LAUSR

Background: Anti-PD-L1 and anti-CTLA-4 agents have demonstrated clinical activity in gastric and gastroesophageal junction cancer (GC/GEJC) tumors. However, response rates are low suggesting clinical benefit in only a subset of the population. This study prospectively evaluated the ability of a tumor-based interferon (IFN)-γ gene signature to identify a subset of GC/GEJC patients more likely to respond to checkpoint inhibitor therapy. Methods: Second and third-line patients were prescreened using archival formalin-fixed paraffin-embedded tissue to assess IFN-γ gene signature (comprising IFNy, CD274, LAG3, and CXCL9) status with a custom, targeted RNA sequencing assay using Ion AmpliSeq (Thermo Fisher Scientific) sequencing technologies. The cutoff for positive was established at the upper tertile of expression from an existing data set. Patients who were positive during prescreening were eligible to screen. Enrolled patients received durvalumab 20 mg/kg and tremelimumab 1 mg/kg IV every 4 weeks (Q4W) for 4 cycles, followed by durvalumab 10 mg/kg Q2W for ≤12 months. Disease assessments were performed every 8 weeks according to Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. Results: As of August 24, 2018, 176 patients were prescreened. In these patients, the IFN-γ gene signature assay had a 70% rate for providing actionable data; 37.5% of prescreened patients had high expression. The primary failure reason was insufficient tissue, resulting in insufficient nucleic acid. 19 patients were enrolled, with a median follow-up of 5.8 months. Drug-related adverse events (AEs) occurred in 8 patients (42%); 4 (21%) had grade 3/4 AEs (fatigue, elevated lipase, decreased appetite, and interstitial lung disease, the latter of which led to treatment discontinuation). There were no drug-related deaths. Objective response rate (ORR) was 15.8% (95% CI, 3.4%-39.6%), including 1 complete response and 2 partial responses; 1 patient had stable disease. Duration of response was 13.3 weeks (range, 8.1-16.3 w). Median progression-free survival (PFS) was 1.8 months (95% CI, 1.6-1.9 mo), and median overall survival (OS) was 7 months (95% CI, 2.4-7.5 mo). Conclusions: Prospective screening of patients using a novel RNA-based IFN-γ gene expression signature was feasible for patient selection with predictable assay performance. Clinical activity of durvalumab + tremelimumab was increased, with a higher ORR in enrolled patients, compared with unselected populations receiving durvalumab and/or tremelimumab (presented at ASCO 2018); however, PFS and OS remained similar. Given the added complexity of patient preselection and lack of substantial improvement in clinical outcomes, these results, while encouraging, do not support further implementation of the IFN-γ gene signature for patient selection in this indication and treatment regimen. Citation Format: Geoffrey Ku, Jeeyun Lee, Heinz-Josef Lenz, Cheng Ean Chee, Takeshi Omori, Keun-Wook Lee, Yee Chao, Daniel Catenacci, Michael Gibson, Deirdre Cohen, Zev Wainberg, Philip Z. Brohawn, Peng He, Siddharth Sheth, Judson Englert, Ronan Kelly, Yung-Jue Bang. Safety and efficacy of durvalumab in combination with tremelimumab in patients with advanced gastric cancer with elevated tumor interferon-γ gene signature [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT057.