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Perioperative therapy is a well-established therapeutic standard in localized T2-T4 urothelial cancer. SWOG 8710, a randomized trial evaluating neoadjuvant chemotherapy with MVAC, demonstrated a progression-free and overall survival (OS) benefit as compared with radical cystectomy alone.

The advantage was primarily seen due to the higher likelihood of pathologic complete remission (pT0) induced by the addition of neoadjuvant chemotherapy. A total of 85% of the pT0 patients on this study were alive at 5 years, and neoadjuvant MVAC (methotrexate/vinblastine/doxorubicin/cisplatin) increased the rate of pT0 to 26% and 22%, respectively, for T2 and T3-4 patients. The pT0 rate was 15% in the cystectomy arm.

The Nordic randomized trial also confirmed the benefit imparted by neoadjuvant cisplatin-based chemotherapy, especially in the T3-4 urothelial carcinoma cohorts.

These studies serve as the backbone for contemporary regimens to be evaluated in muscle-invasive urothelial cancer (MIUC). Adjuvant immunotherapy with nivolumab is FDA-approved post surgical resection in urothelial cancer patients based on the results of Checkmate 274, which showed improvement in relapse-free survival (RFS). Median RFS was 22.8 months in the nivolumab arm and 10 months in the placebo arm. The subsets that received neoadjuvant chemotherapy and the PD-L1 +ve [positive] patients had an increased magnitude of benefit. So there is a robust rationale for evaluating neoadjuvant chemoimmunotherapy followed by adjuvant immunotherapy.

The current study by conducted by the SAKK (Swiss Group for Clinical Cancer Research) group targeted a single-arm contemporary chemotherapy regimen of cisplatin and gemcitabine in combination with immunotherapy (durvalumab) in MIUC.

The study design was based on a primary endpoint of event-free survival (EFS) at 2 years. The EFS rate was 75.7% at 2 years with a lower 90% confidence interval limit of 67.1%, and since this was over 50% per study design, this was considered promising.

The pT0 rate was 29.8% (17 of 57 patients), so minimal incremental benefit was achieved when compared with that seen with the chemotherapy alone. The regimen appeared to be well tolerated, and toxicities were consistent with previously reported information.

However for an otherwise healthy patient population and when immune therapy is incorporated and added to chemotherapy, longer-term follow-up and OS data past 5 years would be necessary prior to making any definite conclusions. In addition to PD-L1 status it would be important to help select the patients likely to maximally benefit from addition of an immune checkpoint inhibitor.

The advantage of adjuvant approach for immune checkpoint therapy is that the pT0 patients were excluded and were spared the potential of long-term toxicities. At present the results of this study do not provide adequate rationale to change current standard of neoadjuvant chemotherapy in cisplatin-eligible patients and postoperative adjuvant immune checkpoint therapy in the patients who do not achieve pT0.

Neoadjuvant enfortumab and pembrolizumab combination is being evaluated in MIUC and is likely to provide a future option that will expand accessibility of the benefits of neoadjuvant chemotherapy to the cisplatin-ineligible patient population.

The financial toxicity of the addition of immune checkpoint therapy, especially without careful biomarker-based selection, is overwhelming and raises the concern of discrepancy of access by socioeconomic strata and in underrepresented minorities.

Ulka Vaishampayan, MD, is professor of Internal Medicine at the University of Michigan; and chair of Phase I Therapeutics, co-leader of the Translational and Clinical Research Program, and chief of medical oncology at Ambulatory Clinical Care at Rogel Cancer Center in Ann Arbor.

Read the study here and a Q&A about it here.