Biologic and clinical relevance of an IFNG mRNA signature (IFNGS) and PD-L1 protein expression in tumor and immune cells in urothelial cancer (UC) patients (pts) treated with durvalumab (D).

Abstract

3037 Background: PD-L1 can be induced by IFNG in tumor cells (TC) and immune cells (IC). TC PD-L1 expression prevalence in UC is low and the relevance of scoring TC (in addition to IC) is not fully understood. We recently reported a positive correlation between high levels of an IFNGS and outcome in a cohort of 30 UC pts treated with D. Here, we assessed the potential predictive value of the IFNGS in an additional 32 pts (total N = 62) and further explored the relationship between the IFNGS and TC and/or IC PD-L1 IHC expression patterns. Methods: Study CP1108 was a phase 1/2 trial evaluating D in pts with solid tumors; 191 UC pts received 10 mg/kg D with median follow up of 8.4 mo. 144 of these pts have available ORR and PD-L1 data and 62 pts have ORR, PD-L1 and IFNGS data. Pts with ≥25% TC or IC were scored as PD-L1 high (TC+ or IC+). Pts within the top tertile of IFNGS ( LAG3, PDL1, CXCL9, and IFNG mRNAs) tumor expression were scored positive. Cox proportional hazards models were used adjusting for age, gender, ECOG, smoking status, line of therapy, and liver metastasis at baseline. ORR was evaluated using RECIST v1.1. Results: IFNGS+ pts had increased ORR (45 vs 16%) and improved PFS (adj HR 0.3; p = 0.005) and OS (adj HR 0.18; p = 0.016) over IFNGS- pts. IFNGS expression was significantly higher in pts who were PD-L1 high (TC+/IC+) compared with TC-/IC- (low/negative) pts (mean IFNGS expression 3.5 vs 1.1; p = 0.0155) and also in TC+ or IC+ vs TC-/IC- (mean IFNGS 2.2 vs 1.1; p = 0.000127). TC-/IC+ and TC+/IC- groups had a mean IFNGS expression of 2 and 2.2 respectively. ORR in all 1108 UC pts with available IHC and ORR data (N = 144) was 29% for TC+/- pts, 36% in TC-/IC+ pts, and 7% in the TC-/IC- pts. Conclusions: IFNGS predicted improved outcomes in a cohort of 62 2L+ UC pts treated with D. TC-/IC- PD-L1 pts had lowest levels of IFNGS expression. Observations that TC+ (and IC+) pts contribute to IFNGS enrichment and that TC+/IC-, and TC-/IC+ pts have increased response vs TC-/IC-pts provides rationale for TC+ inclusion (in addition to IC+) in the SP263 PD-L1 scoring algorithm for UC. IFNGS is an additional potential predictive biomarker in UC pts that warrants further investigation.