e16571 Background: The efficacy of targeted therapies against EGFR and HER2 (ERBB2) has been investigated across multiple cancers, including advanced urothelial carcinoma (aUC). However, the prognostic significance of these alterations remains unclear, particularly in the context of the recent approval of enfortumab vedotin plus pembrolizumab (EVP) as first-line therapy in December 2023. Methods: Flatiron Health's de-identified EHR database was used to identify aUC patients from US cancer clinics 04/09/2021-05/31/2025. Baseline characteristics, first-line treatment (carboplatin, cisplatin, immunotherapy, EVP, or other), and overall survival (OS) time were abstracted. Patients were categorized by EGFR and ERBB2 alteration status—short variants, copy number variants (CNVs), or rearrangements. Chi-square tests evaluated associations of categorical variables. OS in patients with EGFR and ERBB2 alterations versus wild-type (WT) patients was estimated using Kaplan-Meier curves. Log-rank and Cox regression analyses were used to evaluate if EGFR and ERBB2 status modified the effect of first-line therapy on OS. Results: Of the 905 patients identified, 634 were wild type (WT), 209 (23.1%) had ERBB2 alterations, and 79 (8.7%) had EGFR alterations. Of the 209 with ERBB2 alterations, 12 had rearrangements, 103 CNVs, and 138 short variants. Of the 79 with EGFR alterations, 3 had rearrangements, 24 CNVs, and 57 short variants. Alterations were not associated with a specific first-line therapy, race, or ECOG performance status. Men had a higher frequency of ERBB2 alterations vs women (25.6% vs 17.0%, p = 0.0053) but not EGFR alterations (8.9% vs 8.3%, p = 0.80). Patients with ERBB2 alterations had longer OS than WT patients (median 23.2 months vs 16.1 months; HR = 0.57, p <0.000001). Longer OS was associated with ERBB2 CNVs (p<0.0001) and short alterations (p <0.0001). ERBB2 alteration was associated with longer OS compared to WT among patients treated with immunotherapy (HR = 0.48, 95% CI 0.26–0.86, p = 0.014). This finding held true for both ERBB2 CNVs (p = 0.049) and short alterations (p = 0.0084). No difference in OS was observed for patients with EGFR alterations. OS did not significantly differ between patients treated with EVP vs platinum chemotherapy, regardless of EGFR and ERBB2 alteration status. Conclusions: ERBB2 alterations were associated with longer OS compared to WT, especially among patients treated with immunotherapy. EGFR status was not correlated with survival. EGFR and ERBB alterations in aUC. EGFR alterations (n=79) ERBB2 alterations (n=209) WT (n=634) Sig (p) Baseline Characteristics ECOG PS 0-1 (%) 63.3 65.5 64.2 0.942 2-4 (%) 11.4 11.5 13.1 1L Treatment IO (%) 27.8 35.4 33.7 *0.047 EVP (%) 17.7 12.0 12.9 Carboplatin (%) 17.7 21.5 16.8 Cisplatin (%) 20.3 21.1 20.2 Other (%) 12.7 6.7 16.2 Survival mOS (m) 12.0 23.2* 16.1 *p <0.000001 </j
Subramanian et al. (Thu,) studied this question.