Neoadjuvant Immunotherapy Plus Chemotherapy Followed by Concurrent Chemoradiotherapy and Consolidative Immunotherapy for Locally Advanced Non-small Cell Lung Cancer

Neoadjuvant Immunotherapy Plus Chemotherapy Followed by Concurrent Chemoradiotherapy and Consolidative Immunotherapy Compared With Concurrent Chemoradiotherapy and Consolidative Immunotherapy in Locally Advanced Non-small Cell Lung Cancer: A Randomized, Phase III Controlled Study

Consolidative immunotherapy following concurrent chemoradiotherapy, based on the PACIFIC trial, has become the standard treatment for locally advanced non-small cell lung cancer (LANSCLC), leading to a 5-year survival rate of over 40%. The optimal timing of radiotherapy combined with immunotherapy still requires further exploration. This phase III, randomized controlled clinical trial is to investigate the efficacy and safety of neoadjuvant immuno-chemotherapy followed by concurrent chemoradiotherapy and consolidative immunotherapy, compared with concurrent chemoradiotherapy and consolidative immunotherapy in LANSCLC patients.

This phase III, randomized controlled trial aims to investigate the efficacy and safety of neoadjuvant immuno-chemotherapy followed by concurrent chemoradiotherapy and consolidative immunotherapy, compared with concurrent chemoradiotherapy and consolidative immunotherapy in LANSCLC patients. Patients will be randomized in a 2:2:1 ratio to the following three groups: Group A: Patients will receive neoadjuvant chemo-immunotherapy. After neoadjuvant therapy, they will undergo hypofractionated radiotherapy (hypo-RT) and concurrent chemotherapy, followed by consolidative immunotherapy for a maximum duration of 12 months. (2) Group B: Patients will receive neoadjuvant chemo-immunotherapy. After neoadjuvant therapy, they will undergo conventionally fractionated radiotherapy (CFRT) and concurrent chemotherapy, followed by consolidative immunotherapy for a maximum duration of 12 months. (3) Group C: Patients will receive CFRT and concurrent chemotherapy, followed by consolidative immunotherapy for a maximum duration of 12 months.

Inclusion Criteria:

• Signed and Dated Informed Consent: Written informed consent must be provided prior to any study procedures, with the consent form signed and dated by the participant.
• Age Range: Male or female patients aged 18 to 75 years.
• Diagnosis: Patients must have locally advanced, unresectable (stage III) non-small cell lung cancer (NSCLC), with histological or cytological confirmation of the diagnosis.
• Previous Treatment: Patients must not have received prior chemotherapy, radiotherapy, surgery, targeted therapy, or immunotherapy.
• Tumor Sample Requirement: Tumor tissue samples must be provided, and they should be sufficient for analysis. The samples must be unstained and archived.
• Life Expectancy: Patients must have an expected survival of at least 12 weeks.
• Performance Status (PS): The patient's WHO Performance Status (PS) must be 0 or 1.
• Pregnancy Testing: Postmenopausal women, or women who have had a negative urine or serum pregnancy test within 14 days before the study medication (HCG sensitivity ≥ 25 IU/L or equivalent).
• Breastfeeding: Women must not be breastfeeding.
• Women of childbearing potential (WOCBP) must agree to use contraception during the study treatment period and for 5 months after the last dose of the investigational drug (i.e., 30 days [ovulation cycle] + approximately 5 half-lives of the study drug).
• Men who have sexual relations with WOCBP must agree to use contraception during the study treatment period and for 7 months after the last dose of the investigational drug (i.e., 90 days [sperm renewal cycle] + approximately 5 half-lives of the study drug).
• Males with no sperm production are exempt from contraception requirements. WOCBP who are not sexually active are exempt from contraception but must still undergo pregnancy testing as outlined above.
• Organ and Bone Marrow Function: The following laboratory parameters must be met:

Forced expiratory volume in 1 second (FEV1) ≥ 800 mL Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L Platelets ≥ 100 × 10⁹/L Hemoglobin ≥ 9.0 g/dL Calculated creatinine clearance using the Cockcroft-Gault formula ≥ 50 mL/min Serum bilirubin ≤ 1.5 × upper limit of normal (ULN) AST and ALT ≤ 2.5 × ULN

Exclusion Criteria:

• Patients meeting any of the following criteria should not be enrolled in the study:
• Concurrent participation in another clinical trial, except for observational (non-interventional) studies.
• Histological subtype of mixed small-cell and non-small-cell lung cancer. Use of immunosuppressive drugs within 28 days before treatment, except for intranasal or inhaled corticosteroids at physiological doses or systemic corticosteroids ≤10 mg/day of prednisone or equivalent.
• Prior treatment with anti-PD-1 or anti-PD-L1 antibodies.
• Major surgery within 4 weeks prior to enrollment (excluding procedures for vascular access).
• History or active autoimmune diseases within the past two years.
• Active or a history of inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).
• History of primary immunodeficiency.
• History of organ transplantation requiring immunosuppressive therapy.
• Average corrected QT interval (QTc) ≥470 ms calculated from three ECG cycles using the Bazett formula.
• Uncontrolled comorbidities, including but not limited to: Persistent or active infections. Symptomatic congestive heart failure. Poorly controlled hypertension. Unstable angina. Cardiac arrhythmias. Active peptic ulcer disease or gastritis. Active bleeding disorders. Hepatitis C or HIV infection. HBsAg-positive patients with HBV DNA >500 IU/mL. Mental or social conditions that may limit adherence to study requirements or compromise the ability to provide informed consent.
• Known history of tuberculosis.
• Receipt of a live attenuated vaccine within 30 days before study initiation or planned during the study period.
• History of another primary malignancy within the past 5 years, except for adequately treated basal or squamous cell carcinoma of the skin or in situ cervical cancer.
• Pregnancy, breastfeeding, or not using effective contraception (for men and women of reproductive potential).

Patients in the experimental group should not proceed to concurrent chemoradiotherapy if any of the following criteria are met:

• Presence of distant metastases.
• Locoregional progression making definitive concurrent chemoradiotherapy unfeasible due to normal tissue dose constraints (assessed by the radiation oncologist).
• WHO performance status score of 2-4.
• Impaired organ or bone marrow function, including:

Forced expiratory volume in 1 second (FEV1) <800 mL. Absolute neutrophil count (ANC) <1.5 × 10⁹/L. Platelets <100 × 10⁹/L. Hemoglobin <9.0 g/dL. Creatinine clearance (Cockcroft-Gault formula) <50 mL/min. Serum bilirubin >1.5 × upper limit of normal (ULN). AST and ALT >2.5 × ULN.

- Patient withdrawal from the study.

Patients should not proceed to consolidation immunotherapy if any of the following criteria are met:

• Disease progression during concurrent chemoradiotherapy.
• Use of immunosuppressive drugs within 28 days before the first dose of tislelizumab, except for physiological doses of intranasal or inhaled corticosteroids or systemic corticosteroids ≤10 mg/day of prednisone or equivalent. Use of corticosteroids to manage chemoradiotherapy-related toxicity is permitted.
• Persistent unresolved CTCAE grade >2 toxicities from prior chemoradiotherapy.
• Grade ≥2 pneumonitis resulting from prior chemoradiotherapy.
• Any prior grade ≥3 immune-related adverse event (irAE) or unresolved irAE > grade 1.