MRD and Imaging Guided Adaptive Neoadjuvant Therapy for Resectable NSCLC

Neoadjuvant immunotherapy combined with platinum-based doublet chemotherapy has been established as the standard of care for driver-gene-negative (EGFR/ALK wild-type) stage II-IIIB non-small cell lung cancer (NSCLC), yielding pathological complete response (pCR) rates of 30-40%. Nevertheless, a substantial proportion of patients (approximately 60-70%) do not attain pCR, and strategies to further augment the pCR rate through treatment escalation remain an unmet clinical need. Accumulating evidence indicates that failure of ctDNA clearance and radiological stable disease (SD) following two cycles of neoadjuvant therapy are each robust predictors of unfavorable pathological response, and their combined assessment may enable accurate identification of the patient subset least likely to derive benefit from immunotherapy. This single-arm, proof-of-concept study will enroll patients with resectable or borderline resectable, EGFR/ALK wild-type, stage II-IIIB (N2) NSCLC. All participants will initially receive two cycles of a PD-1 inhibitor (nivolumab, pembrolizumab, toripalimab, or tislelizumab) in combination with platinum-based doublet chemotherapy. Following two cycles, patients will undergo ctDNA-MRD assessment and radiological evaluation. Patients in whom ctDNA has not cleared and whose radiological response is stable disease will be assigned to the treatment-escalation group and receive an intensified regimen comprising a PD-1 inhibitor plus anlotinib plus chemotherapy for cycles 3-4, whereas all remaining patients will continue the original regimen. Upon completion of neoadjuvant therapy, patients deemed resectable by a multidisciplinary team (MDT) will proceed to definitive surgery. The primary endpoint is the pCR rate in the treatment-escalation population. This study seeks to establish a precision escalation strategy guided by ctDNA-MRD in conjunction with imaging response, thereby providing an effective therapeutic approach for patients with NSCLC who respond poorly to immunotherapy and informing the design of subsequent confirmatory trials.

Inclusion Criteria: 1. Voluntary participation with signed informed consent. 2. Previously untreated, histologically confirmed, resectable or borderline resectable stage II-IIIA or IIIB (N2) non-small cell lung cancer, per the 8th edition AJCC staging. 3. Negative for EGFR and ALK driver alterations, confirmed by next-generation sequencing (NGS) or RT-PCR on tumor tissue; blood-based NGS permitted when tissue is insufficient. 4. Sufficient tumor tissue for PD-L1 immunohistochemistry and NGS testing, with baseline tissue reserved for construction of a tumor-informed, fixed panel for subsequent MRD detection. 5. Age ≥18 years, either sex. 6. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. 7. Adequate cardiac function with left ventricular ejection fraction (LVEF) \>50%. 8. Adequate pulmonary function (FEV1 \>1.5 L and DLCO \>50%) to tolerate definitive lung cancer resection. 9. Adequate bone marrow function: white blood cell count \>4×10⁹/L, neutrophil count \>1.5×10⁹/L, hemoglobin \>10 g/dL, and platelet count \>100×10⁹/L. 10. Adequate renal function with glomerular filtration rate \>60 mL/min. 11. Adequate hepatic function: total bilirubin \