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Japan's Ministry of Health, Labour and Welfare Approves PADCEV™ (enfortumab vedotin) with KEYTRUDA® (pembrolizumab) for First-Line Treatment of Radically Unresectable Urothelial Carcinoma

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Astellas Pharma Inc. announced that Japan's Ministry of Health, Labour and Welfare (MHLW) has approved PADCEV™ (enfortumab vedotin) with KEYTRUDA® (pembrolizumab) as a combination therapy for the first-line treatment of adult patients with radically unresectable urothelial carcinoma. This approval is based on the EV-302 clinical trial, which showed significant improvements in overall survival and progression-free survival compared to platinum-containing chemotherapy.

Key findings from the EV-302 trial include:

  • Median overall survival: 31.5 months for the combination therapy vs. 16.1 months for chemotherapy
  • 53% reduction in risk of death
  • Median progression-free survival: 12.5 months for the combination therapy vs. 6.3 months for chemotherapy
  • 55% reduction in risk of cancer progression or death

This approval offers an alternative to platinum-containing chemotherapy, the current standard of care for first-line treatment of radically unresectable urothelial cancer in Japan.

Astellas Pharma Inc. ha annunciato che il Ministero della Salute, del Lavoro e del Welfare del Giappone (MHLW) ha approvato PADCEV™ (enfortumab vedotin) in combinazione con KEYTRUDA® (pembrolizumab) come terapia combinata per il trattamento di prima linea di pazienti adulti con carcinoma uroteliale radicalmente irresecabile. Tale approvazione si basa sul trial clinico EV-302, che ha mostrato miglioramenti significativi nella sopravvivenza generale e nella sopravvivenza libera da progressione rispetto alla chemioterapia a base di platino.

I risultati chiave dello studio EV-302 includono:

  • Sopravvivenza generale mediana: 31.5 mesi per la terapia combinata contro 16.1 mesi per la chemioterapia
  • Riduzione del 53% del rischio di morte
  • Sopravvivenza mediana libera da progressione: 12.5 mesi per la terapia combinata contro 6.3 mesi per la chemioterapia
  • Riduzione del 55% del rischio di progressione tumorale o morte

Questa approvazione offre un'alternativa alla chemioterapia a base di platino, attualmente standard di cura per il trattamento di prima linea del carcinoma uroteliale radicalmente irresecabile in Giappone.

Astellas Pharma Inc. anunció que el Ministerio de Salud, Trabajo y Bienestar de Japón (MHLW) ha aprobado PADCEV™ (enfortumab vedotina) junto con KEYTRUDA® (pembrolizumab) como una terapia combinada para el tratamiento de primera línea en pacientes adultos con carcinoma urotelial radicalmente irresecable. Esta aprobación se basa en el ensayo clínico EV-302, que mostró mejoras significativas en la supervivencia general y en la supervivencia libre de progresión en comparación con la quimioterapia que contiene platino.

Los hallazgos clave del ensayo EV-302 incluyen:

  • Supervivencia general mediana: 31.5 meses para la terapia combinada frente a 16.1 meses para la quimioterapia
  • Reducción del 53% en el riesgo de muerte
  • Supervivencia libre de progresión mediana: 12.5 meses para la terapia combinada frente a 6.3 meses para la quimioterapia
  • Reducción del 55% en el riesgo de progresión del cáncer o muerte

Esta aprobación ofrece una alternativa a la quimioterapia que contiene platino, que es el estándar actual de atención para el tratamiento de primera línea del cáncer urotelial radicalmente irresecable en Japón.

Astellas Pharma Inc.는 일본 후생노동성(MHLW)이 PADCEV™(엔포르투맙 베도틴)과 KEYTRUDA®(펨브롤리주맙)근치적으로 절제가 불가능한 요로상피암 성인 환자의 1차 치료를 위한 병합 요법으로 승인했다고 발표했습니다. 이 승인은 EV-302 임상 시험을 기반으로 하며, 이 시험은 백금 포함 화학요법에 비해 전체 생존율과 무진행 생존율에서 상당한 개선을 보여주었습니다.

EV-302 시험의 주요 결과는 다음과 같습니다:

  • 중앙 전체 생존율: 병합 요법 31.5개월 vs. 화학요법 16.1개월
  • 사망 위험 53% 감소
  • 중앙 무진행 생존율: 병합 요법 12.5개월 vs. 화학요법 6.3개월
  • 암 진행 또는 사망 위험 55% 감소

이 승인은 일본에서 근치적으로 절제가 불가능한 요로상피암의 1차 치료를 위한 현재의 표준 치료법인 백금 포함 화학요법에 대한 대안을 제공합니다.

Astellas Pharma Inc. a annoncé que le ministère japonais de la Santé, du Travail et du Bien-Être (MHLW) a approuvé PADCEV™ (enfortumab vedotin) associé à KEYTRUDA® (pembrolizumab) en tant que thérapie combinée pour le traitement de première ligne des patients adultes atteints de carcinome urotéthial radicalement non résécable. Cette approbation repose sur l', qui a montré des améliorations significatives de la survie globale et de la survie sans progression par rapport à la chimiothérapie contenant du platine.

Les résultats clés de l'essai EV-302 incluent :

  • Survie globale médiane : 31,5 mois pour la thérapie combinée contre 16,1 mois pour la chimiothérapie
  • Réduction de 53 % du risque de décès
  • Survie sans progression médiane : 12,5 mois pour la thérapie combinée contre 6,3 mois pour la chimiothérapie
  • Réduction de 55 % du risque de progression du cancer ou de décès

Cette approbation offre une alternative à la chimiothérapie contenant du platine, qui est le standard actuel des soins pour le traitement de première ligne du carcinome urotéthial radicalement non résécable au Japon.

Astellas Pharma Inc. gab bekannt, dass das japanische Ministerium für Gesundheit, Arbeit und Wohlstand (MHLW) PADCEV™ (Enfortumab Vedotin) in Kombination mit KEYTRUDA® (Pembrolizumab) als Kombinationsbehandlung für die Erstlinientherapie von erwachsenen Patienten mit radikal nicht resezierbarem Urotheliom genehmigt hat. Diese Genehmigung basiert auf der EV-302-Studie, die signifikante Verbesserungen in der Gesamtüberlebensrate und progressionsfreien Überlebensrate im Vergleich zur platinhaltigen Chemotherapie zeigte.

Wesentliche Erkenntnisse aus der EV-302-Studie umfassen:

  • Mittlere Gesamtüberlebenszeit: 31,5 Monate für die Kombinationsbehandlung gegenüber 16,1 Monaten für die Chemotherapie
  • 53%ige Reduktion des Sterberisikos
  • Mittlere progressionsfreie Überlebenszeit: 12,5 Monate für die Kombinationsbehandlung gegenüber 6,3 Monaten für die Chemotherapie
  • 55%ige Reduktion des RISIKOS für Krebsprogression oder Tod

Diese Genehmigung bietet eine Alternative zur platinhaltigen Chemotherapie, die derzeit der Standard der Pflege für die Erstlinientherapie von radikal nicht resezierbarem Urothelkarzinom in Japan ist.

Positive
  • Approval of PADCEV™ with KEYTRUDA® as first-line treatment for radically unresectable urothelial carcinoma in Japan
  • Significant improvement in median overall survival (31.5 months vs. 16.1 months) compared to chemotherapy
  • 53% reduction in risk of death with the combination therapy
  • Substantial increase in median progression-free survival (12.5 months vs. 6.3 months)
  • 55% reduction in risk of cancer progression or death
  • First approved combination treatment for radically unresectable urothelial cancer in Japan as an alternative to chemotherapy
Negative
  • Presence of Grade 3 or higher adverse events related to the treatment combination, including maculo-papular rash, hyperglycemia, and neutropenia

- Approval based on the EV-302 trial where the treatment combination nearly doubled median overall survival and significantly extended progression free survival compared to platinum-containing chemotherapy, the current standard of care for first-line treatment of radically unresectable urothelial carcinoma1

- Approval follows priority review designation from the Ministry of Health, Labour and Welfare, granted on the basis of the clinical usefulness of the treatment combination and the seriousness of the disease for which it is intended2

TOKYO, Sept. 24, 2024 /PRNewswire/ -- Astellas Pharma Inc. (TSE:4503, President and CEO: Naoki Okamura, "Astellas") today announced that Japan's Ministry of Health, Labour and Welfare (MHLW) has approved PADCEV™ (enfortumab vedotin [genetical recombination]) with MSD's KEYTRUDA® (pembrolizumab [genetical recombination]) as a combination therapy for the first-line treatment of adult patients with radically unresectable urothelial carcinoma. This is the first approved combination treatment for radically unresectable urothelial cancer in Japan to offer an alternative to platinum-containing chemotherapy, the current standard of care for first-line treatment.

In Japan, bladder cancer is the 9th most common cancer, with over 34,500 new cases diagnosed and 11,000 deaths reported from the disease in 2022.3 Particularly poor outcomes are associated with the latter stages of the disease, with global five-year survival rates of 39% and 8% for locally advanced and metastatic urothelial cancer, respectively.4

The approval by the MHLW was supported by results from the Phase 3 EV-302 clinical trial (also known as KEYNOTE-A39) which explored the efficacy and safety of enfortumab vedotin in combination with pembrolizumab in patients with previously untreated locally advanced or metastatic urothelial cancer (la/mUC). Results showed that the treatment combination resulted in a median overall survival of 31.5 months (95% CI: 25.4-NR) compared to 16.1 months (95% CI: 13.9-18.3) with platinum-containing 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 progression-free survival 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). The safety results in EV-302 are consistent with those previously reported for this combination in EV-103 in cisplatin-ineligible patients with la/mUC. The most common (≥3%) Grade 3 or higher adverse events (AEs) related to treatment with enfortumab vedotin in combination with pembrolizumab were maculo-papular rash, hyperglycemia, neutropenia, peripheral sensory neuropathy, diarrhea, and anemia. No new safety issues were identified. 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) Congress and published in the New England Journal of Medicine.1

Ahsan Arozullah, M.D., M.P.H., Senior Vice President, Head of Oncology Development, Astellas
"Today's approval by Japan's MHLW expands the benefits of treatment with enfortumab vedotin in combination with pembrolizumab to patients living with radically unresectable urothelial carcinoma in Japan. These patients will now have an alternative to platinum-containing chemotherapy to treat this devastating disease, helping to improve patient outcomes, extend lives and give further hope to the patients and families that we serve."

In addition to this latest approval, enfortumab vedotin in combination with pembrolizumab was approved by the European Commission in August 2024 for the first-line treatment of adult patients with unresectable or metastatic urothelial cancer, who are eligible for platinum-containing chemotherapy. Furthermore, in December 2023, the U.S. Food and Drug Administration approved the use of the combination therapy for adult patients with locally advanced or metastatic urothelial cancer.

Astellas has already reflected the impact from the approval for enfortumab vedotin in Japan in its financial forecast for the current fiscal year ending March 31, 2025.

About EV-302
The EV-302 trial is an open-label, randomized, controlled Phase 3 study, evaluating enfortumab vedotin in combination with pembrolizumab versus platinum-containing 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 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 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) Congress and published in the New England Journal of Medicine.1

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.5 Urothelial cancer accounts for 90% of global bladder cancers and can also be found in the renal pelvis, ureter, and urethra.6,7 If bladder cancer has spread to surrounding organs or muscles, it is called locally advanced disease.8 If the cancer has spread to other parts of the body, it is called metastatic disease.9 Globally, approximately 12% of cases are locally advanced or metastatic urothelial cancer at diagnosis.10

About PADCEV™ (enfortumab vedotin [genetical recombination])
PADCEV (enfortumab vedotin [genetical recombination]) 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.11,12 Non-clinical 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).11

PADCEV is indicated in Japan as monotherapy for the treatment of adult patients with radically unresectable urothelial carcinoma that has progressed after anti-cancer chemotherapy, and in combination with KEYTRUDA® (pembrolizumab) for the first-line treatment of adult patients with radically unresectable urothelial carcinoma.13

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).

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-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.

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. 

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.

Important Safety Information
For important Safety Information for PADCEV, please see the Package Insert.

About Astellas
Astellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world. We are promoting the Focus Area Approach that is designed to identify opportunities for the continuous creation of new drugs to address diseases with high unmet medical needs by focusing on Biology and Modality. Furthermore, we are also looking beyond our foundational Rx focus to create Rx+® healthcare solutions that combine our expertise and knowledge with cutting-edge technology in different fields of external partners. Through these efforts, Astellas stands on the forefront of healthcare change to turn innovative science into VALUE for patients. For more information, please visit our website at https://www.astellas.com/en.

About the Astellas, Pfizer and Merck Collaboration
Astellas and Pfizer have a clinical collaboration agreement with Merck to evaluate the combination of Astellas' and Pfizer's PADCEV™ (enfortumab vedotin) and Merck's KEYTRUDA® (pembrolizumab) in patients with previously untreated metastatic urothelial cancer. KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Rahway, NJ, USA (known as MSD outside of the United States and Canada).

Astellas Cautionary Notes
In this press release, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas. These statements are based on management's current assumptions and beliefs in light of the information currently available to it and involve known and unknown risks and uncertainties. A number of factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and in laws and regulations, relating to pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii) delays in new product launches, (iv) the inability of Astellas to market existing and new products effectively, (v) the inability of Astellas to continue to effectively research and develop products accepted by customers in highly competitive markets, and (vi) infringements of Astellas' intellectual property rights by third parties.

Information about pharmaceutical products (including products currently in development) which is included in this press release is not intended to constitute an advertisement or medical advice.

1 Powles T, et al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024;390:875-888.
2 Pharmaceuticals and Medical Devices Agency. Drug Reviews. Available at:
https://www.pmda.go.jp/english/review-services/reviews/0001.html. Last accessed: September 2024.
3 International Agency for Research on Cancer. Global Cancer Observatory. Cancer Today: 2022. Available at: https://gco.iarc.who.int. Last accessed: September 2024.
4 National Cancer Institute. Bladder Cancer Prognosis and Survival Rates. Available at: https://www.cancer.gov/types/bladder/survival. Last accessed: September 2024.
5 National Cancer Institute. What is bladder cancer? (February 2023) Available at: https://www.cancer.gov/types/bladder. Last accessed: September 2024.
6 Leow JJ, et al. Optimal management of upper tract urothelial carcinoma: Current perspectives. Onco Targets Ther. 2020;13:1-15.
7 Petros FG. Epidemiology, clinical presentation, and evaluation of upper-tract urothelial carcinoma. Transl Androl Urol. 2020;9(4):1794-8.
8 National Cancer Institute. NCI dictionary of cancer terms: Locally advanced cancer. Available at: https://www.cancer.gov/publications/dictionaries/cancer-terms/def/locally-advanced-cancer. Last accessed: September 2024.
9 American Cancer Society. If you have bladder cancer. (March 2024). Available at: https://www.cancer.org/cancer/types/bladder-cancer/if-you-have-bladder-cancer.html. Last accessed: September 2024.
10 National Cancer Institute. Cancer stat facts: bladder cancer. Available at: https://seer.cancer.gov/statfacts/html/urinb.html. Last accessed: September 2024.
11 European Medicines Agency. PADCEV EMA SmPC. Available at: https://www.ema.europa.eu/en/documents/product-information/padcev-epar-product-information_en.pdf. Last accessed: September 2024.
12 Challita-Eid PM, 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.
13 Astellas Press Release. Japan's MHLW Approves PADCEV® (enfortumab vedotin) for Advanced Urothelial Cancer. Available at: https://www.astellas.com/en/news/17206. Last accessed: September 2024.

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FAQ

What is the new treatment approved for urothelial carcinoma in Japan?

Japan's MHLW has approved PADCEV™ (enfortumab vedotin) with KEYTRUDA® (pembrolizumab) as a combination therapy for the first-line treatment of adult patients with radically unresectable urothelial carcinoma.

How effective is the PADCEV™ and KEYTRUDA® combination compared to chemotherapy for urothelial carcinoma?

The combination therapy showed a median overall survival of 31.5 months compared to 16.1 months with chemotherapy, representing a 53% reduction in risk of death. It also improved median progression-free survival to 12.5 months versus 6.3 months with chemotherapy.

What are the main side effects of the PADCEV™ and KEYTRUDA® combination for urothelial carcinoma?

The most common Grade 3 or higher adverse events included maculo-papular rash, hyperglycemia, neutropenia, peripheral sensory neuropathy, diarrhea, and anemia.

How does this approval impact Astellas Pharma Inc. (ALPMY) financially?

Astellas has already reflected the impact of this approval in its financial forecast for the fiscal year ending March 31, 2025, suggesting a positive financial outlook for the company.

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