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

Simple Summary Antibody-drug conjugates (ADCs) and immune checkpoint inhibitors (ICIs) are two promising therapeutic modalities against many types of cancers. However, many patients develop resistance. The resistance mechanisms to ADCs and ICIs have been comprehensively illuminated in this review. A combination of ADCs and ICIs has been explored to overcome resistance to ADC or ICI single treatment. Recently, a clinical study demonstrated that a combination of enfortumab vedotin (EV), an ADC against Nectin-4, with the ICI pembrolizumab achieves remarkable clinical efficacy as the first-line therapy for the treatment of locally advanced or metastatic urothelial carcinoma. The underlying mechanism is likely due to the enhancement of pembrolizumab-induced anticancer immunity mediated by EV. With the emerging use of combination therapy strategy, it is critical to understand the mechanism of successful and/or failed clinical studies for the future development of combination therapy of ADCs with ICIs.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.