Padcev (enfortumab vedotin-ejfv)

P2, N=28, Recruiting, Mayo Clinic | Trial completion date: Nov 2026 --> Jun 2028 | Trial primary completion date: Nov 2026 --> Jun 2028

A 64-year-old man with metachronous metastatic urothelial carcinoma originating from the right renal pelvis underwent nectin-4-targeted [68Ga]Ga-NECT-224 PET/CT prior to initiation of nectin-4-targeted antibody-drug conjugate (ADC) therapy with enfortumab-vedotin (PADCEV), in combination with pembrolizumab. Subsequent [68Ga]Ga-NECT-224 PET/CT restaging revealed multiple new lesions with intense nectin-4 expression. This case illustrates the potential of [68Ga]Ga-NECT-224 PET/CT to visualize heterogeneous nectin-4 expression, its potential in therapy guidance, and highlights the need for theranostic strategies in patients retaining target expression despite cytotoxic therapy resistance.

Conventional chemotherapy and first-generation antibody-drug conjugates (ADCs), such as ado-trastuzumab emtansine (T-DM1), were limited by non-specific cytotoxicity, heterogeneous drug-antibody ratios, linker instability, and insufficient bystander killing, yielding modest efficacy in heavily pretreated populations...Clinically, trastuzumab deruxtecan demonstrated meaningful progression-free survival benefit in HER2-low metastatic breast cancer, while enfortumab vedotin reduced mortality risk in platinum- and immunotherapy-refractory urothelial carcinoma, establishing ADC efficacy across solid tumor histologies...Trastuzumab deruxtecan carries a 15.4% incidence of interstitial lung disease, including fatal events, and sacituzumab govitecan is associated with grade 3 or higher neutropenia in approximately 51% of patients. Furthermore, next-generation ADCs are not resistance-proof, with antigen downregulation, payload efflux, and impaired internalization emerging as clinically relevant escape mechanisms. Biomarker-driven patient selection, rigorous toxicity monitoring, and prospective trials addressing resistance will be essential to realizing the full and durable potential of this drug class.

P=N/A, N=40, Not yet recruiting, University of Florence

P1/2, N=6, Not yet recruiting, Pfizer Inc.

In cisplatin-ineligible MIBC, the KEYNOTE-905/EV-303 trial demonstrated significant survival benefit with perioperative enfortumab vedotin plus pembrolizumab. In advanced RCC, KEYMAKER-U03 demonstrated improved progression-free survival with HIF-2α-based triplet therapy, the LenCabo study supported lenvatinib plus everolimus in later lines and the CALYPSO trial highlighted limited benefit of empiric combinations without biomarker selection. Emerging approaches including transcriptomic stratification (OPTIC RCC) and circulating biomarkers (KIM-1, ctDNA) support a shift toward biologically guided treatment selection.

PBC is often considered as a subsequent treatment after EVP therapy, except in patients with FGFR gene alterations. PBC followed by avelumab maintenance therapy may represent a feasible subsequent treatment option for selected patients with mUC who achieve disease control after EVP therapy.

Enfortumab vedotin (NECTIN4-ADC), a NECTIN4-targeting antibody-drug conjugate, has shown substantial efficacy in urothelial carcinoma, yet primary and acquired resistance remain major barriers to durable benefit...Pharmacologic inhibition of AKR1C1 restores ADC uptake, increases payload delivery, and enhances therapeutic sensitivity in preclinical models. Together, these findings define a clinically relevant target-high but uptake-defective resistance state and establish altered membrane trafficking as a therapeutic target for overcoming ADC therapy failure in cancer.

In this carefully selected elderly MIBC patient, neoadjuvant enfortumab vedotin combined with toripalimab was well tolerated and associated with marked tumor regression and a favorable pathological response on post-treatment TURBT. Bladder preservation was attempted, illustrating the feasibility of this regimen and generating a hypothesis for future investigation.

By conjugating indocyanine green (ICG) to enfortumab vedotin, we develop NECTIN4-ICG, a BC-specific fluorescence imaging probe...NECTIN4-ICG also enables fluorescence-guided TURBT, enhancing real-time visualization, margin assessment, and carcinoma in situ detection with a favorable safety profile. This clinical trial is registered under ChiCTR2200067094 and ChiCTR2400092677.

P1/2, N=12, Not yet recruiting, University of Washington

P3, N=390, Recruiting, Astellas Pharma Global Development, Inc. | Not yet recruiting --> Recruiting