A phase I study of enfortumab vedotin in Japanese patients with locally advanced or metastatic urothelial carcinoma

Shunji Takahashi,Motohide Uemura,Akito Yamaguchi,Takeshi Kadokura,Elaina M Gartner,Atsushi Takamoto,Takashi Inoue,Yoshihide Kawasaki,Rio Akazawa,Amal Melhem-Bertrandt,Toshiki Tanikawa,Tomokazu Kimura

doi:10.1007/s10637-019-00844-x

Abstract

SummaryLocally advanced or metastatic urothelial cancer is an aggressive form of cancer with high recurrence rates and low survival. Nectin-4 is a cell adhesion molecule commonly expressed in several tumors, including high expression in urothelial cancer. Enfortumab vedotin is an antibody–drug conjugate composed of an anti-Nectin-4 humanized monoclonal antibody linked to the microtubule disrupting agent, monomethyl auristatin E. In this phase I study (NCT03070990), Japanese patients with locally advanced/metastatic urothelial cancer treated with prior chemotherapy, or ineligible for cisplatin, were randomized 1:1 to receive 1.0 mg/kg (Arm A) or 1.25 mg/kg (Arm B) enfortumab vedotin on Days 1, 8, and 15 of each 28-day cycle. Assessing the pharmacokinetic and safety/tolerability profiles of enfortumab vedotin were primary objectives; investigator-assessed antitumor activity (RECIST v1.1) was a secondary objective. Seventeen patients (n = 9, Arm A; n = 8, Arm B) received treatment. Pharmacokinetic data suggest a dose-dependent increase in enfortumab vedotin maximum concentration and area under the concentration–time curve at Day 7. Enfortumab vedotin was well tolerated across both doses. Dysgeusia and alopecia (n = 9 each) were the most common treatment-related adverse events. Regardless of attribution, grade ≥ 3 adverse events occurring in ≥2 patients were anemia and hypertension (n = 2 each). One patient achieved a confirmed complete response (Arm A) and five achieved confirmed partial responses (n = 3, Arm A; n = 2, Arm B). Objective response and disease control rates were 35.3% and 76.5%, respectively. In Japanese patients with locally advanced/metastatic urothelial cancer, enfortumab vedotin is well tolerated with preliminary antitumor activity and a pharmacokinetic profile consistent with prior reports.

Highlights

And historically advanced stages of urothelial carcinoma have been difficult to treat
A total of 24 Japanese patients with locally advanced or metastatic urothelial cancer (UC) gave informed consent to participate in the study and prior to randomization five patients failed screening
All patients had prior cisplatin-based treatment; one patient in Arm A was previously treated with an immune checkpoint inhibitor

Summary

Introduction

And historically advanced stages of urothelial carcinoma have been difficult to treat. In Japan, the 2012 incidence rate for locally advanced or metastatic urothelial cancer (UC) was estimated as 2.8 per 100,000 patients [1]. Chemotherapy combinations of cisplatin plus gemcitabine, or cisplatin plus methotrexate, vinblastine, and doxorubicin, are the established, standard first-line regimens for the treatment of locally advanced or metastatic UC throughout the United States, Europe, Canada, and Japan [2, 3]. Carboplatin with gemcitabine is frequently an alternative regimen for these patients [4]. While the initial response rates range from 50% to 70%, few patients have durable responses and many patients become resistant to the initial treatment, and for those patients who fail on first-line chemotherapy, the 5-year survival rate is low (5%) [1]

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Discussion

Conclusion