522P - Broad detection of alterations predicted to confer lack of benefit from EGFR antibodies or sensitivity to targeted therapy in advanced colorectal cancer

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KRAS mutation represented the first genomic biomarker to predict lack of benefit from anti-EGFR antibody therapy in advanced colorectal cancer (CRC). Expanded RAS testing has further refined the treatment approach, but understanding of genomic alterations underlying primary and acquired resistance, as well as alterations predicting response to targeted therapies is limited and further study is needed. We prospectively analyzed 4,422 clinical samples from patients with advanced CRC using hybrid-capture based comprehensive genomic profiling (CGP) at the request of the individual treating physicians. Comparison with prior molecular testing results when available was performed to assess concordance. We identified RAS/RAF pathway mutation or amplification in 62% of cases, including samples harboring KRAS mutations outside of the codon 12/13 hotspot region in 6.4% of cases. Among cases with KRAS non-codon 12/13 alterations for which prior test results were available, 79/90 (88%) were missed by focused testing. Of 1,644 RAS/RAF wild-type cases analyzed by CGP, 28% harbored a genomic alteration (GA) associated with resistance to anti-EGFR therapy in advanced CRC including mutation of PIK3CA, EGFR, and ERBB2 genes. We also identified other targetable GA including novel kinase fusions, RTK amplification, activating point mutations, as well as microsatellite instability. Comprehensive genomic profiling reliably detects alterations associated with lack of benefit to anti-EGFR therapy in advanced CRC while simultaneously identifying alterations potentially important in guiding treatment. The use of CGP during the course of clinical care allows for the refined selection of appropriate targeted therapies and clinical trials, increasing the chance of clinical benefit and avoiding therapeutic futility.