Seattle Genetics Announces Potential Accelerated Approval Pathway in the US for PADCEV (enfortumab vedotin-ejfv) in Combination with Immune Therapy…

Posted: April 2, 2020 at 7:42 pm

BOTHELL, Wash.--(BUSINESS WIRE)-- Seattle Genetics, Inc.. (Nasdaq:SGEN) today provided an update on the phase 1b/2 multicohort EV-103 trial (also known as KEYNOTE-869) of PADCEVTM (enfortumab vedotin-ejfv) in combination with anti-PD-1 therapy pembrolizumab for the treatment of patients with unresectable locally advanced or metastatic urothelial cancer who are unable to receive cisplatin-based chemotherapy in the first-line setting. Based on recent discussions with the U.S. Food and Drug Administration (FDA), data from the randomized cohort K, along with other data from the EV-103 trial evaluating PADCEV combined with pembrolizumab as first-line therapy for cisplatin-ineligible patients, could potentially support registration under accelerated approval regulations in the United States. PADCEV 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.1

We are excited that EV-103 provides PADCEV with a potential pathway for U.S. accelerated approval in first-line metastatic urothelial cancer, said Roger Dansey, M.D., Chief Medical Officer at Seattle Genetics. Our initial data on the combination of PADCEV and pembrolizumab in previously untreated patients who could not receive cisplatin are encouraging.

EV-103 is a multi-cohort, open-label, multicenter phase 1b/2 trial of PADCEV alone or in combination, evaluating safety, tolerability and efficacy in muscle invasive urothelial cancer, and in locally advanced or metastatic urothelial cancer in first- or second-line settings. Cohort K from EV-103 is intended to enroll 150 patients randomized 1:1 to PADCEV monotherapy or PADCEV in combination with pembrolizumab in locally advanced or metastatic urothelial cancer patients who are ineligible for cisplatin-based chemotherapy. The primary outcome measure is objective response rate (ORR) per blinded independent central review (BICR) using RECIST 1.1 and duration of response (DoR).

In addition to EV-103, the recently initiated EV-302 phase 3 randomized clinical trial is intended to support global registrations and potentially serve as a confirmatory trial if accelerated approval is granted based on EV-103. The EV-302 trial is evaluating the combination of PADCEV and pembrolizumab with or without chemotherapy versus chemotherapy alone in patients with previously untreated locally advanced or metastatic urothelial cancer. Importantly, EV-302 includes metastatic urothelial cancer patients that are either eligible or ineligible for cisplatin-based chemotherapy. The trial is expected to enroll 1,095 patients and has dual primary endpoints of progression-free survival and overall survival. Both the EV-103 and EV-302 trials are being conducted in collaboration with Astellas and Merck.

FDA recently granted Breakthrough Therapy designation for PADCEV in combination with pembrolizumab for the treatment of patients with unresectable locally advanced or metastatic urothelial cancer who are unable to receive cisplatin-based chemotherapy in the first-line setting based on initial results from the EV-103 trial.

PADCEV (enfortumab vedotin-ejfv) was approved by the FDA in December 2019 and is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a platinum-containing chemotherapy before (neoadjuvant) or after (adjuvant) surgery or in a locally advanced or metastatic setting. PADCEV was approved under the FDAs Accelerated Approval Program based on tumor response rate. Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.2

About Bladder and Urothelial Cancer

It is estimated that approximately 81,000 people in the U.S. will be diagnosed with bladder cancer in 2020.3 Urothelial cancer accounts for 90 percent of all bladder cancers and can also be found in the renal pelvis, ureter and urethra.4 Globally, approximately 549,000 people were diagnosed with bladder cancer in 2018, and there were approximately 200,000 deaths worldwide.5

About PADCEV

PADCEV 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.6,7 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).8 PADCEV is co-developed by Astellas and Seattle Genetics.

Important Safety Information

Warnings and Precautions

Adverse Reactions

Serious adverse reactions occurred in 46% of patients treated with PADCEV. The most common serious adverse reactions (3%) were urinary tract infection (6%), cellulitis (5%), febrile neutropenia (4%), diarrhea (4%), sepsis (3%), acute kidney injury (3%), dyspnea (3%), and rash (3%). Fatal adverse reactions occurred in 3.2% of patients, including acute respiratory failure, aspiration pneumonia, cardiac disorder, and sepsis (each 0.8%).

Adverse reactions leading to discontinuation occurred in 16% of patients; the most common adverse reaction leading to discontinuation was peripheral neuropathy (6%). Adverse reactions leading to dose interruption occurred in 64% of patients; the most common adverse reactions leading to dose interruption were peripheral neuropathy (18%), rash (9%) and fatigue (6%). Adverse reactions leading to dose reduction occurred in 34% of patients; the most common adverse reactions leading to dose reduction were peripheral neuropathy (12%), rash (6%) and fatigue (4%).

The most common adverse reactions (20%) were fatigue (56%), peripheral neuropathy (56%), decreased appetite (52%), rash (52%), alopecia (50%), nausea (45%), dysgeusia (42%), diarrhea (42%), dry eye (40%), pruritus (26%) and dry skin (26%). The most common Grade 3 adverse reactions (5%) were rash (13%), diarrhea (6%) and fatigue (6%).

Lab Abnormalities

In one clinical trial, Grade 3-4 laboratory abnormalities reported in 5% were: lymphocytes decreased, hemoglobin decreased, phosphate decreased, lipase increased, sodium decreased, glucose increased, urate increased, neutrophils decreased.

Drug Interactions

Specific Populations

For more information, please see the full Prescribing Information for PADCEV here.

About Seattle Genetics

Seattle Genetics, Inc. is a global biotechnology company that discovers, develops and commercializes transformative medicines targeting cancer to make a meaningful difference in peoples lives. The company is headquartered in Bothell, Washington, and has offices in California, Switzerland and the European Union. For more information on our robust pipeline, visit https://www.seattlegenetics.com and follow @SeattleGenetics on Twitter. For information on our response to the COVID-19 pandemic, please visit our website.

About the Astellas and Seattle Genetics Collaboration

Seattle Genetics and Astellas are co-developing PADCEV under a collaboration that was entered into in 2007 and expanded in 2009. Under the collaboration, the companies are sharing costs and profits on a 50:50 basis worldwide.

About the Seattle Genetics, Astellas and Merck Collaboration

Seattle Genetics and Astellas entered a clinical collaboration agreement with Merck to evaluate the combination of Seattle Genetics and Astellas PADCEV and Mercks 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., Kenilworth, NJ, USA.

Seattle Genetics Forward-Looking Statements

Certain statements made in this press release are forward looking, such as those, among others, relating to the potential of data from the EV-103 clinical trial to support accelerated approval in the U.S. of PADCEV in combination with pembrolizumab for the treatment of patients with unresectable locally advanced or metastatic urothelial cancer who are unable to receive cisplatin-based chemotherapy in the first-line setting; the possibility of using data from the EV-302 clinical trial to obtain global regulatory approval or confirm accelerated approval of PADCEV in the referenced first line setting; clinical development plans relating to PADCEV; the therapeutic potential of PADCEV; and its possible safety, efficacy, and therapeutic uses, including in the first-line setting. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include the possibility that ongoing and subsequent clinical trials of PADCEV may fail to produce data sufficient to support regulatory approvals; the fact that FDA has not made a final determination regarding whether the data from the EV-103 clinical trial will be sufficient to support accelerated approval in the U.S.; the risk that the COVID-19 pandemic could delay our ability to conduct the EV-103 clinical trial and delay FDAs regulatory timelines, including with respect to any potential accelerated approval; the fact that adverse events or safety signals may occur and that adverse regulatory actions or other setbacks could occur as PADCEV advances in clinical trials even after promising results in earlier clinical trials. More information about the risks and uncertainties faced by Seattle Genetics is contained under the caption Risk Factors included in the companys Annual Report on Form 10-K for the year ended December 31, 2019 filed with the Securities and Exchange Commission. Seattle Genetics disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

1Challita-Eid P, 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):3003-13.2 PADCEV [package insert]. Northbrook, IL: Astellas, Inc.3 American Cancer Society. Cancer Facts & Figures 2020. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf. Accessed 02-20-2020.4 American Society of Clinical Oncology. Bladder cancer: introduction (10-2017). https://www.cancer.net/cancer-types/bladder-cancer/introduction. Accessed 05-09-2019.5 International Agency for Research on Cancer. Cancer Tomorrow: Bladder. http://gco.iarc.fr/tomorrow.6 Challita-Eid P, 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):3003-13.7 PADCEV [package insert]. Northbrook, IL: Astellas, Inc.8 PADCEV [package insert]. Northbrook, IL: Astellas, Inc.

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Seattle Genetics Announces Potential Accelerated Approval Pathway in the US for PADCEV (enfortumab vedotin-ejfv) in Combination with Immune Therapy...

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