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

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

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.

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

References

    1. Bharmal M, Guenther S, Kearney M, Kempel-Waibel A (2017) Epidemiology of locally advanced or metastatic urothelial cancer in the US, Europe and Japan. Value in health 20:Abstract PCN45.
    1. Witjes JA, Comperat E, Cowan NC, De Santis M, Gakis G, Lebret T, Ribal MJ, Van der Heijden AG, Sherif A, European Association of U EAU guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2013 guidelines. Eur Urol. 2014;65(4):778–792. doi: 10.1016/j.eururo.2013.11.046.
    1. Milowsky MI, Rumble RB, Booth CM, Gilligan T, Eapen LJ, Hauke RJ, Boumansour P, Lee CT. Guideline on muscle-invasive and metastatic bladder cancer (European association of urology guideline): American society of clinical oncology clinical practice guideline endorsement. J Clin Oncol. 2016;34(16):1945–1952. doi: 10.1200/JCO.2015.65.9797.
    1. De Santis M, Bellmunt J, Mead G, Kerst JM, Leahy M, Maroto P, Gil T, Marreaud S, Daugaard G, Skoneczna I, Collette S, Lorent J, de Wit R, Sylvester R. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol. 2012;30(2):191–199. doi: 10.1200/JCO.2011.37.3571.
    1. Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee JL, Fong L, Vogelzang NJ, Climent MA, Petrylak DP, Choueiri TK, Necchi A, Gerritsen W, Gurney H, Quinn DI, Culine S, Sternberg CN, Mai Y, Poehlein CH, Perini RF, Bajorin DF, Investigators K. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015–1026. doi: 10.1056/NEJMoa1613683.
    1. Challita-Eid PM, Satpayev D, Yang P, An Z, Morrison K, Shostak Y, Raitano A, Nadell R, Liu W, Lortie DR, Capo L, Verlinsky A, Leavitt M, Malik F, Avina H, Guevara CI, Dinh N, Karki S, Anand BS, Pereira DS, Joseph IB, Donate F, Morrison K, Stover DR. Enfortumab vedotin antibody-drug conjugate targeting nectin-4 is a highly potent therapeutic agent in multiple preclinical cancer models. Cancer Res. 2016;76(10):3003–3013. doi: 10.1158/0008-5472.CAN-15-1313.
    1. Rikitake Y, Mandai K, Takai Y. The role of nectins in different types of cell-cell adhesion. J Cell Sci. 2012;125(Pt 16):3713–3722. doi: 10.1242/jcs.099572.
    1. Uhlen M, Fagerberg L, Hallstrom BM, Lindskog C, Oksvold P, Mardinoglu A, Sivertsson A, Kampf C, Sjostedt E, Asplund A, Olsson I, Edlund K, Lundberg E, Navani S, Szigyarto CA, Odeberg J, Djureinovic D, Takanen JO, Hober S, Alm T, Edqvist PH, Berling H, Tegel H, Mulder J, Rockberg J, Nilsson P, Schwenk JM, Hamsten M, von Feilitzen K, Forsberg M, Persson L, Johansson F, Zwahlen M, von Heijne G, Nielsen J, Ponten F. Proteomics. Tissue-based map of the human proteome. Science. 2015;347(6220):1260419. doi: 10.1126/science.1260419.
    1. Wu C, Orozco C, Boyer J, Leglise M, Goodale J, Batalov S, Hodge CL, Haase J, Janes J, Huss JW, 3rd, Su AI. BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources. Genome Biol. 2009;10(11):R130. doi: 10.1186/gb-2009-10-11-r130.
    1. Pavlova NN, Pallasch C, Elia AE, Braun CJ, Westbrook TF, Hemann M, Elledge SJ. A role for PVRL4-driven cell-cell interactions in tumorigenesis. Elife. 2013;2:e00358. doi: 10.7554/eLife.00358.
    1. Rosenberg JE, Sridhar SS, Zhang J, Smith DC, Ruether JD, Flaig TW, Baranda JC, Lang JM, Plimack ER, Sangha RS, Heath EI, Merchan JR, Quinn DI, Srinivas S, Milowsky MI, Wu C, Gartner EM, Melhem-Bertrandt A, Petrylak DP (2018) Updated results from the enfortumab vedotin phase 1 (EV-101) study in patients with metastatic urothelial cancer (mUC). J Clin Oncol 36(suppl 15):4504–4504. 10.1200/JCO.2018.36.15_suppl.4504
    1. Petrylak D, Perez RP, Zhang J, Smith DC, Ruether JD, Sridhar SS, Sangha RS, Lang JM, Heath EI, Merchan JR, Gartner EM, Chu R, Aaand B, Donate F, Jackson L, Adams J, Melhem-Bertrandt A, Rosenberg JE (2017) A phase 1 study of enfortumab vedotin: updated analysis of patients with metastatic urothelial cancer. J Clin Oncol 35(suppl 15):106.
    1. Petrylak D, Smith DC, Flaig TW, Zhang J, Sridhar SS, Ruether JD, Plimack ER, Merchan JR. Enfortumab vedotin (EV) in patients (Pts) with metastatic urothelial carcinoma (mUC) with prior checkpoint inhibitor (CPI) failure: a prospective cohort of an ongoing phase 1 study. J Clin Oncol. 2018;16(suppl 6):431–431. doi: 10.1200/JCO.2018.36.6_suppl.431.
    1. Komlodi-Pasztor E, Sackett D, Wilkerson J, Fojo T. Mitosis is not a key target of microtubule agents in patient tumors. Nat Rev Clin Oncol. 2011;8(4):244–250. doi: 10.1038/nrclinonc.2010.228.
    1. Donaghy H. Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates. MAbs. 2016;8(4):659–671. doi: 10.1080/19420862.2016.1156829.

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