Astellas Submits Clinical Trial Applications in China for Enfortumab Vedotin, a Breakthrough Therapy ADC Targeting Nectin-4

Today, the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) announced that Astellas had submitted two clinical trial applications for injectable enfortumab vedotin in China, which have been accepted for review. This is an antibody-drug conjugate (ADC) targeting Nectin-4. It previously received Breakthrough Therapy Designation and Priority Review from the U.S. Food and Drug Administration (FDA) and was approved for marketing in the United States in late 2019 for the treatment of patients with locally advanced or metastatic urothelial carcinoma. Notably, this marks the first time the product has been submitted for clinical trial approval in China.

Screenshot source: CDE official website

Enfortumab vedotin is an antibody-drug conjugate developed jointly by Seattle Genetics and Astellas, created by linking an anti-Nectin-4 monoclonal antibody to the microtubule-disrupting agent MMAE. It utilizes Seattle Genetics’ proprietary antibody-drug conjugation technology. Nectin-4 is a cell adhesion molecule expressed on the surface of various solid tumors and is highly expressed in urothelial carcinoma.

At the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, enfortumab vedotin “stunned” the audience with its efficacy results in the treatment of advanced bladder cancer. Specifically, the drug achieved an objective response rate (ORR) of 44% in 125 patients, including a complete response rate of 12%. Notably, among patients who had previously received at least three prior therapies, the ORR was 41%; among patients refractory to PD-1 and PD-L1 inhibitors, the ORR was also 41%; and even in patients with liver metastases, the ORR reached 38%. It is important to note that therapeutic options for these patients were extremely limited, rendering their condition virtually “untreatable.”

Based on these positive results, the U.S. FDA approved enfortumab vedotin for marketing to treat patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-based chemotherapy and PD-1/PD-L1 inhibitor therapy. This approval came nearly four months ahead of the scheduled PDUFA date. Enfortumab vedotin has become a representative new paradigm for treating patients with advanced urothelial carcinoma whose disease progressed after chemotherapy and immunotherapy.

▲Mechanism of Action of Enfortumab Vedotin (Image source: Seattle Genetics official website)

This September, enfortumab vedotin met the primary endpoint of overall survival in a Phase 3 clinical trial for patients with locally advanced or metastatic urothelial carcinoma. Specifically, it reduced the risk of patient death by 30% and significantly improved progression-free survival, lowering the risk of disease progression or death by 39%. The survival outcomes obtained in this confirmatory trial are good news for patients whose disease continued to progress after platinum-based chemotherapy and immunotherapy. Based on these positive interim analysis results, the clinical trial will be terminated early.

According to earlier press releases issued by Seattle Genetics and Astellas, the results of this study will be submitted to the U.S. FDA as confirmatory trial data to support the conversion of enfortumab vedotin’s accelerated approval to full approval. These results will also support global regulatory submissions. Meanwhile, the companies will continue to explore the potential of this product in the treatment of urologic tumors.

Notably, the combination therapy of enfortumab vedotin and the PD-1 inhibitor pembrolizumab has also received Breakthrough Therapy Designation from the FDA as a first-line treatment for previously untreated patients with locally advanced or metastatic urothelial carcinoma.

Globally, approximately 580,000 people were diagnosed with bladder cancer in 2020. Urothelial carcinoma accounts for 90% of all bladder cancers and can also occur in the renal pelvis, ureters, and urethra. After failure of initial platinum-based chemotherapy, 80% of patients with advanced disease do not respond to PD-1 or PD-L1 inhibitor therapy.

References:

[1] Center for Drug Evaluation (CDE), National Medical Products Administration of China. Retrieved Oct 10, 2020, from http://www.cde.org.cn/news.do?method=changePage&pageName=service&frameStr=21#

[2] FDA approves new type of therapy to treat advanced urothelial cancer. Retrieved December 18, 2019, from https://www.fda.gov/news-events/press-announcements/fda-approves-new-type-therapy-treat-advanced-urothelial-cancer

[3] Seattle Genetics and Astellas Announce PADCEV® (enfortumab vedotin-ejfv) Significantly Improved Overall Survival in Phase 3 Trial in Previously Treated Locally Advanced or Metastatic Urothelial Cancer. Retrieved September 18, 2020, from https://www.businesswire.com/news/home/20200918005101/en

[4] Seattle Genetics and Astellas Receive FDA Breakthrough Therapy Designation for PADCEV™ (enfortumab vedotin-ejfv) in Combination with Pembrolizumab in First-Line Advanced Bladder Cancer, Retrieved February 19, 2020, from https://www.businesswire.com/news/home/20200219005512/en

[5] Seattle Genetics and Astellas Announce Antibody-Drug Conjugate Enfortumab Vedotin Produced Tumor Response Rate of 44 Percent in Patients with Most Common Type of Advanced Urothelial (Bladder) Cancer, Retrieved June 3, 2019, from https://seattlegenetics.gcs-web.com/news-releases/news-release-details/seattle-genetics-and-astellas-announce-antibody-drug-conjugate

Source: Pharma Outlook

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