Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy

Abstract

Purpose: Locally advanced or metastatic urothelial carcinoma is an incurable disease with limited treatment options, especially for patients who were previously treated with platinum and anti-programmed death 1 or anti-programmed death ligand 1 (PD-1/L1) therapy. Enfortumab vedotin is an antibody-drug conjugate that targets Nectin-4, which is highly expressed in urothelial carcinoma.

Methods: EV-201 is a global, phase II, single-arm study of enfortumab vedotin 1.25 mg/kg (intravenously on days 1, 8, and 15 of every 28-day cycle) in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum chemotherapy and anti-PD-1/L1 therapy. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by blinded independent central review. Key secondary end points were duration of response, progression-free survival, overall survival, safety, and tolerability.

Results: Enfortumab vedotin was administered to 125 patients with metastatic urothelial carcinoma. Median follow-up was 10.2 months (range, 0.5 to 16.5 months). Confirmed objective response rate was 44% (95% CI, 35.1% to 53.2%), including 12% complete responses. Similar responses were observed in prespecified subgroups, such as those patients with liver metastases and those with no response to prior anti-PD-1/L1 therapy. Median duration of response was 7.6 months (range, 0.95 to 11.30+ months). The most common treatment-related adverse events were fatigue (50%), any peripheral neuropathy (50%), alopecia (49%), any rash (48%), decreased appetite (44%), and dysgeusia (40%). No single treatment-related adverse events grade 3 or greater occurred in 10% or more of patients.

Conclusion: Enfortumab vedotin demonstrated a clinically meaningful response rate with a manageable and tolerable safety profile in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum and anti-PD-1/L1 therapies.

Trial registration: ClinicalTrials.gov NCT03219333.

FIG 1.

CONSORT diagram. Three patients were discontinued from the study before receiving study treatment; 1 due to clinical deterioration, 1 per patient decision, and 1 due to low hemoglobin levels after screening and enrollment. This latter patient met all eligibility criteria, including adequate hemoglobin level and was enrolled in the study; however, the patient’s hemoglobin levels were subsequently found to be low and the investigator withdrew the patient from the study as a result.

FIG 2.

Response among patients with metastatic urothelial carcinoma per blinded independent central review. (A) Swimmer plot of the objective responses (n = 55) (according to RECIST v1.1.) from the start of treatment to disease progression, as determined by blinded independent central review, or death. At the time of analysis, 44% of responders had ongoing responses. (B) Waterfall plot of the best percentage of change from baseline in the sum of the diameters of target lesions as identified per RECIST v1.1. Target lesions were reduced in 84% of patients (92 of 110) who were evaluable—that is, had target lesions and adequate postbaseline assessment). Dashed line indicates threshold for partial response (−30%), but is not necessarily indicative of response. CR, complete response; ORR, overall response rate; PR, partial response.

FIG 3.

Objective response in key prespecified subgroups per blinded independent central review. This prespecified subgroup analysis was performed on the full analysis set of all patients who received any amount of enfortumab vedotin (N = 125). Historical control response rate is 10%, as indicated by dashed line. The programmed death ligand 1 (PD-L1) combined positive score (CPS) was defined as the percentage of tumor and infiltrating immune cells with PD-L1 expression of the total number of tumor cells. The upper tract was defined as the renal pelvis, ureter, and kidney. Data are given as No. (%), unless otherwise noted. (†) Bellmunt risk score was not available for 1 patient. (‡) Anti-PD-1 or anti-PD-L1 therapy. (§) Five patients did not have tumor samples evaluable for PD-L1 expression levels. ECOG, Eastern Cooperative Oncology Group; ORR, objective response rate; UC, urothelial carcinoma.

FIG A1.

Kaplan-Meier estimate of duration of response for responders per blinded independent central review. PD, progressive disease.

FIG A2.

Kaplan-Meier estimate of duration of response for responders per investigator assessment. PD, progressive disease.

FIG A3.

Waterfall plot of the best percentage change from baseline of target lesions per investigator. Waterfall plot of the best percentage of change from baseline in the sum of the diameters of target lesions according to RECIST, version 1.1, per investigator. Overall, 114 patients were evaluable for target lesion response, and 11 patients were not evaluable. Dashed line indicates approximate threshold for partial response (−30%), but is not necessarily indicative of response. ORR, overall response rate.

FIG A4.

Kaplan-Meier estimate of progression-free survival per investigator in the full analysis set.

FIG A5.

Kaplan-Meier estimate of progression-free survival per blinded independent central review in the full analysis set.

FIG A6.

Kaplan-Meier estimate of overall survival in the full analysis set.