Non-Small Cell Lung Cancer
Conditions
Keywords
Non-Small Cell Lung Cancer (Stage III, Bulky Disease, Potentially Resectable)
Brief summary
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.
Interventions
Participants 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).
DRUGTislelizumab
200 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.
DRUGCarboplatin
AUC 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.
DRUGCisplatin
75 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.
DRUGPemetrexed
500 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.
DRUGPaclitaxel
175 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.
PROCEDURERadical Lung Resection Surgery
Definitive 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.
Sponsors
Sichuan Cancer Hospital and Research Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Major Pathological Response (MPR) Rate | Assessed at the time of surgical resection, performed 4-6 weeks (±7 days) after the last dose of neoadjuvant therapy. | 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%. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 1-Year Event-Free Survival (EFS) Rate | At 1 year after enrollment | 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 | At the time of surgical resection | 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) | At the pre-operative imaging assessment (within 14 days before surgery) | 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) | At the pre-operative imaging assessment (within 14 days before surgery) | DCR is defined as the proportion of participants whose best overall response is CR, PR, or Stable Disease (SD) per RECIST v1.1. |
| R0 Resection Rate | At the time of surgery | R0 resection rate is defined as the proportion of participants who undergo radical surgery and have microscopically negative margins (R0) on final pathology. |
| 1-Year Overall Survival (OS) Rate | At 1 year after enrollment | OS is defined as the time from enrollment to death from any cause. The 1-year OS rate will be estimated using the Kaplan-Meier method. |
| Time to Distant Metastasis (TTDM) | During post-operative follow-up (assessed at 1 month after surgery, then every 3 months for the first 2 years, and every 6 months for years 3-5, with chest/abdominal CT and, if indicated, brain MRI/CT) | TTDM is defined as the time from enrollment to the first documented distant metastasis. |
| Safety and Tolerability | From signing of informed consent through 90 days after the last dose (SAEs reported up to 90 days; SAEs considered related to study drugs reported beyond 90 days) | Safety endpoints include: (a) incidence, severity, and relationship to study drugs of all adverse events (AEs), treatment-emergent AEs (TEAEs), serious AEs (SAEs), and immune-related AEs (irAEs); (b) proportion of participants discontinuing treatment due to AEs; (c) changes from baseline in vital signs, physical examination findings, and laboratory parameters (hematology, serum chemistry, urinalysis, ECG, etc.). AEs will be graded according to NCI CTCAE v5.0. |
Countries
China
Contacts
CONTACTbin hu, PhD
CONTACTpeng xu, PhD
Outcome results
None listed