Enfortumab vedotin highly active in previously treated advanced urothelial carcinoma

Medical writer: Kara Nyberg, PhD

Enfortumab vedotin, a novel antibody-drug conjugate (ADC), demonstrated pronounced activity in patients with advanced urothelial carcinoma who experienced progression after prior treatment with platinum chemotherapy and an immune checkpoint inhibitor. Results from the pivotal phase II EV-201 study conducted in the United States and Japan showed that single-agent enfortumab vedotin yielded an objective response rate (ORR) of 44%, far surpassing the typical ORR of approximately 11% observed with single-agent chemotherapy in the second- and third-line settings (Abstract LBA4505).

Objective responses to enfortumab vedotin were seen in all patient subgroups evaluated (range, 33% to 60%), even those with poor prognostic features indicative of aggressive disease. Most notably, strong responses emerged regardless of whether patients did or did not have liver metastases (38% and 48%, respectively) and whether they did or did not respond to prior anti–PD-1/PD-L1 therapy (56% and 41%, respectively).

“If approved, enfortumab vedotin may have the potential to become a new standard of care in patients who have [experienced progression] after platinum-based chemotherapy as well as PD-1/PD-L1 inhibitors”—patients who otherwise face a dearth of therapeutic options, concluded Daniel P. Petrylak, MD, of the Yale School of Medicine, who presented the EV-201 findings.

The phase II results are highly consistent with data from the dose-finding phase I study of enfortumab vedotin, which demonstrated an ORR of 42% among patients with advanced urothelial cancer who previously received treatment with a PD-1/PD-L1 inhibitor.¹ The U.S. Food and Drug Administration (FDA) granted enfortumab vedotin a breakthrough therapy designation on the basis of phase I data. Now, with the EV-201 data, plans are underway to seek FDA approval of enfortumab vedotin later this year.

Enfortumab vedotin works by targeting nectin-4, a cell adhesion molecule highly expressed in urothelial cancers and other solid tumours. After binding to nectin-4 on the cell surface, enfortumab vedotin becomes internalized and processed by lysosomes, which liberate the drug’s cytotoxic payload, monomethyl auristatin E. Then, monomethyl auristatin E disrupts microtubule assembly, leading to cell cycle arrest and apoptosis.

The EV-201 trial features a single treatment arm in which 1.25 mg/kg of intravenous enfortumab vedotin is administered on days 1, 8, and 15 of each 28-day cycle and includes two patient cohorts. Dr. Petrylak presented the results for the 125 patients in cohort 1, all of whom previously received platinum-based therapy as well as a PD-1/PD-L1 inhibitor. Enrollment is ongoing for cohort 2, which comprises platinum-naive, cisplatin-ineligible patients previously treated with a PD-1/PD-L1 inhibitor.

The 44% ORR observed with enfortumab vedotin in cohort 1 was based on blinded independent central review and consisted of both complete responses (12%) and partial responses (32%). Overall, 84% of evaluable patients showed some degree of tumour shrinkage. Objective responses occurred quickly, at a median of 1.8 months after treatment initiation, and lasted for a median of 7.6 months. With single-agent enfortumab vedotin, the median progression-free survival reached 5.8 months, and the median overall survival was 11.7 months.

The toxicity associated with enfortumab vedotin was manageable. Neutropenia (8%), anaemia (7%), and fatigue (6%) were some of the most common grade 3/4 treatment-related adverse events (TRAEs), as categorized by preferred term. Grade 3/4 TRAEs of special interest, as categorized by the medical dictionary for regulatory activities term, included rash (12%), hyperglycemia (6%), and peripheral neuropathy (3%). Overall, 12% of patients discontinued therapy because of TRAEs, the most common of which was peripheral sensory neuropathy (6%). Of note, one patient in the study died of interstitial lung disease—an event deemed related to enfortumab vedotin therapy but that was confounded by the use of high-dose corticosteroids for a suspected pulmonary infection.

To confirm the findings of EV-201, the global, randomized, controlled, phase III EV-301 trial (NCT03474107), which opened recently, will compare enfortumab vedotin against standard single-agent chemotherapy in patients with locally advanced or metastatic urothelial cancer previously treated with platinum chemotherapy and a PD-1/PD-L1 inhibitor.

Discussant Andrea Necchi, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumouri, Italy, commented that the enfortumab vedotin data are “so clear, so good.” However, verification of the results in the phase III setting will be critical, as will identification of a biomarker to detect those patients most likely to respond to the ADC. Dr. Necchi also questioned whether the favorable outcomes of EV-201 are specific to enfortumab vedotin or are common to other ADCs, such as sacituzumab govitecan, which recently demonstrated similar positive findings in heavily pre-treated urothelial cancer.²

Despite these uncertainties, Dr. Necchi thinks that ADCs are best positioned as the standard of care in metastatic urothelial carcinoma after progression occurs during treatment with a checkpoint inhibitor because of the cumulative efficacy with this sequence of compounds observed to date.

1. Rosenberg JE, et al. J Clin Oncol. 2019;37(suppl; abstr 377).


2. Tagawa ST, et al. J Clin Oncol. 2019;37(suppl; abstr 354).

Posted on 15 July, 20191 July, 2021