The final analysis of the Phase III NExUS (NSCLC research Experience Utilizing Sorafenib) trial evaluating sorafenib (Nexavar? (1), Bayer Healthcare Pharmaceuticals, Inc and Onyx Pharmaceuticals, Inc.) tablets in patients with advanced non-squamous non-small cell lung cancer (NSCLC) showed that the study did not meet its primary endpoint of improving overall survival in the first-line setting.

Non-small cell lung cancer (NSCLC) (2) accounts for 85-90% of diagnosed lung cancers and is a disease in which malignant (cancer) cells form in the tissues of the lung. It is characterized by several types of lung cancers, each of which grow and spread in different ways, including: squamous cell carcinoma, adenocarcinoma, and large cell carcinoma.

Every year 1.4 million people worldwide will be diagnosed with lung cancer. There are nearly 205,000 new cases in the United States and approximately 375,000 new cases in Europe each year. Annual deaths as a result of non small cell lung cancer are estimated at 160,000 in the United States and 342,000 in Europe.

Trial Design

NExUS, a phase III, randomized, double-blind, placebo-controlled study evaluated trial, evaluated sorafenib versus placebo in combination with two chemotherapeutic agents, gemcitabine and cisplatin, in treatment-naive non-small cell lung cancer patients.

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The primary endpoint was overall survival, and secondary endpoints included progression-free survival, tumor response and safety. Patients were randomized to receive 400 mg of oral sorafenib or matching placebo twice daily, in addition to gemcitabine and cisplatin for up to six cycles. Subsequently, patients continued in a maintenance phase where sorafenib or placebo was administered as a single agent. The study enrolled approximately 900 patients from sites throughout Europe, South America, Asia Pacific and the Middle East.

A positive secondary endpoint of progression-free survival (PFS) was observed in the trial. The safety and tolerability of the treatment triplet was as expected and did not show any new or unexpected toxicities. Data from this study are expected to be presented at an upcoming scientific meeting.

Enrollment in NExUS commenced in February 2007. In 2008, based on the results seen in a previous sorafenib first-line NSCLC Phase III trial, the NExUS study protocol was amended to stop enrolling and treating squamous cell carcinoma patients. Of the squamous cell patients who were enrolled in the NExUS trial before the amendment, a higher mortality was observed. This finding was consistent with what was seen in the previous trial.

Differentiated Mechanism
Sorafenib, an oral anti-cancer therapy, is currently approved in more than 90 countries the treatment of hepatocellular carcinoma (HCC), or liver cancer and in more than 95 countries for the treatment of patients with advanced renal cell carcinoma (RCC), or kidney cancer. Sorafenib inhibits both the tumor cell and tumor vasculature. In preclinical studies, Sorafenib has been shown to inhibit members of two classes of kinases thought to be involved in both cell proliferation (growth) and angiogenesis (blood supply) ? two important processes that enable cancer growth. These kinases included Raf kinase, VEGFR-1, VEGFR-2, VEGFR-3, PDGFRB, KIT, FLT-3 and RET.

Sorafenib is also being evaluated by the companies, international study groups, government agencies and individual investigators as a single agent or combination treatment in a wide range of cancers, including lung, thyroid, breast, ovarian and colorectal cancer and as an adjuvant therapy for liver and kidney cancer.

Further analysis
Bayer and Onyx will further review the findings of the NExUS analysis to determine what, if any, impact these data might have on other ongoing clinical trials evaluating the safety and efficacy of sorafenib.

“Bayer and Onyx are disappointed with these results, in particular, for patients who are suffering from this deadly disease,” said Dr. Dimitris Voliotis, Vice President, Global Clinical Development Oncology, Bayer HealthCare. “We are confident in our clinical trial program exploring Nexavar’s potential in a variety of tumor types, including lung cancer. Based on encouraging data from a recently presented prospective biomarker trial and Phase II signal-generating lung cancer studies, we believe it’s critical to continue our evaluation of Nexavar in combination with targeted agents and as a monotherapy in later lines of treatment in lung cancer patients.”

Sorafenib is being evaluated by the companies and individual investigators in a variety of treatment settings for patients with non-small cell lung cancer, including a Phase III monotherapy study in the third- and fourth-line setting and Phase II studies in combination with other therapies in the second-line setting.

(1) Nexavar? (sorafenib) tablets is a registered trademark of Bayer Healthcare Pharmaceuticals, Inc.
(2) Ferlay J, et al., GLOBOCAN 2002. Cancer Incidence, Mortality and Prevalence Worldwide. IARC CancerBase No.5, Version 2.0. IARCPress, Lyon, 2004.

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