Immunotherapy-Based Trials Challenge Chemotherapy Dominance in MIBC

Emerging immunotherapy-based perioperative regimens, bladder-sparing approaches, and tri-modality therapies are poised to reshape the muscle-invasive bladder cancer (MIBC) treatment paradigm, according to Waddah Arafat, MD.

In an interview with OncLive®, Arafat highlighted the potential future clinical implications of the ongoing KEYNOTE-B15/EV-304 trial (NCT04700124), which is evaluating perioperative enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) vs neoadjuvant chemotherapy in patients with cisplatin-eligible MIBC.1

He also noted the safety profile of the phase 3 NIAGARA trial (NCT03732677) regimen of perioperative durvalumab (Imfinzi) plus neoadjuvant gemcitabine plus cisplatin (n = 530) vs neoadjuvant gemcitabine plus cisplatin alone (n = 526). In the trial, the rates of grade 3/4 treatment-related adverse effects (AEs) were comparable between the 2 arms, at 40.6% vs 40.9%, respectively.2 Immune-mediated AEs occurred in 20.9% of patients in the durvalumab arm vs 3.0% of those in the comparison arm. In a previous article, Arafat dove into the clinical implications of the NIAGARA trial.

Arafat is an associate professor of internal medicine and a member of the Division of Hematology and Oncology at the University of Texas (UT) Southwestern Medical Center; as well as medical director of the Clinical Cancer Informatics Program at the UT Southwestern Harold C. Simmons Comprehensive Cancer Center in Dallas.

OncLive: Now that the MIBC treatment paradigm has expanded to include the NIAGARA trial regimen, what might the future look like regarding the role of doxorubicin—part of dose-dense MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin)—in this population?

Arafat: As it stands, there are no big trials to try to spare patients doxorubicin. There are some attempts to integrate more novel therapies into a perioperative chemotherapy regimen. However, what is also going to be important is to wait for the perioperative enfortumab vedotin/pembrolizumab data, mainly from the KEYNOTE-B15/EV-304 trial, because those might be practice-changing in the same way as the metastatic data from the phase 3 EV-302 trial [NCT04223856]. It’s too early to tell, and we cannot draw conclusions this early in the trial. However, [positive data from EV-304] would only spare [patients] doxorubicin, [but they] would spare [patients] chemotherapy altogether.

What has been your clinical experience with using the NIAGARA trial regimen? How is it different from using chemotherapy?

I [have not observed] compound toxicity. It is just [associated with] additional set of toxicities that are related to the immunotherapy that would not necessarily worsen the pre-existing or known AEs associated with chemotherapy. [The NIAGARA regimen is] manageable with just the known sets of toxicities associated with both chemotherapy and immunotherapy. It does not necessarily [confer] a significant outcome change in performance status, fatigue, or bone marrow suppression. However, [the regimen is associated with] its own potential immune-related AEs that need to be monitored as with any time we use immunotherapy.

Looking ahead, what multidisciplinary MIBC management strategies might come to the forefront?

Besides the recent NIAGARA trial and the awaited data from EV-304, the main additional focus [in this paradigm is] on the use of tri-modality therapy for patients undergoing a bladder-sparing approach. This was significantly highlighted at the 2024 ASTRO Annual Meeting with a lot of retrospective and some prospective data showing at least equivalence of outcomes when comparing standard neoadjuvant chemotherapy followed by surgery vs tri-modality therapy, which is maximal transurethral resection of bladder tumor followed by concurrent chemoradiation. There are still some limitations to that comparison because it does not take into consideration the role of adjuvant immunotherapy and how that affects outcomes.

There is still a bit of uncertainty about the role of neoadjuvant chemotherapy prior to tri-modality therapy. There are still answers we are awaiting to hear from our radiation oncology colleagues at future conferences, but [there is a] growing use of tri-modality therapy for the right patients, which is not every patient. We have to have the right candidate lesion and the right location to administer tri-modality therapy, and that would usually be discussed with patients who are motivated to undergo this approach.

References

1. Perioperative enfortumab vedotin (EV) plus pembrolizumab (MK-3475) versus neoadjuvant chemotherapy for cisplatin-eligible muscle invasive bladder cancer (MIBC) (MK-3475-B15/​ KEYNOTE-B15 /​ EV-304) (KEYNOTE-B15). ClinicalTrials.gov. Updated December 24, 2024. Accessed August 5, 2025. https://clinicaltrials.gov/study/NCT04700124
2. Powles T, Catto JWF, Galsky MD, et al. Perioperative durvalumab with neoadjuvant chemotherapy in operable bladder cancer. N Engl J Med. 2024;391(19):1773-1786. doi:10.1056/NEJMoa2408154