PD42-05 EXPANDING THE USE OF TARGETED THERAPY FOR UROTHELIAL BLADDER CANCER (UBC): NON-FGFR3 RECEPTOR TYROSINE KINASE (RTK) GENE REARRANGEMENTS (REAR) AND FUSIONS (FUS)

Abstract

You have accessJournal of UrologyCME1 May 2022PD42-05 EXPANDING THE USE OF TARGETED THERAPY FOR UROTHELIAL BLADDER CANCER (UBC): NON-FGFR3 RECEPTOR TYROSINE KINASE (RTK) GENE REARRANGEMENTS (REAR) AND FUSIONS (FUS) Andrea Necchi, Dean Pavlick, Gennady Bratslavsky, Joseph Jacob, Oleksandr Kravtsov, Philippe Spiess, Petros Grivas, Vamsi Parini, Brennan Decker, Lin Douglas, Danziger Natalie, Levy Mia Alyce, and Jeffrey Ross Andrea NecchiAndrea Necchi More articles by this author , Dean PavlickDean Pavlick More articles by this author , Gennady BratslavskyGennady Bratslavsky More articles by this author , Joseph JacobJoseph Jacob More articles by this author , Oleksandr KravtsovOleksandr Kravtsov More articles by this author , Philippe SpiessPhilippe Spiess More articles by this author , Petros GrivasPetros Grivas More articles by this author , Vamsi PariniVamsi Parini More articles by this author , Brennan DeckerBrennan Decker More articles by this author , Lin DouglasLin Douglas More articles by this author , Danziger NatalieDanziger Natalie More articles by this author , Levy Mia AlyceLevy Mia Alyce More articles by this author , and Jeffrey RossJeffrey Ross More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002603.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: After the regulatory approval of erdafitinib targeting FGFR genomic alterations (GA), molecular profiling and targeted therapy indications may further expand in UBC. We queried a large database of advanced UBC to study the landscape of RTK ReAr and Fus to categorize additional targets beyond FGFR1-3 that have potential to further personalize treatment of this disease. METHODS: We analyzed data from 8,233 UBC cases, which underwent hybrid capture-based comprehensive genomic profiling (CGP). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression in tumor cells was assessed by IHC (Dako 22C3). RESULTS: A total of 1,210 (14.7%) UBC featured known and likely large-scale (LS) internal ReAr with 414 (5%) ReAr in RTK genes. The ReAr/fus were distributed among ABL1 (3), ALK (3), BRAF (29), CDK12 (44), CDK8 (1), EGFR (10), ERBB2 (3), FGFR1 (2), FGFR2 (16), FGFR3 (231), FLT3 (1), MAO2K4 (4), NTRK1 (7), NTRK2 (5), NTRK3 (7), RAF1 (31), RET (8) and ROS1 (9). LS ReAr were divided into LS ReAr-associated gene deletions (1%), truncations (1%), rearrangements (61%) and fusions (37%). FGFR3 fus accounted for 81% of RTK fus with BRAF and RAF1 both at 2%. The greatest frequencies of kinase ReAr were in CDK12 (29%), FGFR3 (16%), RAF1 (13%) and BRAF (12%). Additional noteworthy ‘targetable’ RTK ReAR and fus included NTRK1-3 (19 cases), ROS1 (9 cases), RET (8 cases) and ALK (1 case). 407 (98.4%) of the RTK ReAr/fus-positive UBC had only 1 RTK ReAr/fus GA and 7 (1.6%) had 2 ReAr ReAr/fus, 6 (85.7%) of which involved FGFR3. Compared with LS ReAR negative UBC, the LS ReAR UBC cases revealed similar gender and age characteristics, MSI status, similar frequencies of TMB ≥ 10 mut/Mb and PD-L1 expression in tumor cells ≥1% and ≥50%. CONCLUSIONS: At a 5% frequency, potentially ‘targetable’ RTK gene rearrangements and fusions are a rare but important opportunity to further personalize treatment selection of UBC, including RTK inhibitors, PARP inhibitors (CDK12) and immunotherapy. This potential for clinical trials supports broader CGP, compared to targeted FGFR sequencing, in order to uncover additional opportunities for precision therapies that have the potential to improve patient outcomes. Source of Funding: Foundation Medicine © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e696 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Andrea Necchi More articles by this author Dean Pavlick More articles by this author Gennady Bratslavsky More articles by this author Joseph Jacob More articles by this author Oleksandr Kravtsov More articles by this author Philippe Spiess More articles by this author Petros Grivas More articles by this author Vamsi Parini More articles by this author Brennan Decker More articles by this author Lin Douglas More articles by this author Danziger Natalie More articles by this author Levy Mia Alyce More articles by this author Jeffrey Ross More articles by this author Expand All Advertisement PDF DownloadLoading ...