A multicenter phase ii, single arm study of durvalumab with carboplatin plus etoposide for 4 cycles followed by durvalumab maintenance in patients with metastatic pulmonary large-cell neuroendocrine carcinoma (LCNEC) – DUPLE trial

Large cell neuroendocrine carcinoma (LCNEC) of the lung is a rare and highly aggressive malignancy that shares biological and clinical features with both small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). Recent genomic analyses have identified two main molecular subtypes of LCNEC with potential prognostic and therapeutic implications: type I (“NSCLC-like”), characterized by a more epithelial profile, and type II (“SCLC-like”), enriched for neuroendocrine features. However, whether these molecular subtypes translate into distinct clinical behaviors remains unclear. Due to the rarity of LCNEC, available evidence is limited and mainly derived from small retrospective studies, and treatment strategies are largely extrapolated from those used in SCLC and NSCLC. In extensive-stage SCLC, the addition of programmed death-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitors to first-line platinum–etoposide chemotherapy has demonstrated a significant survival benefit. On this basis, it was hypothesized that a similar approach could be effective in LCNEC. The DUPLE trial is an ongoing phase II, multicenter, single-arm study evaluating the combination of durvalumab, an anti–PD-L1 monoclonal antibody, with carboplatin–etoposide chemotherapy in treatment-naïve patients with metastatic pulmonary LCNEC. A total of 46 patients were enrolled. During the induction phase, patients received carboplatin (AUC 5, day 1), etoposide (100 mg/m², days 1–3), and durvalumab (1500 mg, day 1) every 3 weeks for four cycles. This was followed by a maintenance phase with durvalumab 1500 mg every 4 weeks, for up to 24 additional cycles, corresponding to a maximum treatment duration of 2 years, or until disease progression, unacceptable toxicity, loss of clinical benefit, or patient withdrawal. The primary endpoint of the study is the 1-year overall survival rate, which is not yet mature. Preliminary analyses indicate that the combination regimen is feasible, with a manageable safety profile, fulfilling the secondary objective of the trial.