Abstract SY33-01: The development of crizotinib in molecularly targeted patient populations
Authors: Christensen James G. 
Published: August 2012

Abstract
Dysregulation of receptor tyrosine kinases (RTKs) is implicated in the pathogenesis of several human cancers. Crizotinib (PF-2341066) is a small-molecule inhibitor of the anaplastic lymphoma kinase (ALK), c-Met/HGFR, and ROS receptor tyrosine kinases. The rationale for use of this mechanism to treat cancer is supported by a paradigm in oncology that robust clinical efficacy can be obtained with well-tolerated inhibitors directed toward oncogenic tyrosine kinases that are genetically altered through activating mutations, gene translocations, or gene amplification. Nonclinical studies with crizotinib indicated that it selectively inhibited growth or exhibited cytoreductive activity in only a subset of cancer cell lines or tumor models in vivo as a single agent. It was then determined that the selective activity observed was could be mapped back to genetic defects in crizotinib RTK targets (i.e., ALK, MET, or ROS) exhibited by the majority of these selected cancer cell lines or tumor models. Studies utilizing clinical specimens also indicated that many of the genetic abnormalities identified in functional genomics studies were also present in selected patient populations.
One particular genetic event involving the ALK gene locus sparked futher study of crizotinib. An inversion within chromosome 2p resulting in the formation of a fusion gene product comprising portions of the echinoderm microtubule associated protein-like 4 (EML4) gene and the ALK gene was discovered in 2007 by Mano and colleagues in archived NSCLC clinical specimens. A subsequent series of published studies indicated that EML4-ALK inversion events included at least 9 fusion variants, each comprised of the same portion of the ALK C-terminal kinase domain and each resulting in expression of catalytically active kinase fusion protein variants. Expression of EML4-ALK specifically in lung alveolar epithelial cells in transgenic mice demonstrated numerous bilateral lung adenocarcinomas with 100% penetrance only a few weeks after birth, confirming the potent oncogenic activity of the fusion kinase. Collectively, a series of studies utilizing archived NSCLC specimens across a broad set of ethnicities indicated that the incidence of ALK gene rearrangements ranged from 2-7%. This group of studies also indicated that the vast majority of ALK gene rearrangements were observed in lung adenocarcinoma specimens compared with squamous or small cell. Importantly, ALK gene rearrangements are rarely coincident with EGFR, HER2, or KRAS mutations, indicating it is a distinct disease subtype. In addition, crizotinib demonstrated potent activity against NPM-ALK (nucleophosmin-anaplastic lymphoma kinase), an oncogenic fusion protein variant of the Anaplastic Lymphoma Kinase, which results from a chromosomal translocation which is implicated in the pathogenesis of human anaplastic large cell lymphoma. Furthermore, an extensive body of literature indicates that c-Met/HGFR is one of the most frequently mutated or otherwise abnormally activated RTKs (receptor tyrosine kinase) in various human cancers. Tumor types in which c-Met/HGFR was reported to be genetically altered by mutation or gene amplification include oncology indications with a strong unmet medical need such as renal, metastatic colorectal, glioma, non-small cell lung, gastric, and head and neck cancers. In addition to the rationale for crizotinib based on the genetic dysregulation of its tyrosine kinase targets, an additional rationale is based on its predicted ability to target multiple processes that are common to cancer progression in a variety of tumors. Inappropriate activation of c-Met/HGFR is implicated in dysregulation of multiple tumor oncogenic processes such as mitogenesis, survival, angiogenesis, invasive growth, and especially in the metastatic process. Finally, the ROS gene locus has also been recently identified as an oncogenic fusion protein in non-small cell lung cancers, glioblastoma, and cholangiocarcinoma.
The collective data set indicating that crizotinib exhibited selective activity in cell lines or models bearing genetic alterations in crizotinib RTK targets and the observation of genetic alterations of ALK, MET, and ROS in defined patient populations resulted in the design of clinical trials to evaluate crizotinib in patients prescreened for selected genetic abnormalities. These trials were initiated at the time of the identification of the recommended Phase 2 dose for crizotinib. This molecularly-enriched cohort includes patients with malignancies that are positive for ALK chromosomal translocations (including EML4-ALK-positive non-small cell lung cancer [NSCLC]), ALK gene amplification, c-Met amplification or mutations, ROS translocations, or for chromosomal translocations/fusions that lead to altered transcriptional regulation of c-Met and/or HGF. For ALK positive patients, in one study there were 119 patients with ALK-positive NSCLC enrolled in this trial. Of these patients, 71 had either a complete response (2) or a partial response (69) for an overall response rate of 61%. Median duration of response (DR) for patients experiencing disease response was 48 weeks. Median Progression Free Survival (PFS) for all patients was 9.2 months (95% CI: 7.6, 10.3), with a median duration of follow-up for PFS of 8.0 months. In addition to responses observed in ALK-positive NSCLC patients there have been multiple hints of clinical activity in other patient populations. The additional patient populations for which crizotinib demonstrated objective responses or tumor reductions included ALK fusion positive Inflammatory Myofibroblastic Tumor (IMT), ALK fusion positive Anaplastic large Cell Lymphoma (ALCL), MET amplification positive NSCLC, GBM, and gastric cancer, and ROS fusion positive NSCLC. The broader study of clinical activity in other patient populations is ongoing to determine the extent and breadth of preliminary activity observed. Crizotinib was generally well tolerated in clinical studies with the most common adverse reactions (≥25%) are vision disorder, nausea, diarrhea, vomiting, edema, and constipation. Key ongoing efforts include the continued identification of patient populations that could potentially benefit from treatment with crizotinib, the study of mechanisms of resistance, and the potential to develop rational molecularly targeted combination strategies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY33-01. doi:1538-7445.AM2012-SY33-01