Mechanistic Insights into the Successful Development of Combination Therapy of Enfortumab Vedotin and Pembrolizumab for the Treatment of Locally Advanced or Metastatic Urothelial Cancer

Caroline Taylor; Kamai M Patterson; Devira Friedman; Silvia M Bacot; Gerald M Feldman; Tao Wang

doi:10.3390/cancers16173071

Mechanistic Insights into the Successful Development of Combination Therapy of Enfortumab Vedotin and Pembrolizumab for the Treatment of Locally Advanced or Metastatic Urothelial Cancer

Cancers (Basel). 2024 Sep 4;16(17):3071. doi: 10.3390/cancers16173071.

Authors

Caroline Taylor¹, Kamai M Patterson¹, Devira Friedman¹, Silvia M Bacot¹, Gerald M Feldman¹, Tao Wang¹

Affiliation

¹ Office of Pharmaceutical Quality Research, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.

Abstract

Antibody-drug conjugates (ADCs) consist of an antibody backbone that recognizes and binds to a target antigen expressed on tumor cells and a small molecule chemotherapy payload that is conjugated to the antibody via a linker. ADCs are one of the most promising therapeutic modalities for the treatment of various cancers. However, many patients have developed resistance to this form of therapy. Extensive efforts have been dedicated to identifying an effective combination of ADCs with other types of anticancer therapies to potentially overcome this resistance. A recent clinical study demonstrated that a combination of the ADC enfortumab vedotin (EV) with the immune checkpoint inhibitor (ICI) pembrolizumab can achieve remarkable clinical efficacy as the first-line therapy for the treatment of locally advanced or metastatic urothelial carcinoma (la/mUC)-leading to the first approval of a combination therapy of an ADC with an ICI for the treatment of cancer patients. In this review, we highlight knowledge and understanding gained from the successful development of EV and the combination therapy of EV with ICI for the treatment of la/mUC. Using urothelial carcinoma as an example, we will focus on dissecting the underlying mechanisms necessary for the development of this type of combination therapy for a variety of cancers.

Keywords: antibody–drug conjugate; anticancer combination therapy; enfortumab vedotin; immune checkpoint inhibitors; pembrolizumab; urothelial carcinoma.

Publication types

Review

Grants and funding

This project was supported in part by the appointment of C.T., K.M.P., and D.F., to the Research Participation Program at the Center for Drug Evaluation and Research, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and the U.S. Food and Drug Administration. The project is also supported by a grant from the Office of the Chief Scientist, the U.S. Food and Drug Administration, and a grant from the Office of Pharmaceutical Quality Center of Excellence (COE) in Immunology, the U.S. Food and Drug Administration.