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Xalkori (Crizotinib) Tops Chemotherapy in Lung Cancer Trial

Phase III data show prolonged progression-free survival

PROFILE 1014, a phase III study of the anaplastic lymphoma kinase (ALK) inhibitor Xalkori (crizotinib, Pfizer), has met its primary objective of significantly prolonging progression-free survival (PFS) in previously untreated patients with ALK-positive advanced non-squamous non–small-cell lung cancer (NSCLC) compared with standard platinum-based chemotherapy regimens.

PROFILE 1014 is the second positive phase III study that compared crizotinib with chemotherapy, a standard of care for patients with advanced NSCLC.

Xalkori (crizotinib) was first approved in 2011 through the FDA’s accelerated approval program. It was granted regular approval in 2013 in the U.S. based on the results of the PROFILE 1007 trial, a phase III study demonstrating that crizotinib significantly prolonged PFS in previously treated patients with ALK-positive advanced NSCLC compared with single-agent chemotherapy.

In the PROFILE 1007 study, 347 patients (56% female; median age, 50 years) were randomly assigned to receive crizotinib 250 mg orally twice daily (n = 173) or chemotherapy (n = 174). Chemotherapy consisted of pemetrexed 500 mg/m2 (if pemetrexed naïve; n = 99) or docetaxel 75 mg/m2 (n = 72) intravenously (IV) every 21 days. Patients in both treatment arms continued treatment until documented disease progression or intolerance to therapy occurred, or until the investigator determined that the patient was no longer experiencing a clinical benefit. A total of 112 patients (64%) assigned to the chemotherapy arm subsequently received crizotinib after disease progression.

Median PFS was 7.7 months in the crizotinib group compared with 3.0 months in the chemotherapy group (P < 0.001). In a secondary analysis, median overall survival was 20.3 months for crizotinib versus 22.8 months for chemotherapy (P = 0.54). A partial tumor response was noted in 65% of the crizotinib-treated patients compared with 20% of the placebo-treated patients (P < 0.001). One patient (0.6%) in the crizotinib group achieved a complete response.

Crizotinib is an inhibitor of receptor tyrosine kinases, including ALK, hepatocyte growth factor receptor (HGFR, c-Met), ROS1 (c-ros), and recepteur d’origine nantais (RON). Translocations can affect the ALK gene, resulting in the expression of oncogenic fusion proteins. The formation of ALK fusion proteins results in activation and dysregulation of the gene’s expression and signaling, which can contribute to increased cell proliferation and survival in tumors expressing these proteins. Crizotinib demonstrated concentration-dependent inhibition of ALK, ROS1, and c-Met phosphorylation in cell-based assays using tumor cell lines, and demonstrated antitumor activity in mice bearing tumor xenografts that expressed EML4- or NPM-ALK fusion proteins or c-Met.

Xalkori (crizotnib) is currently indicated for the treatment of patients with metastatic NSCLC whose tumors are ALK-positive, as detected by an FDA-approved test.

Lung cancer is the leading cause of cancer death worldwide. 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 advanced (metastatic) disease, where the 5-year survival rate is only 5%.

Sources: Pfizer; March 25, 2014; and Xalkori Prescribing Information; November 2013.

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