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.
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.
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.
Single group
Spatially Fractionated Radiotherapy (SFRT)
RadiationParticipants receive lattice radiation therapy to the primary lung tumor. The gross tumor volume (GTV) is delineated, and lattice target volumes (GTV-Lattice) are generated using a hexagonal close-packed model within the tumor. Volumetric modulated arc therapy (VMAT) plans are designed. Prescription dose: GTV receives 20 Gy in 5 fractions, and GTV-Lattice receives 60 Gy in 5 fractions. After plan verification, treatment is delivered on 3 non-consecutive working days (e.g., Monday, Wednesday, Friday).
Tislelizumab
Drug200 mg administered via intravenous infusion on Day 1 of each 21-day cycle (Q3W) for 2 to 4 cycles, starting on Day 8-15 following SFRT.
Carboplatin
DrugAUC 5 administered via intravenous infusion on Day 1 of each 21-day cycle (Q3W) for 2 to 4 cycles. Used in combination with either pemetrexed (for non-squamous histology) or paclitaxel (for squamous histology), at the investigator's discretion.
Cisplatin
Drug75 mg/m² administered via intravenous infusion on Day 1 of each 21-day cycle (Q3W) for 2 to 4 cycles. Used in combination with either pemetrexed (for non-squamous histology) or paclitaxel (for squamous histology), at the investigator's discretion. Adequate hydration and antiemetic prophylaxis are required.
Pemetrexed
Drug500 mg/m² administered via intravenous infusion on Day 1 of each 21-day cycle (Q3W) for 2 to 4 cycles. Indicated only for patients with non-squamous NSCLC. Vitamin B12 and folic acid supplementation are required per standard practice.
Paclitaxel
Drug175 mg/m² administered via intravenous infusion on Day 1 of each 21-day cycle (Q3W) for 2 to 4 cycles. Indicated only for patients with squamous NSCLC. Premedication to prevent hypersensitivity is required per standard practice.
Radical Lung Resection Surgery
Procedure/SurgeryDefinitive radical surgery is performed 4 to 6 weeks (±7 days) after the last dose of neoadjuvant therapy. Surgical approaches include minimally invasive techniques (video-assisted thoracoscopic surgery \[VATS\] or robotic-assisted surgery) or open thoracotomy. Procedures include lobectomy, bilobectomy, pneumonectomy, or sleeve resection, combined with ipsilateral systematic mediastinal lymph node dissection.
Major Pathological Response (MPR) Rate
MPR is defined as the proportion of participants with ≤10% viable tumor cells remaining in the resected primary tumor specimen. Assessment method: based on the longest diameter (a cm) of the gross tumor, at least one pathological section per cm is stained with H\&E; the percentages of viable tumor cells, necrosis, stroma, and inflammatory cells are calculated for each section, and the average percentage of viable tumor cells is derived. MPR is achieved when this average is ≤10%.
1-Year Event-Free Survival (EFS) Rate
EFS is defined as the time from enrollment to the first occurrence of any of the following events: (a) disease progression per RECIST v1.1 before surgery precluding resection; (b) local disease progression preventing surgery; (c) postoperative local, regional, or distant recurrence; or (d) death from any cause. The 1-year EFS rate will be estimated using the Kaplan-Meier method.
Pathological Complete Response (pCR) Rate
pCR is defined as the absence of residual invasive viable tumor cells in both the resected primary tumor and all sampled regional lymph nodes (i.e., ypT0/Tis ypN0) upon pathological evaluation.
Objective Response Rate (ORR)
ORR is defined as the proportion of participants whose best overall response is either Complete Response (CR) or Partial Response (PR) per RECIST v1.1.
Disease Control Rate (DCR)
DCR is defined as the proportion of participants whose best overall response is CR, PR, or Stable Disease (SD) per RECIST v1.1.
Non-delayed Surgery Rate
Defined as the proportion of participants who undergo surgery within ≤42 days from the completion of neoadjuvant therapy (i.e., last dose of study drug).
Surgical Complication Rate
Defined as the proportion of participants who experience intraoperative or perioperative complications of Grade ≥3 or serious complications.
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