Docetaxel or pemetrexed with or without cetuximab in recurrent or progressive non-small-cell lung cancer after platinum-based therapy: a phase 3, open-label, randomised trial

Summary Background Available preclinical and phase 2 clinical data suggest that the addition of cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor (EGFR), to chemotherapy might improve outcome in patients with advanced non-small-cell lung cancer (NSCLC). We aimed to assess whether the addition of cetuximabto chemotherapy improved progression-free survivalin patients with recurrent or progressive NSCLC after platinum-based therapy. Methods In this unmasked, open-label randomised phase 3 trial we enrolled patients with metastatic, unresectable, or locally advanced NSCLC from 121 sites in Canada and the USA. Eligible patients were those aged 18 years or older who had experienced progressive disease during or after one previous platinum-based regimen. Initially, patients were randomly assigned to receive either pemetrexed(500 mg/m 2 ) or docetaxel(75 mg/m 2 ) and then randomly assigned within each group to receive their chemotherapy with or without cetuximab(400 mg/m 2 at first dose and 250 mg/m 2 weekly thereafter) until disease progression or unacceptable toxicity. However, after a change in the standard of care, investigators chose whether to treat with pemetrexedor docetaxelon a patient-by-patient basis. The primary analysis was changed to compare progression-free survivalwith cetuximabplus pemetrexedversus pemetrexed, on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT00095199. Findings Between Jan 10, 2005, and Feb 10, 2010, we enrolled 939 patients; data for one patient was accidentally discarded. Of the remaining 938 patients, 605 received pemetrexed(301 patients with cetuximaband 304 alone) and 333 received docetaxel(167 in combination with cetuximaband 166 alone). Median progression-free survivalwith cetuximabplus pemetrexedwas 2·9 months (95% CI 2·7–3·2) versus 2·8 months (2·5–3·3) with pemetrexed(HR 1·03, 95% CI 0·87–1·21; p=0·76). The most common grade 3–4 adverse events with cetuximabplus pemetrexedwere fatigue (33 [11%] of 292 patients), acneiform rash (31 [11%]), dyspnoea (29 [10%]), and decreased neutrophil count (28 [10%]), and with pemetrexedalone were dyspnoea (35 [12%] of 289 patients), decreased neutrophil count (26 [9%]), and fatigue (23 [8%]). A significantly higher proportion of patients in the cetuximabplus pemetrexedgroup (119 [41%] of 292 patients) experienced at least one serious adverse event than those patients in the pemetrexedgroup (85 [29%] of 289 patients; p=0·0054). Nine (3%) of 292 treated patients in the cetuximaband pemetrexedgroup died of adverse events compared with five (2%) of 289 treated patients in the pemetrexedalone group. Interpretation The use of cetuximabis not recommended in combination with chemotherapy in patients previously treated with platinum-based therapy. Funding Eli Lilly and Company and ImClone Systems LLC, a wholly owned subsidiary of Eli Lilly and Company.