Comparative Effectiveness of Immunotherapy Regimens

Abstract

Immune checkpoint inhibitors (ICIs) have reshaped the treatment landscape for advanced solid tumours, yet head-to-head comparisons between regimens remain scarce. Clinicians routinely choose between PD-1 inhibitors (nivolumab, pembrolizumab), PD-L1 inhibitors (atezolizumab, durvalumab), CTLA-4 inhibitors (ipilimumab), and combination strategies without robust comparative effectiveness data to guide selection. We conducted a retrospective multicentre analysis of 5,842 patients with advanced NSCLC, melanoma, renal cell carcinoma (RCC), or urothelial carcinoma treated with ICI-based regimens across five European comprehensive cancer centres (Tallinn, Zurich, Berlin, Amsterdam, and Barcelona) between January 2016 and December 2021. We compared five immunotherapy strategies: anti-PD-1 monotherapy, anti-PD-L1 monotherapy, anti-CTLA-4 + anti-PD-1 combination, ICI + chemotherapy combination, and ICI + anti-angiogenic combination. Our Immunotherapy Comparative Effectiveness Score (ICES) integrates overall survival benefit, progression-free survival, objective response rate, immune-related adverse event (irAE) burden, and quality-adjusted survival. ICI + chemotherapy achieved the highest ICES for NSCLC (0.928), driven by superior PFS (median 8.8 months) and ORR (48.2%). Anti-CTLA-4 + anti-PD-1 combination achieved the highest ICES for melanoma (0.934) with the best long-term OS (5-year rate 42.8%). Anti-PD-1 monotherapy offered the best toxicity-adjusted benefit across indications (lowest grade 3-4 irAE rate at 12.4%). These findings provide the first large-scale multicentre European comparative effectiveness framework for ICI regimen selection.