FDA Approves New Drug, PADCEV to Treat Locally Advanced or Metastatic Urothelial Cancer

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%), dyspnea (3%), and rash (3%). Fatal adverse reactions occurred in 3.2% of patients, including acute respiratory failure, aspiration pneumonia, cardiac disorder, and sepsis (each 0.8%).

Regarding drug safety, the most common adverse reaction leading to discontinuation was peripheral neuropathy (6%). The most common adverse reactions (≥20%) were fatigue (56%), peripheral neuropathy (56%), decreased appetite (52%), rash (52%), alopecia (50%), nausea (45%), dysgeusia (42%), diarrhea (42%), dry eye (40%), pruritus (26%) and dry skin (26%). The most common Grade ≥3 adverse reactions (≥5%) were rash (13%), diarrhea (6%) and fatigue (6%). Patients may experience eye disorders and vision changes while taking Padcev.

The FDA approval of PADCEV is welcome news for patients with  locally advanced or metastatic urothelial cancer. However, PADCEV is an antibody-drug conjugate that releases MMAE via proteolytic cleavage. MMAE is primarily metabolized by CYP3A4 in vitro.

Also, grapefruit increases toxicity of PADCEV by affecting hepatic and intestinal enzyme CYP3A4 metabolism. Concomitant use with a strong CYP3A4 inhibitor may increase free MMAE exposure, which may increase the incidence or severity of PADCEV toxicities.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of PADCEV to FDA’s MedWatch Reporting System.

PADCEV is co-developed by Astellas and Seattle Genetics under a collaboration that was entered into in 2007 and expanded in 2009. Under the collaboration, the companies are sharing costs and profits on a 50:50 basis worldwide. The U.S. FDA granted the approval of Padcev to Astellas Pharma US Inc.

Astellas Pharma US, Inc., based in Tokyo, Japan, is a bio pharmaceuticals company dedicated to improving the health of people around the world through the provision of innovative and reliable pharmaceutical products. For more information, visit  the website at https://www.astellas.com/en.

Seattle Genetics, Inc., based in Bothell, Washington, US  is an emerging multi-product, global biotechnology company that develops and commercializes transformative therapies targeting cancer to make a meaningful difference in people’s lives. 

References

1.  www.fda.gov/news-events  December 18, 2019.

2   J Clin Oncol  2019;37(29):2592-600.

3   Cancer Res  2016;76(10):3003-13.

4   National Cancer Institute. (2019) https://seer.cancer.gov/statfacts/html/urinb.html

5   American Society of Clinical Oncology (2017). https://www.cancer.net/cancer-types/bladdercancer/introduction

About the Author:

Lin Zhang, M.D., senior director of a health care industry company in the United States. With the experience in clinical medicine, biotechnology, health industry and other fields, he is responsible for the research and development of plant medicine, functional food and health products. He was a clinician and worked for the National Cancer Institute, FDA and the National Cancer Center of Japan for many years.

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