An expanded Phase I clinical trial finds that the large majority (approximately 90%) of patients with advanced non-small cell lung cancer (NSCLC) with a specific form of the ALK (anaplastic lymphoma kinase) responded to treatment with the investigational ALK inhibitor, crizotinib (PF-02341066 or 1066), and more than half of these patients experienced tumor shrinkage.

Crizotinib is a selective, ATP-competitive, small molecule, orally bioavailable inhibitor of the ALK and MET/HGF receptor tyrosine kinases.

Trial and treatment
?Many of these patients had received three or more prior treatments, and we would expect only about 10% to respond,? said lead author Yung-Jue Bang, MD, PhD, professor in the Department of Internal Medicine at Seoul National University College of Medicine in Seoul, Korea. ?These results are quite dramatic, and represent an important improvement over what we would see with standard chemotherapy for patients with metastatic disease.?

When the ALK gene fuses with another gene (EML4), it promotes lung cancer cell growth by encoding the production of a tumor-specific protein called anaplastic lymphoma kinase, or ALK ? an enzyme that is critical for the growth and development of cancer cells.

Not all patients with lung cancer or NSCLC carry the ELM4-ALK fusion. Patients with this gene inversion are typically non-smokers who do not have mutations in the epidermal growth factor receptor gene (EGFR) or in the KRAS gene.

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The echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) fusion oncogenes have been reported in approximately 4% of all cases of NSCLC. Crizotinib, which is taken orally, works by inhibiting the ALK enzyme. About one in 20 lung cancer patients in the United States are estimated each year to be diagnosed with ALK-positive NSCLC.

Safety profile
To date, the study assessed crizotinib in 76 ALK patients with NSCLC, most of whom had adenocarcinoma and were nonsmokers or former smokers. All of the patients had the ALK gene fusion. Nearly all patients (87% at 8 weeks) who received crizotinib to date responded to this treatment and experienced tumor shrinkage or disease stabilization. Among those, 57% had tumor shrinkage.

The median duration of treatment was approximately six months (25.5+ weeks). The drug candidate was associated with a good safety profile. Gastrointestinal toxicities, including nausea (55%) and vomiting (39%), were the most frequent adverse events.

The study did not have a control group but a randomized, Phase III trial (PROFILE-1007) has begun, comparing crizotinib to standard second-line chemotherapy.

Plenary Session
Lead Author: Yung-Jue Bang, MD, PhD, Seoul National University College of Medicine, Seoul, Korea
Date: Sunday, June 6, 2010, 2:30-2:45 PM CDT
Location: N Hall B1
Abstract: 3
Title: Clinical activity of the oral ALK inhibitor, PF-02341066, in ALK positive patients with non-small cell lung cancer (NSCLC).
Authors: Y. Bang, E. L. Kwak, A. T. Shaw, D. R. Camidge, A. J. Iafrate, R. G. Maki, B. J. Solomon, S. I. Ou, R. Salgia, J. W. Clark.

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