Genotyping circulating tumor DNA identifies metastatic colorectal cancer (mCRC) patients highly sensitive to Sym004

Abstract

Background: Acquired resistance of mCRC patients (pts) to anti-EGFR monoclonal antibodies (mAbs) is frequently due to mutations in RAS/BRAF and EGFR extracellular domain (ECD), and amplifications in MET/ERBB2. Studies suggest that some anti- EGFR mAb refractory pts retain tumor EGFR-dependency potentially targetable by more efficacious agents such as Sym004 - a mixture of two non-overlapping mAb targeting EGFR for degradation. A Phase 2b trial of Sym004 in 254 mCRC pts tissue RAS wt that relapsed on anti-EGFR blockade was recently completed. Method(s): Baseline circulating tumor (ct)DNA profiles (Guardant360, Guardant Health, N=193 pts) were obtained from blood samples collected from pts in the Sym004 Phase2b trial. Serial blood samples during treatment were analyzed for EGFRECD mutation dynamics. Result(s): High mutant allele frequency (MAF>20%) of KRAS/NRAS was found in 5% of pts and BRAF V600E and EGFR-ECD mutations in 6.7% and 25% of pts, respectively. At least 1 of these mechanisms of resistance was identified in 32% of the pts. Mutations in KRAS, NRAS, and BRAF V600E, and amplifications of ERBB2 and MET were more likely to co-occur with EGFR-ECD mutations, demonstrating genomic complexity developed as a result of EGFR blockade. Comparative analysis of MAFs of driver genes indicated that EGFR-ECD mutations are subclonal events. The absence of any EGFR-ECD/BRAF/high RAS MAF mutation at baseline was associated with a significantly improved OS in the Sym004 treated pts as compared to control arm with investigator's choice chemotherapy. Sym004 has previously been demonstrated to retain in vitro efficacy in EGFR-ECD mutated cancer cells, and ctDNA monitoring demonstrated decrease in EGFR-ECD in Sym004 treated pts. This suggests that EGFR-ECD mutated cells are targeted by Sym004, but this activity does not translate into clinically meaningful OS benefit, likely due to other co-occuring resistance mechanisms. Conclusion(s): Comprehensive liquid biomarker profiling of 193 mCRC pts captured high intrapatient heterogeneity following anti-EGFR therapy, and identified a highly Sym004 sensitive mCRC pts subset with a RAS/RAF/EGFR-ECD wild type profile. Our data indicates heterogeneous responses of different subclones to targeted agents in mCRC.