539P - Tumor Heterogeneity and Efficacy of First-Line Cetuximab + Folfiri in Kras Mutant Metastatic Colorectal Cancer (Mcrc) Patients (Pts) of the Capri Goim Trial

Abstract

ABSTRACT Aim: Cetuximab treatment in mCRC is restricted to pts with KRAS and NRAS wt tumors. Recent data suggest that low levels of KRAS mutant alleles might confer resistance to anti-EGFR therapies. Methods: In the CAPRI GOIM trial, KRAS exon 2 wt mCRC pts received first line cetuximab plus FOLFIRI. Primary endpoint was progression-free survival (PFS). Tumor samples were assessed by next generation sequencing (NGS) with the Ion AmpliSeq™ Lung and Colon Cancer Panel that covers over 500 mutations in hot spot regions of 22 genes. The allelic frequency of mutant KRAS, NRAS, BRAF and PIK3CA was normalized for the neoplastic cell content and multiplied by 2 to obtain the Heterogeneity Score (HS), which corresponds to the fraction of neoplastic cells carrying a specific mutation. Results: NGS analysis was performed in 182 cases. Forty-five cases (24.7%) had mutations in KRAS, 24 (13.2%) in PIK3CA, 15 (8.2%) in BRAF, and 13 (7.1%) in NRAS. KRAS and NRAS mutations were mutually exclusive, whereas PIK3CA and BRAF mutations were detected in RAS mutant tumors. The KRAS HS ranged between 12 and 260, indicating a wide heterogeneity of KRAS mutant alleles content in CRC. However, the KRAS HS mean value of 90,93 and median value of 84,44 suggested that in most CRC the majority of neoplastic cells carry a mutant KRAS allele. Similar findings were observed for NRAS (HS range 35,5-146,67; mean 102,77; median 117,14). In contrast, in BRAF (HS range 17,14-120; mean 54,82; median 54,29) and PIK3CA (HS range 14,29-120; mean 54,82; median 54,29) mutant cases only a fraction of neoplastic cells seem to carry the mutant allele. The RR was 70% in KRAS mutant pts with an HS 40 pts (high KRAS; n.35); mPFS were 7,97 and 8,37 months for low KRAS and high KRAS subgroups, respectively. Importantly, 7/10 low KRAS tumors had additional mutations in PIK3CA (n.6), TP53 (n.4), BRAF (n.2), ERBB2 (n.1), FGFR3 (n.1), and/or FBXW7 (n.1). Conclusions: Pts carrying low levels of mutant KRAS alleles showed a mPFS similar to pts with high KRAS mutant allele frequency. However, this phenomenon could be due to the complex mutational profile of CRC rather than to the KRAS mutational status. Disclosure: N. Normanno: Advisory Boards: Merck Serono, Amgen; F. Ciardiello: Advisory Boards: Roche, Merck Serono, Astellas, Bayer. All other authors have declared no conflicts of interest.