FDA Approval Summary: Enfortumab Vedotin for Locally Advanced or Metastatic Urothelial Carcinoma

Abstract

On December 18, 2019, the FDA granted accelerated approval to enfortumab vedotin-ejfv (PADCEV; Astellas and Seattle Genetics) for treatment of patients with locally advanced or metastatic urothelial cancer who have previously received a programmed cell death protein 1 or programmed death ligand 1 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% confidence interval (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).

Case Report: Enfortumab Vedotin for Metastatic Urothelial Carcinoma: A Case Series on the Clinical and Histopathologic Spectrum of Adverse Cutaneous Reactions From Fatal Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis to Dermal Hypersensitivity Reaction

“…Alternatively, the dermatologic sequalae observed could be attributed solely to the MMAE payload without Nectin-4 direction. This is supported by the common occurrence of skin rash as an adverse event in trials evaluating other antibody-drug conjugates that incorporate MMAE, occurring in 31% of patients with classical Hodgkin lymphoma treated with brentuximab vedotin monotherapy, 44% of patients treated with glemutumumab vedotin, and 13–31% of patients treated with polatuzumab vedotin ( 10 ). Lastly, dermatologic toxicities from prior immune checkpoint inhibitor treatment cannot be entirely ruled out as delayed onset of SJS/TEN >8 weeks following exposure have been cited ( 11 , 12 ).…”

Antibody–drug conjugates in solid tumors: a look into novel targets

“…Almost all patients had detectable nectin-4 expression, with a median H-score of 290 (range 14-130) [39]. Notably, response to EV was independent from H-score [43].…”

“…Notably, previously reported ORR and DOR of alternative therapies for mUC in this setting are significantly lower [41,42]. Safety analysis was conducted on 310 patients from 3 different trials [43]. Most frequently reported toxicities of any grade were fatigue, peripheral neuropathy along with gastrointestinal and skin toxicities.…”

“…Many of these toxicities (hyperglycemia, skin rash and peripheral neuropathy) have been described also for other ADCs carrying MMAE and have been attributed mainly to the payload [44]. Skin toxicity instead may be at least partially classified as on-target/ off-tumor toxicity, being nectin-4 highly expressed by cutaneous cells [43]. Nectin-4 expression was not requested for inclusion in abovementioned trials.…”

Exatecan Antibody Drug Conjugates Based on a Hydrophilic Polysarcosine Drug-Linker Platform

“…These agents possess reduced systemic toxicity and aim to improve the narrow therapeutic window associated with conventional chemotherapies. One hundred years after the emergence of the Magic Bullet concept [ 2 ], 10 ADCs are now clinically approved, 5 of which were approved during the past two years [ 3 , 4 , 5 , 6 , 7 ]. More than 90 ADCs are currently under clinical evaluation [ 8 , 9 ].…”