EGFR, HER2 alterations in advanced urothelial carcinoma (aUC): A retrospective analysis on survival outcomes.

787 Background: EGFR alterations (EGFR-alt) and HER2 alterations (ERBB2-alt) are each seen in approximately 4% of advanced urothelial carcinomas (aUC). Given the success of targeted therapies in other solid tumor malignancies such as breast and lung cancers, proper prognostication and targeted therapy development is critical for HER2 and EGFR mutations in aUC. Methods: Between 1/1/2017 and 5/1/2024, aUC patients were identified from US cancer clinics in Flatiron Health’s de-identified electronic health record database. Baseline characteristics, treatment history, and clinical outcomes were abstracted on patients with EGFR-alt or ERBB2-alt (single-nucleotide variant (SNV), copy number variant (CNV), or rearrangement) on Next Generation Sequencing. Chi-square and t-tests were used for used for univariate analysis. Progression free survival (PFS) and overall survival (OS) of EGFR-alt and ERBB2-alt versus wild type (WT) patients were estimated via Kaplan Meier curves and compared via log-rank analysis and Cox regression. Results: 1110 patients met inclusion criteria, of which 786 were wild-type (WT), 238 had ERBB2 alterations and 80 had EGFR alterations. 51 (5%) had single nucleotide variants (SNV) in EGFR and 155 (14%) in ERBB2. 4 ( 65 years vs < 65 (p = 0.06, p = 0.43, p = 0.67, respectively). There was no difference in cisplatin, carboplatin, immunotherapy use for SNV (p = 0.24), rearrangement (p = 0.52), or CNV (p = 0.36). Patients with ERBB2-alt had longer PFS compared to WT patients (median 9.3 months vs 6.3 months; p = 0.005), and longer OS than WT patients (median 22.8 vs 16.5, p = 0.04). PFS for ERBB2 SNV was longer than WT on multivariate analysis (6.6 months vs. 5.0 months, p = 0.02). For EGFR alterations, PFS was comparable to WT (4.8 vs 5.0; p = 0.259), and OS was not significantly improved vs WT (15.2 vs 14.0, p = 0.737). There was no association between EGFR and ERBB2 rearrangements with PFS (p = 0.4) or OS (p = 0.3). There was no association between EGFR and ERBB2 CNV with PFS (p = 1) or OS (p = 0.9). Conclusions: In aUC patients, ERBB2-alt were associated with longer PFS and OS compared to WT or EGFR-alt patients, particularly with ERBB2 SNV alterations.