Crizotinib plus Companion Diagnostic Test Approved in NSCLC

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FDAlogoOn August 26, 2011, the FDA granted accelerated approval to Pfizer’s crizotinib (Xalkori) for the 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 FDA approved the first-of-its-kind Vysis ALK Break-Apart FISH Probe Kit (Abbott Molecular) concurrently with the crizotinib approval. This companion diagnostic test is designed to detect rearrangements of the anaplastic lymphoma kinase (ALK) gene in NSCLC.

About 1% to 7% of those with NSCLC have the ALK gene abnormality. Patients with this form of lung cancer are typically nonsmokers.

Key Trials

The approval was based on two multicenter 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% of patients were white, 30% were Asian, 48% were male, and 84% had an Eastern Cooperative Oncology Group (ECOG performance status of 0 or 1. Fewer than 3% of patients were current smokers. Approximately 96% had adenocarcinoma, 95% had metastatic disease, and 94% had received prior systemic treatment for NSCLC.

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


The most common adverse reactions (≥ 25%) 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% of patients included increased alanine aminotransferase and neutropenia. Crizotinib has been associated with severe, life-threatening, or fatal treatment-related pneumonitis with a frequency of 1.6% 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.

Accelerated Approval

Crizotinib was reviewed under the FDA’s priority review program, and was approved under the FDA’s accelerated approval program.

“The approval of [crizotinib] 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 [crizotinib] are important options for treating patients with this disease and may ultimately result in fewer side effects.” ■