Abstract 1773: A baseline IFNG gene expression signature correlates with clinical outcomes in durvalumab-treated advanced NSCLC cancer patients
Authors: Brandon W. Higgs, Chris A. Morehouse, Katie Streicher, Philp Z. Brohawn, Keith Steele, Marlon Rebelatto, Fernanda Pilataxi, Carlos Bais, Li Shi, Xiaoping Jin, Joyce Antal, Ashok Gupta, Koustubh Ranade
Journal: Cancer Research (2017)

Abstract Durvalumab (D) is a human IgG1 monoclonal antibody which inhibits PDL1 binding to PD-1 and CD80, restoring antitumor immunity. In D-treated (tx) NSCLC patients (pts), we previously reported high baseline levels of tumoral PD-L1 protein and IFNγ mRNA expression associated with improved ORRs, PFS and OS. Here, a gene expression signature of baseline tumors associates with improved outcomes on D. CP1108/NCT01693562 was a nonrandomized phase 1/2 trial evaluating D in advanced previously tx NSCLC or other solid tumors. By 29APR2016, 304 NSCLC pts received 10 mg/kg Q2W of D ≤12 months with median 18.8 months follow up. RNA sequencing of frozen biopsies was conducted on 97 NSCLC tumors of sufficient quality with matched IHC for tumoral PD-L1 on 92 fresh or archival biopsies. Among 21 pre-identified immune-related genes, mRNAs for IFNG, LAG3, CXCL9, and PDL1 individually correlated best with outcomes in NSCLC after adjustment for sex, age, prior therapy, histology, ECOG and smoking. A signature was developed as mean mRNA levels of the four genes; signatures &amp;gt;upper tertile were IFNG signature positive (IFNGS+). Analysis was performed on NSCLC, then applied to 30 available urothelial bladder cancer (UBC) biopsies. NSCLC with ≥25% tumor cells stained for PD-L1 at any intensity were PD-L1+. 29 NSCLC had pre/post-treatment tumors for mRNA analysis. KM and Cox PH models were used. IFNGS+ D-tx NSCLC pts had higher ORR, median PFS and OS compared to PDL1+, PDL1-, and IFNGS- pts (Table 1); IFNGS+ UBC D-tx pts also correlated with these outcomes. Following D treatment, IFNGS was induced in NSCLC pts (FC=2; p=0.0046) regardless of clinical response. High levels of pre-treatment IFNGS in NSCLC pts associated with greater benefit from D. D induces IFNGS within the tumor microenvironment. Observations from other tumor types will be presented. Table 1. Clinical outcomes by IFNGS or PD-L1 status # Pts (# events [OS;PFS])ORR % (95% CI)Median OS months (95% CI)OS adjusted HRa; pMedian PFS months (95% CI)PFS adjusted HRa; pNSCLCIFNGS+32 (16;21)37.5 (21.7,56.3)24.6 (10.3,NA)0.42; 0.00827.5 (3.6,NA)0.32; 0.00028IFNGS-65 (40;51)6.2 (2.0,15.8)6.5 (4.8,15.7)1.4 (1.4,2.6)PDL1 TPS&amp;gt;=25%38 (18;25)28.9 (16.0,46.1)20.5 (6.6,NA)0.53; 0.07883.6 (1.7,14.6)0.60; 0.0823PDL1 TPS&amp;lt;25%54 (35;43)7.4 (5.8,25.5)9.1 (5.4,21.1)1.5 (1.4,3.9)NR=Not Reached; NA=Not Applicable; aAdjusted for covariates. TPS= tumor proportion score Ventana SP263 assay Citation Format: Brandon W. Higgs, Chris A. Morehouse, Katie Streicher, Philp Z. Brohawn, Keith Steele, Marlon Rebelatto, Fernanda Pilataxi, Carlos Bais, Li Shi, Xiaoping Jin, Joyce Antal, Ashok Gupta, Koustubh Ranade. A baseline IFNG gene expression signature correlates with clinical outcomes in durvalumab-treated advanced NSCLC cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1773. doi:10.1158/1538-7445.AM2017-1773