Enfortumab Vedotin With Pembrolizumab Shows Promise as First-Line Therapy For Those Ineligible for Cisplatin


Enfortumab vedotin in combination with pembrolizumab showed a manageable safety profile and promising progression free survival and overall survival for locally advanced or metastatic urothelial cancer.

The gold standard, first-line therapy for locally advanced or metastatic urothelial cancer, is cisplatin-based combination chemotherapy. However, there are about one half of patients who are ineligible to receive these cisplatin-based therapies. For these patients, carboplatin and gemcitabine can be used, but are less efficacious. Additionally, about 60% of cisplatin-ineligible patients receiving first-line therapy do not receive subsequent second-line therapies. Enfortumab vedotin in combination with pembrolizumab was effective and safe as a first-line therapy in cisplatin-ineligible patients in a phase 1b/2 study, EV-103 trial (NCT03288545), Cohort A, serving as the basis for further evaluation in this study, using Cohort K.

3d rendered illustration of the anatomy of a cancer cell | Image Credit: Sebastian Kaulitzki - stock.adobe.com

Image Credit: Sebastian Kaulitzki - stock.adobe.com

Cohort Kwas used to analyze the effectiveness of EV-103 phase 1b/2 study and involved the treatment of enfortumab vedotin monotherapy or enfortumab vedotin in combination with pembrolizumab as a first-line treatment for cisplatin-ineligible patients with previously untreated locally advanced/metastatic urothelial carcinoma.

Patients included werecisplatin-ineligible adults with histologically documented locally advanced/metastatic urothelial carcinoma of all types, had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, and were eligible for pembrolizumab treatment. Patients were excluded from the trial if they had previous systemic treatment for locally advanced or metastatic disease within 12 months, previous treatment with immunotherapy (eg, programmed cell death protein-1 [PD-1], programmed cell death ligand-1 [PD-L1], or PD-L2) inhibitors, stimulatory or inhibitory T-cell receptor agents), enfortumab vedotin or another monomethyl auristatin-based antibody-drug conjugate, a grade 2 or higher sensory or motor neuropathy, current clinically significant toxicity from previous treatment, central nervous system metastases, or uncontrolled diabetes mellitus. Patients were givenenfortumab vedotin 1.25 mg/kg intravenously (IV) over 30 minutes on days 1 and 8 for a 3 week cycle, with a maximum total dose 125 mg, and pembrolizumab 200 mg IV over 30 minutes once weekly for 3 weeks. This study observed the confirmed objective response rate (cORR) according to RECIST version 1.1 per blinded independent central review, serving as the primary outcome measure. Secondary measures included disease control rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.

Of the 151 patients, 77 received enfortumab vedotin and pembrolizumab and 74 received enfortumab vedotin as a monotherapy. Seventy-six patients were treated with enfortumab vedotin and pembrolizumab and 73 patients were treated with enfortumab vedotin. The median DOR was 9 months (range, 0.6-26.1 months), with a median of 11 cycles with the combination and the median DOR was 5.5 months (range, 0.5-26.9 months), with a median of 8 cycles with enfortumab vedotin alone. The cORR was 64.5% (95% CI) in patients receiving enfortumab vedotin and pembrolizumab, with a complete response achieved in 8 patients (10.5%) and a partial response in 41 patients (53.9%). At 12 months, 65.4% of responders maintained a response. The cORR was 45.2% (95% CI) in patients receiving only enfortumab vedotin, a complete response was achieved in 4.1% of patients and partial response in 41.1% of patients. The OS rate at 12 months was 80.7% for the combination and 70.7% for enfortumab vedotin alone. The most common treatment-related adverse effects (TRAE) with the combination arm were fatigue, peripheral sensory neuropathy, alopecia, and maculopapular rash. The most commonly seen TRAE with enfortumab vedotin monotherapy included skin reactions and peripheral neuropathies. Maculopapular rash was the most common grade 3 or higher TRAE. Peripheral neuropathies due to either treatment led to discontinuation of therapy for 11.8% of patients.

About The EV-103 Trial

Trial Name: A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer (EV-103)

ClinicalTrial.gov: NCT03288545

Sponsor: Astellas Pharma Global Development Inc

Competition Date (Estimated): December 2026

A need exists for an effective first-line treatment option for cisplatin-ineligible patients. Enfortumab vedotin in combination with pembrolizumab showed a manageable safety profile and promising PFS and OS results that will continue to evolve with follow-up phase 3 trials that are ongoing. No new safety hazards were observed with the combination treatment and seems to carry durable responses as it serves as a current first-line therapy option for cisplatin-ineligible patients based on previous findings with Cohort A. Although monotherapy was not the primary focus of this study, this treatment option too demonstrated a manageable safety profile that is consistent with previous findings. Cohort K paralleled previously reported results in relation to these 2 therapy arms and highlighted the continuing need for a new first line treatment option for a rising patient population.


O'Donnell PH, Milowsky MI, Petrylak DP, et al. Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer. J Clin Oncol. 2023;41(25):4107-4117. doi:10.1200/JCO.22.02887

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