On July 26, 2024 Astellas Pharma Inc. (TSE: 4503, President and CEO: Naoki Okamura, "Astellas") reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion recommending approval of PADCEV (enfortumab vedotin, an antibody-drug conjugate [ADC]) in combination with KEYTRUDA (pembrolizumab, a PD-1 inhibitor) for the first-line treatment of adult patients with unresectable or metastatic urothelial cancer, who are eligible for platinum-containing chemotherapy (Press release, Astellas, JUL 26, 2024, View Source [SID1234645104]).
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Ahsan Arozullah, MD, MPH, Senior Vice President and Head of Oncology Development, Astellas
"Treatment options available to patients with unresectable or metastatic urothelial cancer are currently limited mainly to platinum-containing chemotherapy. The data underpinning the CHMP’s approval recommendation show that this combination could change how clinicians manage first-line treatment of this disease. We are delighted that the CHMP recognized the potential for enfortumab vedotin in combination with pembrolizumab as first-line treatment for patients with unresectable or metastatic urothelial cancer."
The positive CHMP opinion is based on data from the Phase 3 EV-302 clinical trial (also known as KEYNOTE-A39) which showed enfortumab vedotin in combination with pembrolizumab significantly extends overall survival (OS) and progression-free survival (PFS) compared to platinum-containing chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC). Treatment with the combination resulted in a median OS of 31.5 months (95% CI: 25.4-NR) compared to 16.1 months (95% CI: 13.9-18.3) with chemotherapy, representing a 53% reduction in risk of death (Hazard Ratio [HR]=0.47; 95% Confidence Interval [CI]: 0.38-0.58; P<0.00001). The median PFS of 12.5 months (95% CI: 10.4-16.6) with the combination compared to 6.3 months (95% CI: 6.2-6.5) with chemotherapy represents a 55% reduction in the risk of cancer progression or death (HR=0.45; 95% CI: (0.38-0.54); P<0.00001). During the EV-302 trial, approximately 30% of patients completed treatment with chemotherapy and then went on to receive maintenance therapy with avelumab, a PD-L1 inhibitor, which is reflective of current real world clinical practice.1 Results were presented at the 2023 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress and published in the New England Journal of Medicine.
Europe has the highest rate of new bladder cancer cases in the world.3 Every year, more than 165,000 people are diagnosed with the disease in the European Union (EU), and it claims the lives of over 50,000 people.3
Not only does bladder cancer affect a person’s physical functioning throughout the disease journey, patients and caregivers also report significant impacts on quality of life and mental well-being which are often exacerbated by late detection and challenging pathways to diagnosis.4
The positive opinion will now be reviewed by the European Commission (EC), which has the authority to approve medicines in all 27 EU member states as well as Iceland, Liechtenstein and Norway.5
In December 2023, the U.S. Food and Drug Administration (FDA) approved enfortumab vedotin in combination with pembrolizumab for the treatment of adult patients with la/mUC.6 In April 2022, the EC approved enfortumab vedotin as a monotherapy for the treatment of adult patients with la/mUC who have previously received a platinum-containing chemotherapy and a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor.7
Astellas has already reflected the impact from this result in its financial forecast for the current fiscal year ending March 31, 2025.
For more information, please see the press release "European Medicines Agency Validates Type II Variation Application for PADCEV (enfortumab vedotin) with KEYTRUDA (pembrolizumab) for First-Line Treatment of Advanced Bladder Cancer" issued on January 29, 2024.
About EV-302
EV-302 is an ongoing, open-label, randomized, controlled Phase 3 trial, evaluating enfortumab vedotin in combination with pembrolizumab versus platinum-containing chemotherapy in patients with previously untreated la/mUC. The trial enrolled 886 patients with previously untreated la/mUC who were eligible for cisplatin- or carboplatin-containing chemotherapy regardless of PD-L1 status. Patients were randomized to receive either enfortumab vedotin in combination with pembrolizumab or platinum-containing chemotherapy. The dual primary endpoints of this trial are OS and PFS per RECIST v1.1 by blinded independent central review (BICR). Select secondary endpoints include ORR per RECIST v1.1 by BICR, DOR per RECIST v1.1 by BICR, and safety.1
The most common (≥3%) Grade 3 or higher adverse events related to treatment with enfortumab vedotin and pembrolizumab were maculo-papular rash, hyperglycemia, neutropenia, peripheral sensory neuropathy, diarrhea, and anemia. The safety results in EV-302 are consistent with those previously reported with this combination in EV-103 in cisplatin-ineligible patients with la/mUC. No new safety issues were identified.1
The EV-302 trial is part of an extensive clinical program evaluating this combination in multiple stages of urothelial cancer and other solid tumors. Findings from EV-302 were presented at the 2023 European Society for Medical Oncology (ESMO) (Free ESMO Whitepaper) Congress and were published in the New England Journal of Medicine.
For more information on the EV-302 trial (NCT04223856) go to View Source
About Bladder and Urothelial Cancer
Urothelial cancer, or bladder cancer, begins in the urothelial cells, which line the urethra, bladder, ureters, renal pelvis, and some other organs.8 Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter, and urethra.9,10 If cancer is not able to be treated with surgery, it is called unresectable.11 If cancer has spread to surrounding organs or muscles, it is called locally advanced disease.12 If cancer has spread to other parts of the body, it is called metastatic disease.13 Approximately 12% of cases are unresectable locally advanced or metastatic urothelial cancer at diagnosis.14
Bladder cancer is diagnosed in approximately 614,000 people and causes 220,000 deaths worldwide each year.15 In Europe, bladder cancer is the fifth most common cancer;16 more than 165,000 people are diagnosed with the disease in the EU each year.3 Continuous treatment and surveillance makes bladder cancer one of the most expensive cancer types over the lifetime of a patient and, in fact, have been shown to be the costliest cancer when compared to other malignancies.17
About PADCEV (enfortumab vedotin)
PADCEV (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.7,18 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).7
PADCEV is currently indicated in the EU as monotherapy for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a platinum-containing chemotherapy and a programmed death receptor-1 or programmed death-ligand 1 inhibitor.7
Ongoing Investigational Trials
EV-302 (NCT04223856) is an open-label, randomized, controlled Phase 3 trial, evaluating enfortumab vedotin in combination with pembrolizumab versus platinum-containing chemotherapy in patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC) who were eligible for cisplatin- or carboplatin-containing chemotherapy regardless of PD-L1 status.
EV-103 (NCT03288545) is an ongoing, multi-cohort, open-label, multicenter Phase 1b/2 trial investigating enfortumab vedotin alone or in combination with pembrolizumab and/or chemotherapy in first- or second-line settings in patients with la/mUC and in patients with muscle-invasive bladder cancer (MIBC).
EV-104 (NCT05014139) is a Phase 1 trial exploring enfortumab vedotin in patients with non-muscle invasive bladder cancer (NMIBC). The trial will be conducted in two-parts, assessing dose escalation and dose expansion with enfortumab vedotin when administered intravesically as a monotherapy.
Enfortumab vedotin in combination with pembrolizumab is being investigated in an extensive program in multiple stages of urothelial cancer, including two Phase 3 clinical trials in MIBC in EV-304 (NCT04700124, also known as KEYNOTE-B15) and EV-303 (NCT03924895, also known as KEYNOTE-905). The use of enfortumab vedotin in combination with pembrolizumab in second-line urothelial cancer and MIBC has not been proven safe or effective.
EV-202 (NCT04225117) is an ongoing, multi-cohort, open-label, multicenter Phase 2 trial investigating enfortumab vedotin alone in patients with previously treated advanced solid tumors. This trial also has a cohort that is investigating enfortumab vedotin in combination with pembrolizumab in patients with previously untreated recurrent / metastatic head and neck squamous cell carcinoma.
EV-203 (NCT04995419) is a Phase 2, multicenter, single-arm bridging trial in China designed to evaluate the efficacy, safety, and pharmacokinetic performance of enfortumab vedotin as treatment for patients in China. A total of 40 patients were enrolled in the trial.
Important Safety Information
For Important Safety Information for enfortumab vedotin please see the full Summary of Product Characteristics at: View Source