U.S. Food and Drug Administration Approval: Crizotinib for Treatment of Advanced or Metastatic Non–Small Cell Lung Cancer That Is Anaplastic Lymphoma Kinase Positive

Shakun M Malik,Richard Pazdur,Brenda Gehrke,Whitney Helms,Lijun Zhang,Anshu Marathe,Virginia Ellen Maher,Karen E Bijwaard,Diane Hanner,Qi Liu,Robert L Becker,Pengfei Song,Shenghui W Tang,Robert Justice

doi:10.1158/1078-0432.ccr-13-3077

Shakun M Malik, Richard Pazdur + Show 12 more

https://doi.org/10.1158/1078-0432.ccr-13-3077

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On August 26, 2011, the U.S. Food and Drug Administration (FDA) approved crizotinib (XALKORI Capsules, Pfizer Inc.) for treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK) positive as detected by an FDA-approved test. The Vysis ALK Break-Apart FISH Probe Kit (Abbott Molecular, Inc.) was approved concurrently. In two multicenter, single-arm trials, patients with locally advanced or metastatic ALK-positive NSCLC previously treated with one or more systemic therapies received crizotinib orally at a dose of 250 mg twice daily. In 119 patients with ALK-positive NSCLC by local trial assay, the objective response rate (ORR) was 61% [95% confidence intervals (CI), 52%-70%] with a median response duration of 48 weeks. In 136 patients with ALK-positive NSCLC by the to-be-marketed test, the ORR was 50% (95% CI, 42%-59%) with a median response duration of 42 weeks. The most common adverse reactions (≥25%) were vision disorder, nausea, diarrhea, vomiting, edema, and constipation. Accelerated approval was granted on the basis of the high ORRs and durable responses. On November 20, 2013, crizotinib received full approval based on an improvement in progression-free survival in patients with metastatic ALK-positive NSCLC previously treated with one platinum-based chemotherapy regimen.

Highlights

Until recently, first-line treatment for advanced non– small cell lung cancer (NSCLC) was platinum-based doublet chemotherapy
Anaplastic lymphoma kinase (ALK), known as ALK tyrosine kinase receptor or CD246, is an enzyme that in humans is encoded by the ALK gene and that plays an important role in brain development
The oncogenic potential of the ALK gene can be generated by chromosomal rearrangement resulting in the formation of fusion products with any of several other genes and by DNA mutations within the gene itself

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First-line treatment for advanced non– small cell lung cancer (NSCLC) was platinum-based doublet chemotherapy. Stable disease noted in two patients with ALK-positive NSCLC during the dose-escalation phase led to an amendment providing an expansion cohort of patients with ALK-positive NSCLC who received the recommended phase II regimen of 250 mg orally b.i.d. Testing of tumor tissue for ALK gene rearrangement was performed by local laboratories. Study 1005 was a multicenter, single-arm phase II trial of crizotinib 250 mg administered orally b.i.d in patients with advanced NSCLC after tumor progression on at least one line of chemotherapy [15]. The diagnostic test used to detect ALK fusion events was performed by central laboratories using the to-be-marketed Vysis ALK Break-Apart FISH assay In both trials, the primary efficacy endpoint was objective response rate (ORR) based on investigator assessment (INV) with imaging assessments at baseline and every other cycle. No patient experienced liver failure, but there was one potential Hy’s law case and four patients required permanent discontinuation of treatment due to liver enzyme elevations

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