Research shows potential target for enfortumab vedotin therapy in urothelial carcinoma

Research shows potential target for enfortumab vedotin therapy in urothelial carcinoma

Under the direction of PD Dr. Niklas Klümper, assistant doctor at the Department of Urology at the University Hospital of Bonn (UKB) and Clinician Scientist of the BMBF-funded ACCENT program and PD Dr. Markus Eckstein, senior physician at the Institute of Pathology at the Erlangen University Hospital of the Friedrich-Alexander University Erlangen-Nuremberg (FAU), an interdisciplinary research team has published new findings that indicate which patients with advanced urothelial carcinoma could particularly benefit from the new targeted therapy with the antibody-drug conjugate enfortumab vedotin. The study was published yesterday in the renowned journalJournal of Clinical Oncologyidentifies NECTIN4 Amplification as a promising genomic biomarker for predicting treatment response to enfortumab vedotin. These findings could represent a significant advance in improved treatment of this type of cancer.

As an alternative to chemotherapy for the treatment of aggressive advanced and metastatic urothelial carcinomas, a new class of drugs called antibody-drug conjugates has recently become available. Enfortumab vedotin (EV) is the first drug in this new class to be approved by the EMA for the treatment of patients and patients with metastatic urothelial carcinoma. Given the extremely promising results of the EV-302 trial, which showed a nearly doubling of survival rate with the combination therapy of EV and pembrolizumab, an immune checkpoint inhibitor, compared to conventional platinum-based chemotherapy in untreated patients with metastatic urothelial carcinoma, the use of EVs is expected to increase significantly in the future.

Modern targeted oncological therapy

Antibody-drug conjugates consist of an antibody that is directed against a target structure on tumor cells and is combined with a highly toxic chemotherapy drug. This combines the selectivity of targeted antibody therapy with the cytotoxic potential of conventional chemotherapy, representing an innovative and new oncological therapeutic approach.

Research for more targeted therapy: precision oncology

The long-term effectiveness of the new drug EV has so far been demonstrated in an uncharacterized group of patients with metastatic urothelial carcinoma. The research team led by PD Dr. Niklas Klümper (UKB) and PD Dr. Markus Eckstein (Erlangen University Hospital) therefore wanted to analyze in more detail which patients effectively benefit from EV therapy in order to be able to use it more specifically - and vice versa, to identify patients who benefit less or not from EV, as they could possibly be treated more effectively with other therapies.

Nectin-4, the target of EV, is located on chromosome 1q23.3. This gene section is increased in around 20-25 percent of urothelial carcinomas, which is referred to as amplification. The aim of the new study was to examine NECTIN4 Reinforcements as a potential genomic biomarker to predict treatment response to the drug EV in patients with advanced urothelial carcinoma.

“We have successfully developed and applied a simple FISH (fluorescence in situ hybridization) test)The is specific to NECTIN4. This assay was found to be a reliable method for identifying NECTIN4 amplification. Our studies demonstrated that the presence of NECTIN4 amplification is a robust biomarker of response to EV therapy. In fact, over 90 percent of patients with NECTIN4 amplification showed a tumor response to EV therapy, compared to about 30 percent of patients without this amplification," says PD Dr. Markus Eckstein. These new findings can help better select patients for this promising therapy "NECTIN4 amplification is a promising biomarker for predicting treatment response to EV." Interestingly, in addition to urothelial carcinomas, NECTIN4 amplification is also common in other solid tumors, such as lung and breast cancer. The consideration of NECTIN4 amplification could therefore also be an exciting option for other tumor types in order to select patients more specifically for anti-NECTIN4-targeted therapy. Further studies on this topic are needed, but our work could be the starting signal for the establishment of new targeted treatment strategies,”says PD Dr. Niklas Klümper.

Both study leaders also agree that without the great support of all colleagues involved from the numerous oncology centers in Germany, Austria, the Netherlands and the USA and of course without the consent of the patients to participate in the study, it would never have been carried out successfully.

The study was funded and initiated by the German Research Foundation (DFG) as part of the DFG junior academy UroAgeCare of the German Society for Urology (DGU). “This underlines the high relevance of promoting clinician science programs for medical progress,” says Prof. Michael Hölzel, mentor of PD Dr. Klümper within the program.

Sources: