Pharmaceutical giant Pfizer Inc. announced this week that it has initiated the rolling submission of a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for crizotinib (PF-02341066), an oral first-in-class anaplastic lymphoma kinase (ALK) inhibitor in development for the treatment of patients with advanced non-small cell lung cancer (NSCLC) whose tumors are ALK-positive. Pfizer expects to complete the submission in the first half of 2011.
?This action represents a significant step in the registration process for crizotinib (PF-02341066). Pfizer is committed to working collaboratively with the FDA as we move forward in the submission process with the ultimate goal of offering a new treatment option for patients with advanced ALK-positive NSCLC,? said Garry Nicholson, president and general manager, Pfizer Oncology Business Unit.
The FDA?s Fast Track process is designed to facilitate development and expedite review of drugs that treat serious or life-threatening diseases and demonstrate the potential to address unmet medical need. Pfizer was granted Fast Track designation by the FDA for crizotinib (PF-02341066) in December 2010. The rolling submission, which is available to medicines that have received Fast Track designation, allows completed portions of the crizotinib (PF-02341066) NDA to be submitted and reviewed by the FDA on an ongoing basis.
With more than one million deaths from lung cancer occur each year worldwide, lung cancer is the leading cause of cancer death in men and the second leading cause of cancer death in women.[2,14]
NSCLC accounts for about 85% of lung cancer cases and remains difficult to treat, particularly in the metastatic setting. Approximately 75% of NSCLC patients are diagnosed late with metastatic, or advanced, disease, where the five-year survival rate is only 6%.[3,3] In addition, the current standard of care for advanced NSCLC demonstrates a response rate of only about 15%.
In lung adenocarcinoma, certain mutations such as echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (ALK) are associated with lower sensitivity to chemotherapy, when used conventionally as the first-line therapy in the advanced stage of the disease.
Crizotinib (PF-02341066) is an oral first-in-class selective ATP-competitive small-molecule that inhibits the anaplastic lymphoma kinase (ALK)  and c-Met (mesenchymal endothelial transition factor)/ Hepatocyte Growth Factor Receptor (HGFR) tyrosine kinases and their oncogenic variants (eg, ALK or c-Met/HGFR mutant variants).[9, 11]
Alterations in the ALK gene are believed to be a key driver of tumor development in cancers like NSCLC, and approximately 3-5% of NSCLC tumors are ALK-positive.  By inhibiting ALK, crizotinib (PF-02341066) blocks signaling in a number of cell pathways that are critical for the growth and survival of tumor cells.
Mechanism of Action Consistent with this mechanism of action, crizotinib demonstrated dose-dependent inhibition of phosphorylation of ALK and c-Met/HGFR and selected variants as well as their kinase target dependent functions in tumor cells both in vitro and in vivo. In addition, crizotinib exhibited potent and selective growth inhibitory activity against tumor cells exhibiting amplification of the c-Met/HGFR gene locus or translocation/inversion of the ALK gene locus (ie, EML4-ALK, the most common 2p23 rearrangement associated with the ALK gene, or NPM-ALK fusion variants).
Crizotinib demonstrated antitumor efficacy, including marked cytoreductive antitumor activity, in tumor models implanted in athymic mice that expressed activated c-Met or NPM-ALK, providing further rationale for study in clinical trials in selected patient populations.
The development of crizotinib constitutes a considerable progress for patients with NSCLC. An analysis was presented by Yung-Jue Bang, MD, PhD, of Seoul National University Hospital, South Korea, on behalf of his colleagues during the Plenary Session at ASCO’s 2010 Annual Meeting showed that treatment with crizotinib (PF-02341066) has produced an objective response rate (ORR) of 57%, disease control rate (DCR) of 87%, and progression-free survival (PFS) probability at 6 months of 72%, with an excellent safety profile, in patients with NSCLC. 
According to Dr. Bang the data provides proof of principle for rapid clinical development from targeted identification to clinical validation and supports molecular selection of patients with NSCLC for appropriately targeted therapies.
A New Subgroup
Activation of Epidermal Growth Factor Receptor (EGFR) protein via ligand binding stimulates protein tyrosine kinase, which leads to activation of signaling pathways associated with cell growth and survival. The overexpression of EGFR protein as well as EGFR gene activating mutations in the tyrosine kinase domain leads to tumor growth and progression. Therefore, EGFR has become an important target for anti-cancer drug therapy.
Around 10% of patients with NSCLC have an abnormality or a mutation involving EGFR. Increasing evidence show that lung cancer patients with tumors that has such a mutation, benefit from treatment with the EGFR inhibitor erlotinib, an EGFR tyrosine kinase erlotinib inhibitors (TKIs) that can prevent activation of the signaling pathways and improve survival in selected patients with NSCLC. The average response rate is 70%. As a result, this drug has become a first-line therapy and is used in this patient subgroup.
The EML4-ALK translocation defines a new molecular subgroup of NSCLC with distinctive clinical and pathologic features.  EML4-ALK arises from fusion between the 5? end of the EML4 gene and the 3? end of the ALK gene. Patients with ALK rearrangements are generally younger than most patients with NSCLC.  EML4-ALK rearrangements are more common in adenocarcinomas of patients who never smoked (or only smoked lightly) and whose tumors lack EGFR and KRAS mutations. Histology is typically characterized by mucin production and either a solid growth pattern containing signet-ring cells (more likely in Western patients) or acinar growth pattern (more likely in Asian patients). 
ALK gene rearrangements are found in about 3% to 5% of NSCLC patients without a mutation involving EGFR. Because these 2 biomarkers are mutually exclusive it means that there is now around 10 – 15% of NSCLC patients who can be treated with targeted therapies.
In addition to the regulatory submissions with the FDA and the European Medicines Agency, Pfizer also announced plans for submission of a for two other investigational oncology compounds in 2011 ? axitinib, an oral and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2 and 3, for the treatment of patients with metastatic Renal Cell Carcinoma (mRCC), and bosutinib, an oral dual Src and Abl kinase inhibitor, for the treatment of Chronic Myeloid Leukemia (CML).
U.S. Food and Drug Administration. Fast Track, Accelerated Approval
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