Padcev and advanced urothelial cancer

Padcev received accelerated approval for the treatment of locally advanced or metastatic urothelial cancer announced on Dec. 18, 2019.It specifically targets the cell adhesion molecule Nectin-4, which is highly expressed in urothelial cancers.

“Antibody-drug conjugates are strategic tools 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, MD, director of FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in FDA’s Center for Drug Evaluation and Research.

“Padcev (enfortumab vedotin-ejfv) is an antibody-drug conjugate that targets Nectin-4, a cell surface protein expressed on bladder cancer cells and a cell-killing agent, monomethyl auristantin E.”

Padcev is indicated for the treatment of adult patients with locally advanced (when cancer has grown too large to be surgically removed) or metastatic (when cancer cells spread to other parts of the body) urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor and a platinum-containing chemotherapy.Platinum-containing chemotherapy, PD-1 and PD-L1 inhibitors are standard treatments for patients with bladder cancer, the sixth most common cancer in the U.S. Urothelial cancer, accounting for more than 90% of bladder cancers, begins in cells that line the bladder and nearby organs. Padcev represents a new type of therapy for patients with advanced urothelial cancer whose disease has progressed on chemotherapy and immunotherapy.

“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,” Dr. Jonathan E. Rosenberg, medical oncologist and chief of genitourinary medical oncology service at Memorial Sloan Kettering Cancer Center in New York, said in a press release.

Approval was based on clinical data from EV-201, a single-arm phase 2 multicenter trial of 125 patients with locally advanced or metastatic urothelial cancer who had previously received treatment with a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy.

“The Padcev clinical trial enrolled a range of patients whose cancer was difficult to treat, including those whose disease had spread to the liver,” Rosenberg added.

The overall response rate, reflecting the percentage of patients who had a certain amount of tumor shrinkage, was 44%, with 12% having a complete response and 32% having a partial response. The median duration of response was 7.6 months.

The most frequently reported adverse effects for individuals taking enfortumab vedotin-ejfv included fatigue, peripheral neuropathy, decreased appetite, rash, alopecia nausea, altered taste, diarrhea, dry eye, pruritis, and dry skin. Patients’ blood glucose levels should be monitored closely, and patients should also be monitored for new or worsening peripheral neuropathy.Infusion site extravasation may occur. Women who are pregnant or breastfeeding should not take the medication.

The first-in-class antibody-drug conjugate is approved under the FDA’s Accelerated Approval Program, which allows approval of a medicine based on a surrogate endpoint if the medicine fills an unmet medical need for a serious condition. In this instance, the accelerated approval was based on tumor response rate.

Continued approval will be contingent upon further evaluation to verify and describe the clinical benefit of the drug in a confirmatory trial.

“The FDA approval of PADCEV is welcome news for patients with bladder cancer,” Andrea Maddox-Smith, chief executive officer of the Bladder Cancer Advocacy Network, said in the release. “Though new medicines for bladder cancer have been approved in recent years, most people living with advanced stages of this disease face a difficult journey with few treatment options”,she added.

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