Over a decade of insights into genomic profiling in metastatic colorectal cancer from a phase I setting.

e15588 Background: Despite recent advancements in the treatment of metastatic colorectal cancer (mCRC), including the introduction of new targeted therapies, the prognosis remains poor, highlighting the need for further progress in precision oncology. We report the impact of comprehensive genomic profiling over a decade in 661 patients with mCRC at the Phase I Unit, Department of Oncology, Rigshospitalet, Copenhagen, Denmark. Methods: A prospective, single-center, single-arm open label study (NCT02290522) was conducted, enrolling patients with advanced cancer referred to a Phase I Unit. Fresh tumor tissue was obtained for whole genome or exome sequencing, RNA sequencing, and SNP array analysis. In cases where fresh tumor tissue was unavailable, archived formalin-fixed paraffin-embedded tumor tissue or circulating tumor DNA extracted from plasma were obtained. Each individual genomic report was reviewed and discussed by a multidisciplinary tumor board dedicated to precision medicine. Actionable alterations were classified retrospectively (Jan2025) according to the ESMO Scale for the Clinical Actionability of molecular Targets (ESCAT). When possible, patients were treated with a regimen matched to the genomic profile. Results: Between April 2013 and December 2024, 661 patients with mCRC and exhausted treatment options were enrolled. Genomic profiles were obtained in 558 patients (84%). At least one actionable target was identified in 397 patients (71%) with a total of 637 actionable alterations including CEACAM5 expression (N = 271, 68%), homologous recombination deficiency (N = 70, 18%) and BRAF V600E mutation (N = 62, 16%). A total of 89 patients (representing 22% of the patients with an actionable target) received 95 genomic-guided treatments (range 1-3): 53 actionable targets were classified as ESCAT I/II and 42 as ESCAT III/IV. An overall response rate of 12% (CI95%: 0.05 – 0.19) was observed among the assessable treatments. The median progression-free survival and median overall survival were 3.44 months (CI95%: 2.82 – 4.52) and 7.47 months (CI95%: 6.3 – 9.05). Conclusions: This extensive study highlights the potential of genomic profiling in identifying actionable targets and matching patients with mCRC to targeted therapies.