Toripalimab Combined With Platinum-based Chemotherapy With or Without H1 Receptor Antagonist in the Perioperative Treatment of Resectable Non-small Cell Lung Cancer

Toripalimab Combined With Platinum-based Chemotherapy With or Without H1 Receptor Antagonist (Diphenhydramine) in the Perioperative Treatment of Resectable Non-small Cell Lung Cancer: A Single-center, Randomized Controlled Phase II Clinical Trial

The goal of this clinical trial is to evaluate the efficacy and safety of H1 receptor antagonist (diphenhydramine) combined with toripalimab plus standard platinum-based chemotherapy in the perioperative setting in subjects with operable NSCLC.

The subjects of this study are patients with histologically or cytologically confirmed stage II-III NSCLC (AJCC Version 9) who are planned to receive neoadjuvant therapy with toripalimab combined with standard platinum-based chemotherapy. Eligible subjects were randomized at a 1:1 ratio to receive 3-4 cycles of neoadjuvant diphenhydramine (an H1 receptor antagonist) plus toripalimab and standard platinum-based chemotherapy, or toripalimab plus platinum-based chemotherapy alone, followed by treatment response evaluation and definitive surgery. After surgery, the experimental group will receive maintenance therapy with diphenhydramine (an H1 receptor antagonist) plus toripalimab for 13-14 cycles, while the control group will receive toripalimab monotherapy for the same 13-14 cycles.

Inclusion Criteria:

• Voluntarily participate in this study, sign the informed consent form, have good compliance, and are willing to cooperate with follow-up visits;

• Aged 18-75 years, regardless of gender;

• ECOG performance status score of 0-1;

• Expected survival time ≥ 3 months;

• - Pathologically/radiologically confirmed stage II-III NSCLC (AJCC 9th Edition). For adenocarcinoma/adenosquamous carcinoma, EGFR wild-type and ALK fusion-negative required before enrollment;

• No prior systemic anti-tumor therapy;

• At least one measurable lesion per RECIST 1.1. Previously irradiated lesions are measurable if progression is confirmed;

• Adequate organ function, as evidenced by meeting the following laboratory parameters:

  1. Absolute Neutrophil Count (ANC) ≥ 1.5 × 10⁹/L without administration of granulocyte colony-stimulating factor within the past 14 days;
  2. Platelet count ≥ 80 × 10⁹/L without blood transfusion within the past 14 days;
  3. Hemoglobin > 8 g/dL without blood transfusion or erythropoietin administration within the past 14 days;
  4. Total bilirubin ≤ 1.5 × Upper Limit of Normal (ULN);
  5. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2.5 × ULN (for subjects with liver metastasis, AST or ALT ≤ 5 × ULN is acceptable);
  6. Serum creatinine ≤ 1.5 × ULN and creatinine clearance rate (calculated by the Cockcroft-Gault formula) ≥ 60 mL/min;
  7. Adequate coagulation function, defined as International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 × ULN;
  8. Normal thyroid function, defined as Thyroid Stimulating Hormone (TSH) within the normal range. If baseline TSH is outside the normal range, subjects with total triiodothyronine (T3) (or free triiodothyronine [FT3]) and free thyroxine (FT4) within the normal range are also eligible for enrollment;
  9. Myocardial enzyme profile within the normal range;

• Females of childbearing potential: negative pregnancy test (urine/serum) within 3 days pre-first dose (Cycle 1 Day 1); serum test required if urine test unconfirmed. Non-childbearing females: postmenopausal ≥ 1 year, surgically sterile or hysterectomized;

• Subjects at risk of conception: use contraception with annual failure rate < 1% during treatment and 120-180 days post-last dose;

Exclusion Criteria:

• Lung metastases from other primary malignancies;
• Other systemic malignancies (excluding radically treated skin basal/squamous cell carcinoma or resected carcinoma in situ);
• Current or prior myasthenia gravis;
• Current or prior angle-closure glaucoma;
• Current or prior benign prostatic hyperplasia;
• Diphenhydramine allergy;
• Pyloroduodenal obstruction, peptic ulcer-induced pyloric stenosis or bladder neck stenosis;
• Prior radiation therapy meeting any: 1) ≥ 30% bone marrow irradiated within 14 days pre-treatment; 2) Lung lesion radiation > 30 Gy within 6 weeks pre-treatment (must recover from radiation toxicity to Grade ≤ 1, no glucocorticoids, no radiation pneumonitis history);
• Current participation in other interventional clinical studies, or received investigational agents/devices within 4 weeks pre-first dose;
• Systemic anti-lung cancer Chinese patent medicines or immunomodulators (thymosin, interferon, interleukin; excluding local pleural effusion control) within 2 weeks pre-first dose;
• Active autoimmune diseases requiring systemic therapy (disease-modifying drugs, glucocorticoids, immunosuppressants) within 2 years pre-first dose (replacement therapy not considered systemic);
• Ongoing systemic glucocorticoids (excluding topical) or immunosuppressants within 7 days pre-first dose (physiological doses: prednisone ≤ 10 mg/day or equivalent permitted);
• Uncontrolled pleural/peritoneal effusion (eligible if no drainage needed or effusion stable 3 days post-drainage cessation);
• Prior allogeneic organ transplantation (except corneal) or hematopoietic stem cell transplantation;
• Inadequate recovery from prior intervention toxicities/complications (not resolved to Grade ≤ 1 or baseline, excluding fatigue/alopecia);
• Known HIV infection (HIV 1/2 antibody positive);
• Other conditions deemed unsuitable by investigator;