FDA Grants Regular Approval to Crizotinib for ALK-Positive NSCLC


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The U.S. Food and Drug Administration (FDA) has granted regular approval for crizotinib (Xalkori) 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.

The approval was based on demonstration of superior progression-free survival and overall response rate for crizotinib-treated patients compared to chemotherapy in patients with ALK-positive NSCLC with disease progression after platinum-based doublet chemotherapy. Crizotinib was previously granted accelerated approval in August 2011 based on durable objective response rates of 50% and 61% in two single-arm, open-label studies.

Prolonged Progression-Free Survival

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 situhybridization on central laboratory testing.

Patients were randomly assigned to receive either crizotinib at 250 mg orally twice daily (n = 173) or chemotherapy (n = 174). Patients randomly assigned to chemotherapy received pemetrexed (Alimta) (58%) or docetaxel (42%) if they had received prior pemetrexed. Approximately 64% of patients on the chemotherapy arm subsequently received crizotinib.

The trial demonstrated significantly prolonged progression-free survival for crizotinib treatment compared to chemotherapy (hazard ratio [HR] = 0.49, 95% confidence interval [CI] = 0.37–0.64, P < .0001). Median progression-free survival was 7.7 and 3.0 months on the crizotinib and chemotherapy arms, respectively.

The overall response rate was significantly higher for the crizotinib arm (65% vs 20%) with median response durations of 7.4 and 5.6 months in the crizotinib and chemotherapy arms, respectively. No difference in overall survival was noted between the two arms (HR= 1.02, 95% CI = 0.68–1.54) in a planned interim analysis.

Adverse Reactions

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

Safety data from this trial were evaluated in 172 crizotinib-treated patients. Serious adverse events were reported in 37% of crizotinib-treated patients. The most common serious adverse reactions to crizotinib were pneumonia, pulmonary embolism, dyspnea, and interstitial lung disease. Fatal adverse reactions occurred in nine crizotinib-treated patients. ■


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