Author Manuscript Published OnlineFirst on September 22, 2020; DOI: 10.1158/1078-0432.CCR-20-2275 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Title: FDA Approval Summary: Enfortumab Vedotin for Locally Advanced or Metastatic Urothelial Carcinoma Authors: Elaine Chang1, Chana Weinstock1, Lijun Zhang1, Rosane Charlab1, Sarah E. Dorff1, Yutao Gong1, Vicky Hsu1, Fang Li1, Tiffany K. Ricks1, Pengfei Song1, Shenghui Tang1, Peter E. Waldron1, Jingyu Yu1, Eias Zahalka1, Kirsten B. Goldberg2, Richard Pazdur1,2, Marc R. Theoret1,2, Amna Ibrahim1, Julia A. Beaver1 Authors’ Affiliations: 1Center for Drug Evaluation and Research, U.S. Food and Drug Administration; 2Oncology Center of Excellence, U.S. Food and Drug Administration Running Title: FDA Approval Summary: Enfortumab vedotin Corresponding Author: Elaine Chang, Office of Oncologic Diseases, CDER, U.S. Food and Drug Administration, WO22 Room 2169, 10903 New Hampshire Avenue, Silver Spring, MD 20993. Phone 240-402-2628. Fax: 301-796-9909. Email: [email protected]. Note: This is a U.S. Government work. There are no restrictions on its use. Disclosure of Potential Conflicts of Interest: The authors report no financial interests or relationships with the commercial sponsors of any products discussed in this report. Word count: Abstract 200; Text 2996; Tables = 3; Figures = 1 ; References = 18 1 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 22, 2020; DOI: 10.1158/1078-0432.CCR-20-2275 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract On December 18, 2019, the Food and Drug Administration (FDA) granted accelerated approval to enfortumab vedotin-ejfv (PADCEVTM; Astellas and Seattle Genetics) for treatment of patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1 or PD-L1 inhibitor, and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting. Substantial evidence of effectiveness for this application is obtained from Cohort 1 of the single arm, multicenter study EV-201. Patients received enfortumab vedotin (EV) 1.25 mg/kg (up to a maximum dose of 125 mg) intravenously on Days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity. Confirmed objective response rate in the 125-patient efficacy population determined by blinded independent central review was 44% (95% CI: 35.1, 53.2), with complete responses in 12%. Median response duration was 7.6 months (95% CI: 6.3, not estimable). Grade 3-4 adverse reactions occurred in 73% of patients. Hyperglycemia, peripheral neuropathy, ocular disorders, skin reactions, infusion site extravasations, and embryo-fetal toxicity are labeled as warnings and precautions for EV. The article summarizes the data and the FDA thought process supporting accelerated approval of EV. This approval may be contingent upon verification and description of clinical benefit in confirmatory trial(s). 2 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 22, 2020; DOI: 10.1158/1078-0432.CCR-20-2275 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction Urinary bladder cancer accounted for approximately 17,670 deaths in 2019 in the U.S.1 Although most urothelial carcinomas are non-muscle invasive at diagnosis and can be managed effectively with intravesical therapies and/or surgical resection, about half of patients relapse after cystectomy, with distant metastases being more common than local relapse.2 Additionally, approximately 4% of patients have locally advanced or metastatic disease at diagnosis.1 Standard of care for the first line treatment of patients with advanced disease is platinum-containing combination chemotherapy, such as gemcitabine and cisplatin (GC) or methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC).3 In the U.S., pembrolizumab has received regular approval for the treatment of locally advanced or metastatic urothelial carcinoma (la/mUC) after initial chemotherapy treatment. Both pembrolizumab and atezolizumab have received accelerated approval for the frontline treatment of patients with PD-L1-positive la/mUC and who are not eligible for a platinum-containing regimen, and for all treatment-naïve patients who are chemotherapy-ineligible in frontline. Avelumab has received regular approval for first-line maintenance treatment of patients without disease progression after initial platinum-containing chemotherapy, in addition to approval in the second-line setting. Durvalumab, and nivolumab have also received accelerated approval in the second line. Patients with la/mUC previously treated with a platinum-containing regimen and immunotherapy have limited therapeutic options (Table 1). Recently, erdafitinib received accelerated approval by the FDA for patients with susceptible FGFR3 or FGFR2 alterations, although this only represents approximately 20% of patients with urothelial carcinoma of the bladder and almost 40% of patients with upper tract urothelial carcinoma.4-6 Other chemotherapeutic agents, including taxanes, may also be used in this setting. None of these other 3 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 22, 2020; DOI: 10.1158/1078-0432.CCR-20-2275 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. single agent chemotherapies are curative and overall response rate (ORR) and duration of response (DOR) are low. Enfortumab vedotin-ejfv (hereafter, EV) is a Nectin-4-directed antibody-drug conjugate and an original biologic that has not previously received marketing approval for any indication by any regulatory agency. It was granted breakthrough therapy designation in 2018, meeting criteria with preliminary clinical evidence indicating that the drug could demonstrate substantial improvement over available therapy on a clinically significant endpoint. Upon submission of the marketing application in 2019, EV was granted priority review. The priority review designation is granted if the drug demonstrates evidence of improved effectiveness or safety, and sets a 6- month timeline for FDA review. However, FDA reviewed and approved EV in approximately 3 months. EV was the first biologic approved that specifically targets Nectin-4 as a directed antibody to deliver a toxic microtubule inhibitor conjugated payload. The indication is for the treatment of patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1 or PD-L1 inhibitor, and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting. Herein we discuss FDA’s benefit- risk analysis of the marketing application that led to the approval of EV for patients with refractory la/mUC. Chemistry EV is a Nectin-4-directed antibody-drug conjugate (ADC). The ADC is a fully human IgG1-kappa antibody conjugated to the microtubule-disrupting agent, monomethyl auristatin E (MMAE), via a protease-cleavable maleimidocaproyl valine-citrulline linker (SGD-1006). Nectin-4 is a transmembrane protein expressed in multiple cancers, particularly urothelial, breast, lung, pancreatic, and ovarian cancers.7 Higher levels of expression of Nectin-4 have been 4 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on September 22, 2020; DOI: 10.1158/1078-0432.CCR-20-2275 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. associated with disease progression and/or poor prognosis in breast, lung, and pancreatic cancers.8-10 Nonclinical Pharmacology and Toxicology The anticancer activity of EV was demonstrated by the ADC binding to Nectin-4– expressing cells, followed by endocytosis of the ADC–Nectin-4 complex, and MMAE release via proteolytic cleavage of the linker. MMAE disrupts microtubule dynamics, subsequently inducing cell cycle arrest and finally triggering apoptotic cell death. Results from intravenous repeat-dose toxicity studies in rats for up to 13 weeks indicated the potential for EV to impair male reproductive function and fertility. In rats and monkeys, additional target organs of toxicities included skin, bone marrow, liver, ocular system, and gastrointestinal tract. MMAE was reported to be genotoxic in the in vivo rat bone marrow micronucleus study by the aneugenic mechanism. In the dose-range-finding embryo-fetal development study in rats, EV was administered intravenously during the period of organogenesis to pregnant rats at maternal exposures approximately similar to the exposures at the recommended human dose of 1.25 mg/kg. EV caused maternal toxicity, embryo-fetal lethality, skeletal anomalies and structural malformations that included gastroschisis, malrotated hindlimb, absent forepaw, malpositioned internal organs and fused cervical arch. Clinical Pharmacology Dose Selection The proposed dosing regimen was supported by EV-201 and exposure-response analysis for efficacy and safety. The proposed dosing regimen of EV is 1.25 mg/kg (up to a maximum