RAS status in circulating-tumor DNA (ctDNA) and outcomes during rechallenge treatments with anti-EGFR antibodies in metastatic colorectal cancer (mCRC).

Abstract

166 Background: We have evaluated rechallenge treatment with irinotecan plus cetuximab (JACCRO CC-08, n = 36) or panitumumab (JACCRO CC-09, n = 25) in patients (pts) with KRAS wild-type mCRC [Tsuji A, WCGC 2018], and the primary endpoint of PFS rate at 3 months was met in both trials. RAS status in ctDNA may potentially predict responders of the rechallenge treatment in mCRC resistant to anti-EGFR antibody [Cremolini C, JAMA Oncol 2018]. Methods: A post-hoc biomarker study was performed to investigate an association between RAS status in ctDNA and clinical outcomes in the JACCRO phase II trials comprised mCRC pts who achieved a clinical benefit from 1st-line anti-EGFR antibody-based therapy, then had a disease progression at 2nd-line treatment. RAS status in ctDNA was analyzed at the time points of baseline, 8 weeks, and progression using OncoBEAM RAS CRC Kit for specific KRAS/ NRAS mutations, using cut-off value defined as the number of beads with amplified-mutant molecules specifically set per each codon. Results: Sixteen pts (median 67.5-y old, 50% of PS0, 25% of right-sided primary, cet/pani: 4/12) were enrolled in this study, with response rate of 0% and disease control rate (DCR) of 62.5%. RAS mutations (mt) were found at the baseline in 6 out of 16 pts (all left-sided pts with KRAS codon 12, codon 61 and/or NRAS codon 61 mt simultaneously). Pts without RAS mt at baseline experienced longer PFS in 1st-line treatment (11.5 vs. 9.0 m). The DCR was 33% in pts with RAS mt in ctDNA, while it was 80% in pts without RAS mt at baseline. Pts with RAS mt at baseline had significantly shorter PFS and OS than pts without RAS mt [median PFS 2.3 vs 4.7 m, HR 6.2 (95%CI 1.6-30.5), p = 0.013; median OS 3.8 vs. 16.0 m, HR 12.4 (95%CI 2.7-87.7), p = 0.0028]. Six of 10 pts without RAS mt at baseline acquired RAS mt ( KRAS/ NRAS codon 12 or 61) in ctDNA at progression, however there was no difference in survival between pts with/without RAS mt at progression. Conclusions: Our study demonstrated that RAS status in ctDNA using OncoBEAM RAS CRC Kit predicts survival of rechallenge treatment with anti-EGFR antibody in mCRC pts. These data can support the application of RAS monitoring into clinical practice. Clinical trial information: UMIN000015914/UMIN000015916.