A new drug, PADCEV (enfortumab vedotin-ejfv) to treat patients with locally advanced or metastatic urothelial cancer, was approved under the FDA’s Accelerated Approval Program based on tumor response rate on last Wednesday. (1)
Padcev represents a new type of breakthrough therapy for patients with advanced urothelial cancer who have previously received a PD-1/PD-L1 inhibitor and a platinum-based chemotherapy.
PADCEV is a first-in-class antibody-drug conjugate (ADC) in the targeted treatment of cancer. “These conjugates combine the ability of monoclonal antibodies to target specific receptors on cancer cells and then deliver a drug to the cancer cell,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research.
Additionally, PADCEV is directed against Nectin-4, a cell surface protein and highly expressed in bladder cancer cells and a cell-killing agent, monomethyl auristantin E (MMAE), which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis). (2-3)
Bladder cancer is the fourth most commonly diagnosed malignancy in men in the United States. An estimated 80,000 people in the U.S. will be diagnosed with bladder cancer this year. It occurs more often in men than in women, and more often in whites than in blacks according to the U.S. National Cancer Institute. (4)
There are 3 types of bladder cancer include:
- Urothelial cancer. Also called transitional cell carcinoma, occurs in the cells that line the inside of the bladder. These cells are able to stretch when the bladder is full and shrink when it is emptied. Most bladder cancers begin in the transitional cells. Urothelial carcinoma is the most common type of bladder cancer in the United States.
- Squamous cell carcinoma. Cancer that forms in squamous cells (thin, flat cells that line the bladder). Cancer may form after long-term infection or irritation. Squamous cell bladder cancer is rare in the United States. It's more common in parts of the world where a certain parasitic infection (schistosomiasis) is a common cause of bladder infections.
- Adenocarcinoma. Cancer that begins in glandular cells. Glandular cells in the bladder urothelium make substances such as mucus. (5)
“Metastatic urothelial cancer is an aggressive and devastating disease with limited treatment options, and the approval of PADCEV is a significant advance for these patients who previously had limited options after initial therapies failed,” said Jonathan E. Rosenberg, M.D., Medical Oncologist, Chief, Genitourinary Medical Oncology Service, Memorial Sloan Kettering Cancer Center in New York.
The FDA's approval of PADCEV is based on clinical data from the pivotal trial EV-201, a single-arm phase II multi-center trial that enrolled a range of patients (125 cases) with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-L1 inhibitor and a platinum-based chemotherapy. (3) This study found that the primary endpoint of confirmed objective response rate (ORR) was 44 percent per blinded independent central review (55/125; 95% Confidence Interval [CI]: 35.1, 53.2). Among patients treated with the single-agent PADCEV, 12 percent (15/125) experienced a complete response, meaning no cancer could be detected at the time of assessment, and 32 percent (40/125) experienced a partial response, meaning a decrease in tumor size or extent of cancer in the body. The median duration of response (DoR), a secondary endpoint, was 7.6 months (95% CI: 6.3, not estimable [NE]).
A global, randomized phase III confirmatory clinical trial (EV-301) is underway.
The recommended PADCEV dose is 1.25 mg/kg (up to a maximum dose of 125 mg) administered as an IV infusion over 30 minutes on days 1, 8 and 15 of a 28-day cycle until disease progression or unacceptable toxicity.
During the clinical trial, the most common serious adverse reactions associated with PADCEV were (≥3%) were urinary tract infection (6%), cellulitis (5%), febrile neutropenia (4%), diarrhea (4%), sepsis (3%), acute kidney injury (3%), dys...
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