PADCEV® (enfortumab vedotin-ejfv) with KEYTRUDA® (pembrolizumab) Approved by FDA as the First and Only ADC Plus PD-1 to Treat Advanced Bladder Cancer

Astellas Pharma Inc. and Pfizer Inc. today announced that on December 15, 2023 the U.S. Food and Drug Administration (FDA) has approved PADCEV® (enfortumab vedotin-ejfv, an antibody-drug conjugate [ADC]) with KEYTRUDA® (pembrolizumab, a PD-1 inhibitor) for the treatment of adult patients with locally advanced or metastatic urothelial cancer (la/mUC). This combination is the first approved to offer an alternative to platinum-containing chemotherapy, the current standard of care in first-line la/mUC.

The approval is based on results from the Phase 3 EV-302 clinical trial (also known as KEYNOTE-A39), which demonstrated the combination nearly doubled median overall survival (OS) and median progression-free survival (PFS) in patients with previously untreated la/mUC compared to platinum-containing chemotherapy. Findings from EV-302 were presented at the European Society for Medical Oncology (ESMO) Congress 2023. EV-302 also serves as the confirmatory trial for the U.S. accelerated approval of this combination for adult patients with la/mUC who are not eligible to receive cisplatin-containing chemotherapy (approved in April 2023) and expands the labeled indication to include patients who are eligible to receive cisplatin chemotherapy. EV-302 is also serving as the basis for global submissions.

Ahsan Arozullah, M.D., M.P.H., Senior Vice President, Head of Oncology Development, Astellas

"Today's FDA approval represents a paradigm change in the treatment of advanced bladder cancer and provides hope to the thousands of Americans impacted by this aggressive disease. This achievement is notable, as it is the first regimen approved in advanced urothelial cancer that has demonstrated superiority to platinum chemotherapy, the gold standard of care for decades."

Roger Dansey, M.D., Chief Development Officer, Oncology, Pfizer

"In the Phase 3 EV-302 study, the combination of PADCEV and pembrolizumab demonstrated survival benefit for patients with advanced bladder cancer, nearly doubling median OS and median PFS compared with chemotherapy. We hope the approval of this combination will transform the standard of care for advanced bladder cancer and give patients more time with their loved ones."

The EV-302 study met its dual primary endpoints of OS and PFS compared to platinum-containing chemotherapy. 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). Consistent OS and PFS results were observed across pre-defined subgroups, including cisplatin eligibility and PD-L1 expression level. Cisplatin eligible and ineligible subgroups (n=244 and 198, respectively) saw a 47% and 57% reduced risk of death, respectively, and a 52% and 57% reduced risk of progression or death, respectively. PD-L1 and high PD-L1 expression subgroups (n=184 and 254, respectively) saw a 56% and 51% reduced risk of death, respectively, and a 50% and 58% reduced risk of progression or death, respectively.

The most common (≥20%) all-grade adverse events (AEs), including laboratory abnormalities, related to treatment with enfortumab vedotin and pembrolizumab were increased aspartate aminotransferase, increased creatinine, rash, increased glucose, peripheral neuropathy, increased lipase, decreased lymphocytes, increased alanine aminotransferase, decreased hemoglobin, fatigue, decreased sodium, decreased phosphate, decreased albumin, pruritus, diarrhea, alopecia, decreased weight, decreased appetite, increased urate, decreased neutrophils, decreased potassium, dry eye, nausea, constipation, increased potassium, dysgeusia, urinary tract infection and decreased platelets. 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.

Please see Important Safety Information at the end of this press release, including BOXED WARNING for PADCEV (enfortumab vedotin-ejfv).

Thomas Powles, M.R.C.P., M.D., Professor of Genitourinary Oncology at Queen Mary University of London; Director, Barts Cancer Center, London; EV-302 Primary Investigator

"Advanced bladder cancer is a common cause of cancer-related death. The overall survival benefit seen in the EV-302 trial demonstrates the potential for PADCEV in combination with pembrolizumab to impact first-line treatment of patients with locally advanced or metastatic urothelial carcinoma. In my opinion, this is a meaningful advancement over platinum-based chemotherapy in the systemic treatment of these patients."

Andrea Maddox-Smith, CEO, Bladder Cancer Advocacy Network (BCAN)

"Despite advances in the treatment of advanced bladder cancer, there remains a need for therapies that extend patients' lives. Our network is thrilled that the FDA has approved a new treatment option, and we are excited about the hope it will provide to members of the bladder cancer patient community."

About EV-302

The EV-302 trial is an open-label, randomized, controlled Phase 3 study, evaluating enfortumab vedotin in combination with pembrolizumab versus chemotherapy in patients with previously untreated la/mUC. The study 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 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 objective response rate (ORR) and duration of response (DOR) per RECIST v1.1 by BICR, and safety.

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.i

If bladder cancer has spread to surrounding organs or muscles, it is called locally advanced disease. If the cancer has spread to other parts of the body, it is called metastatic disease. ii

Globally, approximately 573,000 new cases of bladder cancer and 212,000 deaths are reported annually.iii

It is estimated that approximately 82,290 people in the U.S. will be diagnosed with bladder cancer in 2023.iv

Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter, and urethra. ii

Approximately 12% of cases are locally advanced or metastatic urothelial cancer at diagnosis.v

Ongoing Investigational Trials

The EV-302 trial (NCT04223856) is an open-label, randomized, controlled Phase 3 study, evaluating the impact of treatment with enfortumab vedotin in combination with pembrolizumab versus 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.  

The EV-103 trial (NCT03288545) is an ongoing, multi-cohort, open-label, multicenter Phase 1b/2 study 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).

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 MIBC has not been proven safe or effective.

The EV-202 trial (NCT04225117) is an ongoing, multi-cohort, open-label, multicenter Phase 2 study investigating enfortumab vedotin alone in patients with previously treated advanced solid tumors. This study 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.

About PADCEV® (enfortumab vedotin-ejfv)

PADCEV (enfortumab vedotin-ejfv) is a first-in-class antibody-drug conjugate (ADC) that is directed to Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.vi Nonclinical data suggest the anticancer activity of PADCEV 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).

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