First-Line Crizotinib versus Chemotherapy in <i>ALK</i>-Positive Lung Cancer

TLDR

The study compares first‑line crizotinib with standard chemotherapy in patients with advanced ALK‑positive non‑small‑cell lung cancer. In an open‑label phase 3 trial, 343 treatment‑naïve patients were randomized to oral crizotinib 250 mg twice daily or to pemetrexed plus cisplatin or carboplatin every three weeks for up to six cycles, with crossover to crizotinib permitted after progression. Crizotinib significantly extended progression‑free survival (10.9 vs 7.0 months, HR 0.45), achieved higher objective response rates (74 % vs 45 %), improved symptom burden and quality of life, and had a distinct safety profile compared with chemotherapy, while overall survival was similar. The trial was funded by Pfizer and registered as PROFILE 1014 (ClinicalTrials.gov NCT01154140).

Abstract

The efficacy of the ALK inhibitor crizotinib as compared with standard chemotherapy as first-line treatment for advanced ALK-positive non-small-cell lung cancer (NSCLC) is unknown.We conducted an open-label, phase 3 trial comparing crizotinib with chemotherapy in 343 patients with advanced ALK-positive nonsquamous NSCLC who had received no previous systemic treatment for advanced disease. Patients were randomly assigned to receive oral crizotinib at a dose of 250 mg twice daily or to receive intravenous chemotherapy (pemetrexed, 500 mg per square meter of body-surface area, plus either cisplatin, 75 mg per square meter, or carboplatin, target area under the curve of 5 to 6 mg per milliliter per minute) every 3 weeks for up to six cycles. Crossover to crizotinib treatment after disease progression was permitted for patients receiving chemotherapy. The primary end point was progression-free survival as assessed by independent radiologic review.Progression-free survival was significantly longer with crizotinib than with chemotherapy (median, 10.9 months vs. 7.0 months; hazard ratio for progression or death with crizotinib, 0.45; 95% confidence interval [CI], 0.35 to 0.60; P<0.001). Objective response rates were 74% and 45%, respectively (P<0.001). Median overall survival was not reached in either group (hazard ratio for death with crizotinib, 0.82; 95% CI, 0.54 to 1.26; P=0.36); the probability of 1-year survival was 84% with crizotinib and 79% with chemotherapy. The most common adverse events with crizotinib were vision disorders, diarrhea, nausea, and edema, and the most common events with chemotherapy were nausea, fatigue, vomiting, and decreased appetite. As compared with chemotherapy, crizotinib was associated with greater reduction in lung cancer symptoms and greater improvement in quality of life.Crizotinib was superior to standard first-line pemetrexed-plus-platinum chemotherapy in patients with previously untreated advanced ALK-positive NSCLC. (Funded by Pfizer; PROFILE 1014 ClinicalTrials.gov number, NCT01154140.).