Background: Co-occurring alterations in tumor suppressor genes (TSG) have been described as determinants of disease heterogeneity in EGFR-mutant non-small cell lung cancer (NSCLC), however, detailed analyses of their impact on patient outcomes are limited. Methods: Patients with EGFR-mutant NSCLC treated with EGFR tyrosine kinase inhibitors (TKIs) at the Yale Cancer Center who had tumor genomic profiling either before EGFR-TKI therapy (pre-TKI) or at disease progression (post-TKI) were included. Whole exome sequencing (WES) of paired pre- and post-TKI tumor specimens were performed for a subset of patients. The cohort was divided into three subgroups based on alterations in TP53 and five additional TSGs (RB1, NF1, ARID1A, BRCA1 and PTEN): patients with tumors harboring a TP53 mutation plus a mutation in at least 1 additional TSG (TP53^mut/TSG^mut), patients with tumors harboring a TP53 mutation without an additional TSG mutation (TP53^mut/TSG^wt), and patients with TP53^wt tumors. Clinical characteristics including progression-free (PFS) and overall survival (OS) were assessed. Results: One-hundred-one patients were included in this retrospective study. TP53 mutations were identified in 65 (64%) tumors, of which 23 (35%) and 42 (65%) were classified as TP53^mut/TSG^mut and TP53^mut/TSG^wt, respectively. Among those cases with paired WES available (n = 34), frequencies of alterations in the six included TSGs did not significantly differ between pre- and post-TKI tumor specimens. In the full study cohort, the presence of a TP53 mutation was associated with numerically worse PFS (HR 1.46, CI 0.97 – 2.21, p = 0.09) and OS (HR 1.68, CI 1.05 – 2.70, p = 0.04) on first-line EGFR-TKI. Strikingly, after dividing the TP53^mut cohort into TP53^mut/TSG^mut and TP53^mut/TSG^wt cases, alterations in additional TSG were found to drive the poor outcomes: TP53^mut/TSG^mut cases had significantly worse PFS and OS on first-line EGFR TKI than TP53^mut/TSG^wt(mPFS 8.0 vs 10.6 months, p = 0.006; mOS 30.0 vs 33.3 months, p = 0.12) or TP53^wt cases (mPFS 8.0 vs 12.6 months, p < 0.0001; mOS 30.0 vs 48.8 months, p = 0.001). There was no significant difference in PFS or OS between patients with TP53^mut/TSG^wt and TP53^wt tumors. Similar outcome differences between the three groups were found in patients who received osimertinib in the second-line setting. Conclusions: The inferior outcomes associated with EGFR/TP53-mutant NSCLC tumors may be due to additional TSG alterations rather than TP53 mutational status alone. Alterations in the investigated TSGs did not appear to emerge under EGFR-TKI therapy, which suggests that they are truncal. Our findings may have implications for understanding the biologic underpinnings of differential outcomes to EGFR TKIs.