China’s National Medical Products Administration (NMPA) has approved enfortumab vedotin (Padcev™ ; Astellas Pharma and Pfizer; see ADC drugmap) in combination with pembrolizumab (keytruda®; Merck Sharp & Dohme Corp., a subsidiary of Merck & Co) for adult patients with locally advanced or metastatic urothelial cancer (la/mUC).
The treatment combination will provide a new therapeutic option to patients with la/mUC in China and offer an alternative to platinum-containing chemotherapy, the standard of care for nearly 40 years.[1][2]
Enfortumab vedotin is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer. 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).[1]
Bladder cancer leads to significant morbidity and mortality across China. Over 92,000 people were diagnosed with bladder cancer in 2022, and approximately 41,000 deaths were reported as a result of the disease. [3]
In China, the incidence rate of bladder cancer in 2022 ranked 11th among all cancers, with over 92,000 new cases diagnosed that year. [3] The five year prevalence of bladder cancer in China is estimated to be 2.5/100,000 cases, or 276,102 cases. [3]
Majority of Bladder Cancers
Urothelial cancer, or bladder cancer, which accounts for 90% of all bladder cancers, is a debilitating and frequently aggressive form of cancer. [4] When the disease is diagnosed at a late stage, survival rates are often extremely poor, driving the urgent need for new treatment strategies that can extend patients’ lives.
The disease generally begins in the urothelial cells, which line the urethra, bladder, ureters, renal pelvis, and some other organs. [5] Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter, and urethra. [4][6][7] If bladder cancer has spread to surrounding organs or muscles, it is called locally advanced disease. [8] If the cancer has spread to other parts of the body, it is called metastatic disease.[9] Approximately 12% of cases are locally advanced or metastatic urothelial cancer at diagnosis. [10]
Continuous treatment and surveillance makes bladder cancer one of the most expensive cancer types over the lifetime of a patient, and the costliest cancer when compared to other malignancies.[11]
Approval
“The NMPA approval of enfortumab vedotin in combination with pembrolizumab is the first non-platinum treatment for Chinese patients with advanced urothelial cancer that can be used in the first-line setting,” noted Professor Guo Jun, Lead Primary Investigator of the EV-302 trial in China, Director of the Department of Urologic Oncology and Melanoma/Sarcoma, Beijing Cancer Hospital, China, Vice Chairman and Chief-Secretary of the Chinese Society of Clinical Oncology (CSCO)
“The results of the EV-302 study demonstrate that this combination nearly doubled median overall survival (OS), and increased median progression-free survival (PFS), overall response rate and complete response rate compared to platinum-based chemotherapy. These results were seen in a broad population of patients with locally advanced or metastatic urothelial cancer, regardless of patients’ biomarker status, cisplatin eligibility or liver metastasis. I believe that this new treatment regimen will change the clinical treatment landscape of urothelial carcinoma in China and bring hope of longer survival to more Chinese patients with advanced urothelial carcinoma,” Jun added.
Limited options available
“The current first-line treatment strategy for advanced urothelial carcinoma in China is platinum-based chemotherapy, with very limited clinical options available. The approval of enfortumab vedotin in combination with pembrolizumab represents the first treatment regimen in the past 20-30 years that has shown superiority over platinum-based chemotherapy in the entire population. We hope that this combination could become the future standard of care treatment,” Professor Huang Jian, Lead Primary Investigator of the EV-302 Study in China, Chairman of the Urology Subcommittee of the Chinese Medical Association, Department of Urology at Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Another step forward
“We are delighted that the NMPA has recognized the benefits that enfortumab vedotin has offered to patients with previously treated locally advanced or metastatic urothelial cancer in China following its approval in August 2024. This latest approval in combination with pembrolizumab marks another step forward in our mission to bring new, innovative treatment strategies to patients in China. We look forward to making a significant impact on patients’ lives, helping to slow disease progression and give them precious more time,” Ahsan Arozullah, M.D., M.P.H., Senior Vice President, Head of Oncology Development, Astellas.
Supporting studies
The NMPA’s approval of enfortumab vedotin in combination with pembrolizumab is supported by the results from the Phase 3 EV-302 clinical trial, also known as KEYNOTE-A39.
The trial demonstrated that the treatment combination improved median overall survival (OS) and median progression-free survival (PFS) with statistically significant and clinically meaningful results in patients with previously untreated la/mUC compared to platinum-containing chemotherapy.
A median OS of 31.5 months (95% CI: 25.4-NR) was achieved with the treatment combination compared to 16.1 months (95% CI: 13.9-18.3) with platinum-containing chemotherapy, representing a 53% reduction in risk of death (Hazard Ratio [HR]=0.47; 95% Confidence Interval [CI]: 0.38-0.58; P<0.00001). A median PFS of 12.5 months (95% CI: 10.4-16.6) was reported with the treatment combination compared to 6.3 months (95% CI: 6.2-6.5) with platinum-containing chemotherapy, representing a 55% reduction in the risk of cancer progression or death (HR=0.45; 95% CI: (0.38-0.54); P<0.00001). The safety results were consistent with those previously reported with this treatment combination, and no new safety issues were identified. [1]
The most common (≥3%) Grade 3 or higher adverse events related to treatment with enfortumab vedotin and pembrolizumab were maculo-papular rash, hyperglycemia, neutropenia, peripheral sensory neuropathy, diarrhea, and anemia. The safety results in EV-302 are generally consistent with the known safety events previously reported with each agent alone, and with the safety profile of this combination in EV-103 in cisplatin-ineligible patients with la/mUC. No new safety issues were identified.[1]
The EV-302 trial is part of an extensive clinical program evaluating this combination in multiple stages of urothelial cancer and other solid tumors. Findings from EV-302 were presented at the 2023 European Society for Medical Oncology (ESMO) Congress and were published in the New England Journal of Medicine.[2]
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Clinical trials
Enfortumab Vedotin and Pembrolizumab vs. Chemotherapy Alone in Untreated Locally Advanced or Metastatic Urothelial Cancer (EV-302) – ClinicalTrials.gov ID NCT04223856
A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer (EV-103) – ClinicalTrials.gov ID NCT03288545
A Study to Evaluate Enfortumab Vedotin (ASG-22CE) in Chinese Participants With Locally Advanced or Metastatic Urothelial Cancer Who Previously Received Platinum-containing Chemotherapy and Programmed Cell Death Protein-1 ( PD 1) / (Programmed Death Ligand-1 (PD-L1) Inhibitor Therapy – ClinicalTrials.gov ID NCT04995419
Perioperative Enfortumab Vedotin (EV) Plus Pembrolizumab (MK-3475) Versus Neoadjuvant Chemotherapy for Cisplatin-Eligible Muscle Invasive Bladder Cancer (MIBC) (MK-3475-B15/ KEYNOTE-B15 / EV-304) (KEYNOTE-B15) ClinicalTrials.gov ID NCT04700124
Perioperative Pembrolizumab (MK-3475) Plus Cystectomy or Perioperative Pembrolizumab Plus Enfortumab Vedotin Plus Cystectomy Versus Cystectomy Alone in Participants Who Are Cisplatin-ineligible or Decline Cisplatin With Muscle-invasive Bladder Cancer (MK-3475-905/KEYNOTE-905/EV-303) – ClinicalTrials.gov ID NCT03924895
A Study of Intravesical Enfortumab Vedotin For Treatment of Patients With Non-muscle Invasive Bladder Cancer (NMIBC) – ClinicalTrials.gov ID NCT05014139
A Study to Evaluate Enfortumab Vedotin in Subjects With Locally Advanced or Metastatic Malignant Solid Tumors (EV-202) – ClinicalTrials.gov ID NCT04225117
Summary of Product Characteristics (Europe)
Enfortumab vedotin (Padcev™ ; Astellas Pharma and Pfizer) [SPC]
Highlights of Prescribing Information (USA)
Enfortumab vedotin (Padcev™ ; Astellas Pharma and Pfizer)[Prescribing Information]
References
[1] Challita-Eid PM, et al. Enfortumab vedotin antibody-drug conjugate targeting nectin-4 is a highly potent therapeutic agent in multiple preclinical cancer models. Cancer Res. 2016;76(10):3003-13.
[2] Powles T, Valderrama BP, Gupta S, et al. Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer. N Engl J Med. 2024;390:875-888.
[3] International Agency for Research on Cancer (IARC). Global Cancer Observatory. China factsheet. (2022). Online. Last accessed in January 2025.
[4] Leslie SW, Soon-Sutton TL, Aeddula NR. Bladder Cancer: StatPearls. (Updated 2024 Aug 15]. Online. Last accessed in January 2025.
[5] National Cancer Institute. What is bladder cancer? (February 2023) Online. Last accessed in January 2025.
[6] Leow JJ, Liu Z, Tan TW, et al. Optimal management of upper tract urothelial carcinoma: Current perspectives. Onco Targets Ther. 2020;13:1-15.
[7]Petros FG. Epidemiology, clinical presentation, and evaluation of upper-tract urothelial carcinoma. Transl Androl Urol. 2020;9(4):1794-8.
[8] National Cancer Institute. NCI dictionary of cancer terms: Locally advanced cancer. Online. Last accessed in January 2025.
[9] American Cancer Society. If you have bladder cancer. (March 2024). Online. Last accessed in January 2025.
[10] National Cancer Institute. Cancer stat facts: bladder cancer. Online. Last accessed in January 2025.
[11] Aly A, Johnson C, Doleh Y, et al. The real-world lifetime economic burden of urothelial carcinoma by stage at diagnosis. J Clin Pathw. 2020;6(4):51-60.
Featured Image: Using fire as a symbol of cancer of the internal organs, including bladder, liver, and kidneys. Courtesy: © 2017. Fotolia. Used with permission.
DOI: 10.14229/jadc.2025.01.08.002
