Molecular selection for colorectal cancer (CRC) patients receiving cetuximab: Final results of a prospective study.

Abstract

596 Background: Many markers for a “beyond-RAS” selection of CRC patients receiving cetuximab have been suggested, but none entered clinical practice mainly because prospective validation was lacking. Aim of our study was to evaluate if a molecular profile prospectively analysed was able to predict patients’ clinical outcome more accurately than RAS status alone. Methods: K-RAS (exons 2, 3, 4) wild-type CRC patients, candidates to second/third-line cetuximab with chemotherapy were prospectively allocated, after informed consent, into 2 groups on the basis of their molecular profile: favourable (BRAF and PIK3CA exon 20 wild type, EGFR GCN >2.6, HER-3 Rajkumar score <8, IGF-1 immunostaining <2) and unfavourable (any of the previous markers altered or mutated). After the introduction of N-RAS status (exons 2, 3, 4) only RAS wild type patients were considered eligible for the study. Primary aim was response rate (RR). To detect a difference in terms of RR among patients with an unfavourable profile (estimated around 25%) and patients with a favourable profile (estimated around 60%) required sample size was 46 patients. Secondary endpoints were PFS and OS. Results: 46 patients were enrolled. 17 patients (37%) were allocated to the favourable and 29 patients (63%) to the unfavourable profile. Patients resulted comparable for clinical characteristics (age, sex, ECOG PS, previous treatments, number of metastatic sites). Patients with the unfavourable profile showed 2 BRAF mutations, 3 PIK3CA exon 20 mutations, 18 cases of EGFR GCN <2.6, 20 cases of HER-3 and 16 cases of IGF-1 overexpression respectively. RAS analysis of patients enrolled before the introduction of all RAS status (35 patients) revealed 1 N-RAS mutation (3%) in a patient already allocated to the unfavourable group for HER-3 overexpression. RR in the favourable and unfavourable group was 11/17 (65%) and 2/29 (7%) (p= 0.007) respectively. The favourable group also showed an improved median PFS (8 months vs. 3 months, p <0.0001) and OS (15 months vs. 6 months, p <0.0001). Conclusions: A beyond RAS selection may further improve clinical outcome. This approach may also allow an early switch to alternative treatment for unfavourable profile patients.