Development of an externally controlled trial from a single-arm study to assess first-line immunochemotherapy in advanced large cell neuroendocrine lung carcinomas: a study protocol from the FIRST-NEC GFPC 01-2022 trial.

BACKGROUND

Large-cell neuroendocrine carcinomas (LCNECs) of the lung are rare tumours with poor prognosis. A platinum-based regimen is currently the recommended first-line treatment for advanced LCNECs. Retrospective studies suggest potential benefit from immune checkpoint inhibitors (ICIs) but prospective data is lacking.

METHODS AND ANALYSIS: The ongoing phase II FIRST-NEC (First-line treatment for NeuroEndocrine Carcinoma) externally-controlled trial evaluates the efficacy and safety of durvalumab combined with platinum-etoposide as first-line treatment in locally advanced, ineligible for local therapy or patients with metastatic LCNEC. Histopathological diagnosis is centrally confirmed. All patients receive four induction cycles once every 3 weeks with durvalumab 1500 mg and platinum-etoposide. Durvalumab is maintained once every four weeks for up to 24 additional cycles. The primary endpoint is the 12-month progression-free rate (12M-PFR) as per central radiological review. Secondary endpoints include progression-free survival (PFS), overall survival (OS) and safety. Efficacy is assessed every 10 patients using a Bayesian approach, with a futility rule stopping the trial if the probability that 12M-PFR ≤15% exceeds 80%. Based on an A'Hern-Fleming design, 51 evaluable patients are required. Given the rarity of LCNEC, we developed an innovative approach based on target trial emulation to compare the survival outcomes of ICI plus chemotherapy (PFS and OS) to an external control arm (real-world PFS and OS), using real-world data from the Epidemiological Strategy and Medical Economics-Advanced and Metastatic Lung Cancer database.

ETHICS AND DISSEMINATION: This clinical trial received approval from the competent authorities on 14 March 2024. The results from the final clinical report will be published in medical journals.

PROTOCOL IDENTIFIER: V.2.0 dated 11 December 2024.

TRIAL REGISTRATION NUMBER: NCT06393816.