Adjuvant immunotherapy for muscle-invasive urothelial carcinoma: Considerations for targeting patients

While neoadjuvant chemotherapy and radical surgery represent mainstay treatments for muscle-invasive urothelial carcinoma (MIUC), recurrence with lethal metastasis remains high and highlights the need for adjuvant therapies in MIUC, like immunotherapy, already in use for metastatic UC with favourable results. This review provides an overview of the key clinical trials investigating adjuvant immune checkpoint inhibitors (ICIs) for MIUC and their clinical implications; in particular, examining factors that may be relevant in guiding adjuvant therapy to patients, such as ICI therapy choice, tumour subtype and the clinical utility of biomarkers, specifically PD-L1 status and circulating tumour DNA (ctDNA). Of the three key trials CheckMate-274, IMvigor010 and AMBASSADOR, anti-PD1 inhibitors nivolumab and pembrolizumab have shown statistically significant improvements in disease-free survival (DFS) compared to controls, highlighting their promising use as seen with nivolumab's approval into clinical practice. Results are conflicting on the association of PD-L1 tumour expression with treatment outcome, yet ctDNA has emerged as a key biomarker from IMvigor010, showing not only prognostic value but also association between its clearance and atezolizumab treatment benefit derived. Notably, it remains uncertain across the trials whether adjuvant treatment efficacy differs by tumour origin (upper tract or lower tract disease), and larger subgroup numbers are needed for future trials in order to adequately assess statistical significance of speculative associations. Altogether, study findings support increasing clinical incorporation of adjuvant nivolumab and pembrolizumab into the MIUC setting, and emphasise ctDNA's utility as a biomarker for MIUC, demonstrating roles in both prognostication and prediction of treatment benefit.