Drugs Xagena
Urothelial carcinoma (UC) is the tenth most common cancer worldwide. Only 5% of cases are diagnosed in the metastatic setting. However, around 50% of patients who underwent cystectomy for a localized disease will eventually develop metastases.
In the metastatic setting, the sequence of Platinum-based chemotherapy (CT) followed by maintenance Avelumab represents the standard of care nowadays, after improving overall survival (OS) and progression-free survival (PFS) compared to Platinum-based chemotherapy plus best supportive care.
Immune checkpoint inhibitors (ICIs) are also used in the Platinum-progressive setting, improving survival over the alternative chemotherapy regimens, mainly taxanes and, in Europe, Vinflunine.
Moreover, ICIs - Pembrolizumab and Atezolizumab - are approved in the first line for Platinum-ineligible patients.
However, despite considerable progress, metastatic urothelial carcinoma (mUC) remains incurable, as over half of patients do not respond to treatments.
Intrinsic or acquired resistance to chemotherapy and immune checkpoint inhibitors leads to a median overall survival (mOS) that still now does not overcome 21 months, with a 5 year survival rate less than 10%.
Less than 1 out of 5 metastatic urothelial carcinoma patients carries mutations of the fibroblast-growth factor receptors (FGFR) and is a candidate for FGFR inhibitors, such as Erdafitinib, in the Platinum-progressive setting.
However, no effective treatments besides these regimens have been recently approved. In this scenario, antibody-drug conjugates (ADCs), such as Enfortumab vedotin (EV) and Sacituzumab govitecan (SG), have been studied to fill the gap of survival and response of metastatic urothelial carcinoma patients.
Antibody-drug conjugates are small molecules with an anticancer drug linked to a monoclonal antibody: the antibody binds the cell surface receptors, and then the anticancer drug is released into the intracellular environment.
The review focuses on Enfortumab vedotin, which has been approved by the Food and Drug Administration (FDA) and the European Medical Agency (EMA) for metastatic urothelial carcinoma patients progressing to Platinum and immune checkpoint inhibitors.
Enfortumab vedotin is an effective and tolerable antibody-drug conjugate with exceptional activity in treating patients with metastatic urothelial carcinoma. Although serious skin rash is a rare but potentially severe side effect that may occur early, close monitoring during the initial cycles is recommended. Peripheral neuropathy is a common side effect that can limit the dose in patients responding well to treatment. In contrast to Platinum-based chemotherapy, Enfortumab vedotin appears to be less nephrotoxic and well tolerated in patients with impaired renal function, particularly relevant for those with UTUC. The mechanisms of response and resistance to Enfortumab vedotin remain a significant area of research with a particular interest in biomarker identification. Enfortumab vedotin plus Pembrolizumab is a promising combination regimen that is well-tolerated and effective in Cisplatin-ineligible patients. Although the optimal combination and sequencing of Enfortumab vedotin with other agents (e.g., chemotherapy, targeted therapy, immune checkpoint inhibitors, and antibody-drug conjugates) are still unknown, Enfortumab vedotin will be able to expand the options for treating patients with metastatic urothelial carcinoma in the next few years. ( Xagena )
Maiorano BA et al, Front Oncol 2023:13:1254906.
XagenaMedicine_2023
