Purpose: This multicenter, open-label, phase I/IIa study was undertaken to establish the safety/toxicity profile of cetuximab in combination with gemcitabine and carboplatin in patients with chemotherapy-naïve, epidermal growth factor receptor-positive, stage IV non-small-cell lung cancer. Secondary objectives were to gather preliminary evidence of efficacy including tumor response rate, time to progression, and overall survival. Patients and Methods: Thirty-five patients received a total of 264 3-week cycles of treatment with cetuximab, carboplatin, and gemcitabine. An initial dose of cetuximab 400 mg/m2 intravenously was administered the first week, followed by weekly doses of 250 mg/m2. Carboplatin (area under the curve = 5, day 1) and gemcitabine 1,000 mg/m2 on days 1 and 8 were administered every 3 weeks. Patients were evaluated for tumor response after every two cycles of therapy. Results: The most frequently reported adverse events related to cetuximab included an acne-like rash (88.6%), dry skin (34.3%), asthenia and skin disorders (31.4%), mucositis/stomatitis (25.7%), fever/chills (20%), and nausea/vomiting (17.1%). The majority of these toxicities were mild to moderate. One patient withdrew from the study because of a grade 3 allergic reaction. Myelosuppression was the most frequently observed toxicity related to chemotherapy. Responses among 35 assessable patients included 10 partial responses (28.6%). Twenty-one patients had stable disease. The median time to progression was 165 days, and the median overall survival was 310 days. Conclusion: The combination of cetuximab, carboplatin, and gemcitabine was well tolerated with an acceptable toxicity profile. Most grade 3 adverse events were attributable to chemotherapy. The response rate and median survival are encouraging and warrant additional investigation. © 2005 by American Society of Clinical Oncology.