ctDNA dynamics and targeted therapies associated with genetic mutations in patients with colorectal cancer.

3597 Background: Colorectal cancer (CRC) is a heterogeneous disease with various genetic mutations that guide targeted therapy decisions, as outlined by NCCN guidelines. Here we evaluated the proportion of CRC patients receiving targeted therapies using Natera’s proprietary Real-World Database. Methods: Whole-exome sequencing (WES) data of tumor samples from CRC patients undergoing tumor-informed ctDNA testing CRC were analyzed. WES was performed on tumor tissue as part of the assay design workflow for Signatera™ molecular residual disease testing, ordered between June 2019 and July 2024. From the overall cohort of 47,476 CRC cases, we selected those with BRAF V600 (prevalence 13.7%) or KRAS G12C (prevalence 3.3%) actionable mutations, resulting in 8,473 patients included in the analysis. We utilized commercially available claims data to identify targeted therapy usage among clinical cases in our database. We examined the use of 3 different FDA-approved targeted therapies in patients with CRC. Results: Among 8,473 CRC patients with clinically actionable mutations in BRAF or KRAS, the majority had a BRAF V600 mutation (78.6%; N = 6,662) followed by KRAS G12C (21.4%; N = 1,811). Staging information was available for 93.9% (7,953/8,473) cases, with 15.6% stage IV at first ctDNA testing and 1.5% (123/7953) upstaged to stage IV at subsequent testing. An additional 6.7% (487/7,233) cases were categorized as recurrent/metastatic based on treatment information from claims records. Overall rates of treatment with corresponding targeted therapies were 4.0% (264/6,662) and 3.3% (60/1,811) for BRAF and KRAS , respectively. Within the subgroup of confirmed recurrent/metastatic cases (N = 1,727), targeted therapy rates were 18.9% (233/1241) for BRAF and 10.7% (52/486) for KRAS . No therapy overlap and no discordant cases (i.e., BRAF therapy was not given to KRAS mutated cases, and vice versa) were observed. Targeted therapy was typically started after the start of ctDNA testing ( KRAS : in 96.7%, 58/60 cases, median 422 days after, BRAF : in 75.8%, 200/264 cases, median 200 days after). ctDNA clearance rate on therapy (i.e. conversion from ctDNA+ to ctDNA-) was observed to be 37.6% (56/149) which matches objective response rates previously reported for radiological assessment. Conclusions: In this analysis, we demonstrate the utility of the commercial claims database to provide insights into different treatment modalities considered for patients with actionable mutations. Understanding patterns of ctDNA dynamics during targeted therapy can potentially act as a surrogate of treatment efficacy and may guide future clinical trials.