Comprehensive clinical and genomic characterization of advanced urachal and non-urachal adenocarcinomas of the urinary tract.

e16618 Background: Adenocarcinomas of the urinary tract, including urachal (UA) and non-urachal (NUA) subtypes, are rare tumors lacking standard systemic treatments. We aim to define the efficacy of targeted therapies post-chemotherapy (chemo) progression. Methods: We retrospectively reviewed records of 62 and 45 patients (pts) with advanced UA and NUA, respectively, at MD Anderson from 2000 to 2023. Advanced disease was defined as Sheldon stages IVA/IVB for UA and TNM stage IV for NUA. Two radiologists assessed responses using RECIST version 1.1. Results: First-line (1L) chemo was received by 57 UA pts and 39 NUA pts. NUA pts had either bladder (19, 48.7%) or urethral (20, 51.3%) origin. Chemo + EGFRi strategies included either cetuximab or panitumumab, while Chemo + VEGFi ones included bevacizumab. Visceral metastasis was present in 45 (78.9%) and 23 (59%) pts in UA and NUA, respectively. The most frequent metastatic sites were lung (24, 53.3%), peritoneum (21, 46.7%), liver (7, 15.6%) and bone (6, 13.3%) in UA, versus lung (11, 47.8%), bone (7, 30.4%) and liver (4, 17.4%) in NUA. Median OS (mOS) from 1L chemo was 17 mo [95% CI: 11.8 - 26] and 16.9 mo [95% CI: 8.1 – 23.3], respectively. Chemo responses were mainly in 1L, with ORRs of 22% and 25% with 5-FU based regimens in UA and NUA, respectively (Table). Subsequent chemo + EGFRi or VEGFi showed ORRs of 5.3% and 12.5% in UA but no responses in NUA. Genomic sequencing for 25 UA and 12 NUA pts showed frequent alterations in TP53 , MYC , KRAS , SMAD4 and GNAS in UA, versus TP53 , KRAS , PTPRD in NUA. All three KRAS mutations in NUA were G12D. Twelve UA pts had KRAS alterations, mostly amplification (n = 3), G12D (n = 3) and G12V (n = 2). mOS from metastatic disease was lower for UA pts with KRAS alterations (n = 12) than those without (n = 13) (17.7 mo vs. 29.4 mo, HR = 2.4 [95% CI: 1-5.9], p = 0.02). Conclusions: Beyond active frontline 5-FU based regimens, subsequent chemo with either EGFRi or VEGFi shows limited efficacy in advanced UA. Non-5-FU based chemo shows more activity in NUA, aligning genomically with urothelial cancer. The prognostic value of KRAS alterations and the role of KRAS as a promising therapeutic target in UA, genomically resembling colorectal cancer, merits further study. Responses 1L Chemo Subsequent Tx 5-FU based Non-5-FU based 5-FU based chemo Non-5-FU based chemo Chemo + EGFRi EGFRi mono Chemo + VEGFi UA(n=57) CR 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) PR 11 (22%) 0 (0%) 0 (0%) 0 (0%) 1 (5.3%) 0 (0%) 1 (12.5%) SD 23 (46%) 2 (28.6%) 2 (33.3%) 5 (41.7%) 8 (42.1%) 3 (50%) 2 (25%) PD 13 (26%) 5 (71.4%) 4 (66.7%) 7 (58.3%) 7 (36.8%) 3 (50%) 5 (62.5%) NE 3 (6%) 0 (0%) 0 (0%) 0 (0%) 3 (15.8%) 0 (0%) 0 (0%) Total (n) 50 7 6 12 19 6 8 NUA(n=39) CR 0 (0%) 1 (14.3%) 0 (0%) 0 (0%) 0 (0%) * 0 (0%)