Complement activation mediates cetuximab inhibition of non-small cell lung cancer tumor growth in vivo
8022 Background: KRAS mutations occur in NSCLC with a frequency of 15-25% and have been associated with a poor response to EGFR tyrosine kinase inhibitors. In colorectal cancer, benefit from the EGFR-targeted monoclonal antibody cetuximab is largely limited to patients (pts) whose tumors are KRAS wild-type (WT). However, in cetuximab-treated NSCLC, a predictive role for KRAS mutations has not been established. We evaluated KRAS status in specimens from two cetuximab-based front-line multicenter SWOG phase II trials in advanced NSCLC. METHODS DNA extracted from archival tumor and plasma specimens from S0342 (carboplatin-paclitaxel plus sequential vs. concurrent cetuximab) and S0536 (carboplatin-paclitaxel-cetuximab-bevacizumab) was analyzed for KRAS mutations by micro-dissection/sequencing and/or Scorpion-ARMS (DxS LTD). RESULTS For S0342, 45 archival tissues and 90 plasma specimens were analyzed. Combined, KRAS mutations were detected in 24% of pts. No differences between mutant and WT tumors were observed for response rate (p=0.62) or progression-free survival (PFS; p=0.65). Overall survival (OS) was non-significantly higher for pts with WT vs. mutant KRAS [median OS: 11 vs. 8 mo.; p=0.39]. When evaluated with EGFR copy number analysis conducted previously (JCO 10:3351, 2008), pts with both low EGFR copy number and mutant KRAS trended towards a worse OS [7 mo. vs. 17 mo. for all others, p=0.08, n=31]. For S0536, 6/26 pt specimens (23%) harbored KRAS mutations. In the limited sample set available from S0536, no associations were observed between KRAS status and clinical outcome [response rate: p=0.83; PFS: p=0.93; OS p=0.89]. CONCLUSIONS These data suggest that KRAS mutations may not play a significant predictive role for cetuximab-based therapy in NSCLC, contrary to colorectal cancer. KRAS analysis in recently completed phase III trials of chemotherapy ± cetuximab will be of interest to confirm these observations. Trends in favorable OS in pts with WT KRAS may reflect prognostic effects of KRAS mutations. [Table: see text].