Updated findings from EV-103, a phase Ib/II clinical trials of enfortumab vedotin* (Padcev™; Astellas Pharma/Seattle Genetics) in combination with pembrolizumab (Keytruda®; Merck Sharp & Dohme Corp., a subsidiary of Merck & Co) to be presented during an oral session at the 2020 ASCO Genitourinary Cancers Symposium (February 13-15, 2020 in the Moscone West Building, San Francisco, CA), shrank tumors in the majority of patients.
The initial results from this study were presented at the European Society of Medical Oncology (ESMO) Congress in September 2019.
It is estimated that approximately 81,000 people in the U.S. will be diagnosed with bladder cancer in 2020.5 Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter, and urethra.  Globally, approximately 549,000 people were diagnosed with bladder cancer in 2018, and there were approximately 200,000 deaths worldwide.
The recommended first-line treatment for patients with advanced urothelial cancer is cisplatin-based chemotherapy. For patients who are ineligible for cisplatin, such as people with kidney impairment, a carboplatin-based regimen is recommended. However, fewer than half of patients respond to carboplatin-based regimens and outcomes are typically poorer compared to cisplatin-based regimens.
The disease represents a major unmet medical need.
EV-103 investigated enfortumab vedotin in previously untreated patients with locally advanced or metastatic urothelial cancer who were ineligible for treatment with cisplatin-based chemotherapy. Forty-five patients were treated with the combination of enfortumab vedotin + pembrolizumab and were evaluated for safety and efficacy.
After a median follow-up of 11.5 months, the study results continue to meet outcome measures for safety and demonstrate encouraging clinical activity for this platinum-free combination in a first-line setting.
Enfortumab vedotin is a first-in-class antibody-drug conjugate or ADC that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.
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).
The drug was approved by the U.S. Food and Drug Administration (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 a platinum-containing chemotherapy before (neoadjuvant) or after (adjuvant) surgery or in a locally advanced or metastatic setting. Enfortumab vedotin 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.
Standard of care
“Cisplatin-based chemotherapy is the standard treatment for first-line advanced urothelial cancer. [This approach is] however, [not] an option for many patients,” noted Jonathan E. Rosenberg, M.D., Medical Oncologist and Chief, Genitourinary Medical Oncology Service at Memorial Sloan Kettering Cancer Center in New York.
“I’m encouraged by these interim results, including a median progression-free survival of a year for patients who received the platinum-free combination of enfortumab vedotin and pembrolizumab in the first-line setting,” Rosenberg added.“These updated data are encouraging and provide support for the recently initiated phase III trial EV-302 that includes an arm evaluating enfortumab vedotin in this platinum-free combination in the first-line setting,” explained Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics.
Andrew Krivoshik, M.D., Ph.D., Senior Vice President and Oncology Therapeutic Area Head at Astellas, added: “These additional results support continued evaluation of enfortumab vedotin in combination with other agents and at earlier stages of treatment for patients with urothelial cancer.”
In the study, 58% (26/45) of patients had a treatment-related adverse event greater than or equal to Grade 3: An increase in lipase (18%; 8/45), rash (13%; 6/45), hyperglycemia (13%; 6/45) and peripheral neuropathy (4%; 2/45).
These rates were similar to those observed with enfortumab vedotin monotherapy.
Eighteen percent (8/45) of patients had treatment-related immune-mediated adverse events of clinical interest greater than or equal to Grade 3 that required the use of systemic steroids (arthralgia, dermatitis bullous, pneumonitis, lipase increased, rash erythematous, rash maculopapular, tubulointerstitial nephritis, myasthenia gravis).
None of the adverse events of clinical interest were Grade 5 events. Six patients (13%) discontinued treatment due to treatment-related adverse events, most commonly peripheral sensory neuropathy. As previously reported, there was one death deemed to be treatment-related by the investigator attributed to multiple organ dysfunction syndromes.
The data demonstrated the combination of enfortumab vedotin plus pembrolizumab shrank tumors in the majority of patients, resulting in a confirmed Objective Response Rate (ORR) of 73.3% (33/45; 95% Confidence Interval (CI): 58.1, 85.4) after a median follow-up of 11.5 months (range, 0.7 to 19.2).
Responses included 15.6% (7/45) of patients who had a complete response (CR) and 57.8% (26/45) of patients who had a partial response. The median duration of response has not yet been reached (range 1.2 to 12.9+ months). Eighteen (55%) of 33 responses were ongoing at the time of analysis, with 83.9% of responses lasting at least 6 months and 53.7% of responses lasting at least 12 months (Kaplan-Meier estimate). The median progression-free survival was 12.3 months (95% CI: 7.98, -) and the 12-month overall survival (OS) rate was 81.6 percent (95% CI: 62 to 91.8 percent); median OS has not been reached.
EV-103 is an ongoing, multi-cohort, open-label, multicenter phase Ib/II trial of PADCEV alone or in combination, evaluating the safety, tolerability, and efficacy in muscle-invasive, locally advanced and first- and second-line metastatic urothelial cancer.
The dose-escalation cohort and expansion cohort A include locally advanced or metastatic urothelial cancer patients who are ineligible for cisplatin-based chemotherapy. Patients were dosed in a 21-day cycle, receiving an intravenous (IV) infusion of enfortumab vedotin on Days 1 and 8 and pembrolizumab on Day 1. At the time of this initial analysis, 45 patients (5 from the dose-escalation cohort and 40 from the dose-expansion cohort A) with locally advanced and/or metastatic urothelial cancer had been treated with enfortumab vedotin (1.25 mg/kg) plus pembrolizumab in the first-line setting.
The primary outcome measure of the cohorts included in this analysis is safety. Key secondary objectives related to efficacy include Objective Response Rate (ORR), Disease Control Rate (DCR), Duration of Response (DoR), Progression-free Survival (PFS) and Overall Survival (OS). The available data for DoR, PFS, and OS are not yet mature.
Additional cohorts in the EV-103 study will evaluate enfortumab vedotin as a monotherapy or in combination with pembrolizumab or platinum chemotherapy in the first-line setting for metastatic disease; in combination with pembrolizumab and carboplatin or cisplatin in first-line metastatic disease; as a monotherapy or in combination with pembrolizumab in muscle-invasive disease; with pembrolizumab in second-line metastatic disease; and with gemcitabine in first- or second-line metastatic disease. 
A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer (EV-103). – NCT03288545.
*In the United States: enfortumab vedotin-ejfv
 Rosenberg JE, Flaig TW, Friedlander TW, Milowsky MI, Srinivas S, Petrylak DP, Merchan JR, et al., Study EV-103: Preliminary durability results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma. – J Clin Oncol 38, 2020 (Suppl. 6; Abstract #441)
 National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Cancer stat facts: bladder cancer. Online. Last accessed on February 10, 2020.
 International Agency for Research on Cancer. Cancer Tomorrow: Bladder. Online. Last accessed February 10, 2010.
 National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer. Version 4; July 10, 2019. Online. Last accessed on February 10, 2020.
 American Cancer Society. Cancer Facts & Figures 2020. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf. Accessed 01-23-2020.
 PADCEV [package insert]. Northbrook, IL: Astellas, Inc.
 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.
 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):2592-600.