This is a prospective, single-arm, investigator-initiated clinical study (IIT) designed to evaluate the efficacy and safety of nab-paclitaxel combined with local radiotherapy for patients with extensive-stage small cell lung cancer (ES-SCLC) whose disease has progressed after first-line treatment.
Small cell lung cancer (SCLC) is an aggressive type of lung cancer, and extensive-stage SCLC (ES-SCLC) refers to its advanced stage. For patients whose cancer progresses after first-line treatment, there are very limited effective second-line and later-line treatment options. Commonly used clinical regimens such as topotecan and lurbinectedin only provide modest improvements in tumor response and survival, and often cause severe hematological toxicities (represented by bone marrow suppression). This leaves patients in a persistent dilemma of "insufficient efficacy and limited tolerability", highlighting a clear unmet medical need for better treatment options in this population.
Against this background, this study explores a comprehensive treatment strategy using nab-paclitaxel as the chemotherapy backbone, combined with local radiotherapy in eligible patients. Nab-paclitaxel is a nanoparticle albumin-bound form of paclitaxel, with a relatively controllable toxicity profile and manageable administration in clinical practice. Local radiotherapy may create a synergistic effect by improving the tumor immune microenvironment and enhancing local tumor control, with the goal of providing better evidence for a "chemotherapy ± local therapy" combination as a second-line treatment option.
Inclusion Criteria:
* (1) Written informed consent has been signed. (2) Male or female, aged 18-75 years. (3) Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
(4) Histologically or cytologically confirmed extensive-stage small cell lung cancer (ES-SCLC) according to the Veterans Administration Lung Group (VALG) staging system.
(5) Patients with ES-SCLC who have received at least one prior line of systemic therapy.
(6) Patients with previously treated asymptomatic central nervous system (CNS) metastases are eligible if all of the following criteria are met:
* Only supratentorial and cerebellar metastases (i.e., no metastases in the midbrain, pons, medulla oblongata, or spinal cord);
* No requirement for ongoing corticosteroid therapy for CNS disease;
* No stereotactic radiotherapy within 7 days prior to randomization;
* No disease progression observed on imaging from completion of CNS-directed therapy through screening;
⑤ If new asymptomatic CNS metastases are detected on screening imaging, patients must receive radiotherapy and/or resection of CNS lesions. After such treatment, these patients may be randomized without additional brain scans if all other eligibility criteria are satisfied.
(7) Presence of measurable disease as defined by RECIST v1.1. A previously irradiated lesion may be considered measurable only if clear disease progression has occurred after radiotherapy and the lesion is not the only site of disease.
(8) Adequate hematologic and end-organ function as defined by laboratory results obtained within 14 days prior to randomization:
* Absolute neutrophil count (ANC) ≥ 1500 cells/μL without granulocyte colony-stimulating factor support; lymphocyte count ≥ 500 cells/μL;
* Platelet count ≥ 100,000/μL without transfusion; hemoglobin ≥ 9.0 g/dL (may be achieved by transfusion); ③ International normalized ratio (INR) or activated partial thromboplastin time (aPTT) ≤ 1.5 × upper limit of normal (ULN). This criterion applies only to patients not receiving anticoagulation. Patients on anticoagulation must be on a stable dose; ④ Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase ≤ 2.5 × ULN, except: Patients with confirmed liver metastases: AST and/or ALT ≤ 5 × ULN; Patients with confirmed liver or bone metastases: alkaline phosphatase ≤ 5 × ULN;
* Serum bilirubin ≤ 1.25 × ULN. For patients with known Gilbert's disease, serum bilirubin ≤ 3 × ULN is permitted;
* Serum creatinine ≤ 1.5 × ULN. (9) Patients must provide a pre-treatment tumor tissue sample during the study. Any available tumor tissue sample is acceptable. Submission may be completed after enrollment.
Exclusion Criteria:
* Patients meeting any of the following criteria are ineligible:
Active or untreated CNS metastases detected by computed tomography (CT) or magnetic resonance imaging (MRI) during screening or on prior imaging.
Spinal cord compression not radically treated with surgery and/or radiotherapy, or previously diagnosed spinal cord compression without clinical evidence of stable disease for at least 1 week prior to randomization.
Leptomeningeal metastases. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage (once per month or more frequently); indwelling catheters are not permitted.
Uncontrolled or symptomatic hypercalcemia (\> 1.5 mmol/L ionized calcium, serum calcium \> 12 mg/dL, or corrected serum calcium \> ULN).
History of malignancy other than SCLC within 5 years prior to randomization, except for malignancies with negligible risk of metastasis or death (e.g., 5-year OS \> 90%) and curative potential after treatment, such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer with radical surgery, or ductal carcinoma in situ with radical surgery.
Pregnant or lactating women, or women planning pregnancy during the study period.
History of severe allergic, hypersensitivity, or anaphylactic reactions to chimeric, humanized, or human antibodies or fusion proteins.
Known hypersensitivity to any component of biologic medicinal products produced in Chinese hamster ovary (CHO) cells or to the study drug formulation.
History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, and glomerulonephritis.
Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid hormone replacement therapy are eligible.
Patients with type 1 diabetes mellitus controlled on a stable insulin regimen are eligible.
Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo only (patients with psoriatic arthritis are excluded) may be enrolled if:
* Rash involves \< 10% of body surface area; ② Disease is well controlled at baseline requiring only low-potency topical corticosteroids; ③ No acute exacerbation of underlying disease in the past 12 months (no requirement for PUVA, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, high-potency or oral corticosteroids).
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonia, or active pneumonitis on screening chest CT scan.
Severe interstitial lung disease. Positive human immunodeficiency virus (HIV) test. Active hepatitis B (chronic or acute; defined as positive hepatitis B surface antigen \[HBsAg\] at screening) or hepatitis C virus (HCV) infection.
Patients with resolved or prior HBV infection (positive hepatitis B core antibody \[HBcAb\] and negative HBsAg) are eligible. HBV DNA testing must be performed prior to randomization.
Among patients positive for HCV antibody, only those with negative HCV RNA by PCR are eligible.
Active tuberculosis. Severe infection at enrollment, including but not limited to infectious complications requiring hospitalization, bacteremia, severe pneumonia, etc.
Severe cardiovascular disease, such as New York Heart Association (NYHA) Class II or higher heart failure, myocardial infarction within 3 months prior to randomization, unstable arrhythmia, or unstable angina.
Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction \< 50% must be on optimal stable therapy as judged by the treating physician, with cardiology consultation if necessary.
Major surgery within 28 days prior to randomization (except diagnostic surgery) or expected major surgery during the study.
History of allogeneic bone marrow transplantation or solid organ transplantation.
Any other disease, metabolic dysfunction, physical finding, or laboratory abnormality that, in the investigator's judgment, would contraindicate use of the study drug, interfere with interpretation of study results, or place the patient at high risk of treatment-related complications.
Prior receipt of anti-tumor therapy for ES-SCLC. Treatment with any other investigational agent or participation in another therapeutic clinical trial within 28 days prior to randomization.
Live attenuated vaccine within 4 weeks prior to randomization or anticipated need for such vaccines during the study.
Prior treatment with CD137 agonists, immune checkpoint blockade therapy, anti-PD-1, or anti-PD-L1 therapeutic antibodies.
Systemic immunosuppressive therapy within 2 weeks prior to randomization, including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor (anti-TNF) agents.
Patients receiving short-term, low-dose systemic immunosuppression (e.g., single-dose dexamethasone for nausea) may be eligible after discussion and approval by the investigator and medical monitor.
Use of inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for orthostatic hypotension, and low-dose corticosteroid replacement for adrenal insufficiency is permitted.
History of hypersensitivity to platinum agents or etoposide.
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