Atezolizumab in Large Cell Neuroendocrine Carcinoma (LANCE)

Effectiveness of Atezolizumab in Large Cell Neuroendocrine Carcinoma of the Lung and the Value of miR21 and miR-375 as Biomarkers

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.

Study Overview

• Status: Completed
• Conditions: Large Cell Neuroendocrine Carcinoma of the Lung
• Intervention / Treatment: Drug: Carboplatin; Drug: Etoposide; Drug: Atezolizumab

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 1

Contacts and Locations

Study Locations

• Greece
  • Athens, Greece, 11527
    • National and Kapodistrian University of Athens
  • Athens, Greece, 115 27
    • Sotiria Thoracic Diseases General Hospital of Athens
  • Athens
    • Athens, Athens, Greece, 11527
      • OCEBER

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A; 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 for a maximum duration of 24 months, or until disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision, whichever occurred first.	Drug: Carboplatin; SOL.INF 450MG/45ML VIAL ΒΤx1VIALx45ML; Other Names: CARBOPLATIN/HOSPIRA; Drug: Etoposide; ETOPOSIDE/PHARMACHEMIE SOL.INF 100MG/5ML VIAL BT x 10 VIALS x 5 ML; Drug: Atezolizumab; Atezolizumab 1200 mg intravenously every 21 days, administered with platinum-etoposide induction and continued as maintenance in non-progressing patients for up to 24 months, or until disease progression, unacceptable toxicity, withdrawal of consent, or investigator decision, whichever occurred first.; Other Names: Tecentriq
Active Comparator: Arm B; Carboplatin AUC 5 on day 1 plus etoposide 100 mg/m² on days 1-3 every 21 days for 4-6 cycles, followed by observation. Subsequent treatment at disease progression was administered according to standard-of-care practice and physician judgment.	Drug: Carboplatin; SOL.INF 450MG/45ML VIAL ΒΤx1VIALx45ML; Other Names: CARBOPLATIN/HOSPIRA; Drug: Etoposide; ETOPOSIDE/PHARMACHEMIE SOL.INF 100MG/5ML VIAL BT x 10 VIALS x 5 ML

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival	Progression-free survival was defined as the time from treatment initiation to radiographic disease progression according to RECIST v1.1 or death from any cause, whichever occurred first. Patients without documented disease progression or death were censored at the date of last disease assessment or last follow-up.	From treatment initiation through study completion/data cut-off, assessed up to 70 months.
Overall survival	Overall survival was defined as the time from treatment initiation to death from any cause. Patients alive at the time of data cut-off were censored at the date of last confirmed survival follow-up.	From treatment initiation through study completion/data cut-off, assessed up to 70 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate	Overall response rate was defined as the proportion of patients achieving complete response or partial response according to RECIST v1.1.	From treatment initiation through study completion/data cut-off, assessed up to 70 months.
Duration of Response	Duration of response was defined as the time from first documented complete or partial response to radiographic disease progression or death from any cause.	From treatment initiation through study completion/data cut-off, assessed up to 70 months.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and tolerability	Safety and tolerability were assessed by the occurrence of treatment-related adverse events and immune-related adverse events during treatment and follow-up.	From treatment initiation through study completion/data cut-off, assessed up to 70 months.
Treatment-free interval	Treatment-free interval was defined, among patients who completed the maximum 24-month atezolizumab maintenance duration without progression, as the time from atezolizumab discontinuation to documented disease progression, death, or last follow-up.	From atezolizumab discontinuation through progression, death, or data cut-off, assessed up to 46 months.
Exploratory plasma microRNA analysis	Exploratory plasma microRNA expression analysis, including miR-375 and miR-21, was performed in available blood samples. Expression levels were assessed relative to non-cancer volunteer control samples and evaluated descriptively/exploratorily in relation to clinical outcomes.	Blood samples collected at predefined study time points during treatment and follow-up, assessed up to 70 months.

Collaborators and Investigators

• Sponsor: Oncology Center of Biochemical Education And Research
• Investigators: Study Chair: Konstantinos N Syrigos, National and Kapodistrian University of Athens; Principal Investigator: Georgios Evangelou, National and Kapodistrian University of Athens; Study Director: Konstantinos N Syrigos, Konstantinos

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2019
• Primary Completion (Actual): September 1, 2025
• Study Completion (Actual): September 1, 2025

Study Registration Dates

• First Submitted: September 10, 2023
• First Submitted That Met QC Criteria: September 16, 2023
• First Posted (Actual): September 22, 2023

Study Record Updates

• Last Update Posted (Actual): July 8, 2026
• Last Update Submitted That Met QC Criteria: July 6, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Immunotherapy; Immune Checkpoint Inhibitors; Atezolizumab; LCNEC; miR375; Large Cell Neuroendocrine Carcinoma
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Lung Neoplasms; Carcinoma; Carcinoma, Neuroendocrine; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Carbohydrates; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Glucosides; Glycosides; Coordination Complexes; Etoposide; Carboplatin; atezolizumab
• Other Study ID Numbers: UPI-2023-2304

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes