The U.S. Food and Drug Administration (FDA) has approved enfortumab vedotin-ejfv (Padcev®; Astellas Pharma / Pfizer), an antibody-drug conjugate [ADC]) with pembrolizumab (Keytruda®; Merck & Co/MSD), a PD-1 inhibitor, for the treatment of adult patients with locally advanced or metastatic urothelial cancer (la/mUC). This combination is the first approved to offer an alternative to platinum-containing chemotherapy, the current standard of care in first-line la/mUC.

Bladder and Urothelial Cancer
Urothelial cancer, or bladder cancer, begins in the urothelial cells, which line the urethra, bladder, ureters, renal pelvis, and some other organs. [1] If bladder cancer has spread to surrounding organs or muscles, it is called locally advanced disease. If the cancer has spread to other parts of the body, it is called metastatic disease. [2]

Globally, approximately 573,000 new cases of bladder cancer and 212,000 deaths are reported annually. [3]  It is estimated that approximately 82,290 people in the U.S. will be diagnosed with bladder cancer in 2023. [4]

Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter, and urethra. [2] Approximately 12% of cases are locally advanced or metastatic urothelial cancer at diagnosis.[5]

Advertisement #3 

A novel treatment option
Enfortumab vedotin is a first-in-class antibody-drug conjugate (ADC) that is directed to 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)

The approval of the combination is based on results from the Phase 3 EV-302 clinical trial (NCT04223856; also known as KEYNOTE-A39), which demonstrated the combination nearly doubled median overall survival (OS) and median progression-free survival (PFS) in patients with previously untreated la/mUC compared to platinum-containing chemotherapy.

Phase 3 EV-302 clinical trial an open-label, randomized, controlled Phase 3 study, evaluating the impact of treatment with enfortumab vedotin in combination with pembrolizumab versus chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC) who were eligible for cisplatin- or carboplatin-containing chemotherapy regardless of PD-L1 status.

Findings from EV-302 trial  were presented at the European Society for Medical Oncology (ESMO) Congress 2023. EV-302 trial also serves as the confirmatory trial for the U.S. accelerated approval of this combination for adult patients with la/mUC who are not eligible to receive cisplatin-containing chemotherapy (approved in April 2023) and expands the labeled indication to include patients who are eligible to receive cisplatin chemotherapy. EV-302 is also serving as the basis for global submissions.

“Today’s FDA approval represents a paradigm change in the treatment of advanced bladder cancer and provides hope to the thousands of Americans impacted by this aggressive disease. This achievement is notable, as it is the first regimen approved in advanced urothelial cancer that has demonstrated superiority to platinum chemotherapy, the gold standard of care for decades,” noted Ahsan Arozullah, M.D., M.P.H., Senior Vice President, Head of Oncology Development, Astellas

“In the Phase 3 EV-302 study, the combination of PADCEV and pembrolizumab demonstrated survival benefit for patients with advanced bladder cancer, nearly doubling median OS and median PFS compared with chemotherapy. We hope the approval of this combination will transform the standard of care for advanced bladder cancer and give patients more time with their loved ones,” said Roger Dansey, M.D., Chief Development Officer, Oncology, Pfizer*

Trial outcomes
The EV-302 study met its dual primary endpoints of OS and PFS compared to platinum-containing chemotherapy. Treatment with the combination resulted in a median OS of 31.5 months (95% CI: 25.4-NR) compared to 16.1 months (95% CI: 13.9-18.3) with 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).

The median PFS of 12.5 months (95% CI: 10.4-16.6) with the combination compared to 6.3 months (95% CI: 6.2-6.5) with chemotherapy represents a 55% reduction in the risk of cancer progression or death (HR=0.45; 95% CI: (0.38-0.54); P<0.00001). Consistent OS and PFS results were observed across pre-defined subgroups, including cisplatin eligibility and PD-L1 expression level.

Cisplatin eligible and ineligible subgroups (n=244 and 198, respectively) saw a 47% and 57% reduced risk of death, respectively, and a 52% and 57% reduced risk of progression or death, respectively. PD-L1 and high PD-L1 expression subgroups (n=184 and 254, respectively) saw a 56% and 51% reduced risk of death, respectively, and a 50% and 58% reduced risk of progression or death, respectively.

The most common (≥20%) all-grade adverse events (AEs), including laboratory abnormalities, related to treatment with enfortumab vedotin and pembrolizumab were increased aspartate aminotransferase, increased creatinine, rash, increased glucose, peripheral neuropathy, increased lipase, decreased lymphocytes, increased alanine aminotransferase, decreased hemoglobin, fatigue, decreased sodium, decreased phosphate, decreased albumin, pruritus, diarrhea, alopecia, decreased weight, decreased appetite, increased urate, decreased neutrophils, decreased potassium, dry eye, nausea, constipation, increased potassium, dysgeusia, urinary tract infection and decreased platelets.

The safety results in EV-302 are consistent with those previously reported with this combination in EV-103 in cisplatin-ineligible patients with la/mUC. No new safety issues were identified.

“Advanced bladder cancer is a common cause of cancer-related death. The overall survival benefit seen in the EV-302 trial demonstrates the potential for PADCEV in combination with pembrolizumab to impact first-line treatment of patients with locally advanced or metastatic urothelial carcinoma. In my opinion, this is a meaningful advancement over platinum-based chemotherapy in the systemic treatment of these patients,” said Thomas Powles, M.R.C.P., M.D., Professor of Genitourinary Oncology at Queen Mary University of London; Director, Barts Cancer Center, London; EV-302 Primary Investigator

“Despite advances in the treatment of advanced bladder cancer, there remains a need for therapies that extend patients’ lives. Our network is thrilled that the FDA has approved a new treatment option, and we are excited about the hope it will provide to members of the bladder cancer patient community,” said Andrea Maddox-Smith, Chief Executive Officer of the Bladder Cancer Advocacy Network (BCAN)


Note: * Pfizer successfully completed its acquisition of Seagen on December 14, 2023.  Roger Dansey, M.D., the current Chief Development Officer, Oncology, at Pfizer joined Seagen as Chief Medical Officer in 2018, bringing extensive experience in cancer drug development. He was appointed President, Research and Development in 2022. His deep oncology background and proven leadership has helped Seagen evolve into a global, multi-product oncology company.

** Astellas and Seagen entered a clinical collaboration agreement with Merck to evaluate the combination of Astellas’ and Seagen’s enfortumab vedotin and Merck’s pembrolizumab in patients with previously untreated metastatic urothelial cancer. As previously announced, Pfizer Inc. successfully completed its acquisition of Seagen on December 14, 2023.

Clinical trials<
Enfortumab Vedotin and Pembrolizumab vs. Chemotherapy Alone in Untreated Locally Advanced or Metastatic Urothelial Cancer (EV-302) – NCT04223856
A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer (EV-103) – NCT03288545
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) – 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) – NCT03924895
A Study to Evaluate Enfortumab Vedotin in Subjects With Locally Advanced or Metastatic Malignant Solid Tumors (EV-202) – NCT04225117

Highlights of prescribing information
Enfortumab vedotin-ejfv (Padcev®; Astellas Pharma / Pfizer*) [Prescribing Information]
Pembrolizumab (Keytruda®; Merck & Co/MSD) [Prescribing Information]

[1] National Cancer Institute. What is bladder cancer? Online Last accessed on December 14, 2023
[2] American Society of Clinical Oncology. Bladder cancer: introduction (12-2021). Online Last accesses on December 14, 2023
[3] International Agency for Research on Cancer. Cancer Today: bladder globocan 2020 fact sheet (12-2020). Online. Last accesses on December 14, 2023
[4] Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023 Jan;73(1):17-48. doi: 10.3322/caac.21763. PMID: 36633525.
[5] National Cancer Institute. Cancer stat facts: Bladder Cancer. Online. Last accesses on December 14, 2023
[6] Challita-Eid PM, Satpayev D, Yang P, 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.

Featured Image: Bladder Cancer: © 2010 – 2024 Fotolia/Adobe. Used with permission.


Advertisement #4