TP53 co-mutations and survival outcomes in patients (pts) with NSCLC bearing uncommon EGFR alterations.

e20721 Background: Pts with NSCLC bearing uncommon EGFR alterations experienced inferior survival with tyrosine kinase inhibitors (TKIs) vs. those with sensitizing exon 19 deletions or L858R in prior studies. While TP53 co-mutations are well-recognized to be associated with poorer outcomes in sensitizing EGFR-mutant NSCLC, no research to our knowledge has examined the contribution of this adverse co-mutation to the inferior survival observed in pts with uncommon EGFR alterations receiving front-line TKIs. Methods: The Flatiron Health-Foundation Medicine clinical-genomic database (~800 sites of care) was used to evaluate pts (N = 108) with advanced NSCLC (Stage IIIB/IV) bearing uncommon EGFR alterations receiving front-line osimertinib or afatinib from 6/2014 – 9/2024. Kaplan-Meier methods (accounted for left truncation) estimated real-world progression-free survival (rwPFS) and overall survival (OS) in months (m). Comparisons by presence of TP53 co-mutations vs. wild-type were assessed using multivariable Cox regression after adjusting for the covariates gender, age, smoking history, performance status, presence of brain and liver metastases, EGFR subtype (e.g. G917X, L861Q, compound), and TKI received. Results: Of the 108 pts, 30 (27.8%) had G719X, 30 (27.8%) had L861Q, 3 (2.8%) had S768I, 3 (2.8%) had E709X, 2 (1.9%) had L747X, and 40 (37.0%) had compound mutations made-up of ˃ 1 EGFR alteration. Seventy-six (70.4%) pts had a TP53 co-mutation, which is higher than the rate reported for pts with sensitizing EGFR-mutant NSCLC in prior studies. Sixty-nine pts (63.9%) received osimertinib and 39 (36.1%) received afatinib as a front-line TKI. Pts with TP53 co-mutations had a shorter median rwPFS (5.9 m vs. 15.7 m, HR 1.9, 95% CI 1.1-3.3, P = 0.017) and OS (11.0 m vs. 24.7 m, HR 2.4, 95% CI 1.4-4.4, P = 0.003) with front-line TKIs as compared to wildtype pts after adjusting for relevant covariates. In our multivariable model, the TKI received (i.e. osimertinib vs. afatinib) did not alter survival. However, having L861Q correlated with a poorer OS (HR 2.5, 95% CI 1.3-4.7, P = 0.006) and having G719X predicted inferior rwPFS (HR 2.5, 95% CI 1.3-4.5, P = 0.004) and OS (HR 2.3, 95% CI 1.2-4.5, P = 0.016) as compared to pts with compound EGFR mutations. Conclusions: This is the first study to demonstrate that the occurrence of a TP53 co-mutation is a significant predictor of inferior rwPFS and OS in pts with NSCLC bearing uncommon EGFR alterations. Although conventional thought is that pts with uncommon EGFR alterations derive less benefit from TKIs, our analysis suggests TP53-wildtype pts experience survival comparable to that of pts with sensitizing EGFR alterations in the real-world. Pts possessing uncommon EGFR alterations with a TP53 co-mutation critically need more effective therapies. Emerging strategies that target mutant p53 may benefit this high-risk subgroup.