Large-cell neuroendocrine carcinoma (LCNEC) of the lung is a rare and aggressive malignancy with limited prospective evidence to guide systemic treatment. This prospective, non-randomized, real-world study evaluated the effectiveness and safety of atezolizumab in combination with platinum-etoposide chemotherapy in treatment-naïve patients with metastatic lung-derived LCNEC.

Patients who received atezolizumab were treated with carboplatin, etoposide, and atezolizumab, followed by atezolizumab maintenance in patients without disease progression for up to 24 months, or until disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision, whichever occurred first. Patients in the control cohort received carboplatin and etoposide alone.

The main clinical outcomes were progression-free survival, overall survival, overall response rate, and duration of response. Exploratory translational analyses included plasma microRNA assessment, including miR-375 and miR-21, in available blood samples.

This is a prospective, non-randomized, real-world clinical study evaluating the effectiveness and safety of atezolizumab in combination with platinum-etoposide chemotherapy in patients with treatment-naïve metastatic large-cell neuroendocrine carcinoma (LCNEC) originating from the lung.

The study was conducted at the 3rd Department of Medicine, National and Kapodistrian University of Athens, Sotiria General Hospital for Chest Diseases, Athens, Greece. Consecutive eligible patients were enrolled between November 2019 and August 2022. Final clinical follow-up for the updated long-term survival analysis was performed with a data cut-off date of September 1, 2025.

The protocol was approved by the Institutional Scientific Council and Ethics Committee of Sotiria General Hospital and was conducted in accordance with Good Clinical Practice principles and the Declaration of Helsinki. All patients provided written informed consent before enrollment.

Eligible patients were adults with histologically confirmed metastatic lung-derived LCNEC, no prior systemic treatment for metastatic disease, ECOG performance status 0-2, and measurable disease according to RECIST v1.1. Patients with brain metastases at diagnosis were eligible after appropriate management, including whole-brain radiotherapy when clinically indicated.

Because atezolizumab was not approved for metastatic LCNEC, access to atezolizumab was obtained through individual off-label reimbursement requests submitted to the Greek National Organization for Healthcare Services Provision (EOPYY). Patients granted reimbursement approval received carboplatin, etoposide, and atezolizumab, whereas patients not granted approval received carboplatin and etoposide alone and served as a contemporaneous real-world control cohort. No study drug was provided through a sponsor-funded or industry-sponsored access programme.

Patients in the atezolizumab cohort received carboplatin AUC 5 on day 1 plus etoposide 100 mg/m² on days 1-3 every 21 days for 4-6 cycles, with atezolizumab 1200 mg every 21 days. Patients without disease progression after induction therapy continued atezolizumab maintenance.

The original study concept allowed atezolizumab maintenance until disease progression or unacceptable toxicity. During early study conduct, before any patient reached the 24-month treatment landmark and before long-term outcome analyses were performed, maintenance atezolizumab was prospectively capped at a maximum duration of 24 months for patients with ongoing disease control. This finite-duration strategy was applied uniformly to all eligible non-progressing patients. Atezolizumab maintenance was therefore continued for up to 24 months, or until disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision based on clinical judgment, whichever occurred first.

Patients in the control cohort received carboplatin and etoposide for 4-6 cycles, followed by observation. Crossover to protocol-specified off-label immunotherapy at disease progression was not part of the study protocol and was not operationally feasible in the absence of an approved indication, study-drug provision, or a dedicated access programme. Subsequent therapies were administered according to standard-of-care practice, regulatory and reimbursement availability, and physician judgment.

Tumor response was assessed using computed tomography and clinical evaluation according to RECIST v1.1. The main clinical endpoints were progression-free survival, overall survival, overall response rate, and duration of response. Progression-free survival was defined as the time from treatment initiation to disease progression or death from any cause, whichever occurred first. Overall survival was defined as the time from treatment initiation to death from any cause. Overall response rate was defined as the proportion of patients achieving complete or partial response according to RECIST v1.1. Duration of response was defined as the time from first documented response to radiographic disease progression or death.

Exploratory translational analyses included plasma microRNA assessment in available blood samples. Blood samples were collected at predefined time points and processed according to standard procedures. Plasma RNA was isolated, followed by cDNA synthesis and microRNA quantification using the miRCURY LNA SYBR Green PCR Kit. miR-103a-3p was used as a reference gene. Control samples were obtained from volunteers without a cancer diagnosis.

Statistical analyses were performed using R software. Because of the rarity of metastatic LCNEC and the exploratory nature of the study, no formal power calculation was performed. Survival outcomes were estimated using the Kaplan-Meier method, and treatment groups were compared using log-rank testing and Cox proportional hazards models. Analyses were conducted according to the assigned treatment cohort.

Cohorts A and B:

Inclusion Criteria:

• Histologically confirmed Stage IV (metastatic) or unresectable locally advanced LCNEC
• No prior treatment
• With or without brain metastasis, if symptomatic patients should be treated with WBRT first
• Performance Status ≤ 2
• Life expectancy > 3 months
• Written informed consent
• Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

Exclusion Criteria:

• Prior treatment with chemotherapy, immunotherapy, targeted small molecule therapy, or radiation therapy (except WBRT for brain metastasis from LCNEC)
• Active or history of autoimmune disease or immune deficiency
• Treatment with systemic immunosuppressive medications with the following exceptions:

Patients who have received acute, low-dose systemic immunosuppressant medication (≤ 10 mg/day oral prednisone or equivalent) or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study after Medical Monitor approval has been obtained.

• Major surgical procedure other than for diagnosis within 4 weeks before initiation of study treatment, or anticipation of need for a major surgical procedure during the study
• Active malignancy or malignancy within 3 years
• Active tuberculosis
• Current severe, uncontrolled systemic disease other than cancer
• Known clinically significant liver disease
• Treatment with any other investigational agent or participation in another clinical study with therapeutic intent