Panel Weighs in on Future Directions for Urothelial Carcinoma Treatment

A roundtable discussion, moderated by Vadim Koshkin, MD, discussed the post-EV-302 world for metastatic urothelial carcinoma, as well as recent trial data from the American Society of Clinical Oncology Genitourinary Cancers Symposium 2024. Dr. Koshkin was joined by Petros Grivas, MD, PhD; Karine Tawagi, MD; Terence Friedlander, MD; and Guru Sonpavde, MD.

In the final segment of the roundtable series, the panel concludes with their forward-thinking thoughts on the impending direction of urothelial carcinoma treatment.

Watch previous segments in this series.

—

Dr. Koshkin: I will ask the whole panel: What are the future directions? How do we build on the success of this EV/pembro regimen? Is it with triplet therapies upfront, intensifying therapy upfront, or with better second-line therapy, some form of better maintenance after EV?

Dr. Friedlander: Understanding resistance to EV is crucial. About 70% of patients respond, with approximately 40% experiencing long-term durable responses. So, why do some respond while others do not? There’s data suggesting that Nectin4 is preserved after treatment with EV. Perhaps resistance is not due to the loss of Nectin4, the surface protein, but rather resistance to the drug itself. Other mechanisms, such as the linker in the ADC, could be at play. This understanding will drive the development of various treatments, such as other agents targeting Nectin4, small molecules, CAR-T cells, bispecific engagers, and radio pharmaceuticals. It is an exciting time with numerous trials underway. We must grasp why EV stops working to advance future therapies.

Dr. Grivas: Indeed, understanding mechanisms of resistance is a significant gap. Neoadjuvant trials could help in this regard. For instance, analyzing cystectomy tissue or biopsy samples from metastatic disease post-progression on EV can provide valuable data. Genomic alterations may also shed light on relevant pathways. As for building upon EV/pembro in the frontline setting, there are two strategies: combining ADCs and possibly adding an IO, or adding another checkpoint or immunomodulator to reduce toxicity while maintaining efficacy. Exploring both pathways is essential.

Dr. Tawagi: The ongoing KEYMAKER-U04 study is investigating EV/Pembro with LAG, which has shown reduced toxicity and promising efficacy in melanoma. Additionally, TIGIT, another immunomodulatory drug, holds potential in this space. Exciting developments ahead.

Dr. Koshkin: There is a lot of compelling data to anticipate from future conferences, as well as from this one.

Dr. Friedlander: Neoadjuvant studies, including the 304 trial of EV/PEMBRO, may significantly impact the use of these therapies. Administering them neoadjuvantly could change the landscape of metastatic treatment. We must also consider new targets like TROP 2, HER2, and FGFR. The future holds many possibilities.

Dr. Koshkin: Undoubtedly, the treatment space is dynamic, with better options emerging at every conference. It is both amazing and exciting. We have made significant progress but still have a long way to go. Thank you all for your contributions.