Experts Review Perioperative Regimens and Potential Future Strategies for Resectable MIBC

Perioperative Treatment Regimens and the Treatment Paradigm for Resectable MIBC

Ashish M. Kamat, MD, MBBS, FACS, of MD Anderson Cancer Center, hosted a panel discussion focused on the available perioperative treatment regimens for patients with resectable MIBC. Dr. Kamat was joined by three MIBC experts: David H. Aggen, MD, PhD, of Memorial Sloan Kettering Cancer Center, Alexandra Drakaki, MD, PhD, of University of California, Los Angeles, and Raji Shameem, MD, of Orlando Health. Together, the doctors discussed the NIAGARA, KEYNOTE-905/EV-303, and KEYNOTE-B15/EV-304 trials that led to the approval of durvalumab plus gemcitabine–cisplatin and EV–pembro, respectively, as well as the current paradigm for selecting between the two perioperative regimens. 

NIAGARA: Durvalumab Plus Gemcitabine–Cisplatin

The phase 3 NIAGARA trial randomized cisplatin–eligible patients with MIBC undergoing radical cystectomy to either neoadjuvant gemcitabine–cisplatin with perioperative durvalumab or neoadjuvant gemcitabine–cisplatin alone. The estimated 24-month event-free survival (EFS) rate was 67.8% (95% CI, 63.6-71.7) in the durvalumab group and 59.8% (95% CI, 55.4-64) in the control group (HR, 0.68; 95% CI, 0.56-0.82; P < .001). The estimated 24-month overall survival (OS) rate was 82.2% (95% CI, 78.7-85.2) in the durvalumab group and 75.2% (95% CI, 71.3-78.8) in the control group (HR, 0.75; 95% CI, 0.59-0.93; P = .01). The pCR rates were 37.3% and 27.5% with perioperative durvalumab and control, respectively.

NIAGARA was the first trial to demonstrate an OS benefit with the addition of immunotherapy to cisplatin–based chemotherapy in patients with resectable MIBC, and the data led the FDA to approve the perioperative durvalumab regimen. Now, however, the NIAGARA trial needs to be recontextualized after positive findings for perioperative EV–pembro from the KEYNOTE-905/EV-303 and KEYNOTE-B15/EV-304 trials.

KEYNOTE-905/EV-303 and KEYNOTE-B15/EV-304: EV–Pembro

The KEYNOTE-905/EV-303 trial evaluated perioperative EV–pembro versus radical cystectomy alone in cisplatin–ineligible patients with resectable MIBC. At 2 years, the estimated EFS rate was 74.7% in the EV-pembro group and 39.4% in the control group (HR, 0.40; 95% CI, 0.28-0.57; P < .001). The estimated OS rate was 79.7% with EV–pembro and 63.1% with the control group (HR, 0.50; 95% CI, 0.33-0.74; P < .001). The pCR rates were 57.1% and 8.6% (95% CI, 39.5-56.5; P < .001) for the EV–pembro and control groups, respectively. This trial led the FDA to initially approve perioperative EV–pembro for cisplatin–ineligible patients with MIBC.

Subsequently, the KEYNOTE-B15/EV-304 evaluated perioperative EV–pembro versus neoadjuvant gemcitabine–cisplatin in cisplatin–eligible patients with resectable MIBC. The median EFS was not reached (NR) with EV–pembro versus 48.5 months with gemcitabine–cisplatin, and the estimated 24-month EFS rates were 79.4% versus 66.2% (HR, 0.53; 0.41-0.7; P < .0001), respectively. Median OS was NR in either group, although the estimated 24-month OS rate was 86.9% with EV–pembro and 81.3% with gemicitabine–cisplatin (HR, 0.65; 95% CI, 0.48-0.89; P = .0029). The pCR rate was 55.8% with EV–pembro and 32.5% with gemcitabine–cisplatin (95% CI, 16.7-29.8; P < .0001). Based on KEYNOTE-B15/EV-304, the FDA extended the approval for EV–pembro to all patients with resectable MIBC, regardless of cisplatin eligibility, on July 10, 2026. 

Selecting Between the NIAGARA and KEYNOTE Regimens

For cisplatin–eligible patients with MIBC, there is no gold standard between the NIAGARA and KEYNOTE perioperative regimens. Generally, the choice between durvalumab plus gemcitabine–cisplatin and EV–pembro is individualized based on each regimen’s toxicity profile to ensure patients continue to radical cystectomy. 

Common side effects associated with EV–pembro include rash, peripheral neuropathy, hyperglycemia, and ocular effects. Rash or other cutaneous toxicities must be caught early and managed with steroids and dose holds to prevent escalation and not delay surgery. Neuropathy can be dose-limiting, but events usually occur after 4 cycles, limiting the potential impact on surgery completion. EV–pembro may be a less favorable option for patients with preexisting diabetes due to the hyperglycemia risk.

With the NIAGARA regimen, cisplatin has well-established associations with nephrotoxicity, ototoxicity, and myelosuppression, and the addition of durvalumab may introduce immunotherapy–related toxicities including fatigue and gastrointestinal, skin, and respiratory effects. The aggressive hydration requirements for cisplatin infusions may also be unfavorable for patients with congestive heart failure. Split dosing for cisplatin may improve tolerability for patients with poorer renal function, said Dr. Shameem. 

While the current paradigm for selecting between the NIAGARA and EV–pembro regimens is driven by side effect profiles and treatment logistics preferences, hopefully biomarker or histologic subtype data will emerge to guide treatment selection in the future, said Dr. Drakaki. 

Considering pCR and the Potential of Bladder Preservation Strategies

The doctors discussed the value of pathologic complete response (pCR) as a clinical endpoint. The goal of perioperative therapy is to achieve the most possible disease control without compromising or delaying surgery. While pCR is compelling as an early, binary, and often prognostically favorable endpoint, it has not been formally validated for OS in MIBC as it has in breast cancer, said Dr. Aggen. Importantly, the NIAGARA and KEYNOTE trials differed in how they defined pCR and whether pCR outcomes were centrally reviewed, so comparing pCR rates between the trials requires some caution. 

For the MIBC field as a whole, as novel regimens have improved pCR rates after neoadjuvant therapy, the question of sparing patients with strong responses from radical cystectomy has re-emerged. Currently, the International Bladder Cancer Group has suggested some selection criteria for attempting off-protocol systemic therapy or surveillance including clearance of circulating tumor DNA, negative MRI, negative cystoscopy, and negative urinary tumor DNA or cytology Ultimately, stronger biomarker and histologic subtype data are needed to safely guide patient selection for bladder preservation strategies, and radical cystectomy remains an integral part of the treatment paradigm for MIBC for now, said Dr. Kamat.

The Impact of Histologic Subtypes on Treatment Selection

Ideally, each patient’s disease biology should influence treatment decisions, but only a small proportion of patients in the NIAGARA and KEYNOTE trials had histologic subtype features, and the data as a whole are sparse. Notably, neither perioperative regimen is strongly indicated for adenocarcinoma, pure squamous cell carcinoma, or small-cell carcinoma subtypes. Otherwise, for MIBC with squamous differentiation or mixed histologic features, there are no clear data supporting one perioperative regimen over another. Some data suggest that squamous cell tumors, or tumors with squamous components, retain Nectin-4 expression, the target of EV, but these tumors can still be resistant to EV–pembro, said Dr. Aggen. 

Moving forward, further research into Nectin-4 expression across histologic subtypes may impact treatment selection recommendations. Until those data are generated, EV–pembro may be the de facto choice for most histologic subtypes, except for tumors with sarcomatoid differentiation. This subgroup has very low Nectin-4 expression, potentially making the NIAGARA regimen a more potent option. Dr. Drakaki noted she also favors the NIAGARA regimen for patients with squamous differentiation. 

Overall, multiple perioperative regimens are available for patients with resectable MIBC. Currently, selecting between the NIAGARA and KEYNOTE protocols is a personalized decision based on patient, disease, and treatment characteristics, although more refined biomarker and histologic subtype data may guide treatment selection in the future. Studies are also evaluating whether bladder preservation strategies are safe for select patients, but until then radical cystectomy remains an important part of the treatment paradigm for resectable MIBC, said Dr. Kamat.