This week the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation to enfortumab vedotin, an antibody-drug conjugate or ADC, for patients with locally advanced or metastatic urothelial cancer who were previously treated with checkpoint inhibitors (CPI).

Enfortumab vedotin is an investigational ADC composed of an anti-Nectin-4 monoclonal antibody attached to a microtubule-disrupting agent, monomethyl auristatin E or MMAE, a drug which is about 100-1000 times more potent than a standard chemotherapuetic agent such as doxorubicin (Adriamycin/Rubex). The drug incorporates Seattle Genetics’ proprietary linker technology to link the cytotoxic drug with a monoclonal antibody.

Enfortumab vedotin targets Nectin-4, a cell adhesion molecule identified as an ADC target by Astellas, which is expressed on many solid tumors.

MabPlex
 

Expediting development
Breakthrough Therapy Designation is a process designed to expedite the development and review of drugs that are intended to treat a serious or life-threatening condition. It is based upon preliminary clinical evidence indicating that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s).

“The FDA Breakthrough Therapy Designation underscores the potential of enfortumab vedotin as a meaningful treatment for patients with locally advanced or metastatic urothelial cancer. Further, it supports our rapid development plans for this ADC, including the ongoing pivotal study in this patient population,” said Robert Lechleider, M.D., Vice President, Clinical Development at Seattle Genetics.

“Seattle Genetics is an emerging multi-product oncology company, advancing a robust pipeline with the goal of improving outcomes for cancer patients. Enfortumab vedotin is at the forefront of our late-stage clinical pipeline, and we are working closely with our partner and the FDA to bring this potential new treatment to patients as quickly as possible,” Lechleider added.

“Achieving Breakthrough Therapy Designation for enfortumab vedotin is another step forward in our goal to bring an additional treatment option to patients who need it most,” said Steven Benner, M.D., Senior Vice President and Global Therapeutic Area Head, Oncology Development at Astellas.

“With the enfortumab vedotin registrational phase II trial and CPI-combination trial actively underway, Astellas looks forward to expanding development of enfortumab vedotin and its oncology pipeline, including treatments that would target some of the hardest-to-treat cancers.”

Schematic: NCT03219333 is a first patient trial in EV-201, a registrational phase II clinical trial of enfortumab vedotin for patients with locally advanced or metastatic urothelial cancer who have been previously treated with checkpoint inhibitor (CPI) therapy.
The EV-201 study will assess the antitumor activity and safety of enfortumab vedotin to support potential registration under the U.S. Food and Drug Administration’s (FDA) accelerated approval regulations. The primary endpoint of the single-arm, open-label trial is confirmed objective response rate (ORR), per independent review. Secondary endpoints include assessments of overall survival, progression free-survival, safety and tolerability.
The study will enroll approximately 120 patients at multiple centers globally, and enfortumab vedotin will be administered three of every four weeks for the duration of treatment.

Interim Phase I Results
The Breakthrough Therapy Designation was granted based on interim results from the phase I study examining enfortumab vedotin as monotherapy treatment for patients with metastatic urothelial cancer who were previously treated with CPIs.

Enfortumab vedotin is being studied in a pivotal clinical trial, EV-201 (NCT03219333), as monotherapy in this patient setting and in an early-phase clinical trial in combination with CPI therapy, EV-103 (NCT03288545). The companies are also evaluating enfortumab vedotin in other solid tumors, including ovarian and non-small cell lung carcinoma.

Collaboration
Astellas and Seattle Genetics entered into the ADC collaboration in January 2007 and expanded it in November 2009. Under the collaboration, the companies are co-developing and have options to globally co-commercialize enfortumab vedotin.