This week the U.S. Food & Drug Administration (FDA) granted accelerated approval to enfortumab vedotin-ejfv (Padcev™; Astellas Pharma / Seattle Genetics) to treat adult patients with locally advanced or metastatic urothelial or bladder cancer.
The approval is the direct result of a multi-institutional clinical trial led by Yale Cancer Center (YCC) and Smilow Cancer Hospital researchers, which demonstrated EV is an effective treatment for this deadly disease.
“This is very exciting progress as we haven’t had another therapy option for patients whose urothelial or bladder cancer has progressed after chemotherapy or immunotherapy,” said Daniel P. Petrylak, MD, professor of medicine (medical oncology) and urology and co-director of the Cancer Signaling Research Program at Yale Cancer Center.
“To my knowledge, this is most active single drug in urothelial cancer,” Petrylak added.
Petrylak was the senior investigator of a phase II clinical trial that studied the efficacy of enfortumab vedotin for patients. “It’s gratifying to know Yale spearheaded the research effort to get this life-saving therapy to patients,” he said.
Persuasive data from the trial were presented in June 2019 at the annual meeting of the American Society of Clinical Oncology (ASCO) held in Chicago.
Petrylak describes enfortumab vedotin as a “smart bomb.”
The drug is a first-in-class antibody-drug conjugate, a type of highly targeted biopharmaceutical drugs that combine monoclonal antibodies specific to surface antigens present on particular tumor cells with highly potent anti-cancer ‘payload’ agents linked via a chemical linker.
With six approved drugs on the market, ADCs have become a powerful class of therapeutic agents in oncology and hematology.
Nectin-4 + MMAE
In this case of enfortumab vedotin, the antibody is directed against Nectin-4 (Poliovirus Receptor-related 4; PVRL4), a type I transmembrane protein and member of a family of related immunoglobulin-like adhesion molecules, located on the surface of cells and highly expressed in bladder cancer. The antibody is, via a protease-cleavable maleimidocaproyl valine-citrulline linker, conjugated to a small molecule microtubule disrupting agent, monomethyl auristatin E (MMAE).
The new agent is the first FDA approved treatment in the United States for this group patients with locally advanced or metastatic urothelial or bladder cancer. The drug is approved under the Accelerated Approval Program, which is based on tumor response rate. Continued approval of the drug may, however, be contingent upon verification and description of clinical benefit in confirmatory trials.
The trial showed the drug produced responses in 44% of patients with locally advanced or metastatic urothelial cancer who had been previously treated with chemotherapy and checkpoint inhibitors.
Among 125 patients who had received both standard chemotherapy plus a checkpoint inhibitor and enfortumab vedotin, 12% had a complete response, with no detectable sign of cancer after treatment. Median overall survival was 11.7 months. Notably, 36% of people whose cancer had metastasized to the liver — a site that has been resistant to both standard chemotherapy and immune therapy — responded to the treatment.
According to the American Cancer Society, more than 80,000 people are diagnosed with bladder cancer each year in the United States, with an estimated 17,000 people dying from the disease.
There is no routine screening recommended, so most people do not undergo any tests to detect bladder cancer unless they experience symptoms. Signs and symptoms of the disease include blood in the urine, painful or frequent urination, urinary incontinence and pain in the abdominal area.
“The FDA approval of enfortumab vedotin is welcome news for patients with bladder cancer,” noted Andrea Maddox-Smith, Chief Executive Officer, Bladder Cancer Advocacy Network (BCAN).
“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.
“Our work continues as there are still many patients who need other treatment options,” Petrylak added.
“We have proceeded with a phase I trial to examine the drug’s benefits for people who are newly diagnosed with advanced urothelial cancer but are ineligible for platinum chemotherapy. Additionally, another phase I trial is looking at treating advanced or metastatic disease by combining enfortumab vedotin with the checkpoint inhibitor pembrolizumab,” he concluded.
The FDA granted the approval of enfortumab vedotin to Astellas Pharma approximately three months before the goal date. The drug is jointly marketed by Astellas and Seattle Genetics.
Enfortumab vedotin-ejfv is available in 20 mg and 30 mg and is supplied as a sterile, preservative-free, white to off-white lyophilized powder in single-dose vials of one 20 mg single-dose vial (NDC 51144-020-01) and one 30 mg single-dose vial (NDC 51144-030-01)
For more information about access and reimbursement support to help patients access enfortumab vedotin [click here].
A Study of Enfortumab Vedotin for Patients With Locally Advanced or Metastatic Urothelial Bladder Cancer (EV-201) – NCT03219333
A Study of Enfortumab Vedotin in Japanese Subjects With Locally Advanced or Metastatic Urothelial Carcinoma – NCT03070990
A Study to Evaluate Enfortumab Vedotin Versus (vs) Chemotherapy in Subjects With Previously Treated Locally Advanced or Metastatic Urothelial Cancer (EV-301) – NCT03474107
An Expanded Access Treatment Protocol of Enfortumab Vedotin in Subjects With Locally Advanced or Metastatic Urothelial Carcinoma – NCT04136808
A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer (EV-103) – NCT03288545
A Study of Escalating Doses of ASG-22CE Given as Monotherapy in Subjects With Metastatic Urothelial Cancer and Other Malignant Solid Tumors That Express Nectin-4 – NCT02091999
A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-based Treatment Combinations in Patients With Locally Advanced or Metastatic Urothelial Carcinoma After Failure With Platinum-Containing Chemotherapy (MORPHEUS mUC) – NCT03869190
 Highlights of Prescription Information Padcev™. Astellas, Inc. [Package Insert]
 Rosenberg JE, O’Donnell PH, Balar AV, et al. Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy. J Clin Oncol. 2019;37(29):2592–2600. doi:10.1200/JCO.19.01140 [Pubmed][Article]
 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):3003–3013. doi:10.1158/0008-5472.CAN-15-1313 [Pubmed][Article]
 American Society of Clinical Oncology. Bladder cancer: introduction (10-2017). Online. Last accessed December 17, 2019.
 National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer stat facts: bladder cancer. Online. Last accessed December 17, 2019.