FLEX: Cetuximab in Combination with Platinum-Based Chemotherapy (CT) Improves Survival Versus CT Alone in the 1st-line Treatment of Patients (pts) with Advanced Non-Small Cell Lung Cancer (NSCLC)

Objective: To demonstrate superior overall survival (OS) for the EGFR-targeted antibody cetuximab (Erbitux) in combination with CT compared to CT alone in the 1st-line treatment of advanced NSCLC. Methods: Pts with EGFR-expressing advanced NSCLC were randomized 1:1 to cetuximab (400 mg/m 2 initial dose, then 250 mg/m 2/wk) + CT (cisplatin 80 mg/m 2 d1 and vinorelbine 25 mg/m 2 d1, d8 q3w) or CT alone. The primary endpoint was OS time. Results: A total of 1125 pts (557 cetuximab + CT/ 568 CT alone) were randomized: median age 59 (range 18-83) years; male: 70%; stage IV: 94%; adenocarcinoma: 47%; squamous cell carcinoma: 34%; ECOG PS 2: 17%. A planned survival analysis was performed after 868 events. OS was significantly improved in the cetuximab + CT arm vs CT (median 11.3 vs 10.1 months; HR (95% CI): 0.871 (0.762- 0.996); p=0.0441). Pre-specified subgroup analyses demonstrated that the addition of cetuximab provided a substantial benefit in Caucasians across all histologies. Pts in the cetuximab + CT arm who developed an acne-like rash of any grade within the first 3 wks and who were still alive after the first cycle (n=290) had a longer OS than those without acne-like rash (n=228) (median (95% CI): 14.3 months (12.1-15.7) vs 8.1 months (6.9-10.4)). The response rate was also significantly improved in the cetuximab + CT arm vs CT (36.3% (95% CI: 32.3-40.4%) vs 29.2% (95% CI: 25.5-33.2%); p=0.012). While PFS was comparable in both arms, time to treatment failure was significantly improved in the cetuximab + CT arm vs CT (4.2 vs 3.7 months; HR (95% CI): 0.859 (0.761-0.971); p=0.015). Treatment was generally well tolerated. The most frequent grade 3/4 adverse events (cetuximab + CT vs CT) were: neutropenia 52.7% vs 51.4%; febrile neutropenia 21.7% vs 15.5%; anemia 13.9% vs 16.7%, and acne-like rash 10.4% vs 0.2%. Conclusions: The addition of cetuximab to standard CT significantly improved OS versus CT alone. The safety profile of cetuximab + CT was predictable and manageable. The FLEX study is the first to demonstrate a survival benefit of a targeted agent in combination with platinum-based CT across all histological subtypes in 1st-line NSCLC.