Influence of KRAS G13D mutations on outcome in patients with metastatic colorectal cancer (mCRC) treated with first-line chemotherapy with or without cetuximab.

Abstract

3511 Background: Addition of cetuximab (cet) to first-line chemotherapy (CT) was shown to significantly improve clinical benefit in patients (pts) with KRAS wild-type (wt) mCRC. Pts with KRAS codon 12 or 13 mutations are excluded from cet treatment. Studies suggest that not all KRAS mutations are equivalent in their biological effects. We investigated the influence of the KRAS codon 13 mutation G13D on clinical outcome compared with pts with other KRAS tumor mutations or KRAS wt tumors in a pooled analysis of pts from the CRYSTAL and OPUS studies. Methods: Variation of the treatment effect by KRAS mutation status, and the effect of KRAS mutation status within each treatment group for response, progression-free (PFS) and overall survival (OS) was investigated. Results: There were 689 pts in each treatment arm: 447 vs 398 pts had KRAS wt tumors, 41 vs 42 pts had KRAS G13D mutant tumors and 201 vs 249 pts had tumors with other KRAS mutations, for the CT and CT+cet arms, respectively. Heterogeneous treatment effects were seen for all endpoints across the mutation types with significant treatment interaction by KRAS mutation status for response (p<0.0001), PFS (p<0.0001) and OS (p=0.0219). Compared with pts with KRAS wt tumors those with G13D mutations had a similar relative treatment effect but at a much lower effect level (Table). Conclusions: These observations suggest a heterogeneous treatment effect according to tumor KRAS mutation status. Pts with KRAS G13D mutant mCRC appear to benefit from the addition of cet to first-line CT. Further prospectively generated clinical investigations are necessary to confirm these data. N Response % PFS mo OS mo CT CT+cet CT CT+cet CT CT+cet KRAS wt 845 38.5 57.3 7.6 9.6 19.5 23.5 Odds ratio/HR* [95% CI] P value 2.17 [1.64–2.86] <0.0001 0.66 [0.55–0.80] <0.0001 0.81 [0.69–0.94] 0.0063 KRAS G13D 83 22.0 40.5 6.0 7.4 14.7 15.4 Odds ratio/HR* [95% CI] P value 2.41 [0.90–6.45] 0.0748 0.60 [0.32–1.12] 0.1037 0.80 [0.49–1.30] 0.37 KRAS other mutations 450 43.8 30.5 8.5 6.4 17.7 15.5 Odds ratio/HR* [95% CI] P value 0.56 [0.38–0.83] 0.0037 1.42 [1.10–1.83] 0.0069 1.14 [0.93–1.40] 0.1964 * Odds and HRs are for CT+cet vs CT groups. Abbreviation: HR, hazard ratio.