FDA Approves Crizotinib (Xalkori) for Non-Small-Cell Lung Cancer Patients With ALK Mutation

The U.S. Food and Drug Administration (FDA) has announced the accelerated approval of crizotinib (Xalkori) for the treatment of locally advanced or metastatic non–small-cell lung cancer (NSCLC) in patients who express an abnormal anaplastic lymphoma kinase (ALK) gene.

As was the case with the recent approval of vemurafenib (Zelboraf) for the treatment of melanoma, the FDA has also approved a companion diagnostic called the Vysis ALK Break Apart FISH Probe Kid to detect whether a patient carries the ALK gene abnormality.

"The approval of Xalkori with a specific test allows the selection of patients who are more likely to respond to the drug," said Richard Pazdur, MD, director of the Office of Oncology Drug Products in the FDA's Center for Drug Evaluation and Research. "Targeted therapies such as Xalkori are important options for treating patients with this disease and may ultimately result in fewer side effects."

The ALK fusion gene is a key oncogenic driver in a subset of NSCLC patients and represents one of the newest targets for lung cancer treatment. About 1% to 7% of those with NSCLC have the ALK gene fusion.

According to Ramaswami Govindan, MD, Medical Oncology Section, Washington U at St. Louis, there is increasing interest in studying the EML4-ALK fusion in NSCLC. "This is quite stunning," he said, in an interview conducted by CancerNetwork earlier this year at the 2011 American Society of Clinical Oncology (ASCO) annual meeting, "because we did not know about this until a few years ago and within the short span of 4 years we have actually learned about the business of this transcript."

Dr. Govindan pointed out that there is now a very good understanding of the mechanisms of resistance. "And of course we have the drug that actually works very well in this population, that's crizotinib," said Dr. Govindan. "In this meeting we learned a little bit more about how this group of patients-that's the ALK-positive patients-do without crizotinib, the answer is not so well, with crizotinib, sure, they do significantly better."

Initial phase II findings from the PROFILE 1005 trial, a study that included 136 patients with ALK-rearranged NSCLC who progressed after at least 1 treatment of chemotherapy for late-stage disease (including treated brain metastases) were presented at ASCO's annual meeting. In evaluable patients, 63 of 76 (83%) had target lesion shrinkage, 41 of which had a tumor shrinkage of at least 30%. Nine patients died during the trial, 2 were found to be treatment related.

In a study of overall survival, also presented at ASCO in June, of 82 ALK-positive patients treated with crizotinib, overall survival was 77% after 1 year and 64% after 2 years. Overall survival did not differ based on sex. Median overall survival for this group has not been reached. By comparison, ALK-positive patients who were not treated with crizotinib had an overall survival of  73% after 1 year and 33% after 2 years. Median overall survival for this group was 20 months.

The drug was approved under the FDA's accelerated approval program, which allows the agency to approve a drug to treat a serious disease based on clinical data showing that the drug has an effect on an endpoint that is reasonably likely to predict a clinical benefit to patients.

The most common side effects reported for patients treated with crizotinib included vision disorders, nausea, diarrhea, vomiting, edema, and constipation. Vision disorders included visual impairment, flashes of light, blurred vision, floaters, double vision, sensitivity to light, and visual field defects.

Crizotinib use has also been associated with pneumonitis, which can be life-threatening. Patients with treatment-related pneumonitis should permanently stop treatment with crizotinib. The drug should not be used in the treatment of pregnant women.