Toward optimizing patient selection for EGFR antibody therapies in metastatic colorectal cancer: outcomes and resistance features in real-world data

•One-third of RAS/BRAF WT mCRC has EGFR mAb primary resistance gene alterations.•ERBB2, RTK, and RAS/PI3K pathway gene alterations were associated with EGFR mAb resistance.•RAS/BRAF/EGFR mutations and KRAS/MET amplification are more prevalent post-EGFR mAb treatment.•Acquired RTK resistance alterations are associated with EGFR mAb time of exposure.•Comprehensive genomic profiling detects a broad set of gene alterations of EGFR mAb primary resistance in mCRC. BackgroundPatients with metastatic colorectal cancer (mCRC) with RAS- or BRAF-mutant tumors do not benefit from epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) therapy. Among patients with RAS/BRAF wild-type (WT) tumors, a substantial portion still do not benefit from EGFR mAb treatment. Using real-world clinicogenomic data, we investigated the impact of primary and acquired genomic resistance alterations upon treatment outcomes and determined the prevalence of alterations before and after EGFR mAb treatment.Materials and methodsThis study utilized a de-identified mCRC clinicogenomic database from ∼280 US cancer clinics between March 2014 and April 2023. We examined real-world progression-free survival (rwPFS) and overall survival (rwOS) between patients with and those without pre-specified genomic alterations (PSGAs) by Cox models and an adjusted risk score. Genomic alterations were also compared between samples collected before and after EGFR mAb therapy.ResultsNearly, one-third of microsatellite stable (MSS) RAS/BRAF WT tumors harbor intrinsic resistance alterations before treatment. MSS mCRC patients with WT RAS/BRAF tumors having resistance alterations within the PSGA set non-canonical RAS/RAF/MAPK and PI3K/PTEN/AKT pathway components; ERBB2 alterations; alternative receptor tyrosine kinases (RTKs) including FGFR1, FGFR2, EGFR, MET, RET, PDGFRA, and NRTK1 fusion demonstrated decreased rwPFS and/or rwOS on first-line EGFR mAb treatment. The prevalence of RAS/RAF/MAPK and RTK alterations was higher in samples collected after EGFR mAb therapy. The risk of acquiring an RTK resistance alteration increased with the total duration of EGFR mAb treatment.ConclusionsDetection of genomic resistance alterations in MSS RAS/BRAF WT patients confers less favorable EGFR mAb treatment outcomes. The duration of EGFR mAb treatment increased the risk of emergence of an acquired resistance alteration. Patients with metastatic colorectal cancer (mCRC) with RAS- or BRAF-mutant tumors do not benefit from epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) therapy. Among patients with RAS/BRAF wild-type (WT) tumors, a substantial portion still do not benefit from EGFR mAb treatment. Using real-world clinicogenomic data, we investigated the impact of primary and acquired genomic resistance alterations upon treatment outcomes and determined the prevalence of alterations before and after EGFR mAb treatment. This study utilized a de-identified mCRC clinicogenomic database from ∼280 US cancer clinics between March 2014 and April 2023. We examined real-world progression-free survival (rwPFS) and overall survival (rwOS) between patients with and those without pre-specified genomic alterations (PSGAs) by Cox models and an adjusted risk score. Genomic alterations were also compared between samples collected before and after EGFR mAb therapy. Nearly, one-third of microsatellite stable (MSS) RAS/BRAF WT tumors harbor intrinsic resistance alterations before treatment. MSS mCRC patients with WT RAS/BRAF tumors having resistance alterations within the PSGA set non-canonical RAS/RAF/MAPK and PI3K/PTEN/AKT pathway components; ERBB2 alterations; alternative receptor tyrosine kinases (RTKs) including FGFR1, FGFR2, EGFR, MET, RET, PDGFRA, and NRTK1 fusion demonstrated decreased rwPFS and/or rwOS on first-line EGFR mAb treatment. The prevalence of RAS/RAF/MAPK and RTK alterations was higher in samples collected after EGFR mAb therapy. The risk of acquiring an RTK resistance alteration increased with the total duration of EGFR mAb treatment. Detection of genomic resistance alterations in MSS RAS/BRAF WT patients confers less favorable EGFR mAb treatment outcomes. The duration of EGFR mAb treatment increased the risk of emergence of an acquired resistance alteration.