Cisplatin-based combination chemotherapy has been widely accepted as the first-line treatment option for cisplatin-eligible patients diagnosed with locally advanced or metastatic urothelial cancer (mUC) of the bladder and upper urinary tract. And while these tumors are indeed very sensitive to this treatment, only a small proportion of patients may be cured, and most cases of mUC recur eventually.
However, cisplatin-related toxicity is a major concern and, as a result, not all patients with urothelial cancer are appropriate candidates for cisplatin therapy.
“Approximately half of the patients with advanced urothelial carcinoma are ineligible for cisplatin-based chemotherapy,” said Ahsan Arozullah, M.D., M.P.H., Senior Vice President and Head of Development Therapeutic Areas, Astellas.
Patients are generally considered cisplatin-ineligible because of age or comorbidities including impaired renal function, neuropathy, and heart failure. For these patients, there are only limited treatment options, especially for cisplatin-ineligible patients previously treated with PD-1 or PD-L1 therapy.
Another treatment option
Enfortumab vedotin-ejfv (Padcev®; Astellas, Seagen), a first-in-class antibody-drug conjugate (ADC) is directed at Nectin-4, a protein located on the surface of cells and highly expressed in urothelial carcinoma.
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 results in cell cycle arrest (when the cells are not reproducing and apoptosis (programmed cell death).
In February 2020, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation for enfortumab vedotin in combination with pembrolizumab (Keytruda®; Merck & Co/MSD) for patients with unresectable locally advanced mUC who are ineligible to receive cisplatin-based chemotherapy in the first-line setting. The designation is based on results from the dose-escalation cohort and expansion Cohort A of the phase 1b/2 trial, EV-103, evaluating patients with la/mUC who are ineligible to receive cisplatin-based chemotherapy treated in the first-line setting with enfortumab vedotin in combination with pembrolizumab.*
Results from the phase 1b/2 EV-103 clinical trial, also known as KEYNOTE-869, evaluated enfortumab vedotin in combination with the anti-PD-1 therapy pembrolizumab as first-line treatment in patients with unresectable la/mUC who are ineligible to receive cisplatin-based chemotherapy, showed positive topline results.
Cohort K of the EV-103 study investigated enfortumab vedotin alone (n=73) or in combination with pembrolizumab (n=76) as first-line treatment in adult patients with unresectable la/mUC who are ineligible to receive cisplatin-based chemotherapy. In this trial, the enfortumab vedotin monotherapy study arm is intended to characterize the activity of enfortumab vedotin alone in this patient population.
Key outcome measures for this study included objective response rate (ORR) per blinded independent central review (BICR) using RECIST 1.1 and assessment of safety; Duration of Response (DOR), disease control rate and progression-free survival per BICR and investigator assessment; overall survival; and assessment of safety.
In patients treated with enfortumab vedotin and pembrolizumab, results demonstrated a 64.5% confirmed objective response rate (ORR) (95% CI: 52.7 to 75.1) per blinded independent central review (BICR), the primary endpoint of Cohort K. In the study a median duration of response (DOR) per BICR was not reached.
The study results were also observed to be generally consistent with previously reported efficacy and safety results of the EV-103 dose-escalation cohort and expansion Cohort A.
“We intend to discuss Cohort K results with regulatory authorities as we seek to develop a new first-line treatment combination for these patients,” Arozullah added.
The most frequently reported treatment-emergent adverse events Grade 3 or greater that occurred in more than 5% of patients were rash maculo-papular, anemia, lipase increased, urinary tract infection, hyperglycemia, fatigue, neutropenia, hematuria, diarrhea, acute kidney injury, hyponatremia, chronic kidney disease, weight decreased, syncope, hypophosphatemia, pneumonitis, sepsis, and alanine aminotransferase increased.
“We are encouraged by the positive topline results of Cohort K for the combination of enfortumab vedotin and pembrolizumab in first-line locally advanced or metastatic urothelial cancer, and we look forward to sharing results at an upcoming medical meeting,” said Roger Dansey, M.D., interim Chief Executive Officer and Chief Medical Officer at Seagen.
Note: * Astellas, Seagen, and Merck & Co are investigating enfortumab vedotin plus pembrolizumab as part of extensive collaboration, including three Phase 3 studies: the EV-302/KEYNOTE-A39 trial intended to confirm these results, as well as EV-304/KEYNOTE-B15 and EV-303/KEYNOTE-905 in muscle-invasive bladder cancer.
A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer (EV-103) – NCT03288545
Enfortumab Vedotin and Pembrolizumab vs. Chemotherapy Alone in Untreated Locally Advanced or Metastatic Urothelial Cancer (EV-302/KEYNOTE-A39) – NCT04223856
Perioperative Pembrolizumab (MK-3475) Plus Cystectomy or Perioperative Pembrolizumab Plus Enfortumab Vedotin Plus Cystectomy Versus Cystectomy Alone in Participants Who Are Cisplatin-ineligible or Decline Cisplatin With Muscle-invasive Bladder Cancer (MK-3475-905/KEYNOTE-905/EV-303) – NCT03924895
Perioperative Enfortumab Vedotin (EV) Plus Pembrolizumab (MK-3475) Versus Neoadjuvant Chemotherapy for Cisplatin-eligible Muscle Invasive Bladder Cancer (MIBC) (MK-3475-B15/ KEYNOTE-B15 / EV-304) (KEYNOTE-B15) – NCT04700124
Highlights of Prescribing Information
Enfortumab vedotin-ejfv (Padcev®; Astellas, Seagen) [Prescribing Information]
Pembrolizumab (Keytruda®; Merck & Co/MSD)[Prescribing Information]
Cisplatin (Platinol®; Bristol Myers Squibb/BMS) [Prescribing Information]
 Powles T, Rosenberg JE, Sonpavde GP, Loriot Y, Durán I, Lee JL, Matsubara N, Vulsteke C, Castellano D, Wu C, Campbell M, Matsangou M, Petrylak DP. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med. 2021 Mar 25;384(12):1125-1135. doi: 10.1056/NEJMoa2035807. Epub 2021 Feb 12. PMID: 33577729; PMCID: PMC8450892.
 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.
 C.J. Hoimes, J.E. Rosenberg et.al. EV-103: Initial results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma. Annals of Oncology 30 (Supplement 5): v356–v402, 2019.
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