Adjuvant immunotherapy in high-risk muscle-invasive urothelial cancer: an updated meta-analysis of randomized controlled trials

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Introduction: Neoadjuvant cisplatin-based chemotherapy followed by radical surgery is the standard treatment for muscle-invasive urothelial carcinoma (MIUC). The Checkmate-274 and AMBASSADOR trials have demonstrated improvements in disease-free survival (DFS) with adjuvant immunotherapy. Consequently, this meta-analysis aimed to assess the effectiveness of strategies involving checkpoint inhibitors in managing high-risk MIUC. Patients and Methods: We searched PubMed, Embase, Cochrane, ClinicalTrials.gov, EAU24, and ASCO GU abstracts for randomized controlled trials (RCTs) comparing adjuvant PD-1 and PD-L1 inhibitors against control (placebo or observation) for MIUC. Outcomes included DFS, grade ≥ 3 adverse events (AEs), and overall survival (OS). Heterogeneity was assessed using I2 statistics, employing a random-effects model for analysis. Results: In a cohort of 2,220 patients from three RCTs, 1,113 (50.14%) underwent adjuvant immunotherapy. This treatment significantly increased DFS (HR 0.76; 95% CI 0.65-0.90; p < 0.01), particularly in lower tract tumors (HR 0.71; 95% CI 0.56-0.91; p < 0.01). No substantial DFS improvement surfaced in the upper tract subgroup (p = 0.28) (p-interaction = 0.01). PD-L1 status (p-interaction = 0.83) and previous neoadjuvant chemotherapy (p-interaction = 0.11) did not significantly affect outcomes. However, immunotherapy correlated with higher grade ≥ 3 AEs (RR 1.47; p<0.01), with no notable difference in OS (p=0.07). Conclusions: Adjuvant PD-1/PD-L1 inhibitors notably enhance MIUC DFS, particularly in lower tract tumors, regardless of PD-L1 status. These findings support immunotherapy, especially anti-PD1, as a valuable adjuvant treatment strategy for high-risk MIUC patients. Micro abstractThis meta-analysis investigates the use of adjuvant anti-PD1/PDL1 therapy for high-risk muscle-invasive urothelial cancer (MIUC). By analyzing data from three randomized controlled trials involving 2,220 patients, the study demonstrates that immune checkpoint inhibitors, particularly PD1 inhibitors, significantly improve disease-free survival, regardless of PD-L1 status. These findings support considering ICIs as a viable adjuvant treatment option for patients with MIUC.