An analysis of the prognostic and predictive importance of K-ras mutation status in the National Cancer Institute of Canada Clinical Trials Group BR.21 study of erlotinib versus placebo in the treatment of non-small cell lung cancer

7005 Background: BR.21 demonstrated a significant survival benefit for patients with advanced non-small cell lung cancer (NSCLC) who received erlotinib vs. placebo (hazard ratio HR 0.70, 95% confidence interval CI 0.58–0.85, p<0.001). Tyrosine kinase (TK) domain mutations and high EGFR gene copy number by fluorescent in situ hybridization (FISH) have been associated with significantly higher response rates to erlotinib, while high gene copy number is a better predictor of survival benefit than mutations. K-ras mutation has been associated with non-responsiveness to EGFR TK inhibitors and poorer outcome for patients treated with erlotinib and chemotherapy. The survival impact of K-ras mutation on single agent erlotinib therapy in NSCLC patients remains unknown. Methods: 731 patients were randomized to BR.21 (488 erlotinib, 243 placebo). K-ras mutation analysis was conducted by sequencing in 246 patient samples. Results: K-ras analysis was successful in 206 patients; 30 (14.6%) demonstrated oncogenic mis-sense mutations on codon 12 or 13 (22 on the erlotinib arm and 8 on the placebo arm). For all 206 patients with known K-ras genotype, the HR for erlotinib was 0.77 (95% CI 0.57–1.06, p=0.06). For the 176 K-ras wild type patients, the univariate HR for erlotinib was 0.69 (95% CI 0.49–0.97, p=0.03). In contrast, the HR for the thirty K-ras mutant patients was 1.67 (95% CI 0.62–4.5, p=0.31), with an interaction p value of 0.09. Overall response rates were 5% (1/20) in K-ras mutant patients, and 10.2% (10/98) in K-ras wild type patients. In patients with K-ras genotype known, the multivariate Cox regression model showed that K-ras mutation was significantly associated with shorter survival (HR 1.63, 95% CI 1.06–2.51, p=0.03). Conclusion: In BR.21, patients with K-ras mutation do not appear to derive any survival benefit from erlotinib therapy. However, the numbers of patients are small and results need to be confirmed in other studies. (Supported by the Canadian Cancer Society, Ontario Cancer Research Network, the Jacqueline Seroussi Memorial Foundation for Cancer Research and OSI Pharmaceuticals). Table: see text