FLEX: A randomized, multicenter, phase III study of cetuximab in combination with cisplatin/vinorelbine (CV) versus CV alone in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC)

3 Background: Epidermal growth factor receptor (EGFR) dysregulation is common in NSCLC and is associated with poorer prognosis. This phase III study assessed the efficacy and safety of the EGFR-targeted monoclonal antibody cetuximab in combination with cisplatin/vinorelbine (CV) compared with CV alone in advanced NSCLC. Methods: Patients with EGFR- detectable advanced NSCLC were randomized 1:1 to cetuximab (400 mg/m2 initial dose, then 250 mg/m2/wk) plus C (80 mg/m2 d1) and V (25 mg/m2 d1, d8) q3w (arm A) or CV alone (arm B). The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival, tumor response, disease control, and safety. Randomization was stratified by ECOG performance status (0/1 vs 2) and tumor stage (wet IIIb vs IV). Results: 1,125 patients were randomized: 557 to arm A, 568 to arm B, 70% male, median age 59 (18–83) years, 94% stage IV, 47% adenocarcinoma (AC), 34% squamous cell carcinoma (SCC), 83% ECOG 0/1. Survival analysis was performed after 868 events had occurred. OS was significantly improved in arm A (stratified log-rank test). Preliminary results of prespecified subgroup analyses suggest a greater benefit in Caucasians independent of histology and a general better prognosis in Asians. Analyses of secondary endpoints are ongoing. Conclusions: Cetuximab plus CV demonstrated superior survival over CV alone in patients with advanced EGFR-detectable NSCLC. There was a remarkable difference between the outcome of Asian and Caucasian patients. This is the first study to demonstrate a survival benefit of an EGFR- targeted agent in combination with platinum-based chemotherapy in advanced first-line NSCLC irrespective of histology and confirms the clinical relevance of cetuximab in NSCLC. MedianOS (mo) Arm A Median OS (mo) Arm B HR[95% CI] p-value All (n=1125) 11.3 10.1 0.871 [0.762–0.996] 0.0441 Caucasians (n=945) 10.5 9.1 0.800 [0.692–0.924] 0.0025 with AC (n=412) 12.0 10.2 0.809 [0.644–1.016] 0.0673 with SCC (n=347) 10.2 8.9 0.794 [0.626–1.007] 0.0567 Asians (n=121) 17.6 20.4 1.179 [0.730–1.905] Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Merck Serono Merck