Association of <i>FBXW7</i> mutation with prolonged survival in microsatellite instability–high colorectal cancer treated with immune checkpoint blockade.

3657 Background: Colorectal cancer (CRC) remains a major cause of cancer-related mortality. Biomarkers of response to novel therapies may improve treatment selection and outcomes. Microsatellite instability (MSI-H) is a predictor of response to immune checkpoint blockade (ICI); however, less than half of patients with MSI-H CRC have a durable response to ICI. FBXW7 mutations ( MT) are common in CRC but their prognostic significance in patients treated with ICI is not well studied. Here, we characterized FBXW7 -MT in CRC and their association with ICI outcomes. Methods: A total of 29,446 CRC (MSS, n = 27,323; MSI-H, n = 2,123) samples were tested by next generation sequencing (592, NextSeq; WES, NovaSeq) and WTS (NovaSeq; Caris Life Sciences, Phoenix, AZ). TMB was assessed by nonsynonymous mutations/Mb (high ≥10). Immune cell proportions were estimated using WTS deconvolution (Quantiseq). Real-world median overall survival (mOS) data were derived from insurance claims, calculated from tissue collection or treatment (chemotherapy: CAPEOX, Capecitabine, FOLFIRI, FOLFIRINOX, Fluorouracil, Irinotecan, Oxaliplatin; ICI: Nivolumab, Pembrolizumab) initiation to last contact, and analyzed using Kaplan-Meier. Statistical significance was assessed by chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons (q&lt;0.05). Results: FBXW7 -MT was enriched in MSI-H (29.6% (n=608) vs 9.2% (n=3,025), p&lt;0.05) compared to MSS tumors. Among MSI-H tumors, FBXW7 -MT had higher median TMB (40 vs 37, q&lt;0.05) and numerically higher TMB-high frequency (99.2% vs 97.9%, p=0.05) compared to FBXW7 -WT. Analysis of inferred immune cells revealed that FBXW7 -MT MSI-H CRC had lower median cell fraction (%) of M2 macrophages (2% vs 2.5%) compared to FBXW7 -WT. In MSI-H CRC, FBXW7 -MT patients had better mOS when treated with ICI (48.3 vs 34.2 months, HR 0.68, 95% CI 0.52 – 0.9, p=0.006) compared to FBXW7 -WT, whereas there was no difference in mOS in MSI-H CRC treated with chemotherapy (HR 0.95, p = 0.67) compared to FBXW7 -WT. FBXW7 -MT was not associated with OS in MSS CRC. In MSI-H CRC, R465C / H/L/S (20.6%), R505C/H/L/G (7%) and R479Q/G (3.4%) were the most common FBXW7 hotspot mutations. R465C / H/L/S had better mOS with ICI (HR 0.61, p=0.04) compared to FBXW7 -WT. Multivariable Cox analysis adjusted for TMB and PD-L1 showed FBXW7- MT is an independent predictor of improved OS with ICI in MSI-H CRC (HR 0.69, 95% CI 0.53 – 0.9, p=0.007). Conclusions: This large study is the first to report a positive association with FBXW7 mutation and OS in MSI-H CRC treated with PD1/PD-L1 blockade. While requiring validation in independent cohorts, our findings suggest that FBXW7 -MT is a biomarker of response to ICI and that targeting FBXW7 may be an effective way of augmenting the clinical activity of ICI in MSI-H CRC.