The Efficacy and Safety of Narlumosbart in Combination With Stereotactic Body Radiation Therapy to Improve the Efficacy of First-line Chemotherapy Combined With Immunotherapy in Patients With Bone Metastases From Advanced Non-small Cell Lung Cancer

Efficacy and Safety of Narlumosbart in Combination With Stereotactic Body Radiation Therapy Followed by First-line Chemotherapy Combined With Immunotherapy in Advanced Driver Gene-negative Non-small Cell Lung Cancer Patients With Bone Metastases: A Phase II, Single-arm, Single-center Clinical Trial Protocol

Introduction: Immunotherapy in combination with chemotherapy have been recommended as the first-line treatment of driver-negative advanced non-small cell lung cancer (NSCLC), but the efficacy is worse in NSCLC patients with bone metastases due to the immunosuppressive microenvironment. Studies have shown that not only the nuclear factor kappa-B ligand (RANKL) inhibitors but also Stereotactic Body Radiation Therapy (SBRT) play a significant role in improving the tumor immune microenvironment. Therefore, narlumosbart，a monoclonal antibody (mAb) targeting RANKL，in combination with SBRT may have synergistic effects and improve efficacy of immunotherapy and chemotherapy in driver-negative advanced NSCLC patients with bone metastases.

Methods: This single-arm, single-center phase II clinical trial will enroll NSCLC patients with bone metastases who have not received any systemic therapy. Patients will receive narlumosbart and bone target lesion SBRT in combination with first-line treatment immunotherapy and chemotherapy after screening eligible subjects. Narlumosbart, 120mg/time, subcutaneous injection, will be administered every 4 weeks. For the treatment of SBRT for bone metastases, the dose of 24Gy/3F is used for spinal metastases, and 30Gy/5F or 35Gy/5F is used for non-spinal lesions. Chemotherapy combined with immune checkpoint inhibitor therapy will be used in accordance with the guidelines. The primary endpoint is to assess the objective response rate of NSCLC patients with bone metastases from narlumosbart combined with SBRT and first-line chemotherapy and immunotherapy. The secondary endpoints include safety and tolerability, progression-free survival, overall survival, bone-related events, pain score, and quality of life. Sample size was calculated using the Simon's Two-Stage method. 9 patients will be enrolled in the first stage. If ≥ 2 patients achieve CR/PR, the second stage of enrollment will be performed. If fewer than 2 patients achieve CR/PR, the trial will be terminated. In the second phase, 15 patients will be enrolled. 27 subjects will be enrolled in this project, considering the dropout rate of 10%.

Wangjun Yan AND Zhengfei Zhu are the Co-Principal Investigators of this study.

Study Overview

• Status: Recruiting
• Conditions: NSCLC; Immunotherapy; Stereotactic Body Radiation Therapy (SBRT)
• Intervention / Treatment: Drug: Narlumosbart; Radiation: Stereotactic Body Radiation Therapy

• Study Type: Interventional
• Enrollment (Estimated): 27
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Zhengfei Zhu; Phone Number: +86-18017312901; Email: fuscczzf@163.com
• Study Contact Backup: Name: Wangjun Yan; Phone Number: 13917966770; Email: yanwj@fudan.edu.cn

Study Locations

• China
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China
      • Recruiting
      • Fudan University Shanghai Cancer Center
      • Contact: Zhengfei Zhu; Phone Number: +86-18017312901; Email: fuscczzf@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Signed informed consent prior to the implementation of any trial-related procedures;
• Age 18-80 years old;
• Histologically or cytologically confirmed stage IV NSCLC according to the TNM Classification of Malignant Tumours, 9th edition；
• Histologically confirmed bone metastases requiring local radiotherapy；
• Patients who have not undergone systemic drug therapy for lung cancer (including chemotherapy, targeting, immunotherapy, etc.);
• Driver genes (EGFR, ALK, ROS-1) negative in adenocarcinoma patients (genetic testing not required for squamous cell carcinoma) ;
• At least one evaluable non-bone lesion (refer to RECIST1.1);
• Bone metastases other than the lesions to be radiotherapy do not require local treatment (surgery or radiotherapy) intervention after evaluation;
• ECOG score 0-1 points;
• Expected survival time > 3 months;
• Adequate organ function, defined as meeting all of the following laboratory criteria within 14 days prior to enrollment: 1) ANC ≥1.5×10⁹/L (no G-CSF); 2) Platelets ≥100×10⁹/L (no transfusion); 3) Haemoglobin ≥9 g/dL (no transfusion/EPO); 4) Bilirubin ≤1.5×ULN; 5) AST/ALT ≤2.5×ULN (≤5×ULN if liver metastases); 6) Creatinine ≤1.5×ULN or CrCl ≥60 mL/min; 7) INR/PT ≤1.5×ULN; 8) TSH within normal limits (or FT3/FT4 normal if TSH abnormal); 9) Cardiac enzymes (troponin I, CK-MB) ≤ ULN (isolated abnormalities not clinically significant are permitted).

Exclusion Criteria:

• The pathology is small cell lung cancer (SCLC), including lung cancer mixed with SCLC and NSCLC;
• The lesion is an isolated lesion and can be treated radically;
• Patients who need surgical treatment after the evaluation of the study are not allowed to enroll;
• The radiotherapy lesion to be treated has been treated with radiotherapy or the lesion to be treated cannot be treated with radiotherapy after evaluation;
• Presence of active brain metastases;
• Other malignancies within 5 years (except cured non-melanoma skin cancer or carcinoma in situ);
• Prior treatment with anti-PD-1, anti-PD-L1, or RANKL-targeting agents;
• Active autoimmune disease requiring systemic therapy;
• Presence of clinically uncontrollable pleural effusion/ascites effusion (subjects who do not need to drain the effusion or stop draining for 3 days without significant increase in effusion can be enrolled);
• Known allogeneic organ transplantation (except corneal transplantation) or allogeneic hematopoietic stem cell transplantation;
• Presence of active bone metabolism disease (Paget bone disease, Cushing's syndrome, and hyperprolactinemia), rheumatoid arthritis, uncontrolled hyper/hypothyroidism, hyperparathyroidism/hypoparathyroidism;
• Those who are known to be allergic to the active ingredients or excipients such as sintilimab, pemetrexed, nalusopaimab, carboplatin, cisplatin, paclitaxel, etc., of the drug in this study;
• Have not recovered adequately from toxicity and/or complications induced by any of the interventions (i.e., ≤ grade 1 or to baseline, excluding fatigue or alopecia, prior to initiation of treatment);
• Known history of human immunodeficiency virus (HIV) infection (i.e., HIV 1/2 antibody positive);
• Untreated active hepatitis B (defined as HBsAg positive and HBV-DNA copy number detected at the same time greater than the upper limit of normal in the laboratory department of the research center);
• Hypocalcemia cannot be improved after treatment;
• Previous or current osteomyelitis or osteonecrosis of the jaw; Dental surgery or oral surgery that does not heal; Acute dental or jaw disease requiring oral surgery; Those who plan to undergo invasive dental surgery during the study;
• Use of any of the following anti-bone metabolizing agents within 6 months prior to enrollment: Parathyroid hormone (PTH) or derivatives; Calcitonin; Osteoprotein; Vaccination with a live vaccine within 30 days prior to the first dose (Cycle 1, Day 1);
• Pregnant or lactating women;

• Presence of any serious or uncontrollable systemic disease, such as:

  1. Resting ECG has major abnormalities in rhythm, conduction or morphology and severe symptoms that are difficult to control, such as complete left bundle branch block, heart block above degree II, ventricular arrhythmia or atrial fibrillation;
  2. unstable angina, congestive heart failure, New York Heart Association (NYHA) classification ≥ grade 2 chronic heart failure;
  3. myocardial infarction within 6 months prior to enrollment;
  4. unsatisfactory blood pressure control;
  5. History of non-infectious pneumonitis requiring glucocorticoid therapy within 1 year prior to the first dose, or current presence of clinically active interstitial lung disease;
  6. active tuberculosis;
  7. Presence of active or uncontrolled infection requiring systemic therapy;
  8. Presence of clinically active diverticulitis, abdominal abscess, gastrointestinal obstruction;
  9. Liver diseases such as cirrhosis, decompensated liver disease, acute or chronic active hepatitis;
  10. poorly controlled diabetes mellitus (fasting blood glucose (FBG) >10mmol/L);
  11. Those whose urine routine showed a urine protein ≥++, and confirmed that the 24-hour urine protein was > 1.0 g;
  12. Subjects with mental disorders who are unable to cooperate with treatment; Medical history or evidence of disease, abnormal treatment or laboratory test values that may interfere with the results of the trial, prevent the subject from participating in the study throughout the study, or other conditions that are considered by the investigator to be unsuitable for enrollment in the opinion of the investigator are not suitable for participation in this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Narlumosbart + SBRT; This is a single-arm, phase II trial evaluating the efficacy and safety of narlumosbart (120 mg SC Q4W) combined with stereotactic body radiation therapy (SBRT) and standard first-line chemo-immunotherapy in driver gene-negative advanced NSCLC patients with bone metastases. Narlumosbart is an anti-RANKL mAb. SBRT dose: 24 Gy/3F for spinal lesions; 30-35 Gy/5F for non-spinal lesions, delivered 3 days prior to chemo-immunotherapy. Chemo-immunotherapy follows standard guidelines. Treatment continues until progression, toxicity, or withdrawal.The trial uses Simon two-stage design with H₀=25%, H₁=50%, α=0.05, power=0.8; 9 patients in stage 1, with ≥2 responses triggering stage 2 (+15 patients), and <2 responses stopping the trial. Total sample size is 27 including 10% dropout. A sensitivity analysis is pre-specified: if stage-1 ORR falls between 25% and 40%, protocol revision to H₁=40% with sample size adjustment will be considered, pending ethics approval.

Drug: Narlumosbart; Narlumosbart is a fully humanized anti-RANKL monoclonal antibody (IgG4) with Fab arms identical to denosumab, demonstrating rapid and sustained suppression of bone resorption biomarkers in patients with bone metastases. It will be administered subcutaneously at 120 mg every 4 weeks. Calcium and vitamin D supplementation will be given concurrently to prevent hypocalcemia. Adverse events will be recorded and graded according to CTCAE v5.0. For jaw osteonecrosis, all patients will undergo a mandatory dental examination within 14 days before the first dose, with 3-monthly dental checks during treatment; suspected cases will be managed with oral surgeon consultation. Serum calcium will be monitored at baseline and prior to each dose (every 4 weeks). Corrected calcium <2.0 mmol/L will be managed with oral calcium (500-1000 mg/day) and vitamin D (400-800 IU/day). Severe hypocalcaemia (<1.8 mmol/L or symptomatic) will be treated with intravenous calcium gluconate.; Other Names: chemotherapy; Stereotactic Body Radiation Therapy; Radiation: Stereotactic Body Radiation Therapy; SBRT will be delivered within one week before the first chemo-immunotherapy cycle. All patients undergo contrast-enhanced CT simulation (1-1.5 mm slice thickness); MRI fusion (T1/T2/STIR) is mandatory for spinal metastases. Target delineation: GTV = visible tumor on CT/MRI; CTV = involved vertebral body sector(s) per ISRC guidelines for spinal lesions, or GTV + 3-5 mm margin for non-spinal lesions; PTV = CTV + 1-2 mm margin. Dose prescription: 24 Gy in 3 fractions for spinal metastases; 30-35 Gy in 5 fractions for non-spinal lesions. Treatment plans use VMAT or IMRT. Daily cone-beam CT (CBCT) is performed before each fraction for image guidance; 6-degree-of-freedom couch corrections are used for spinal lesions. Respiratory motion management (e.g., 4D-CT, gating) is applied for mobile lesions if motion exceeds 5 mm. Patient-specific quality assurance (PSQA) is performed before the first fraction, with gamma analysis (3%/2 mm criteria and ≥95% passing rate) required.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Objective response rate, ORR	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of AEs, SAEs, and AE-Related Treatment Discontinuation	To assess the frequency of adverse events (AEs), severe adverse events (SAEs), and treatment discontinuation caused by AEs or SAEs over the study period.	2 years
Progression free survival, PFS	Progression-free survival (PFS) is defined as the time from randomization (or treatment initiation) to the earlier of the first documentation of objective disease progression (per RECIST v1.1) or death due to any caus	2 years
Overall survival (OS)	Overall survival (OS) is defined as the time from treatment initiation to death from any cause. Participants who are alive or lost to follow-up at the time of analysis will be censored at the date of their last known survival status.	2 years
Incidence of bone-related events (SREs)	Incidence of bone-related events (SREs) is defined as the proportion of patients experiencing at least one skeletal-related event (SRE) within the specified time intervals (3, 6, and 12 months). SREs are defined as a composite endpoint including: pathological fracture, spinal cord compression, bone-directed radiotherapy or surgery, or hypercalcaemia of malignancy, as assessed by the investigator.	2 years
Changes in pain score	Changes from baseline in pain score measured by the Brief Pain Inventory-Short Form (BPI-SF, 0-10, higher=worse).	2 years
Changes in quality of life	EORTC QLQ-C30 measures global health, functions, and symptoms (0-100; higher=better for global/function, worse for symptoms) from baseline.	2 years

Collaborators and Investigators

• Sponsor: Fudan University

Study record dates

Study Major Dates

• Study Start (Actual): February 15, 2025
• Primary Completion (Estimated): December 30, 2026
• Study Completion (Estimated): December 30, 2028

Study Registration Dates

• First Submitted: December 13, 2024
• First Submitted That Met QC Criteria: December 13, 2024
• First Posted (Actual): December 17, 2024

Study Record Updates

• Last Update Posted (Actual): September 11, 2026
• Last Update Submitted That Met QC Criteria: September 10, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Carcinoma, Non-Small-Cell Lung; Investigative Techniques; Therapeutics; Surgical Procedures, Operative; Radiotherapy; Stereotaxic Techniques; Neurosurgical Procedures; Drug Therapy; Radiosurgery
• Other Study ID Numbers: 2024-NSCLC-SBRT; SACA-AX202407 (Other Grant/Funding Number: Shanghai Anticancer Association)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified IPD (baseline, efficacy, safety, and biomarker data) will be shared upon reasonable request after publication.
• IPD Sharing Time Frame: After publication of the main results, for a period of 5 years.
• IPD Sharing Access Criteria: Qualified researchers with a methodologically sound proposal and a signed data access agreement. Requests should be directed to the corresponding author.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

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