OVERVIEW

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Enfortumab Vedotin – Padcev®

DRUG CLASS

Antineoplastic Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

ANNOTATED BIBLIOGRAPHY

References updated: 30 November 2023

• Wellstein A, Giaccone G, Atkins MB, Sausville EA. Pathway targeted therapies: monoclonal antibodies, protein kinase inhibitors, and various small molecules. In, Brunton LL Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 1203-36.

  (Textbook of pharmacology and therapeutics).
• FDA. https://www​.accessdata​.fda.gov/drugsatfda_docs​/nda/2019/761137Orig1s000MultiDiscliplineR.pdf

  (FDA website with product labels and initial multidiscipline review of enfortumab vedotin mentions that in the total safety cohort of 310 patients, ALT elevations occurred in 34% of patients and were above 5 times ULN in 3%, led to dose interruption in 2%, and discontinuation in 1% but there were no cases of clinically apparent liver injury with jaundice attributed to therapy).
• Rosenberg JE, O'Donnell PH, Balar AV, McGregor BA, Heath EI, Yu EY, Galsky MD, et al. Pivotal trial of enfortumab vedotin in urothelial carcinoma after platinum and anti-programmed death 1/programmed death ligand 1 therapy. J Clin Oncol. 2019;37:2592-2600. [PMC free article: PMC6784850] [PubMed: 31356140]

  (Among 125 patients with refractory or relapsed, locally advanced or metastatic urothelial cancer treated with enfortumab vedotin, the objective response rate was 44%, while adverse events occurred in most patients including fatigue in 50%, alopecia 49%, decreased appetite 44%, dysgeusia 40%, and peripheral neuropathy 40%, leading to dose reductions in 32% and discontinuation in 12%; ALT elevations arose in 20% that were above 5 times ULN in 2).
• Joubert N, Beck A, Dumontet C, Denevault-Sabourin C. Antibody-drug conjugates: the last decade. Pharmaceuticals (Basel). 2020;13:245. [PMC free article: PMC7558467] [PubMed: 32937862]

  (Review of the development, structure, efficacy, adverse event rates and approval of vector-based chemotherapy using selective delivery by a monoclonal antibody and cancer cell injury by a conjugated cellular toxin [payload] including nine that are FDA approved and six others in pivotal trials).
• Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N Engl J Med. 2021;384:1125-1135. [PMC free article: PMC8450892] [PubMed: 33577729]

  (Among 608 patients with refractory, locally advanced or metastatic urothelial carcinoma treated with enfortumab vedotin [1.25 mg/kg on days 1, 8 and 15 of 28-day cycles] or standard chemotherapy, median overall survival was 13 vs 9 months and overall response rates were 41% vs 18%, and while adverse event rates were similar, enfortumab treated subjects had a higher rate of serious adverse events [46% vs 44%], peripheral sensory neuropathy {46% vs 31%], hyperglycemia [6.4% vs 0.3%], and withdrawal of therapy for ALT elevations [2% vs 0.3% ]; one patient receiving enfortumab died of hepatic dysfunction [no details provided]).
• Yu EY, Petrylak DP, O'Donnell PH, Lee JL, van der Heijden MS, Loriot Y, Stein MN, et al. Enfortumab vedotin after PD-1 or PD-L1 inhibitors in cisplatin-ineligible patients with advanced urothelial carcinoma (EV‑201): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2021;22:872-882. [PubMed: 33991512]

  (Among 89 adults with advanced urothelial carcinoma refractory to therapy with PD-L1 or PD-1 and who were ineligible for cisplatin and were treated with enfortumab vedotin, the overall response rate was 52% and progression free survival 5.8 months, while adverse events were frequent including alopecia in 53%, sensory peripheral neuropathy 44%, ALT elevations 7%, and which were above 5 times ULN in 1%).
• Hoimes CJ, Flaig TW, Milowsky MI, Friedlander TW, Bilen MA, Gupta S, Srinivas S, et al. Enfortumab vedotin plus pembrolizumab in previously untreated advanced urothelial cancer. J Clin Oncol. 2023;41:22-31. [PMC free article: PMC10476837] [PubMed: 36041086]

  (Among 45 adults with advanced or metastatic urothelial cancer ineligible to receive cisplatin who were treated with enfortumab vedotin and pembrolizumab, the objective response rate was 73% and adverse events were considered “manageable”, with sensory neuropathy developing in 56%, fatigue in 51%, alopecia in 49%, and ALT elevations in 20%, none of which were above 5 times ULN or associated with symptoms or jaundice).
• Fu Z, Gao C, Wu T, Wang L, Li S, Zhang Y, Shi C. Peripheral neuropathy associated with monomethyl auristatin E-based antibody-drug conjugates. iScience. 2023;26:107778. [PMC free article: PMC10505985] [PubMed: 37727735]

  (Rates of peripheral neuropathy are higher with antineoplastic monoclonal antibody conjugates with microtubule inhibitors such as vedotin compared to other cytotoxins, overall rates ranging from 8% to 66%, severe rates from <1% to 12%, caused probably by release of the monomethyl auristatin E toxin from the targeted cells to the systemic circulation or by direct uptake of the monoclonal conjugate by peripheral nerve Schwann cells).
• Sun C, Yang X, Tang L, Chen J. A pharmacovigilance study on drug-induced liver injury associated with antibody-drug conjugates (ADCs) based on the Food and Drug Administration Adverse Event Reporting System. Expert Opin Drug Saf. 2023 Oct 29:1-12. Epub ahead of print. [PubMed: 37898875]

  (Analysis of the FDA reporting system [FAERS] for cases of drug induced liver injury submitted between 2004 and 2022, found 17,784 reports, 504 [3%] attributed to antibody-drug conjugates, 202 from the US, the implicated agents being gemtuzumab ozogamicin [n=98], brentuximab vedotin [n=37], trastuzumab emtansine [n=25], enfortumab vedotin [n=16], inotuzumab ozogamicin [n=15], transtuzumab deruxtecan [n=8], and polatuzumab vedotin [3]).