First-Line Crizotinib for ALK-Positive Lung Cancer

A prior phase III study showed that second-line treatment with crizotinib — a small-molecule inhibitor of ALK, MET, and ROS1 kinase — was more effective than chemotherapy in patients with ALK-positive non–small-cell lung cancer (NSCLC; N Engl J Med 2013; 368:2385).

To test whether crizotinib is also more effective than standard chemotherapy as first-line treatment for this population, investigators conducted an industry-funded, international, randomized, open-label, phase III study (PROFILE 1014) involving 343 treatment-naive patients with advanced ALK-positive NSCLC who received six cycles of oral crizotinib or intravenous platinum-pemetrexed chemotherapy. Chemotherapy patients who experienced disease progression could cross over to crizotinib therapy.

Patients who received crizotinib versus chemotherapy achieved improved overall response rate (74% vs. 45%; P<0.001) and improved median progression-free survival (PFS, the primary endpoint; 10.9 vs. 7.0 months; P<0.001). The median overall survival (OS) was not reached in either group; however, the 1-year OS rate was 84% with crizotinib and 79% with chemotherapy. Crizotinib also improved quality of life and reduced lung cancer–related symptoms. The main toxicities with crizotinib were visual disturbances, diarrhea, nausea, and edema; the main toxicities with chemotherapy were nausea, fatigue, vomiting, and anorexia. Grade 3 and 4 elevation of liver-function tests in the crizotinib arm were managed with dose reductions or interruptions. Two patients discontinued crizotinib because of interstitial lung disease.