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Clinical Trial
. 2020 Aug;38(4):1056-1066.
doi: 10.1007/s10637-019-00844-x. Epub 2019 Aug 14.

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

Shunji Takahashi  1 , Motohide Uemura  2 , Tomokazu Kimura  3 , Yoshihide Kawasaki  4 , Atsushi Takamoto  5 , Akito Yamaguchi  6 , Amal Melhem-Bertrandt  7 , Elaina M Gartner  8 , Takashi Inoue  9 , Rio Akazawa  9 , Takeshi Kadokura  9 , Toshiki Tanikawa  10
Affiliations
Clinical Trial

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

Shunji Takahashi et al. Invest New Drugs. 2020 Aug.

Abstract

Locally 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.

Keywords: Immunoconjugates; Japan; Nectins; Neoplasms; Urothelium.

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Conflict of interest statement

Motohide Uemura declares no conflict of interest. Yoshihide Kawasaki declares no conflict of interest. Toshiki Tanikawa declares no conflict of interest. Amal Melhem-Bertrandt is an employee of Astellas Pharma, Inc. Takashi Inoue is an employee of Astellas Pharma, Inc. Rio Akazawa is an employee of Astellas Pharma, Inc. Takeshi Kadokura is an employee of Astellas Pharma, Inc. Elaina M. Gartner is an employee of Seattle Genetics, Inc. Shunji Takahashi declared he has received lecture fees from Eisai, BMS, and Taiho Pharmaceutical Co., Ltd. as well as research funding from MSD, AstraZeneca, Quintiles, Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co. Ltd., Daiihi Sankyo, CMIC, Novartis, and Bayer. Atsushi Takamoto declares having received personal fees from Astellas Pharma, Inc. Tomokazu Kimura declares having received personal fees from Astellas Pharma, Inc. Akito Yamaguchi declares having received compensation for promotional material from Nippion Shinyaku and Coloplast.

Figures

Fig. 1
Fig. 1
Mean Serum Concentration Profile at Cycle 1 of (a) ADC, (b) TAb, (c), and MMAE (Semi-Log Scale Plot). Abbreviations: ADC, antibody–drug conjugate; MMAE, monomethyl auristatin E; TAb, total antibody
Fig. 2
Fig. 2
Time to and Duration of Response. Abbreviations: CR, complete response; PD, progressive disease; PR, partial response
Fig. 3
Fig. 3
Antitumor Effects of Enfortumab Vedotin in Patients With Metastatic UC (a) Change in Tumor Size From Baseline and (b) Percent Change in Tumor Size. Abbreviations: PD, progressive disease; UC, urothelial cancer
See this image and copyright information in PMC

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