On November 20, 2013, the U. S. Food and Drug Administration granted regular approval for crizotinib (Xalkori, 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.
Today’s approval was based on demonstration of superior progression-free survival (PFS) and overall response rate (ORR) for crizotinib-treated patients compared to chemotherapy in patients with ALK-positive NSCLC with disease progression 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 randomized to receive either crizotinib 250 mg orally twice daily (n=173) or chemotherapy (n=174). Patients randomized to chemotherapy received pemetrexed (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 (PFS) for crizotinib treatment compared to chemotherapy [HR=0.49, (95% CI: 0.37, 0.64), p<0.0001]. Median PFS was 7.7 and 3.0 months on the crizotinib and chemotherapy arms, respectively. The ORR 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.
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 was evaluated in 172 crizotinib-treated patients. Serious adverse events were reported in 37% of crizotinib-treated patients. The most common serious adverse reactions of crizotinib were pneumonia, pulmonary embolism, dyspnea, and interstitial lung disease. Fatal adverse reactions occurred in 9 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% and 61% in two single-arm, open-label studies.
The recommended dose and schedule for crizotinib is 250 mg orally, twice daily, with or without food.
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm
, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).