Consolidation Radiotherapy vs. Observation in Oligoresidual Advanced Non-Small Cell Lung Cancer After Chemo-Immunotherapy

Comparing Consolidation Radiotherapy Versus No Radiotherapy for Oligoresidual Disease After First-line Chemotherapy Plus Immunotherapy in Advanced Non-Small Cell Lung Cancer: A Prospective, Randomized Controlled Phase II Clinical Trial

This clinical study investigates whether adding local radiation therapy (radiotherapy) to standard maintenance therapy benefits patients with advanced non-small cell lung cancer (NSCLC) who have a limited number of residual tumors after initial treatment.

The primary objective is to determine if adding targeted radiation therapy to residual lesions prolongs progression-free survival in NSCLC patients with "oligo-residual lesions" (5 or fewer tumors in no more than 3 organs) following first-line chemoimmunotherapy. Researchers hypothesize that combination therapy will slow cancer progression more effectively than maintenance therapy alone.

Eligible participants include adults (18+) with advanced NSCLC who have completed 4-6 cycles of first-line chemoimmunotherapy, show limited residual disease on Positron Emission Tomography-Computed Tomography (PET-CT), and lack specific genetic mutations (Epidermal Growth Factor Receptor [EGFR], Anaplastic Lymphoma Kinase [ALK], etc.).

Patients will be randomized into two groups:

Experimental: Continuation of maintenance therapy (immunotherapy alone or with chemotherapy) plus local radiotherapy to all residual tumors Control: Continuation of maintenance therapy only

The study aims to answer:

Primary: Does adding radiotherapy slow cancer progression more effectively? Secondary: Does it improve overall survival, control residual disease, and what are its effects on safety and quality of life?

Participants will:

Be randomly assigned to a treatment group Receive their designated treatment Undergo regular check-ups and imaging scans Complete quality of life questionnaires Potentially provide blood samples for research This research will help determine optimal treatment approaches for this specific patient population to improve outcomes and quality of life.

The purpose of this clinical study is to find out whether the addition of local radiation therapy (radiotherapy) after standard chemotherapy and immunotherapy is better than continuing maintenance therapy alone for patients with specific types of advanced lung cancer .

Study Objectives and Hypotheses:

The primary objective is to see if the addition of radiation therapy to target residual lesions will prolong the time that a patient's cancer does not get worse (progression-free survival) in patients with advanced non-small cell lung cancer (NSCLC) who have a limited number of tumors (known as "oligo-residual lesions") after receiving first-line chemotherapy in combination with immunotherapy . The researchers hypothesized that patients who receive maintenance therapy plus radiation therapy will have their cancer progress more slowly than patients who receive only maintenance therapy .

Study Population:

This study is for adult patients 18 years of age and older who have been diagnosed with advanced non-small cell lung cancer . These patients have received 4 to 6 cycles of first-line chemotherapy in combination with immunotherapy and have a limited number of tumor lesions on post-treatment imaging (PET-CT) (no more than 5 residual lesions involving no more than 3 organs) and no specific genetic mutations (e.g., Epidermal Growth Factor Receptor [EGFR], Anaplastic Lymphoma Kinase [ALK], etc.).

Study Methods:

Eligible patients will be randomly assigned to one of two groups :

Experimental group: continuation of maintenance therapy (either immunotherapy or chemotherapy combined with immunotherapy, depending on the previous regimen) and local radiotherapy to all residual tumor lesions.

Control group: Continuation of maintenance therapy only.

Key questions to be answered by the study:

Primary question: is the addition of local radiotherapy more effective in slowing cancer progression than maintenance therapy alone in this group of lung cancer patients? Secondary questions include: Does the addition of radiotherapy prolong overall survival? How effective is it in controlling residual disease? What is the safety (side effects) of the treatment and how does it affect the patient's quality of life?

What participants need to do:

Be randomized to one of the treatment groups . Receive the appropriate treatment (maintenance therapy, or maintenance therapy plus radiotherapy) according to their group.

Have regular check-ups and imaging scans to assess the status of the tumor. Complete questionnaires about quality of life. May be asked to provide a blood sample for research . This study will help doctors to better understand how to treat this special group of patients with advanced lung cancer, with a view to improving their outcome and quality of life.

Inclusion Criteria:

1. Voluntary signed written informed consent and compliance with protocol requirements;
2. Age ≥ 18 years;
3. Expected survival time ≥ 3 months;
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1;
5. Histologically or cytologically confirmed advanced non-small cell lung cancer;
6. After receiving 4-6 cycles of first-line platinum-based chemotherapy combined with immunotherapy, PET-CT evaluation shows no disease progression, with no more than 5 lesions not meeting criteria for complete metabolic response, involving no more than 3 organs;
7. All residual lesions can safely receive radiation therapy as assessed by radiation oncologists;
8. Patient can tolerate the radiotherapy process, such as maintaining fixed position;
9. At least one measurable lesion among the oligoresidual lesions according to RECIST v1.1;
10. Agreement to provide archived tumor tissue specimens from primary or metastatic sites, or fresh tissue samples; if unable to provide tumor tissue samples, subjects may be enrolled after investigator assessment if meeting other inclusion/exclusion criteria;
11. Toxicities from previous anti-tumor therapies recovered to ≤ grade 1 per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v5.0) (excluding alopecia, fatigue, pigmentation, hypothyroidism stable on hormone replacement therapy, grade 2 peripheral neuropathy after chemotherapy, and exceptions specified in other inclusion criteria);
12. Laboratory values at screening must meet the following criteria: a) Neutrophils ≥ 1.5×10^9/L b) Platelets ≥ 100×10^9/L c) Hemoglobin ≥ 90g/L (no blood transfusion within 14 days) d) Serum Cr ≤ 1×ULN, endogenous creatinine clearance > 50ml/min (Cockcroft-Gault formula) e) AST ≤ 2.5×ULN; ALT ≤ 2.5×ULN; if liver metastases present, ALT and AST ≤ 5×ULN f) Total bilirubin ≤ 1.5×ULN (except for Gilbert's syndrome subjects, where total bilirubin must be < 51.3μmol/L) g) Thyroid Stimulating Hormone (TSH), Free Triiodothyronine (FT3), Free Thyroxine (FT4) all within ±10% of normal range.

Exclusion Criteria:

1. Archived tumor tissue, pre-treatment tumor biopsy, or histological examination showing evidence of previous small cell or mixed small cell/non-small cell histology;
2. Previous tissue samples or peripheral blood genetic sequencing reports indicating EGFR sensitizing mutations, ALK fusion, or other gene variations that should receive standard first-line targeted therapy; squamous cell carcinoma without genetic testing is presumed negative;
3. Symptomatic brain metastases;
4. Leptomeningeal metastases;
5. Active, known, or suspected autoimmune disease (excluding vitiligo, type I diabetes, residual hypothyroidism due to autoimmune thyroiditis requiring only hormone replacement therapy, or conditions not expected to recur in the absence of external triggers);
6. Active tuberculosis (TB) infection as determined by chest X-ray, sputum examination, and clinical examination. Patients with a history of active pulmonary TB infection within the previous year, even if treated, will be excluded. Patients with a history of active pulmonary TB infection more than 1 year ago will also be excluded unless effective previous anti-TB treatment can be documented;
7. Comorbidities requiring immunosuppressive medication, or requiring systemic or local use of corticosteroids at immunosuppressive doses;
8. Pregnancy or breastfeeding;
9. Interstitial lung disease with symptomatic manifestations, or that may interfere with the detection or management of suspected drug-related pulmonary toxicity;
10. Positive for human immunodeficiency virus antibody (HIVAb), active hepatitis B virus infection (HBsAg positive and HBV-DNA > 10^3 copies/ml), or hepatitis C virus infection (HCV antibody positive and HCV-RNA > lower limit of detection at the research center);
11. History of severe neurological or psychiatric disorders, including but not limited to: dementia, depression, seizures, bipolar disorder, etc.;
12. Receipt of other investigational drugs or treatments within 4 weeks prior to study randomization;
13. Use of any Chinese herbal medicines with anti-tumor activity within 2 weeks prior to study drug administration;
14. History of other malignancies (excluding non-melanoma skin cancer and the following in situ cancers: bladder, gastric, colon, endometrial, cervical/dysplasia, melanoma, or breast), unless complete remission was achieved at least 2 years prior to study enrollment and no additional therapy is required or anticipated during the study period;
15. History of severe cardiac or cerebrovascular disease, e.g., New York Heart Association (NYHA) ≥ class 2 heart failure, acute coronary syndrome (such as myocardial infarction, unstable angina, etc.) within 6 months of screening, acute cerebrovascular disease (such as transient ischemic attack, cerebral infarction, cerebral hemorrhage, etc.) within 6 months of screening;
16. Thromboembolic events requiring therapeutic intervention within 6 months prior to screening, such as unstable deep vein thrombosis, arterial thrombosis, and pulmonary embolism; excluding infusion-related thrombosis;
17. Planned vaccination or vaccination with live vaccines within 28 days prior to study randomization;
18. Other conditions deemed unsuitable for participation in this clinical trial by the investigator due to comorbidities or other circumstances.