Somatic alterations of TP53 and MDM2 associated with response to enfortumab vedotin in patients with advanced urothelial cancer - PubMed (original) (raw)

doi: 10.3389/fonc.2023.1161089. eCollection 2023.

Xiaolin Zhu 1, Rohit Bose 1, Vipul Kumar 1, Edward Maldonado 1, Prianka Deshmukh 1, Chase Shipp 1, Stephanie Feng 1, Michelle S Johnson 1, Austin Angelidakis 1, Daniel Kwon 1, Hala T Borno 1, Ivan de Kouchkovsky 1, Arpita Desai 1, Rahul Aggarwal 1, Lawrence Fong 1, Eric J Small 1, Anthony Wong 1, Sima Porten 1, Jonathan Chou 1, Terence Friedlander 1, Vadim S Koshkin 1

Affiliations

Somatic alterations of TP53 and MDM2 associated with response to enfortumab vedotin in patients with advanced urothelial cancer

Tanya Jindal et al. Front Oncol. 2023.

Abstract

Background: Enfortumab vedotin (EV) is an antibody-drug conjugate approved for patients with treatment-refractory advanced urothelial carcinoma (aUC), however data on biomarkers of response is lacking.

Methods: We retrospectively identified all aUC patients at our institution who received EV monotherapy and had next-generation sequencing (NGS) data available. Patients were considered responders if they had a complete response or partial response on restaging scans during treatment. Observed response rate (ORR) was evaluated by local investigator and compared between responders and non-responders using Chi-squared test. A univariable analysis was conducted using the Cox proportional hazard test to assess for associations between baseline characteristics and most common somatic alterations (in ≥10% of patients) with patient survival outcomes [progression-free survival (PFS) and overall survival (OS)]. Somatic alterations were then individually evaluated in separate multivariate models while accounting for patient and clinical characteristics using Cox regression models.

Results: Among 29 patients treated with EV monotherapy, 27 had available NGS data. Median age was 70, 24 (83%) were men, 19 (62%) were Caucasian, 15 (52%) had pure urothelial histology and 22 (76%) had primary tumor in the bladder. ORR was 41%, and PFS and OS for the overall cohort were 5.1 months and 10.2 months. Responders were enriched among patients with TP53, KDM6A and MDM2 alterations. Patients with these alterations, as well as those with composite TP53/MDM2 alterations (alterations in either TP53 or MDM2), also had increased ORR with EV treatment compared to patients without these alterations. In the univariable analysis, baseline albumin level ≥ 3.0g/dL and presence of composite TP53/MDM2 alterations were associated with a prolonged OS. Baseline ECOG 0/1, TP53 alterations and TP53/MDM2 alterations were associated with a prolonged PFS. In the multivariable analysis, TP53 and TP53/MDM2 alterations were genomic markers predictive of improved PFS after accounting for the relevant clinical characteristics.

Conclusion: In this single-center retrospective analysis of aUC patients treated with EV, presence of TP53 or MDM2 somatic alterations, lower ECOG PS scores (ECOG 0 or 1) and higher albumin levels (≥3 g/dL) were associated with improved outcomes with EV treatment. Prospective and external validation of these findings in larger cohorts is warranted.

Keywords: antibody drug conjugate (ADC); enfortumab vedotin; genetic markers; next generating sequencing; urothelial carcinoma.

Copyright © 2023 Jindal, Zhu, Bose, Kumar, Maldonado, Deshmukh, Shipp, Feng, Johnson, Angelidakis, Kwon, Borno, de Kouchkovsky, Desai, Aggarwal, Fong, Small, Wong, Porten, Chou, Friedlander and Koshkin.

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Conflict of interest statement

IK reports personal fees from Janssen and grant funding from the ASCO Conquer Cancer Foundation and the Prostate Cancer Foundation. LF reports research support from Abbvie, Amgen, Bavarian Nordic, Bristol-Myers Squibb, Dendreon, Janssen, Merck, Roche/Genentech; ownership interests in Actym, Alector, Atreca, Bioatla, Bolt, Immunogenesis, Nutcracker, RAPT, Scribe, and Senti, unrelated to the work here. VSK reports serving in a consulting or advisory role for AstraZeneca, Clovis, Janssen, Pfizer, EMD Serono, Seagen, Astellas, Dendreon, Guidepoint, GLG and ExpertConnect; research funding for the institution from Endocyte, Nektar, Clovis, Janssen, Taiho and Merck, and grant funding from the Prostate Cancer Foundation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest.

Figures

Figure 1

Figure 1

Kaplan-Meier curves: (A) OS and (B) PFS in patients with and without TP53 alterations; (C) OS (D) PFS in patients with and without the composite TP53/MDM2 alterations.

Figure 2

Figure 2

Cross Sectional Imaging of Patients with TP53 and MDM2 Somatic Alterations Pre and Post Treatment with Enfortumab Vedotin. (A) Patient with metastatic UC and TP53 alterations (p.E285* and p.E271Q) who had prior progression on both platinum-based chemotherapy and pembrolizumab. Patient had significant decrease in size of biopsy-confirmed pulmonary metastases after starting treatment with EV and eventually achieved a complete response. Patient continues to have radiographic CR on scans 30 months after EV treatment start. (B) Patient with metastatic UC and MDM2 alteration (amplification) who had prior progression on a clinical trial of an immune checkpoint inhibitor combination regimen with metastases in lungs and liver. Following start of EV treatment, patient had marked reduction of metastatic burden after only 9 weeks and continued on treatment for >18 months.

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