Despite remarkable responses to immune checkpoint blockade (ICB) in some advanced cancers, most patients do not benefit, perhaps due to the complexity of tumor/immune/genome interactions. We implemented a multidisciplinary Molecular Tumor Board (MTB) that reviewed multi-omic cancer characteristics to develop N-of-One therapies for patients in the pan-cancer, advanced, refractory setting. This study evaluates the experience of 80 patients who were presented to the MTB and received a treatment regimen that included ICB. Overall, 60/80 patients (75%) who received ICB following MTB discussion had a high degree of matching between tumor molecular characteristics, including ICB biomarkers (reflected by a high Matching Score (≥50%)) and therapy administered. Patients with high versus low Matching Score experienced significantly longer median progression-free survival (6.4 vs. 3.0 months; p = 0.011) and median overall survival (15.3 vs. 4.7 months; p = 0.014) and higher clinical benefit rates (stable disease ≥6 months/partial response/complete response) (53% vs. 21%, p = 0.019). Although most patients (52/80 (65%)) received a personalized combination therapy (e.g., targeted, hormonal, chemotherapy, or a second immunotherapy agent), administering >1 drug was not associated with outcome. Only degree of matching and age, but no other variables, including individual biomarkers (e.g., microsatellite status, tumor mutational burden, or PD-L1 status), were independently correlated with outcome. In the pan-cancer setting, the MTB facilitated a precision medicine strategy to match therapeutic regimens that included ICB alone or combined with matched targeted drugs to patients with advanced malignancy, which was associated with improved clinical outcomes.