Genomic Biomarkers Associated with Enfortumab Vedotin Outcomes for Patients with Advanced Urothelial Carcinoma: Analysis of UNITE Study Data

Tanya Jindal; Cindy Jiang; Omar Alhalabi; Amanda Nizam; Charles Nguyen; Rafee Talukder; Dimitra Bakaloudi; Matthew Davidsohn; Dory Freeman; Michael Glover; Ali Raza Khaki; Sean Evans; Emily Lemke; Rohit Bose; Woogwang Sim; Cameron Pywell; Arnab Basu; Deepak Kilari; Pedro C Barata; Mehmet A Bilen; Yousef Zakharia; Matthew I Milowsky; Sumit A Shah; Joaquim Bellmunt; Petros Grivas; Hamid Emamekhoo; Nancy B Davis; Shilpa Gupta; Christopher Hoimes; Matthew T Campbell; Ajjai Alva; Vadim S Koshkin

doi:10.1016/j.euo.2024.12.006

Genomic Biomarkers Associated with Enfortumab Vedotin Outcomes for Patients with Advanced Urothelial Carcinoma: Analysis of UNITE Study Data

Eur Urol Oncol. 2024 Dec 20:S2588-9311(24)00289-X. doi: 10.1016/j.euo.2024.12.006. Online ahead of print.

Authors

Tanya Jindal¹, Cindy Jiang², Omar Alhalabi², Amanda Nizam³, Charles Nguyen⁴, Rafee Talukder⁵, Dimitra Bakaloudi⁵, Matthew Davidsohn⁶, Dory Freeman⁶, Michael Glover⁷, Ali Raza Khaki⁷, Sean Evans⁸, Emily Lemke⁹, Rohit Bose¹, Woogwang Sim¹, Cameron Pywell¹⁰, Arnab Basu¹⁰, Deepak Kilari⁹, Pedro C Barata¹¹, Mehmet A Bilen⁸, Yousef Zakharia¹², Matthew I Milowsky¹³, Sumit A Shah⁷, Joaquim Bellmunt⁶, Petros Grivas¹⁴, Hamid Emamekhoo¹⁵, Nancy B Davis¹⁶, Shilpa Gupta³, Christopher Hoimes¹⁷, Matthew T Campbell², Ajjai Alva⁴, Vadim S Koshkin¹⁸

Affiliations

¹ Helen Diller Family Cancer Center, University of California-San Francisco, San Francisco, CA, USA.
² MD Anderson Cancer Center, University of Texas, Houston, TX, USA.
³ Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
⁴ Rogel Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI, USA.
⁵ University of Washington, Seattle, WA, USA.
⁶ Dana Farber Cancer Center, Boston, MA, USA.
⁷ Stanford University, Stanford, CA, USA.
⁸ Winship Cancer Institute, Emory University, Atlanta, GA, USA.
⁹ Medical College of Wisconsin, Milwaukee, WI, USA.
¹⁰ University of Alabama, Birmingham, AL, USA.
¹¹ Seidman Cancer Center, University Hospitals, Cleveland, OH, USA.
¹² University of Iowa, Iowa City, IA, USA.
¹³ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
¹⁴ Fred Hutchinson Cancer Center, University of Washington, Seattle, WA, USA.
¹⁵ Carbone Cancer Center, University of Wisconsin, Madison, WI, USA.
¹⁶ Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.
¹⁷ Duke University, Durham, NC, USA.
¹⁸ Helen Diller Family Cancer Center, University of California-San Francisco, San Francisco, CA, USA. Electronic address: vadim.koshkin@ucsf.edu.

PMID: 39709257
DOI: 10.1016/j.euo.2024.12.006

Abstract

Enfortumab vedotin (EV) is used as monotherapy or combined with pembrolizumab in advanced urothelial carcinoma (aUC), but biomarker data associated with EV outcomes are limited. We identified 170 patients in the UNITE study who received EV monotherapy and had molecular biomarker data available. Outcomes for groups with and without a particular biomarker were compared using logistic regression (unadjusted) for the objective response rate (ORR), and a log-rank test and Cox proportional-hazard models (CPHMs) for progression-free survival (PFS) and overall survival (OS) from EV initiation. Molecular biomarkers were also evaluated in separate multivariable analyses using CPHMs that accounted for clinical characteristics. Median patient age was 70 yr; 78% of the cohort were male and 65% had pure UC histology. Median PFS was shorter for patients with CDKN2A alterations (4.6 vs 6 mo; p = 0.024) and for patients with CDKN2B alterations (4.4 vs 6 mo; p = 0.008). Median OS was longer for patients with high tumor mutational burden (13.6 vs 8.3 mo; p = 0.014). ORR was higher for patients with TSC1 alterations (87% vs 51%; p = 0.018). In multivariable analyses, CDKN2A and CDKN2B alterations were associated with inferior median PFS. This multi-institutional retrospective study of patients with aUC identified potential biomarkers associated with EV monotherapy outcomes that should be further investigated. PATIENT SUMMARY: We investigated genetic changes in urinary tract tumors that might be associated with response to enfortumab vedotin (EV) treatment in patients with advanced disease. Survival after EV treatment was longer for tumors with a higher number of mutations than for tumors with fewer mutations. However, mutations in two genes (CDKN2A and CDKN2B) were associated with worse outcomes after EV treatment. These findings will not affect current clinical practice, but should be investigated further in future studies.

Keywords: Advanced urothelial carcinoma; Antibody-drug conjugate; Enfortumab vedotin; Genomic biomarkers; Tumor mutation burden.