Background: Although, EGFRi including Cetuximab (CTX) and Panitumumab (PMB) is restricted to KRAS wild-type (KRAS^WT) tumors, ~50% of patients still fail to respond to therapy. Using a transcriptional signature as a surrogate for cetuximab response, we previously reported that mutations in APC (APC^MUT) and TP53(TP53^MUT) might predict cetuximab sensitivity, particularly in RAS^WT tumors (Yang M. et al., 2019). The current study aimed to use real world EGFRi treatment and survival data to independently validate these mutations as predictive, high-utility biomarkers of benefit to specific subpopulations of CRC. Methods: CTX/PMB-treated CRC specimens (n=1846) with clinical outcomes and NextGen Sequencing of DNA (592-gene panel or whole exome sequencing) were tested at Caris Life Sciences (Phoenix, AZ). All analyses were performed in MSS tumors, determined by immunohistochemistry of MMR proteins and/or NGS. Tumors with likely pathogenic mutations in KRAS, NRAS or BRAF were considered as RAS^MUT/BRAF^MUT, or RAS^WT/BRAF^WT if no mutation was detected for each gene. Survival on EGFRi was calculated from the initiation of EGFRi to last contact (E-OS) or last dose of EGFRi (E-TOT) using Kaplan-Meir method. Results: While concurrent TP53^MUT/APC^MUT were associated with improved E-OS compared to TP53^MUT alone (hazard ratio [HR]=0.565, p<0.00001), APC^MUT tumors were associated with improved E-OS independent of TP53 mutation status. Compared to APC^WT, APC^MUT were associated with longer E-OS in RAS/BRAF mutant as well as wild-type subpopulations and in left- and right- sided tumors. Furthermore, APC^MUT were associated with improved E-TOT in PMB treated tumors independent of RAS/BRAF mutation status and tumor sidedness (HR range:0.59-0.75, all p<0.05). Conclusions: Our data suggests that the simple application of a high-utility mutational biomarker (APC), may increase the eligibility for successful EGFRi therapy in a substantial subpopulation of RAS/BRAF mt patients as well as right-sided CRC, potentially altering the standard of care. Further validation of this biomarker in a prospective clinical trial is warranted.