Interferon Gamma Messenger RNA Signature in Tumor Biopsies Predicts Outcomes in Patients with Non-Small-Cell Lung Carcinoma or Urothelial Cancer Treated with Durvalumab

Purpose: To identify a predictive biomarker for durvalumab, an anti-programmed death ligand 1 (PD-L1) monoclonal antibody. Experimental Design: RNA sequencing of 97 advanced-stage non-small-cell lung carcinoma (NSCLC) biopsies from a nonrandomized phase 1b/2 clinical trial (1108/NCT01693562) were profiled to identify a predictive signature; 62 locally advanced or metastatic urothelial cancer (UC) tumors from the same study were profiled to confirm predictive utility of the signature. Thirty NSCLC patients provided pre- and posttreatment tumors for messenger RNA (mRNA) analysis. NSCLC with ≥25% tumor cells and UC with ≥25% tumor or immune cells stained for PD-L1 at any intensity were scored PD-L1 positive (PD-L1+). Kaplan-Meier and Cox proportional hazards analyses were used to adjust for gender, age, prior therapies, histology, ECOG, liver metastasis, and smoking. Tumor mutation burden (TMB) was calculated using data from The Cancer Genome Atlas (TCGA). Results: In the NSCLC discovery set, a four-gene interferon gamma (IFN)-positive (IFN+) signature comprising IFN, CD274, LAG3, and CXCL9 was associated with higher overall response rates, longer median progression-free survival, and overall survival compared with signature-low patients. IFN+-signature NSCLC patients had improved survival regardless of immunohistochemistry (IHC) PD-L1 status. These associations were replicated in a UC cohort. The IFN+ signature was induced twofold (P = 0.003) by durvalumab after 8 weeks of therapy in NSCLC patients, and baseline signature was associated with TMB but not survival in TCGA data. Conclusions: The IFN+ mRNA signature may assist in identifying patients with improved outcomes to durvalumab, independent of PD-L1 assessed by IHC.

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