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

Background

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.

Materials and methods

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.

Results

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.

Conclusions

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.