGFR-3, and with even greater potency, BRAF, an oncogene that contributors to the development of many cancers.

The RAF/MEK/ERK signaling pathway plays a key regulatory role in cellular transcription, metaboli, and cytoskeletal arrangements and frequently contributes to tumor cell proliferation and angiogenesis. Under normal physiological conditions growth factor binding to receptor tyrosine kinases at the cell membrane activates this pathway. The level of activity is regulated by the cellular protein RAF1. However a wide range of tumors are characterized by receptor-independent activation of the pathway; this can be due to due to activated RAS or mutant homologues of RAF1 such as CRAF and BRAF rationalizing the evaluation of BAY 43-9006.

Phase I studies of BAY 43-9006 have indicated that a continuous oral dose of 400 mg twice daily is tolerated by patients with grade 3 diarrhea, hand-foot syndrome, and fatigue being the dose-limiting toxicities. In this trial 1 of 7 patients with renal cell carcinoma exhibited a partial response to BAY 43-9006 and 5 patients had stable disease. Recruitment to a phase II clinical trials has now been completed and in September Clinical Cancer Research published preliminary results from a cohort of patients with renal cell carcinoma.

In this phase II trial patients received single-agent BAY 43-9006, 400 mg twice daily continuously, for a 12-week run-in period. At 12 weeks, a radiologic evaluation was performed, and patients with objective responses (25% tumor shrinkage) continued with the drug indefinitely, until disease progression. Patients with stable disease (defined as response between 25% reduction and 25% growth) after the 12-week run-in phase were randomized in a double-blind manner to either active drug or oral placebo. If after this stage any randomized patient progressed on the treatment, their randomization code was broken, and those receiving placebo were rechallenged with open-label BAY 43–9006. Tumor evaluation occurred every 12 weeks after baseline imaging.

At 12 weeks 30% of patients treated with BAY 43-9006 had stable disease and 40% had an objective response. The responses were gradual in most cases, although rapid shrinkage in mass lesions was also observed. Response and ongoing tumor shrinkage continued in some cases for longer than 6 months. As in the preceding phase I study, toxicity data from the study are encouraging with the adverse effects manageable in most patients.

In a recent press release Bayer and Onyx announced further data from the same phase II trial presented at this year's AACR-NCI-EORTC meeting in . These data show that 43% of patients with advanced primary liver cancer experienced stable disease for at least four months and an additional 9% of patients experienced tumor shrinkage following BAY 43-9006 treatment suggesting that this agent has wide-ranging potential extending to cancers that are more common than renal cell carcinoma.

A Phase III randomized controlled trial of single-agent BAY 43-9006 versus placebo has commenced and is planned to accrue 884 patients with renal cell carcinoma who have progressed within 6 months of immunotherapy with interferon or IL-2. The study is due to complete accrual by summer 2005. Results of this clinical study and others, as well as further basic research identifying the molecular mechani of BAY 43-9006 in patients with renal cell carcinoma is eagerly awaited.

Source: Kinase Inhibition with BAY 43-9006 in Renal Cell Carcinoma. Clin Cancer Res. 2004 Sep 15;10(18):6388S-92S.

This article is highlighted in the Ocotber 5th edition of DailyUpdates-Oncology, LeadDiscovery's unique bulletin of breaking journal articles and press releases for the drug discovery community. To access the article and to view today's bulletin click here

(Editorial note: In depth reports on cancer can be found at LeadDiscovery's report center)