Survival with <i>EGFR</i> , <i>HER2</i> alterations in aUC: A multi-institution, real-world cohort.

e16552 Background: Although overexpression of EGFR occurs in up to 74% of advanced urothelial carcinoma (aUC), alterations are rarer, present in only ~4% of cases. While overexpression is associated with inferior survival, the impact of EGFR rearrangements ( EGFR -alt) on survival remains unknown. Likewise, rearrangements in ERBB2 (HER2-alt) are of unclear significance in aUC. Methods: Utilizing Flatiron Health’s nationwide, de-identified electronic health record derived database, aUC patients (pts) with EGFR -alt or HER2 -alt on NGS testing were identified (2016-2024). Baseline characteristics, treatment history, and clinical outcomes were abstracted. Chi-square and t-tests were used for used for univariate analysis. Progression free survival (PFS) and overall survival (OS) on chemotherapy vs immunotherapy (IO) were compared between EGFR -alt, HER2 -alt, wild-type (WT) pts via Kaplan Meier log-rank analysis. Results: Of 11,944 pts with NGS results, 13 pts with EGFR -alt (0.1%) and 26 pts with HER2-alt (0.2%) were identified. Of the EGFR -alt, 11 pts had rearrangements, one duplication, and one deletion. Of HER2 -alt, 25 had rearrangements and one truncation. For EGFR -alt, six pts were female (47%), compared to 28% for the entire cohort (p&lt;0.01). Seven (54%) were White, three (23%) Asian, and one (8%) Hispanic (compared to 1.4% Asian in overall cohort; p&lt;0.01). Median age at diagnosis was 69. For HER2 -alt, six pts were female (23%), and 23 (89%) were White. Median age was also 69. There was no difference between EGFR, HER2 and WT pts in ECOG PS (p=0.42; Table 1). For EGFR -alt pts, four received platinum chemo (31%) and seven received IO (54%) in 1L. For HER2 -alt pts, 11 (42%) received chemo, nine (35%) received IO, and one (4%) received EVP in 1L. mPFS was 4.9m [95% CI:2.9-7.0] for EGFR -alt, 5.4 [4.2-5.8] for HER2 -alt, compared to 8.8 [8.7-8.9] for WT (p=0.02). For EGFR -alt pts, mPFS was 4.1m [2.9-5.1] on 1L IO and 5.2m [3.0-12.2] on chemo (p=0.41). For HER2 -alt pts, mPFS was 4.3m [2.6-5.4] on 1L IO, 5.6m [3.5-6.5] on chemo, and 7.1 [NR] on EVP (p=0.20). mOS was 9.3m [5.4-12.4] for EGFR -alt pts, 9.7m [5.6-13.0] for HER2 -alt, and 13.4 [13.1-13.6] for WT (p&lt;0.01). Conclusions: EGFR and HER2 rearrangements were rare and associated with inferior PFS and OS compared to wild-type. Women and Asian pts were more likely to harbor EGFR rearrangements. Both EGFR and HER 2 rearranged pts had superior PFS on 1L chemo vs IO, though results were not significant, likely due to small sample size. Baseline characteristics, front-line therapy, survival. EGFR -alt HER2 -alt WT Sig (p) Median Age 69 69 67 0.71 Female (%) 47 23 28 &lt;0.01 ECOG (%) 0.64 0-1 69 64 63 ≥2 15 16 16 Race (%) 0.03 White 54 89 80 Asian 23 0 1 Black 0 4 5 Other 8 8 14 <jats:td colspa