Adjuvant Immune Checkpoint Inhibitor Versus Observation After Neoadjuvant Immunochemotherapy and Surgery in High-Risk NSCLC

Although perioperative immune checkpoint inhibitor therapy has improved outcomes in patients with resectable non-small cell lung cancer, the contribution of postoperative immunotherapy following neoadjuvant immunochemotherapy remains uncertain. In particular, it is unclear whether patients with residual high-risk clinicopathologic or molecular features after complete resection derive additional benefit from adjuvant immune checkpoint inhibition.

This prospective, multicenter, randomized, open-label, phase II trial will enroll patients with completely resected non-small cell lung cancer who previously received 2 to 4 cycles of neoadjuvant immune checkpoint inhibitor therapy combined with chemotherapy and who have at least one protocol-defined high-risk feature for postoperative recurrence.

High-risk features include pathologic lymph-node involvement, postoperative pathologic T2 or higher disease, failure to achieve a major pathologic response, pleural invasion, intravascular tumor emboli, high-risk histologic components, or detectable molecular residual disease.

Eligible participants will be randomly assigned in a 1:1 ratio to receive adjuvant sintilimab or observation. Sintilimab will be administered intravenously at a dose of 200 mg every 4 weeks for up to 1 year. Participants in both groups will undergo protocol-defined surveillance for disease recurrence, survival, and adverse events.

The primary objective is to compare the 18-month disease-free survival rate between the two groups. Secondary objectives include the evaluation of disease-free survival, overall survival, and safety. Exploratory objectives include assessment of peripheral and tumor-associated immune biomarkers, T-cell responses, molecular residual disease dynamics, and their associations with clinical outcomes.

Inclusion criteria

• Male or female participants aged 18 to 75 years.
• Histologically or cytologically confirmed non-small cell lung cancer.
• Completion of 2 to 4 cycles of neoadjuvant immune checkpoint inhibitor therapy combined with chemotherapy, followed by complete (R0) surgical resection.
• At least one of the following protocol-defined high-risk features for postoperative recurrence:

• Pathologic lymph-node involvement;
• Postoperative pathologic T2 or higher disease;
• Failure to achieve a major pathologic response, defined as more than 10% residual viable tumor cells in the primary tumor;
• Pleural invasion;
• Intravascular tumor emboli;
• High-risk histologic components, including solid, micropapillary, or adenosquamous components;
• Detectable molecular residual disease.
• For participants with lung adenocarcinoma, absence of sensitizing EGFR mutations and ALK rearrangements. Molecular testing is not mandatory for participants with squamous cell carcinoma according to the current protocol.
• Eastern Cooperative Oncology Group performance status of 0 or 1.
• Adequate organ function within 7 days before randomization, as demonstrated by all of the following:

• Hemoglobin of at least 90 g/L;
• Absolute neutrophil count of at least 1.5 × 10^9/L;
• Platelet count of at least 75 × 10^9/L;
• Total bilirubin no greater than 1.5 times the upper limit of normal;
• Alanine aminotransferase and aspartate aminotransferase no greater than 2.5 times the upper limit of normal;
• Serum creatinine no greater than 1.5 times the upper limit of normal or creatinine clearance of at least 60 mL/min;
• Left ventricular ejection fraction of at least 50%;
• International normalized ratio or prothrombin time no greater than 1.5 times the upper limit of normal.
• Women of childbearing potential must have a negative pregnancy test within 7 days before the first dose and must agree to use effective contraception during the study and for 3 months after the last dose of study treatment. Male participants with partners of childbearing potential must agree to use effective contraception during the study and for 8 weeks after the last dose.
• Ability to understand the study requirements, willingness to provide written informed consent, and ability to comply with study treatment and follow-up procedures.

Exclusion criteria

• Small cell lung cancer or non-small cell lung cancer containing a small cell carcinoma component.
• Incomplete resection, including R1 or R2 resection, or salvage surgery.
• Clinically significant malnutrition as determined by the investigator.
• A history of clinically significant immune-related adverse events during prior treatment, including grade 3 or higher immune-mediated pneumonitis, myocarditis, or another serious immune-related adverse event that, in the investigator's judgment, makes further immune checkpoint inhibitor therapy unsafe.
• Signs, symptoms, or a known history of clinically significant interstitial lung disease.
• Any severe or uncontrolled concurrent medical condition, including:

• Inadequately controlled hypertension;
• Grade 2 or higher myocardial ischemia, myocardial infarction, clinically significant arrhythmia, corrected QT interval of at least 480 milliseconds, or New York Heart Association class II or higher heart failure;
• Active or uncontrolled infection of grade 2 or higher;
• Decompensated liver disease, active hepatitis, or chronic viral hepatitis requiring antiviral therapy;
• Renal failure requiring hemodialysis or peritoneal dialysis;
• Known human immunodeficiency virus infection, another acquired or congenital immunodeficiency disorder, or a history of organ transplantation;
• Poorly controlled diabetes mellitus, defined as fasting blood glucose greater than 10 mmol/L;
• Urine protein of 2+ or greater with a 24-hour urinary protein level greater than 1.0 g;
• Clinically significant coagulation abnormalities or an increased risk of bleeding;
• A seizure disorder requiring treatment.
• A concurrent active malignancy, except for malignancies specifically permitted by the final protocol.
• An active autoimmune disease or another immune-mediated disease requiring systemic treatment.
• Long-term treatment with systemic immunosuppressive therapy or systemic corticosteroids, except for protocol-permitted physiologic replacement therapy.
• An active psychiatric disorder, cognitive impairment, or another condition that would prevent provision of informed consent or adherence to study treatment and follow-up.
• Any other condition that, in the investigator's judgment, makes the participant unsuitable for the study.