Updated data from the phase Ib/II multicohort EV-103 trial (NCT03288545; also known as KEYNOTE-869) of enfortumab vedotin* (Padcev™; Seattle Genetics/Astellas Pharma) in combination with anti-PD-1 therapy pembrolizumab (Keytruda®; Merck & Co) for the treatment of patients with unresectable locally advanced or metastatic urothelial cancer who are unable to receive cisplatin-based chemotherapy in the first-line setting, could potentially support registration under accelerated approval regulations in the United States.

Urothelial cancer or bladder cancer is estimated that approximately 81,000 people in the U.S. will be diagnosed with bladder cancer in 2020.[3] Urothelial cancer accounts for 90 percent of all bladder cancers and can also be found in the renal pelvis, ureter, and urethra.[4] Globally, approximately 549,000 people were diagnosed with bladder cancer in 2018, and there were approximately 200,000 deaths worldwide.[5]

Targeted treatment
Enfortumab vedotin is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.[1][2]

Nonclinical data suggest the anticancer activity of enfortumab vedotin is due to its binding to Nectin-4 expressing cells followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).[2]

Advertisement #3
 

With seven approved drugs on the market, ADCs have become a powerful class of therapeutic agents in oncology and hematology.

Based on the highlights of the prescribing information the recommended dose of enfortumab vedotin is 1.25 mg/kg (up to a maximum of 125 mg for patients ≥ 100 kg) via a 30-minute intravenous infusion on days 1, 8, and 15 of 28-day cycles until disease progression or unacceptable toxicity. Dose modification for adverse events includes stepwise dose reduction to 1.0 mg/kg up to 100 mg, 0.75 mg/kg up to 75 mg, and 0.5 mg/kg up to 50 mg. The prescribing information provides instructions on dose modification, including dose reduction, withholding, and discontinuation for hyperglycemia, peripheral neuropathy, skin reactions, other grades 3 or 4 nonhematologic toxicities, and hematologic toxicities.

The prescribing information warns that enfortumab vedotin should be avoided in patients with moderate or severe hepatic impairment. Furthermore, concomitant use of strong inhibitors of CYP3A4 with enfortumab vedotin may increase exposure to MMAE.

Enfortumab vedotin is co-developed by Astellas and Seattle Genetics.

Accelerated approval
The potential support for registration under the accelerated approval regulations is, according to representatives from Seattle Genetics, based on recent discussions with the U.S. Food and Drug Administration (FDA) and data from the randomized cohort K, along with other data from the EV-103 trial evaluating enfortumab vedotin combined with pembrolizumab as first-line therapy for cisplatin-ineligible patients.

Enfortumab vedotin is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.[1]

“We are excited that EV-103 provides [enfortumab vedotin] with a potential pathway for accelerated approval in the United States in first-line metastatic urothelial cancer,” said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics.

“Our initial data on the combination of enfortumab vedotin and pembrolizumab in previously untreated patients who could not receive cisplatin are encouraging,” Dansey added.

Development
EV-103 is a multi-cohort, open-label, multicenter phase 1b/2 trial of enfortumab vedotin alone or in combination, evaluating the safety, tolerability, and efficacy in muscle-invasive urothelial cancer, and in locally advanced or metastatic urothelial cancer in first- or second-line settings.

Cohort K from EV-103 is intended to enroll 150 patients randomized 1:1 to PADCEV monotherapy or enfortumab vedotin in combination with pembrolizumab in locally advanced or metastatic urothelial cancer patients who are ineligible for cisplatin-based chemotherapy. The primary outcome measure is objective response rate (ORR) per blinded independent central review (BICR) using RECIST 1.1 and duration of response (DoR).

In addition to EV-103, the recently initiated EV-302 phase III randomized clinical trial is intended to support global registrations and potentially serve as a confirmatory trial if accelerated approval is granted based on EV-103. The EV-302 trial is evaluating the combination of enfortumab vedotin and pembrolizumab with or without chemotherapy versus chemotherapy alone in patients with previously untreated locally advanced or metastatic urothelial cancer.

EV-302 also includes metastatic urothelial cancer patients that are either eligible or ineligible for cisplatin-based chemotherapy. The trial is expected to enroll 1,095 patients and has dual primary endpoints of progression-free survival and overall survival. Both the EV-103 and EV-302 trials are being conducted in collaboration with Astellas and Merck.

FDA recently granted Breakthrough Therapy designation for enfortumab vedotin in combination with pembrolizumab for the treatment of patients with unresectable locally advanced or metastatic urothelial cancer who are unable to receive cisplatin-based chemotherapy in the first-line setting based on initial results from the EV-103 trial.

Enfortumab vedotin was approved by the FDA in December 2019 and is indicated 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 platinum-containing chemotherapy before (neoadjuvant) or after (adjuvant) surgery or in a locally advanced or metastatic setting.

The drug was approved under the FDA’s Accelerated Approval Program based on the tumor response rate. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.[2]

Note
*In the United States: enfortumab vedotin-ejfv

Clinical trials
– A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer (EV-103) – NCT03288545
Other clinical trials

Reference
[1] Challita-Eid P, 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):3003-13.
[2] PADCEV / Enfortumab vedotin-ejfv [package insert]. Northbrook, IL: Astellas, Inc.
[3] American Cancer Society. Cancer Facts & Figures 2020. Online. Last accessed March 31, 2020.
[4] American Society of Clinical Oncology. Bladder cancer: introduction (10-2017). Online. last accessed March 31, 2020.
[5] International Agency for Research on Cancer. Cancer Tomorrow: Bladder. Online. Last accessed March 31, 2020.