Clinical outcomes with immune checkpoint inhibitors in patients with FGFR2/3, MTAP or ERBB2 genomic alterations in advanced urothelial carcinoma

Abstract

BackgroundFGFR2/3, MTAP and ERBB2 genomic alterations have treatment targets in advanced urothelial carcinoma (aUC). These alterations may affect tumor microenvironment and outcomes with immune checkpoint inhibitors (ICIs) in aUC. Patients and MethodsWe identified patients with available genomic data in our multi-institution cohort of patients with aUC treated with ICI. Outcomes (observed response rate [ORR], progression-free and overall survival [PFS, OS]) with ICI were compared between patients with and without FGFR 2/3, MTAP, ERBB2 alterations. We compared ORR using logistic regression and PFS/OS using Cox proportional hazards. ResultsOut of 1,514 patients, 276 (18%), 174 (11%) and 208 (14%) patients had known FGFR2/3, MTAP and ERBB2 alteration status, respectively and were treated with ICI in 1L or 2+L. In patients with (vs without) FGFR2/3 alteration, ORR with ICI was 21% (95%CI 14-30%) vs 32% (95%CI 27-38%) (OR 0.54 [95%CI 0.32-0.91]), PFS was significantly shorter in patients with FGFR2/3 alterations (HR=1.36 [95%CI 1.03-1.80], p=0.03); OS was not significantly different between groups (HR=1.22 [95%CI 0.86-1.47]). In patients with (vs without) MTAP alteration, ORR with ICI was 25% (95%CI 10-48%) vs 40% (95%CI 33-47%) (OR 0.52 [95%CI 0.20-1.38]); PFS and OS were non-significantly different. In patients with (vs without) ERBB2 alteration, ORR with ICI was similar (37% vs 35%; OR 1.06, 95%CI 0.57-1.97); PFS and OS were significantly longer in patients with ERBB2 alteration [HR 0.63 (95%CI 0.41-0.95), p=0.03; HR 0.66, [95% CI 0.44-0.97]), respectively. ConclusionOur results support further evaluation of FGFR2/3, MTAP and ERBB2 alterations as putative biomarkers in patients with aUC treated with ICI. MicroabstractImmune checkpoint inhibitors (ICI) improve overall survival in advanced urothelial carcinoma (aUC), but response rates as monotherapy remain modest. We performed a multi-institutional retrospective cohort study comparing outcomes (observed response rate, progression-free and overall survival) between patients with and without tumor genomic alterations (FGFR2/3, MTAP, ERBB2 genes) that may impact the immune tumor microenvironment and affect treatment selection. Our hypothesis-generating results suggest that specific genomic alterations may have association with response and survival with ICI in patients with aUC and support further validation in other retrospective studies and clinical trials.