Introduction

Immune checkpoint inhibition (ICI) as a cancer treatment strategy is evolving rapidly into earlier spaces of disease progression in urothelial carcinoma (UC).¹ ICI has been shown in multiple late-phase clinical trials to significantly improve outcomes in patients with locally advanced and metastatic UC.^2-5 Enthusiasm generated by these results catapulted ICI into the perioperative setting. However, appropriate patient selection remains crucial to minimize adverse events and overtreatment.

Although cisplatin-based chemotherapy continues to be the gold standard systemic treatment option in conjunction with radical cystectomy (RC) for localized muscle-invasive bladder cancer (MIBC),⁶ ICI is now recommended for select patients who are ineligible for or unresponsive to platinum-based regimens.⁷ The utilization of immunotherapy in localized disease is currently approved in 2 distinct disease settings: as adjuvant therapy following RC and in the setting of trimodal therapy with bladder-sparing approaches.⁷

Initial data exploring perioperative ICI monotherapy and combination regimens have shown promising results (Table). We review the available evidence for perioperative immunotherapy, emphasizing the importance of emerging biomarkers of response to improve patient selection for perioperative ICI.

Table. Relevant Published and Ongoing Clinical Trials in Muscle-Invasive Bladder Cancer Exploring the Use of Immune Checkpoint Inhibitor Therapy in the Perioperative Setting

Adjuvant Immunotherapy

Direct targeting and inhibition of the PD-1/PD-L1 axis constitute the basis for response to ICI therapy; however, agents targeting distinct molecules have shown differential response rates. The PD-1 inhibitor nivolumab is the only ICI that is FDA (Food and Drug Administration)–approved and supported by National Comprehensive Cancer Network guidelines in the adjuvant setting for high-risk UC within 120 days of RC.⁷ This approval was based on the phase 3 Checkmate-274 trial, which compared up to 1 year of adjuvant nivolumab vs placebo in patients at high-risk of recurrence (pT3-4a or pN+ in cisplatin-ineligible patients or those who refused cisplatin, or ypT2-4a or ypN+). The study demonstrated a 10-month disease-free survival (DFS) advantage for nivolumab (20.8 months) compared to placebo (10.8 months) and included ∼20% of patients with upper tract disease.⁸ Notably, individuals without pathologic response to neoadjuvant chemotherapy on the RC specimen (≥ypT2) were included in the study (over 40% of the cohort), and those who were chemotherapy naïve were still eligible for adjuvant platinum-based treatment.⁸ Subsequent reports with ∼3 years of follow-up have shown a durable DFS benefit, further cementing the evidence in favor of adjuvant nivolumab.⁹

A separate PD-1 inhibitor is undergoing evaluation in the AMBASSADOR trial (NCT03244384), a phase 3 randomized controlled trial evaluating the effect of adjuvant pembrolizumab vs observation. The trial achieved 95% of its recruitment targets and its data are eagerly awaited. On the other hand, the IMvigor010 trial of the PD-L1 inhibitor atezolizumab failed to show a survival benefit (HR 0.89, 95% CI 0.74-1.08) in the atezolizumab arm.¹⁰ Follow-up analyses suggested that patients with high postcystectomy circulating tumor DNA (ctDNA) burden, a risk factor for relapse, did significantly benefit from this treatment.¹¹ Although future ctDNA analyses are warranted in perioperative ICI trials, the evidence is currently insufficient to recommend atezolizumab based on these results.

Emerging Role of Neoadjuvant and Perioperative ICI Therapy

The current standard-of-care for neoadjuvant treatment includes platinum-based chemotherapy, which has been shown to induce pathologic complete response in 38% of patients.⁶ The addition of ICI to neoadjuvant chemotherapy has been proposed as a safe and well-tolerated alternative which could provide significant benefits to patients with MIBC. Initial reports from the phase 2 BLASST-1 trial (NCT03294304) comparing the combination of nivolumab with standard neoadjuvant chemotherapy showed promising results with pathologic downstaging (≤pT1N0) in over 50% of participants and 12-month DFS rates greater than 80% without additional adverse effects that would delay surgical treatment other than those expected from standard chemotherapy alone.¹² Similarly, clinical trials on cisplatin-ineligible individuals have shown encouraging results that promise to expand the use of ICI therapy to this setting (Table).

Given the potential for toxicity and delayed surgical management with neoadjuvant therapy, together with the favorable outcomes reported with RC and adjuvant anti–PD-1 therapy, identifying patients who may benefit from neoadjuvant ICI therapy has been a major challenge. New biomarkers including ctDNA may help select patients with a higher likelihood of relapse; future studies will need to consider molecular characterization to improve patient selection for neoadjuvant ICI beyond clinical staging alone.

Ongoing clinical trials are exploring perioperative ICI utilization both before and after RC. This strategy seeks to maximize the antitumor immune response while risking a higher adverse event rate. Ongoing studies are exploring both perioperative ICI monotherapy and in combination with other agents (Table).¹³ Enfortumab vedotin (EV), an antibody-drug conjugate targeting nectin-4, has shown benefit in advanced disease both as monotherapy¹⁴ and in combination with ICI.¹⁵ Preliminary results from EV-103/KEYNOTE-869 (NCT03288545) led to the FDA accelerated approval of EV-pembrolizumab combination treatment in locally advanced and metastatic UC.¹⁶ These results have prompted investigators to investigate the use of this regimen in MIBC. A summary of ongoing perioperative ICI monotherapy and combination trials is provided (Table).

Biomarkers to Guide Perioperative ICI Utilization

Mechanistic insights into immune dynamics have led to the identification of several emerging biomarkers of treatment response including high PD-L1 expression, which may predict improved outcomes after ICI.^3,17 Initial analyses from CheckMate-274 suggested a 45% survival benefit in patients with high PD-L1 expression. The effect of nivolumab in this subgroup was significantly more pronounced, with a median DFS of 52.6 months in the “PD-L1 high” group, ∼6 times greater than the placebo arm.⁸ The limitation of PD-L1 positivity in assessing the optimal timing of perioperative immunotherapy is that it is not a feasible dynamic assessment of current disease burden.

ctDNA, a surrogate of micrometastatic disease and high risk of relapse,¹⁸ has the additional benefit of real-time monitoring of disease progression at multiple time points during treatment. ctDNA may be collected at baseline prior to RC, immediately post-RC, and at subsequent points to evaluate molecular dynamics. IMvigor010 data have demonstrated that postcystectomy ctDNA positivity may correlate with response to ICI.¹¹ Ongoing perioperative immunotherapy trials including NABUCCO¹⁹ and IMvigor011²⁰ include plasma and/or urine ctDNA assessments. Future clinical trials that incorporate ctDNA positivity and kinetics may be the key to improving patient selection for neoadjuvant vs adjuvant immunotherapy.

Other biomarkers of response to ICI therapy are the subject of active investigation, including microsatellite instability, tumor mutational burden, and specific genomic alterations.¹⁷ There are currently no validated biomarkers to reliably predict response to ICI in MIBC.

Conclusions

The role of perioperative immunotherapy in UC continues to evolve, with recent trial data establishing its role in the adjuvant setting. Ongoing trials will likely formally expand the use of these agents to the neoadjuvant space for select patients. Challenges in patient selection for neoadjuvant vs adjuvant ICI remain and might be overcome in future studies incorporating ctDNA and molecular analyses to optimize clinical benefit and minimize the adverse effects of overtreatment.