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Clinical Development of Sorafenib (BAY 43–9006) VEGFR and RAF Inhibitor

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Tumor Angiogenesis

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Abstract

Sorafenib is a multi-kinase inhibitor with effects on the tumor cell and tumor vasculature that inhibit proliferation, promote cell death, and disrupt neo-angiogenesis. Originally identified as a Raf kinase inhibitor, sorafenib also inhibits VEGFR-1/-2/-3; PDGF-β receptor (PDGFR-β); Fms-like tyrosine kinase-3 (FLT-3); c-Kit protein (c-Kit); and RET receptor tyrosine kinases. Sorafenib has demonstrated potent anti-tumor activity in preclinical xenograft models of different tumor types by virtue of its anti-angiogenic, anti-proliferative and proapoptotic effects. This orally administered drug is well tolerated and received approval for the treatment of metastatic renal cell carcinoma (RCC) primarily based on a large international trial, the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGETs), in which 903 patients were randomized to receive sorafenib or placebo. At a planned interim analysis, patients treated with sorafenib had a lower risk for death than those treated with placebo. However, improvement in survival did not meet criteria for statistical significance. In a planned interim analysis of 769 patients, sorafenib significantly prolonged median progression-free survival compared with placebo (167 days vs 84 days; hazard ratio 0.44; P<0.000001). Sorafenib has also demonstrated early signs of clinical efficacy, alone or in combination regimens, in patients with advanced hepatocellular carcinoma (HCC) and melanoma. Ongoing phase III trials are currently being conducted to further evaluate sorafenib in HCC, melanoma, and non-small cell lung cancer. This chapter summarizes the discovery, preclinical findings, and clinical development of sorafenib in RCC and its potential use in other tumor types.

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Authors and Affiliations

  1. Bayer AG Pharma Research Center, Germany

    Dr. Dimitris Voliotis (Professor, Director)

  2. Global Clinical Leader Oncology BHC-PH-PD-GMD, Global Clinical Development, D-42096, Wuppertal, Germany

    Dr. Dimitris Voliotis (Professor, Director)

  3. Bayer HealthCare - Pharmaceuticals, 400 Morgan Lane, West Haven, CT, 06516, USA

    J. Dumas

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  1. Dr. Dimitris Voliotis
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Editors and Affiliations

  1. Klinik für Tumorbiologie, Breisacher Str. 117, 79106, Freiburg i. Br., Germany

    Dieter Marmé PhD (Professor) (Professor)

  2. DKFZ, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Norbert Fusenig MD (Professor, former Head of Division of Carcinogenesis and Differentiation) (Professor, former Head of Division of Carcinogenesis and Differentiation)

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Voliotis, D., Dumas, J. (2008). Clinical Development of Sorafenib (BAY 43–9006) VEGFR and RAF Inhibitor. In: Marmé, D., Fusenig, N. (eds) Tumor Angiogenesis. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-33177-3_36

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