The U.S. Food and Drug Administration (FDA) has accepted a supplemental Biologics License Application (sBLA) for priority review for enfortumab vedotin-ejfv (Padcev® ; Astellas/Seagen with pembrolizumab (Keytryuda® ( Merck & Co; Merck Sharp & Dohme/MSD) as a combination therapy for the treatment of adult patients with locally advanced or metastatic urothelial cancer (la/mUC), a form of bladder cancer that has spread to surrounding organs or muscles, or other parts of the body.

Under the Prescription Drug User Fee Act (PDUFA), the FDA has set a target action date of May 9, 2024. The FDA is reviewing the application under its Real-Time Oncology Review (RTOR) program, which aims to explore a more efficient review process to ensure that safe and effective treatments are available to patients as early as possible. If approved, this combination would be the first antibody-drug conjugate + PD-1 inhibitor treatment alternative to cisplatin eligible and ineligible patients.

Urothelial cancer
In 2023 in the United States it is estimated that 82,290 people will be diagnosed with Urothelial cancer, also referred to as bladder cancer, [1] while globally, approximately 573,000 new cases of bladder cancer and 212,000 deaths are reported annually.[6]

Urothelial cancer, is a rare but serious type of cancer that begins in the urothelial cells, which line the urethra, bladder, ureters, renal pelvis, and some other organs.[2]  If the disease has spread to surrounding organs or muscles, it is called locally advanced disease.  It is called metastatic disease if the cancer has spread to other parts of the body. [5]

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Urothelial cancer accounts for 90% of all bladder cancers and can also be found in the renal pelvis, ureter and urethra.[2] Approximately 12% of cases are locally advanced or metastatic urothelial cancer at diagnosis. [3] Most la/mUC patients will progress within nine months and long-term survival rates are poor. [4]

First-in-class
Enfortumab vedotin 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.[7] 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).

Critical need
“We look forward to the FDA’s review of this application, which, if approved, will convert the accelerated approval of the combination based on results from the EV-103 study to standard approval for all first-line locally advanced or metastatic urothelial cancer patients, expanding the indication to cisplatin eligible patients. These patients have a critical need for innovative new therapies, as chemotherapy has been the standard of care for over 30 years. We are committed to delivering on our goal of helping patients with advanced urothelial cancer live longer,” said Ahsan Arozullah, M.D., M.P.H., Senior Vice President, Head of Oncology Development at Astellas.

“Through our clinical development program, data have consistently shown the impact of combining enfortumab vedotin with pembrolizumab for advanced bladder cancer. The FDA’s acceptance of our application is a critical step in our work as we seek to deliver this combination to more patients who currently have few treatment options at the  advanced stage,” added Roger Dansey, M.D., President, Research and Development, Seagen.

Phase 3 study
The sBLA for first-line use of the combination is based on results from the Phase 3 EV-302 clinical trial, also known as KEYNOTE-A39. The study found that the combination improved overall survival (OS) and progression-free survival (PFS) with statistically significant and clinically meaningful results in patients with previously untreated la/mUC compared to platinum-containing chemotherapy. The safety results were consistent with those previously reported with this combination, and no new safety issues were identified.

Breakthrough Therapy
In February 2020, enfortumab vedotin in combination with pembrolizumab was granted Breakthrough Therapy designation by the FDA and the EV-103 sBLA received Priority Review designation in December 2022. In April 2023, the FDA granted accelerated approval to the combination for the treatment of adult patients with la/mUC who are not eligible to receive cisplatin-containing chemotherapy based on tumor response rate and durability of response from the EV-103 trial. The EV-302 trial, which is intended to serve as the confirmatory trial for the U.S. accelerated approval and as the basis for global regulatory submissions, is also intended to expand the indication into the cisplatin-eligible patient population.

Clinical Trials
Enfortumab Vedotin and Pembrolizumab vs. Chemotherapy Alone in Untreated Locally Advanced or Metastatic Urothelial Cancer (EV-302) – ClinicalTrials.gov Identifier: NCT04223856

  • 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 overall response rate (ORR) and duration of response (DOR) per RECIST v1.1 by BICR, and safety.The EV-302 trial is part of an extensive program evaluating this combination in multiple stages of urothelial cancer and other solid tumors. Findings from EV-302, presented as a Late Breaking Abstract (Abstract #LBA6) at the European Society for Medical Oncology (ESMO) Congress 2023 in October, demonstrated that combination of enfortumab vedotin and pembrolizumab improved overall survival (OS) and progression-free survival (PFS) with statistically significant and clinically meaningful results in patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC).The EV-302 study met its dual primary endpoints of OS and PFS, compared to platinum and gemcitabine chemotherapy. Patients treated with enfortumab vedotin and pembrolizumab experienced:
    • Median OS of 31.5 months (95% CI: 25.4-NR) compared to 16.1 months (95% CI: 13.9-18.3) in the chemotherapy arm.
      • Significantly prolonged OS, reducing the risk of death by 53% compared to treatment with chemotherapy (Hazard Ratio [HR]=0.47; 95% Confidence Interval [CI]: 0.38-0.58; P<0.00001).
    • An Independent Data Monitoring Committee determined that OS crossed the pre-specified efficacy boundary at interim analysis.
    • Median PFS of 12.5 months (95% CI: 10.4-16.6) compared to 6.3 months (95% CI: 6.2-6.5) in the chemotherapy arm.
      • 55% reduction in the risk of cancer progression or death compared to treatment with chemotherapy (HR=0.45; 95% CI: (0.38-0.54); P<0.00001).
    • Consistent OS results across all pre-defined subgroups, including cisplatin eligibility and PD-L1 expression level.

    The most common (≥3%) Grade 3 or higher adverse events (AEs) related to treatment with enfortumab vedotin and pembrolizumab were rash maculo-papular, 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.

A Study of Enfortumab Vedotin Alone or With Other Therapies for Treatment of Urothelial Cancer (EV-103) – ClinicalTrials.gov ID NCT03288545

  • The EV-103 trial 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).

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) – ClinicalTrials.gov ID NCT04700124

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) – ClinicalTrials.gov ID NCT03924895

  • 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 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.

A Study to Evaluate Enfortumab Vedotin in Subjects With Locally Advanced or Metastatic Malignant Solid Tumors (EV-202) – ClinicalTrials.gov ID NCT04225117

  • The EV-202 trial 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.

Highlights of Prescription information
Enfortumab vedotin-ejfv (Padcev® ; Astellas/Seagen [Prescribing information]
Pembrolizumab (Keytryuda® ( Merck & Co; Merck Sharp & Dohme/MSD) [Prescribing Information]

Indication
In the United States, enfortumab vedotin-ejfv is indicated:

  • As a single agent, for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC) who:
  • For patients who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and platinum-containing chemotherapy, or
  • are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy.[1]

Enfortumab vedotin, in combination with pembrolizumab, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer (mUC) who are not eligible for cisplatin-containing chemotherapy.[1] This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Reference
[1] Key statistics for Bladder Cancer. American Cancer Society. (n.d.).[Page] Last accessed on October 30, 2023.
[2] National Cancer Institute. What is bladder cancer? [Page] . Last accessed on October 30, 2023.
[3] National Cancer Institute. Cancer stat facts: bladder cancer.[Page] Last accessed on October 30, 2023.
[4] Galsky MD, Pal SK, Lin SW, Ogale S, Zivkovic M, Simpson J, Derleth C, Schiff C, Sonpavde G. Real-World Effectiveness of Chemotherapy in Elderly Patients With Metastatic Bladder Cancer in the United States. Bladder Cancer. 2018 Apr 26;4(2):227-238. doi: 10.3233/BLC-170149. PMID: 29732393; PMCID: PMC5929305.
[5] American Society of Clinical Oncology. Bladder cancer: introduction (12-2021).[Page] . Last accessed on October 30, 2023.
[6] International Agency for Research on Cancer. Cancer Today: bladder globocan 2020 fact sheet (12-2020). [Page] . Last accessed on October 30, 2023.
[7] Challita-Eid PM, Satpayev D, Yang P, An Z, Morrison K, Shostak Y, Raitano A, Nadell R, Liu W, Lortie DR, Capo L, Verlinsky A, Leavitt M, Malik F, Aviña H, Guevara CI, Dinh N, Karki S, Anand BS, Pereira DS, Joseph IB, Doñate F, Morrison K, Stover DR. Enfortumab Vedotin Antibody-Drug Conjugate Targeting Nectin-4 Is a Highly Potent Therapeutic Agent in Multiple Preclinical Cancer Models. Cancer Res. 2016 May 15;76(10):3003-13. doi: 10.1158/0008-5472.CAN-15-1313. Epub 2016 Mar 24. PMID: 27013195.

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