The treatment landscape for urothelial carcinoma is rapidly evolving, marked by recent FDA approvals that necessitate a more personalized approach to patient care. Experts are now focused on optimizing treatment strategies to maximize efficacy while minimizing toxicity.
New Frontline Options
The last 18 months have witnessed the FDA's approval of two potent combination therapies: enfortumab vedotin-ejfv (Padcev) with pembrolizumab (Keytruda) and nivolumab (Opdivo) plus cisplatin and gemcitabine. These approvals, based on landmark clinical trials, have significantly altered the treatment paradigm for locally advanced or metastatic urothelial carcinoma.
David H. Aggen, MD, PhD, a genitourinary medical oncologist and cellular therapist with Memorial Sloan Kettering Cancer Center, emphasized the importance of tailoring therapy during a presentation at the 2024 Chemotherapy Foundation Symposium (CFS). "Now we have two very potent combination entities that are FDA approved in the frontline setting, and the question is, ‘How do we personalize and improve patient selection for frontline treatment now that patients are living, on average, more than 2 years with this aggressive cancer?’"
Enfortumab Vedotin and Pembrolizumab: Efficacy and Toxicity
The approval of enfortumab vedotin and pembrolizumab was based on the phase 3 EV-302/KEYNOTE-A39 trial. While the combination demonstrated significant tumor reduction in most patients, it also presented a considerable toxicity burden. According to Aggen, "what happens for most patients is they respond and their tumor burden decreases, but there's a cumulative toxicity that's a task for patients."
In the EV-302 trial, treatment-related adverse effects (TRAEs) leading to dose reductions occurred in 40.7% of patients on the enfortumab vedotin/pembrolizumab arm and 37.9% in the chemotherapy arm. Treatment discontinuation due to TRAEs was also higher in the enfortumab vedotin/pembrolizumab arm (35.0%) compared to the chemotherapy arm (18.5%). Common TRAEs leading to discontinuation included peripheral sensory neuropathy (10.7%) and pneumonitis (2.0%).
Aggen suggested that adapting the dosing regimen could optimize outcomes. "So, we know that at a year, about 50% of patients are still on therapy or have completed therapy and have not had progression of disease. Yet it's only about 25% of patients within the first 6 months that have progression, and it's in this other 75% of patients with stable disease or better that I think [we] need to be better about adapting the dosing to maximize efficacy and minimize toxicity."
The Role of ctDNA
Circulating tumor DNA (ctDNA) may serve as a valuable tool in guiding treatment decisions. Aggen explained, "The standard of care is to continue enfortumab vedotin and pembrolizumab as long as patients are tolerating and benefiting clinically, but for patients with concerns about toxicity, ctDNA may be another tool that you can use to help tailor treatment."
For instance, patients achieving a complete response and maintaining ctDNA negativity may be candidates for therapy de-escalation.
Nivolumab Plus Chemotherapy: CheckMate 901 Trial
The phase 3 CheckMate 901 study supported the FDA approval of nivolumab plus cisplatin and gemcitabine. The combination demonstrated a median overall survival (OS) of 21.7 months (95% CI, 18.6-26.4) compared to 18.9 months (95% CI, 14.7-22.4) with chemotherapy alone, representing a 22% reduction in the risk of death (HR, 0.78; 95% CI, 0.63-0.96). The median progression-free survival (PFS) was 7.9 months (95% CI, 7.6-9.5) with nivolumab plus chemotherapy and 7.6 months (95% CI, 6.0-7.8) with chemotherapy alone (HR, 0.72; 95% CI, 0.59-0.88).
The objective response rate (ORR) was also higher with nivolumab plus chemotherapy (57.6%; 95% CI, 51.8%-63.2%) compared to chemotherapy alone (43.1%; 95% CI, 37.5%-48.9%).
Future Directions
Currently, enfortumab vedotin plus pembrolizumab is the most common frontline treatment in the US. Upon progression, treatment options include erdafitinib (Balversa) for FGFR-mutated disease, fam-trastuzumab deruxtecan-nxki (Enhertu) for HER2 3+ disease, or platinum-based chemotherapy. However, there is a lack of data to guide optimal sequencing strategies.
Ongoing research explores novel antibody-drug conjugate (ADC) combinations, such as the phase I Double Antibody Drug Conjugate (DAD) trial evaluating sacituzumab govitecan-hziy (Trodelvy) and enfortumab vedotin. A phase I/II extension, DAD-IO, is examining combinations of sacituzumab govitecan plus enfortumab vedotin and pembrolizumab.
Aggen concluded by emphasizing the need for further biomarker research to guide treatment selection. "We really need more biomarker work from these large phase 3 studies to guide treatment selection. If we knew who the patients were that were CRs to nivolumab [plus gemcitabine and cisplatin], it would make that a much more attractive frontline option. And I think future trials now are just beginning to build on [enfortumab vedotin] plus [pembrolizumab] as the treatment backbone."
