Phase III, randomized, open-label study of durvalumab (MEDI4736) in combination with tremelimumab or durvalumab alone versus platinum-based chemotherapy in first-line treatment of patients with advanced/metastatic NSCLC: MYSTIC

Abstract

Background: The blockade of immune checkpoints, such as programmed cell death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), is a promising novel approach in cancer treatment. As these pathways are non-redundant, dual targeting may have additive or synergistic antitumour activity. Durvalumab (MEDI4736) is a selective, high affinity human IgG1 mAb that blocks programmed cell death ligand-1 (PD-L1) binding to PD-1 (IC50 0.1 nM) and CD80 (IC50 0.04 nM), and tremelimumab is a selective human IgG2 mAb inhibitor of CTLA-4. In a Phase 1b study (NCT02000947), durvalumab + tremelimumab has shown encouraging clinical activity (objective response rate [ORR] 33% [95% CI 17-54%] across tremelimumab 1 mg/kg cohorts [n = 27]) and manageable tolerability in patients ( pts) with both PD-L1-positive and -negative NSCLC. NEPTUNE is a Phase 3 study to determine the efficacy and safety of durvalumab + tremelimumab combination therapy versus standard of care (SoC) platinum-based doublets in the first-line treatment of advanced or metastatic NSCLC. Trial design: In this randomised, open-label, multicentre, global, Phase 3 study, approximately 800 immunotherapy- and chemotherapy-naïve pts with advanced or metastatic (Stage IV) NSCLC with no sensitising EGFR mutation nor ALK translocation will be randomised (1:1) to receive durvalumab (20 mg/kg IV every 4 weeks for up to 12 months) + tremelimumab (1 mg/kg IV every 4 weeks for up to 4 doses); or SoC chemotherapy. Stratification factors are PD-L1 status, histology and smoking history. The primary endpoint is overall survival (OS). Secondary endpoints will assess progression-free survival (PFS), ORR, duration of response, and proportion of pts alive and progression free at 12 months using investigator assessments (RECIST v1.1); time from randomisation to second progression; OS, PFS, and ORR in pts with PD-L1-negative NSCLC; safety (CTCAE v4.03) and tolerability; PK; and immunogenicity. Exploratory outcomes include potential biomarkers of response to treatment, and the impact of subsequent anticancer therapies on OS. Study sites are being opened for recruitment.