Efficacy of enfortumab vedotin in advanced urothelial cancer: Analysis from the Urothelial Cancer Network to Investigate Therapeutic Experiences (UNITE) study

Abstract

Background Enfortumab vedotin (EV) is a novel antibody‐drug conjugate approved for advanced urothelial cancer (aUC) refractory to prior therapy. In the Urothelial Cancer Network to Investigate Therapeutic Experiences (UNITE) study, the authors looked at the experience with EV in patient subsets of interest for which activity had not been well defined in clinical trials. Methods UNITE was a retrospective study of patients with aUC treated with recently approved agents. This initial analysis focused on patients treated with EV. Patient data were abstracted from chart reviews by investigators at each site. The observed response rate (ORR) was investigator‐assessed for patients with at least 1 post‐baseline scan or clear evidence of clinical progression. ORRs were compared across subsets of interest for patients treated with EV monotherapy. Results The initial UNITE analysis included 304 patients from 16 institutions; 260 of these patients were treated with EV monotherapy and included in the analyses. In the monotherapy cohort, the ORR was 52%, and it was >40% in all reported subsets of interest, including patients with comorbidities previously excluded from clinical trials (baseline renal impairment, diabetes, and neuropathy) and patients with fibroblast growth factor receptor 3 (FGFR3) alterations. Progression‐free survival and overall survival were 6.8 and 14.4 months, respectively. Patients with a pure urothelial histology had a higher ORR than patients with a variant histology component (58% vs 42%; P = .06). Conclusions In a large retrospective cohort, responses to EV monotherapy were consistent with data previously reported in clinical trials and were also observed in various patient subsets, including patients with variant histology, patients with FGFR3 alterations, and patients previously excluded from clinical trials with an estimated glomerular filtration rate < 30 mL/min and significant comorbidities. Lay Summary Enfortumab vedotin, approved by the Food and Drug Administration in 2019, is an important new drug for the treatment of patients with advanced bladder cancer. This study looks at the effectiveness of enfortumab vedotin as it has been used at multiple centers since approval, and focuses on important patient populations previously excluded from clinical trials. These populations include patients with decreased kidney function, diabetes, and important mutations. Enfortumab vedotin is effective for treating these patients. Previously reported clinical trial data have been replicated in this real‐world setting, and support the use of this drug in broader patient populations.

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

“…This intriguing observation in a treatment setting where predictive biomarker data have been lacking, deserves further validation in independent patient cohorts. Despite the relatively smaller sample size of this cohort, the observed response rate of 41%, as well as mPFS of 5.1 months, and mOS of 10.2 months are consistent with data previously reported by larger clinical trials and retrospective studies in this patient population ( 9 , 12 , 26 ). Consequently, this data, while hypothesis-generating, sheds important light on the biomarker landscape in aUC, where treatment decisions must frequently be made in the refractory setting among the several therapeutic options available.…”

“…Previous analyses have found low albumin levels predict inferior outcomes to ICI in patients with mUC and better ECOG performance scores (<2) predict improved outcomes to ICI in patients with aUC ( 38 , 44 ). Another analysis of EV outcomes in a multicenter cohort UNITE study reported consistent responses to EV in patients with both ECOG PS < 2 and ≥ 2 respectively ( 26 ). The same UNITE study dataset noted numerically higher responses to EV in patients with a pure urothelial histology as compared to patients with a variant histology component (58% vs 42%, p=0.06).…”

“…Other potential characteristics associated with treatment outcomes in patients with mUC include burden of metastatic disease and metastatic sites. In the UNITE study, presence of liver metastases was associated with an increased response rate to EV, but a shorter mOS ( 26 ). In our analysis, the number of patients with liver metastases were too small to assess this as an independent marker, however liver metastases were included within the criteria we did assess, including presence of visceral metastases, Bellmunt criteria and frontline ICI score ( 23 , 24 ).…”

“…Interestingly our findings also suggested that older patients may have improved outcomes with EV treatment. Older patients are generally thought to have inferior treatment outcomes regardless of therapy, although in the UNITE dataset no differences in response to EV were seen based on age ( 26 ). As this was a dataset of mostly significantly pretreated patients, one potential explanation for these findings is that older patients included in the current analysis may have had a less aggressive disease biology leading them to still qualify for EV monotherapy even after having received multiple prior lines of treatment.…”

Her-2 Targeted Therapy in Advanced Urothelial Cancer: From Monoclonal Antibodies to Antibody-Drug Conjugates

“…Erdafitinib is an alternative for platinum-refractory mUC with selected fibroblast growth factor receptor ( FGFR ) alterations ( FGFR2 mutations or FGFR3 mutations/fusions) [ 7 ]. The antibody–drug conjugate enfortumab vedotin, targeting nectin-4, is currently the preferred option for patients with ChT and ICI-refractory disease [ 6 , 8 ].…”