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FDA Approval for Crizotinib

Brand name: Xalkori® 

Regular Approval Granted

Full prescribing information is available, including clinical trial information, safety, dosing, drug-drug interactions, and contraindications.

On November 20, 2013, the Food and Drug Administration (FDA) granted regular approval for crizotinib (Xalkori®, made by Pfizer, Inc.) capsules for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.

This approval was based on demonstration of superior progression-free survival (PFS) and overall response rate (ORR) for crizotinib compared with chemotherapy in patients with ALK-positive NSCLC whose disease progressed after platinum-based doublet chemotherapy. 

An open-label active-controlled multinational randomized trial enrolled 347 patients with ALK-positive metastatic NSCLC. Patients were required to have progressed following platinum-based chemotherapy and to have ALK expression in tumor specimens detected by fluorescence in situ hybridization on central laboratory testing. Patients were randomly assigned to receive either crizotinib 250 mg orally twice daily (n=173) or chemotherapy (n=174). Patients randomly assigned to chemotherapy received pemetrexed (58 percent) or docetaxel (42 percent) if they had received prior pemetrexed. Approximately 64 percent of patients treated with chemotherapy subsequently received crizotinib.

The trial demonstrated significantly prolonged progression-free survival (PFS) for crizotinib treatment compared with chemotherapy [HR=0.49, (95 percent CI: 0.37, 0.64), p<0.0001]. Median PFS was 7.7 for patients treated with crizotinib and 3.0 months for patients treated with chemotherapy. The ORR was significantly higher for patients treated with crizotinib (65 percent vs. 20 percent), with median response durations of 7.4 months for patients treated with crizotinib and 5.6 months for patients treated with chemotherapy. No difference in overall survival was noted between the two groups [HR= 1.02 (95 percent CI: 0.68, 1.54)] in a planned interim analysis.

Common adverse reactions in clinical trials with crizotinib, occurring at an incidence of 25 percent or higher, included visual disorders, nausea, diarrhea, vomiting, constipation, edema, elevated transaminases, and fatigue. 

Safety data from this trial was evaluated for 172 crizotinib-treated patients. Serious adverse events were reported in 37 percent of crizotinib-treated patients. The most common serious adverse reactions in crizotinib-treated patients were pneumonia, pulmonary embolism, dyspnea, and interstitial lung disease. Fatal adverse reactions occurred in nine crizotinib-treated patients and included acute respiratory distress syndrome, arrhythmia, dyspnea, pneumonia, pneumonitis, pulmonary embolism, interstitial lung disease, respiratory failure, and sepsis

Crizotinib was previously granted accelerated approval in August 2011 based on durable objective response rates (ORR) of 50 percent and 61 percent in two single-arm open-label studies. 

The recommended dose and schedule for crizotinib is 250 mg orally, twice daily, with or without food.  

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Accelerated Approval Granted

On August 26, 2011, the FDA granted accelerated approval to crizotinib (Xalkori Capsules, made by Pfizer, Inc.) for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is ALK-positive as detected by an FDA-approved test. The FDA approved the Vysis ALK Break-Apart FISH Probe Kit (Abbott Molecular, Inc.) concurrently with the crizotinib approval. This companion diagnostic test is designed to detect rearrangements of the anaplastic lymphoma kinase (ALK) gene in NSCLC.

The approval was based on two single-arm trials, Study A (N = 136 patients) and Study B (N = 119 patients). Crizotinib, 250 mg, was administered orally twice daily to a total of 255 patients with locally advanced or metastatic ALK-positive NSCLC. Demographic analysis from the combined data of these trials noted that the median age was 52 years, 63 percent of patients were Caucasian, 30 percent were Asian, 48 percent were male and 84 percent had an ECOG performance status of 0 or 1. Fewer than 3 percent of patients were current smokers. Ninety-six percent had adenocarcinoma, 95 percent had metastatic disease, and 94 percent had received prior systemic treatment for NSCLC.

The primary endpoint of both trials was objective response rate (ORR) as assessed by the investigator. In Study A, the ORR was 50 percent (95 percent CI: 42 percent, 59 percent) with a median response duration of 42 weeks. In Study B, the ORR was 61 percent (95 percent CI: 52 percent, 70 percent) with a median response duration of 48 weeks. Complete responses were observed in 1 percent of patients. No differences in ORR by performance status, number of prior chemotherapeutic regimens, or percentage of cells found to have the ALK gene rearrangement were noted.

The most common adverse reactions (at least 25 percent) observed in both studies were vision disorder, nausea, diarrhea, vomiting, edema, and constipation. Vision disorders included visual impairment, photopsia, vision blurred, vitreous floaters, photophobia, and diplopia. Grade 3-4 adverse reactions in at least 4 percent of patients included increased ALT and neutropenia. Crizotinib has been associated with severe, life-threatening, or fatal treatment-related pneumonitis with a frequency of 1.6 percent in clinical trials. All cases occurred within 2 months after the treatment initiation.

The recommended dose and schedule for crizotinib is 250 mg orally twice daily.

 This summary was provided by Richard Pazdur, M.D., director of the FDA's Division of Oncology Drug Products.

The FDA is the division of the U.S. Department of Health and Human Services charged with ensuring the safety and effectiveness of new drugs and other products. (See "Learn How Drugs and Devices Get Approved.") The FDA's mission is to promote and protect the public health by helping safe and effective products to reach the market in a timely way, and monitoring products for continued safety after they are in use.

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  • Updated: November 22, 2013