Accelerated Approval for Enfortumab Vedotin in Locally Advanced or Metastatic Urothelial Cancer

The U.S. Food and Drug Administration (FDA) granted accelerated approval to enfortumab vedotin-ejfv (Padcev™; Astellas Pharma / Seattle Genetics)* for the treatment of adult patients with locally advanced or metastatic 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 before (neoadjuvant) or after (adjuvant) surgery or in a locally advanced or metastatic setting.**

“[Advanced or] metastatic urothelial cancer is an aggressive and devastating disease with limited treatment options, and the approval of enfortumab vedotin is a significant advance for these patients who previously had limited options after initial therapies failed,” said Jonathan E. Rosenberg, MD, Medical Oncologist, Chief, Genitourinary Medical Oncology Service, Memorial Sloan Kettering Cancer Center in New York.

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

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This year** approximately 80,000 patients in the United Sates who have be diagnosed with bladder cancer, the sixth most common cancer. [1] Urothelial cancer, which begins in cells that line the bladder and nearby organs, accounts for approximately 90% of all bladder cancers, a disease which can also be found in the renal pelvis, ureter and urethra. [2]

Approximately 25% of patients diagnosed with urothelial cancer will have muscle-invasive disease and either present with or later develop metastases. Systemic, cisplatin-based chemotherapy is the standard approach for the initial treatment of patients with inoperable locally advanced or metastatic urothelial cancer. Although initial response rates relatively high, the median survival with multiagent chemotherapy is approximately 15 months.

Cisplatin-based combination chemotherapy has demonstrated to results in superior survival when compared with single-agent cisplatin. However, in this approach, cisplatin-related toxicity is a major concern for patients. Furthermore, not all patients with urothelial cancer are candidates for cisplatin therapy.

First-in-class
Enfortumab vedotin, also known as ASG-22ME, is a first-in-class antibody-drug conjugate or ADC that 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.[3][4]

“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,” noted Richard Pazdur, MD, 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.

Conjugate
The Nectin-4 directed antibody-drug conjugate (ADC) is comprised of a fully human anti-Nectin-4 IgG1 kappa monoclonal antibody (AGS-22C3), produced by mammalian (Chinese hamster ovary/CHO) cells, conjugated to the small molecule microtubule disrupting agent, monomethyl auristatin E (MMAE) via a protease-cleavable maleimidocaproyl valine-citrulline (vc) linker (SGD-1006). Conjugation takes place on cysteine residues that comprise the interchain disulfide bonds of the antibody to yield a product with a drug-to-antibody ratio of approximately 3.8:1. The molecular weight is approximately 152 kDa.

Nonclinical data suggest the anticancer activity of enfortumab vedotin is due to its binding to cells expressing Nectin-4, followed by the internalization and release of the anti-tumor payload which result in the cell not reproducing (cell cycle arrest) and in apoptosis (programmed cell death).[3][5]

Accelerated approval
The new agent is the first FDA approved treatment in the United States for this group patients approved under the Accelerated Approval Program, which is based on tumor response rate. However, continued approval of the drug may be contingent upon verification and description of clinical benefit in confirmatory trials.

The FDA’s Accelerated Approval Program allows approval of a medicine based on a surrogate endpoint if the medicine fills an unmet medical need for a serious condition. A global, randomized phase III confirmatory clinical trial (EV-301; NCT03474107) is underway and is also intended to support global registrations.

Welcome news
“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.

“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.

“This approval underscores our commitment to develop novel medicines that address unmet patient needs, and we’re grateful to the patients and physicians whose participation led to this outcome,” said Andrew Krivoshik, MD, Ph.D., Senior Vice President and Oncology Therapeutic Area Head, Astellas.

“Enfortumab vedotin is the first antibody-drug conjugate approved for patients facing this aggressive disease, and it is the culmination of years of innovative work on this technology,” said Roger Dansey, M.D., Chief Medical Officer, Seattle Genetics.

According to a statement by the FDA, enfortumab vedotin received approval approximately three months before the goal date.

Clinical trials
The drug was evaluated in a number of clinical trials. In the phase I dose escalation and expansion study EV-101 (NCT02091999) investigators demonstrated that enfortumab vedotin, administered on days 1, 8, and 15 of every 28-day cycle, had antitumor activity in previously treated patients with metastatic urothelial carcinoma. These patients included patients who received platinum-based chemotherapy and anti–PD-1 or PD-L1 therapy. The pharmacokinetic data from this study demonstrated a half-life of approximately 2 days, supporting the dosing schedule.

The two-cohort, pivotal trial EV-201 (NCT03219333), a global, single-arm phase II multi-center trial that enrolled 125 patients 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] The participating patients received 1.25 mg/kg intravenously on days 1, 8, and 15 of every 28-day cycle.

The primary end point was objective response rate Key secondary end points were duration of response, progression-free survival, overall survival, safety, and tolerability.

In this study, the primary endpoint of confirmed objective response rate (ORR), per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by blinded independent central review, was 44% per blinded independent central review (55/125; 95% Confidence Interval [CI]: 35.1, 53.2). Among patients treated with the single agent enfortumab vedotin, 12% (15/125) experienced a complete response, meaning no cancer could be detected at the time of assessment, and 32% (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]).

Adverse events
In this trial, the most common serious adverse reactions (≥3%) were urinary tract infection (6%), cellulitis (5%), febrile neutropenia (4%), diarrhea (4%), sepsis (3%), acute kidney injury (3%), dyspnea (3%), and rash (3%). 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%).

Availability
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)

Support
For more information about access and reimbursement support to help patients access enfortumab vedotin [click here].

Notes
* In the United states known as enfortumab vedotin-ejfv, rest of thw world enfortumab vedotin.
** Including, but not limited to atezolizumab, nivolumab, and ipilimumab. These agents have been indicated for the treatment of advanced urothelial carcinoma that has progressed during or after previous platinum-based chemotherapy, either for metastatic disease or for progressive disease less than 12 months after adjuvant or neoadjuvant chemotherapy. 
*** 2019

Clinical trials
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

Reference
[1] American Society of Clinical Oncology. Bladder cancer: introduction (10-2017). Online. Last accessed December 17, 2019.
[2] National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer stat facts: bladder cancer. Online. Last accessed December 17, 2019.
[3] Highlights of Prescription Information Padcev™. Astellas, Inc. [Package Insert]
[4] 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]
[5] 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]