NEPTUNE: Phase III study of first-line durvalumab plus tremelimumab in patients with metastatic NSCLC

Abstract

Introduction: NEPTUNE, a phase III, open-label study, evaluated first-line durvalumab plus tremelimumab versus chemotherapy in metastatic NSCLC (mNSCLC). Methods: Eligible patients with EGFR/ALK wild-type mNSCLC were randomized (1:1) to first-line durvalumab (20 mg/kg q4w until progression) plus tremelimumab (1 mg/kg q4w for up to 4 doses) or standard chemotherapy. Randomization was stratified by tumor PD-L1 expression (≥25% vs <25%), histology, and smoking history. The amended primary endpoint was overall survival (OS) in patients with blood tumor mutational burden ≥20 mut/Mb (bTMB ≥20). Secondary endpoints included progression-free survival (PFS) in patients with bTMB ≥20 and safety and tolerability in all treated patients. Results: As of June 24, 2019, 823 patients were randomized (intention-to-treat [ITT]); 512 (62%) were bTMB-evaluable, with 129/512 (25%) having bTMB ≥20 (durvalumab plus tremelimumab [n=69]; chemotherapy [n=60]). Baseline characteristics were balanced in the ITT. Among patients with bTMB ≥20, OS improvement with durvalumab plus tremelimumab versus chemotherapy did not reach statistical significance (HR 0.71 [95% CI, 0.49‒1.05; p=0.081]; median OS, 11.7 vs 9.1 months); the HR for PFS was 0.77 (95% CI, 0.51‒1.15; median PFS, 4.2 vs 5.1 months). In the overall safety population, incidence of grade 3/4 treatment-related adverse events was 20.7% (durvalumab plus tremelimumab) and 33.6% (chemotherapy). Conclusions: NEPTUNE did not meet its primary endpoint of improved OS with durvalumab plus tremelimumab versus chemotherapy in patients with mNSCLC and bTMB ≥20. Despite the amended study design, with a resultant small primary analysis population, therapeutic activity was aligned with expectations based on mechanistic biology and previous studies.