482TiP Global, Phase 3 study of first-line durvalumab (MEDI4736) + tremelimumab vs standard of care platinum-based chemotherapy in advanced/metastatic NSCLC: NEPTUNE

Abstract

Background: There is an urgent need for improved first-line therapy for advanced EGFR and ALK wild-type NSCLC, for which current molecularly targeted therapies are not indicated. Blockade of programmed cell death-1 (PD-1) and cytotoxic Tlymphocyte-associated antigen-4 (CTLA-4) immune checkpoints represents a promising anticancer therapeutic strategy. As PD-1 and CTLA-4 regulate immune responses by different mechanisms, targeting both pathways provides the potential for additive or synergistic effects. Durvalumab is a selective, high-affinity, engineered human IgG1 mAb that blocks programmed cell death ligand-1 (PD-L1) binding to PD-1 and CD80. Tremelimumab is a selective human IgG2 mAb against CTLA-4. In a Phase 1b study (NCT02000947), durvalumab t tremelimumab demonstrated a manageable tolerability profile in advanced NSCLC, with clinical activity observed both in pts with high levels of tumour PD-L1 expression and in pts with low/no tumour PDL1 expression. Trial design: NEPTUNE (NCT02542293) is a randomised, open-label, multicentre, global, Phase 3 study assessing durvalumab ttremelimumab vs standard of care in immunotherapy-and chemotherapy-naïve pts with advanced/metastatic EGFR and ALK wild-type NSCLC. Pts with either PD-L1 high expression or PD-L1 low/no expression (≥25% or<25% of tumour cells with membrane staining, respectively) will be randomised (1:1) to durvalumab (20 mg/kg i.v. q4w for up to 12 months) t tremelimumab (1 mg/kg i.v. q4w for up to 4 doses); or platinum-based doublet chemotherapy. Stratification factors are PD-L1 expression level, histology and smoking history. The primary endpoint is overall survival (OS). Secondary endpoints are progression-free survival (PFS), objective response rate (ORR), duration of response and proportion of pts alive and progression free at 12 months by investigator assessment (RECIST v1.1); time to second progression; OS, PFS and ORR in pts with PD-L1 low/negative NSCLC; safety (CTCAE v4.03) and tolerability; pharmacokinetics; and immunogenicity. Exploratory outcomes include potential biomarkers of response to treatment and impact of subsequent anticancer therapies on OS. Recruitment is ongoing.