Nutritional + Usual Corticosteroids Randomized Trial for Immune-Related pneumoniA - Therapeutic Utilization Evaluation

BACKGROUND:

Immune checkpoint inhibitor-related pneumonitis (CIP) accounts for the largest proportion of fatal immune-related adverse events. Approximately 30% of patients respond poorly to corticosteroid therapy, and long-term high-dose steroids increase the risk of secondary infection. Oxidative stress plays a key role in pulmonary fibrosis. The investigational nutritional products have demonstrated antioxidant and immunomodulatory properties in preclinical and clinical studies.

OBJECTIVES:

Primary: To evaluate the efficacy of nutritional therapy combined with glucocorticoids versus glucocorticoids alone in treating CIP, as measured by time to pneumonitis downgrading and the 3-month downgrading rate.

Secondary: To evaluate safety (AE/SAE incidence, severity), total steroid dose and duration, and changes in 6-minute walk distance (6MWD), modified Medical Research Council dyspnea scale (mMRC), St George's Respiratory Questionnaire (SGRQ), and Leicester Cough Questionnaire (LCQ).

Exploratory: To analyze the relationship between treatment response and changes in T-cell subsets, inflammatory cytokines (IL-1 beta, IL-6, IL-10), KL-6, ALC, CD4+ Th1/Th17, Tregs, NLR, AEC, and gut microbiome.

STUDY DESIGN:

Sixty eligible participants will be randomized 1:1 to:

• Experimental arm: Spirulina-Bifidobacterium capsules 1080 mg twice daily orally, fish oil-grape seed-blueberry soft capsules 1200 mg twice daily orally, and Ganoderma spore oil 800 mg twice daily orally, plus methylprednisolone (dose and tapering per investigator assessment, referencing NCCN Guidelines 2025 v1).
• Control arm: Matching placebo orally plus methylprednisolone (per NCCN Guidelines 2025 v1), tapered until symptoms and imaging improve and then discontinued.

Pneumonitis imaging (chest X-ray or CT) will be assessed at baseline and on Days 3, 7, 14, 28, 42, and 56, and at 2-3 months post-treatment, with additional imaging as clinically indicated. Pneumonitis grade will be determined by an Independent Radiologic Review Committee (IRRC) blinded to treatment allocation.

PARTICIPANTS:

Adults 18-75 years of age with histologically or cytologically confirmed malignancy, who have received at least one cycle of immune checkpoint inhibitor therapy, and who develop Grade 3-4 CIP per CTCAE v5.0 and radiologic grading.

FOLLOW-UP:

All participants will be followed for 2 years or until death, with contacts every 90 (plus or minus 7) days.

Inclusion criteria

• Voluntary participation with full understanding of the study and signed informed consent form.
• Age 18 to 75 years (inclusive) on the day of informed consent signing.
• Histologically or cytologically confirmed malignancy.
• Received at least one cycle of immune checkpoint inhibitor therapy.
• Grade 3-4 immune-related pneumonitis (per CTCAE v5.0 and radiologic grading).
• ECOG performance status 0-2, with expected survival of more than 3 months.
• Adequate organ function based on laboratory results (without transfusion, apheresis, erythropoietin, or granulocyte colony-stimulating factor support within 14 days before the first dose). Women of childbearing potential must have a negative serum pregnancy test within 7 days before first dose.

Exclusion criteria

• Severe cardiac, cerebrovascular, renal, hematologic, or other serious systemic disease, including: NYHA Class III-IV heart failure; acute myocardial infarction or unstable angina within 6 months; severe post-stroke functional impairment (mRS greater than or equal to 3); progressive neurodegenerative disease; Child-Pugh Class B or C liver disease or acute liver failure; CKD stage 4-5 (eGFR less than 30 mL/min/1.73 m2) or requiring dialysis; absolute neutrophil count less than 1.5 x 10^9/L, platelet count less than 50 x 10^9/L, or Grade 3 or higher anemia (Hb less than 8 g/dL).
• Severe allergic constitution or contraindications to the study treatment.
• Significant psychiatric or psychological disorder, or doubts about the treatment plan.
• Investigator judgment that the patient is unsuitable for the trial (e.g., poor follow-up adherence, refusal of supportive care).
• Use of anti-tumor traditional Chinese medicine within 14 days before first dose.
• History of or active inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).
• Severe acute or chronic infection.
• Known alcohol or drug abuse history.
• Pregnancy or breastfeeding.
• Use of antibiotics, probiotic food, or microecological preparations within 2 weeks before enrollment.
• Prior treatment-related lung injury: (a) targeted-therapy-related pulmonary toxicity (prior EGFR-TKI, ALK inhibitor, VEGF inhibitor, or antibody-drug conjugate causing interstitial lung disease or pneumonitis that has not fully resolved, with radiologic fibrosis or persistent functional impairment); (b) thoracic radiation-related lung injury (radiation pneumonitis or radiation fibrosis with irreversible CT findings).
• Use of another investigational drug within 28 days before first dose that, per investigator judgment, would interfere with evaluation of study treatment.
• Gastrointestinal disorder precluding oral administration.