Enfortumab Vedotin-ejfv: A First-in-Class Anti–Nectin-4 Antibody-Drug Conjugate for the Management of Urothelial Carcinoma

Abstract

Objective: To evaluate the pharmacology, pharmacokinetics, clinical efficacy, safety, dosing, cost, and clinical implications of enfortumab vedotin-ejfv (EV) in the treatment of locally advanced or metastatic urothelial carcinoma (UC). Data Sources: A literature search of PubMed (inception to August 2020) was conducted using the terms enfortumab, vedotin, Padcev, and Nectin. Data were also obtained from package inserts, meeting abstracts, and ongoing studies from ClinicalTrials.gov. Study Selection and Data Extraction: All relevant published articles, package inserts, and meeting abstracts evaluating EV for the treatment of UC were analyzed. Data Synthesis: Antibody-drug conjugates (ADCs) deliver potent cytotoxic agents using highly selective monoclonal antibodies. Targeting the near-universal expression of Nectin-4 on UC cells is a viable therapeutic strategy. In a pivotal phase II trial, EV demonstrated an overall response rate of 44%, and a median duration of response of 7.6 months. Estimated overall survival was 11.7 months with a median estimated progression-free survival of 5.6 months. Results were similar among difficult-to-treat patients, including those with liver metastases. Unique toxicity concerns with EV require careful consideration and monitoring. Relevance to Patient Care and Clinical Practice: EV, a first-in-class anti–Nectin-4 ADC, provides impressive response rates with manageable toxicities, making it a promising treatment option for patients with multiply relapsed or refractory UC. Conclusion: The US Food and Drug Administration–approved EV demonstrates antitumor activity in heavily pretreated patients with UC but harbors important adverse effects and financial concerns. Additional studies are required to identify the optimal sequencing, patient population, and place in therapy for EV.

Delivery of Drugs into Cancer Cells Using Antibody–Drug Conjugates Based on Receptor-Mediated Endocytosis and the Enhanced Permeability and Retention Effect

“…Enfortumab vedotin-ejfv (Padcev ® ) against Nectin4, approved for solid cancers such as urothelial cancer in 2019, was intracellularly internalized by endocytosis and was degraded in a lysosome to subsequently release the cytotoxic payload MMAE [ 28 ].…”

Profile of Enfortumab Vedotin in the Treatment of Urothelial Carcinoma: The Evidence to Date

“… 9 Despite the optimistic perspective, there is still lack of data regarding the best timing of EV administration or sequencing and there is yet no standard of care in patients with advanced UC. 30 …”

Systemic and intravesical adoptive cell therapy of tumor-reactive T cells can decrease bladder tumor growth in vivo

“…Enfortumab vedotin has an overall response rate of 44%; however, estimated overall survival is still <12 months. 18 Likewise erdafitinib demonstrated a limited overall response rate (40%) in a particular subset of patients harboring genetic alterations of fibroblast growth factor receptor, with a limited duration of treatment response (an approximate progression-free and overall survival of 6 and 12 months, respectively). 19 Therefore, there is a current pressing need to identify novel treatment strategies for patients with bladder cancer with high-risk localized, locally advanced and metastatic disease.…”

“…Enfortumab vedotin has an overall response rate of 44%; however, estimated overall survival is still <12 months. 18 Likewise erdafitinib demonstrated a limited overall response rate (40%) in a particular subset of patients…”