The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has confirmed its previously adopted positive opinion, recommending approval of enfortumab vedotin (Padcev™; Astellas Pharma and Seagen) as monotherapy for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received platinum-containing chemotherapy and a PD-1/L1 inhibitor.

The CHMP initially adopted a positive opinion of enfortumab vedotin on December 16, 2021, providing its recommendation to the European Commission (EC) for a final decision. During the European Commission’s decision-making process, further safety information was brought to the attention of the CHMP. Following a request from the EC and taking into account the latest information, the CHMP re-adopted its positive opinion.[1] If approved by the European Commission, enfortumab vedotin will be the first antibody-drug conjugate authorized in the European Union for people living with advanced urothelial cancer.

The positive opinion from the CHMP will now be reviewed by the European Commission which decisions are valid in the European Union Member States, as well as Iceland, Norway, and Liechtenstein.[2]

Urothelial Cancer
Urothelial cancer is the most common type of bladder cancer (90 percent of cases) and can also be found in the renal pelvis (where urine collects inside the kidney), ureter (the tube that connects the kidneys to the bladder), and urethra.[3]

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The major cause of urothelial cancer is cigarette smoking. Scientists have demonstrated that there is a strong correlation between the duration and amount of cigarette smoking and cancers at all levels of the urothelial tract. This association holds for both transitional cell and squamous cell carcinomas.[3]

Globally, approximately 573,000 new cases of bladder cancer and 212,000 deaths are reported annually.[4]

Treatment option
Enfortumab vedotin is an antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.[5] Nectin-4 belongs to the nectin family that has diverse physiological and pathological functions in humans.

Nonclinical data suggest the anticancer activity of enfortumab vedotin is due to its binding to Nectin-4 expressing cells followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).[5]

In clinical trials, enfortumab vedotin has shown significantly prolonged survival as compared with standard chemotherapy in patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-based treatment and a PD-1 or PD-L1 inhibitor.[6]

The global EV-301 trial, an open-label, phase 3 trial of enfortumab vedotin for the treatment of patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-containing chemotherapy and had had disease progression during or after treatment with a PD-1 or PD-L1 inhibitor.  The results of this trial, with prespecified interim analysis at the median follow-up, was 11.1 months showed that overall survival was longer in the enfortumab vedotin group than in the chemotherapy group (median overall survival, 12.88 vs. 8.97 months; hazard ratio for death, 0.70; 95% confidence interval [CI], 0.56 to 0.89; P=0.001). The results of the trial also showed that progression-free survival was also longer in the enfortumab vedotin group than in the chemotherapy group (median progression-free survival, 5.55 vs. 3.71 months; hazard ratio for progression or death, 0.62; 95% CI, 0.51 to 0.75; P<0.001).[6]

Clinical Trials
A Study to Evaluate Enfortumab Vedotin Versus (vs) Chemotherapy in Subjects With Previously Treated Locally Advanced or Metastatic Urothelial Cancer (EV-301) NCT03474107.

Highlights of prescribing information
Enfortumab vedotin (Padcev™; Astellas Pharma and Seagen)(Prescribing Information)

[1] European Medicines Agency. Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) February 2022. Online. Last accessed on February 25, 2022.
[2] European Medicines Agency. Authorization of medicines. Online. Last accessed on February 25, 2022.
[3] American Society of Clinical Oncology. Bladder cancer: introduction (9-20). Online. Last accessed February 25, 2022.
[4] Cancer Today. Bladder Cancer Factsheet 2020. Online. Last accessed on February 25, 2022.
[5] 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, Aviña H, Guevara CI, Dinh N, Karki S, Anand BS, Pereira DS, Joseph IB, Doñate 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 May 15;76(10):3003-13. doi: 10.1158/0008-5472.CAN-15-1313. Epub 2016 Mar 24. PMID: 27013195.
[6]Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. doi: 10.1056/NEJMoa2035807. Epub 2021 Feb 12. PMID: 33577729; PMCID: PMC8450892.

Featured image: Exterior view of the European Medicines Agency, EMA, in Amsterdam’s business district, Netherlands.  Photo courtesy: © 2021 – 2022 European Medicines Agency. Used with permission.

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