Association Between Gene Expression Signatures (Sigs) And Pembrolizumab (Pembro) Efficacy In Patients (Pts) With Advanced Urothelial Cancer (Uc)

In the phase 2 KEYNOTE-052 trial in advanced UC, 18-gene T-cell–inflamed gene expression profile (GEP) was positively associated with response to pembro and stromal sig (stroma/EMT/TGF-β) was negatively associated. We explored association of these sigs with efficacy in the phase 3 KEYNOTE-045 trial of pembro vs chemo in platinum-refractory metastatic UC (mUC). Univariate analyses using logistic regression (ORR) and Cox proportional hazard (PFS, OS), adjusted for ECOG PS, were performed, and nominal P values (1-sided, pembro; 2-sided, chemo) without multiplicity adjustment were calculated. Significance was prespecified at 0.05. Clinical utility of GEP and stromal sig was assessed using first tertile and median cutoffs. 291/542 pts (53.7%) had RNA-seq data. GEP was associated with ORR (P=0.05) with pembro; a positive trend was observed for PFS (P=0.09) and OS (P=0.12). GEP was not associated with ORR (P=0.87), PFS (P=0.58), or OS (P=0.98) with chemo. HR estimates using prespecified GEP cutoff suggest trends toward improved PFS and OS for pembro vs chemo in GEP-high group (Table). Stromal sig was not associated with outcomes with pembro (P=0.15 [ORR], 0.30 [PFS], 0.40 [OS]) or chemo (P=0.42 [ORR], 0.09 [PFS], 0.12 [OS]). HR estimates using prespecified stromal sig cutoff suggest trends toward longer PFS and OS in ≥median group; this may be driven by poor performance of chemo in this group vs the hypothesized association with pembro (Table). In this exploratory analysis in pts with mUC from KEYNOTE-045, GEP was positively associated with ORR to pembro but not chemo. GEP continues to serve as a good exploratory gene sig to support the MOA of pembro in highly inflamed tumors. Stromal sig was not associated with outcomes to pembro in KEYNOTE-045. Additional analyses are exploring differences in association of stromal sig with pembro between KEYNOTE-052 and KEYNOTE-045.Table 744PClinical outcomes by GEP and stromal signature cutoff in KEYNOTE-045GEP≥first tertileGEP≥first tertileGEP