Spatially Fractionated Radiotherapy With Tislelizumab and Chemotherapy for Bulky Stage III NSCLC: A Phase II Trial

A Prospective, Single-arm, Multicenter Phase II Clinical Study to Evaluate the Efficacy and Safety of Spatially Fractionated Radiotherapy Combined With Tislelizumab and Platinum-based Doublet Chemotherapy as Induction/Conversion Therapy for Potentially Resectable Stage III Non-small Cell Lung Cancer With Bulky Disease.

This is a prospective, single-arm, multicenter phase II clinical study evaluating the efficacy and safety of spatially fractionated radiotherapy (SFRT) combined with tislelizumab and platinum-based doublet chemotherapy as induction/conversion therapy for patients with potentially resectable stage III non-small cell lung cancer (NSCLC) with bulky disease (primary tumor >5 cm).

SFRT, also known as lattice radiation therapy, is a novel radiotherapy technique that creates alternating high-dose and low-dose regions within the tumor. This approach not only reduces tumor burden but also may enhance anti-tumor immune responses, potentially working synergistically with immunotherapy.

Study participants will receive SFRT to the primary lung tumor (GTV 20 Gy/5 fractions, GTV-Lattice 60 Gy/5 fractions), followed by 2-4 cycles of tislelizumab (200 mg, Q3W) combined with platinum-based doublet chemotherapy. Surgery will be performed 4-6 weeks after the last cycle of neoadjuvant therapy. The first 6 enrolled patients will undergo dose-limiting toxicity (DLT) assessment within 21 days after the first dose of study drug.

The primary endpoint is major pathological response (MPR) rate, defined as the proportion of patients with ≤10% viable tumor cells in the resected specimen. Secondary endpoints include 1-year event-free survival (EFS), pathological complete response (pCR) rate, objective response rate (ORR), disease control rate (DCR), R0 resection rate, 1-year overall survival (OS), time to distant metastasis (TTDM), and safety.

A total of 44 patients will be enrolled across multiple centers in China. An interim analysis will be conducted after 50% of patients are enrolled.

Inclusion Criteria:

• Voluntary agreement to participate and signed written informed consent.
• Cytologically or histologically confirmed (via percutaneous lung biopsy, bronchoscopy, mediastinoscopy, etc.) bulky stage III non-small cell lung cancer (NSCLC) per AJCC 9th edition staging, with primary tumor >5 cm (T3-T4), N0-N2, and no prior chemotherapy, radiotherapy, surgery, or immunotherapy.
• Pulmonary lesion considered potentially resectable by a multidisciplinary team (MDT) including a thoracic surgeon.
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1.
• Adequate hematologic and organ function as demonstrated by:

Absolute neutrophil count ≥ 1,500 × 10⁹/L.

Platelet count ≥ 100 × 10⁹/L.

Hemoglobin > 9.0 g/dL.

Serum creatinine ≤ 1.5 × upper limit of normal (ULN) or creatinine clearance (CrCl) ≥ 40 mL/min.

AST/ALT ≤ 3 × ULN.

Total bilirubin ≤ 1.5 × ULN.

FEV1 ≥ 1.2 L or > 40% of predicted value.

INR/APTT within normal limits.

-Age 18 to 75 years (inclusive).

Exclusion Criteria:

• Has or is suspected of having an autoimmune disease. Note: patients with vitiligo, type I diabetes mellitus, or hypothyroidism (Hashimoto's thyroiditis) requiring only hormone replacement therapy may be enrolled if no significant signs of recurrence are present.
• Requires systemic corticosteroid therapy (>10 mg prednisone or equivalent per day) or other immunosuppressive agents within 14 days after enrollment. Note: inhaled or topical corticosteroids, or adrenal hormone replacement therapy (>10 mg prednisone or equivalent per day) for patients without active autoimmune disease, are permitted.
• Prior history of thoracic radiotherapy.
• Active bleeding prior to treatment.
• Severe cardiac, pulmonary, hepatic, renal, or hematopoietic dysfunction, cachexia, or any condition that would preclude tolerance to radiochemotherapy.
• History of diabetes mellitus for >10 years with poorly controlled blood glucose.
• History of interstitial lung disease or non-infectious pneumonitis.
• NSCLC with known EGFR-sensitizing mutations, ALK fusion gene, or ROS1 rearrangement.
• History of another malignancy (excluding non-melanoma skin cancer and carcinoma in situ of the bladder, stomach, colon, endometrium, cervix, melanoma, or breast) unless the malignancy has been in complete remission for ≥2 years and no additional anti-tumor therapy is required during the study period.
• In the investigator's opinion, medically, psychologically, or physically unable to complete the study or to understand the patient information.
• Prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4, or other agents targeting T-cell co-stimulation or immune checkpoint pathways.
• Active hepatitis B (HBV DNA ≥ 2000 IU/mL or ≥ 10⁴ copies/mL) or hepatitis C (anti-HCV antibody positive and HCV-RNA above the lower limit of detection).
• HIV-positive or diagnosed with acquired immunodeficiency syndrome (AIDS).
• Known or suspected allergy to the study drugs or to any agent used in this trial.
• Pregnant or breastfeeding women.