Background: Sporadic young onset colorectal cancer (YOCRC, ages 30-49) is a public health crisis with a persistent rise in incidence globally. While a proportion of patients (pts) develop YOCRC due to hereditary predisposition, the majority develop sporadic microsatellite stable (MSS) colorectal cancer with limited options beyond standard of care in advanced settings. We report the early phase clinical trial experience at a large academic cancer center to elucidate clues regarding molecular landscape and impact of clinical trials in refractory MSS YOCRC. Methods: Patient and clinical characteristics were summarized using descriptive statistics. Kaplan-Meier method was used to estimate the probabilities of overall survival (OS) and progression free survival (PFS). Log-rank tests were used to assess the differences in OS and PFS between subgroups. Cox proportional hazards regression models were fit to assess the association between OS or PFS and patient characteristics. Statistical analyses were performed using SAS and Splus. Results: 240 MSS YOCRC pts were analyzed. Median age 42.8 (20.5-49), > 80% were white and only 10% black. 21% received at least 3 lines of therapy. The top five mutations were TP53, KRAS, APC, PI3CKA and BRAF^V600E. Median OS was 39.2 months (95% CI: 34.8 – 42.5 months). CTNNB1 mutation was associated with a lower risk of death (HR = 0.28, 95% CI: 0.09 – 0.87, p-value = 0.03) while BRAF^V600Emutation was associated with an increased risk (HR = 3.28, 95% CI: 2.00 – 5.38, p-value < 0.001). Multivariable Cox model for OS revealed both CTNNB1 and BRAF^V600Emutations are significant prognostic factors for OS, unlike KRAS. There was no difference in OS or PFS among pts who entered a mutation specific clinical trial vs. those enrolled on an unmatched clinical trial (p = 0.35, p = 0.68, respectively, log-rank test). Median PFS was 1.9 months (95% CI: 1.8 – 2.1 months). CTNNB1 mutation was associated with a lower risk of progression/death (HR = 0.29, 95% CI: 0.09 – 0.92, p-value = 0.04) while NRAS mutation was associated with an increased risk (HR = 2.13, 95% CI:1.19– 3.80, p-value = 0.01). Among 145 pts who have data on response, 9 had partial response, 41 had stable disease and 95 had progressive disease. BRAF^V600Emutation is associated with a higher probability of response (OR = 6.89, 95% CI: 1.64 – 28.94, p-value = 0.01) and pts enrolled on matched clinical trials had a higher probability of response (OR = 6.23; 95% CI: 1.24 – 31.09, p-value = 0.03). However, increased response did not translate to improved OS. No survival differences were appreciated based on a pts race or BMI. Conclusions: CTNNB1, BRAF^V600E& NRAS mutations may have prognostic implications in YOCRC. Pts enrolled on mutation specific clinical trials did not achieve improved outcomes compared to unselected trials, highlighting aggressive biology, current lack of therapeutic targets and need for novel drug development in sporadic YOCRC.