RAS mutations in EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab (C) in MRI-defined, high-risk rectal cancer (RC).

Abstract

489 Background: Studies indicate that RAS mutations beyond KRAS exons 2-3 may predict anti-EGFRs benefit. EXPERT-C was a randomized phase II trial of neoadjuvant CAPOX and CRT ± C in MRI-defined, high-risk RC. We have previously shown that adding C in KRAS (exons 2-3)/BRAF wild type (WT) patients did not improve complete response (CR) and was associated with a non-significant improvement in progression-free survival (PFS) (HR 0.62, p=0.23) and overall survival (OS) (HR 0.56, p=0.20). The aim of this study was to analyse the impact of RAS mutations on the outcome of C-treated patients in this trial. Methods: Between October 2005 and July 2008, 164 eligible patients were randomly assigned to 4 cycles of CAPOX followed by CRT, surgery, and 4 cycles of adjuvant CAPOX (n=81) or the same regimen plus C (CAPOX-C, n=83). KRAS (exons 2-3) and NRAS (exon 3) mutations were prospectively analysed. Of 90 KRAS/NRAS WT patients, 84 were retrospectively analysed for additional KRAS (exon 4) and NRAS (exons 2/4) mutations by using bi-directional Sanger sequencing. The effect of C on CR, PFS, and OS in patients with RAS WT tumors was analyzed. PFS and OS were estimated with the Kaplan-Meier method and treatment arms compared using a log-rank analysis. Results: Eleven (13%) of 84 patients initially classified as KRAS/NRAS WT were found to have tumours harbouring a mutation in KRAS exon 4 (11%) or NRAS exons 2/4 (2%). Overall, after this retrospective mutation analysis, 78/149 (52%) assessable patients were RAS WT (CAPOX, n=40; CAPOX-C, n=38). After a median follow-up of 63.8 months, in line with the initial analysis, the addition of C in the group of RAS WT patients, was associated with numerically higher, but not statistically significant, rates of CR (15.8% vs. 7.5%, p=0.31), 5-year PFS (78.4% vs. 67.5%, p=0.17) and 5-year OS (83.8% vs. 70%, p=0.20). Conclusions: Although the results of our analysis are potentially affected by the small numbers, in our locally advanced RC population the status of RAS did not appear to significantly improve the selection of patients who may benefit from the use of an anti-EGFR therapy.