Gene expression analysis of tumor biopsies from a trial of durvalumab to identify subsets of NSCLC with shared immune pathways.

3041 Background: We previously reported that NSCLC pts with high pretreatment tumoral IFNG mRNA signature (sig) expression have improved outcomes (ORR, PFS, OS) to the anti-PD-L1 therapy durvalumab (D). To explore the relationship of other immunotherapy targets with the IFNG sig, we evaluated expression of CD137, PD1, PDL1, CTLA4, GITR, OX40, TLR7, TLR8, CD73, TIM3, NKG2A, IDO1, CD40, LAG3, A2AR, CXCR4, iNOS, ARG1, and STAT3 in D-treated NSCLC. Methods: CP1108/NCT01693562 was a nonrandomized phase 1/2 trial evaluating D (10 mg/kg Q2W) in advanced NSCLC. As of 24OCT16, 304 primarily previously-treated pts were enrolled. RNA sequencing was conducted on available tumor specimens from 98 pts. ORR was evaluated using RECIST v1.1. 19 genes were z-scored, scaled and clustered across pt tumors. Each gene was coded binary using 0 as a cut point. The proportion of tumors with concordant or discordant over-expression between a gene and the IFNG sig was calculated. Results: In 43% of evaluable NSCLC pts, mRNAs for PD-1, IDO1, PD-L1, CD40, CTLA4, LAG3, TIM3, TLR8, NKG2A, and CD137 were co-expressed with IFNG sig (Spearman’s rho > = 0.7). In 34% of evaluable pts, TLR7, OX40, GITR, A2AR, and CXCR4 mRNAs had moderate concordance with IFNG sig (0.5 < rho < 0.7) and in 23% of evaluable pts iNOS, CD73, ARG1, and STAT3 had low concordance (rho < 0.5). Within the cluster of pts including high IFNG sig, a small subset expressed high iNOS and CD73; however, pts with high STAT3 or ARG1 formed a distinct cluster within the low IFNG sig subset. The subset with high IFNG sig had an ORR of 24% compared to only 10% in all other subsets combined. Conclusions: Our findings enrich understanding of the immune microenvironment of NSCLC by identifying three broad categories of tumors: tumors with pre-existing immunity that have high IFNg sig and select other IO pathways with enhanced responses to D; tumors with moderate expression of IO genes in which the local microenvironment is crucial; finally a distinct “cold” subset of tumors with high expression of STAT3 or ARG1 and characterized by low or no expression of IFNG sig and other IO genes. These results may aid in identifying the right pts for anti-PD-L1 and in prioritizing immunotherapy combinations.