Adjusting Treatment Before Surgery for Non-Small Cell Lung Cancer Using Blood and Scan Results

Trial details

Who runs it

Peking University People's Hospital

Trial code

NCT07885709

Record updated

21 October 2026

Original description

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.Read full original descriptionShow less

ctDNA-MRD and Imaging Response-Guided Adaptive Escalation of Neoadjuvant Therapy in Resectable and Borderline Resectable Non-Small Cell Lung Cancer: A Single-Arm, Proof-of-Concept Study

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: Voluntary participation with signed informed consent; 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; 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; 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; Age ≥18 years, either sex; Eastern Cooperative Oncology Group (ECOG) performance status 0-1; Adequate cardiac function with left ventricular ejection fraction (LVEF) >50%; Adequate pulmonary function (FEV1 >1.5 L and DLCO >50%) to tolerate definitive lung cancer resection; 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; Adequate renal function with glomerular filtration rate >60 mL/min; Adequate hepatic function: total bilirubin <1.5× upper limit of normal (ULN), aspartate aminotransferase (AST) <3× ULN, and alanine aminotransferase (ALT) <3× ULN; Presence of at least one measurable lesion per RECIST 1.1; Women of childbearing potential must have a negative serum pregnancy test within 3 days prior to enrollment and agree to use effective contraception during study treatment and for 120 days after the last dose. Women of childbearing potential are defined as sexually mature women who (1) have not undergone hysterectomy or bilateral oophorectomy and (2) have not been naturally postmenopausal for 12 consecutive months (cancer-therapy-related amenorrhea does not preclude childbearing potential).

Exclusion: Active hepatitis B or C requiring antiviral therapy; patients with hepatitis B must have HBV-DNA <500 IU/mL and have received at least 14 days of anti-HBV therapy prior to enrollment, with treatment continued during the study; patients with positive HCV RNA are excluded; Prior allogeneic stem cell or solid organ transplantation; Severe or active infection requiring systemic therapy within 4 weeks prior to enrollment, including but not limited to active pulmonary tuberculosis, bacterial infection requiring intravenous antibiotics, active fungal infection, or known human immunodeficiency virus (HIV) infection (HIV antibody positive); Major surgery within 4 weeks prior to enrollment (excluding minimally invasive diagnostic procedures such as diagnostic biopsy, percutaneous lung puncture, EBUS-TBNA, or central venous catheterization), or presence of an unhealed surgical incision, ulcer, or fracture; Prior or concurrent other malignancy (cured low-risk tumors such as basal cell carcinoma, squamous cell carcinoma of the skin, cervical carcinoma in situ, or papillary thyroid carcinoma may be enrolled if, per investigator judgment, they do not affect efficacy or safety evaluation); Receipt of a live or live-attenuated vaccine within 30 days prior to enrollment; Active autoimmune disease or a history of autoimmune disease that may recur, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, autoimmune thyroid disease (adequately controlled hypothyroidism on stable hormone replacement may be permitted), type 1 diabetes mellitus, multiple sclerosis, vasculitis, or glomerulonephritis; Known allergy to carboplatin, paclitaxel, nab-paclitaxel, pemetrexed, or other chemotherapeutic agents; History of allergy to monoclonal antibody drugs; Known allergy to anlotinib or any of its excipients; Psychiatric disorders or any other condition that would preclude compliance with treatment; Known active or uncontrolled interstitial lung disease (ILD) or pulmonary fibrosis, or screening imaging suggestive of ILD/non-infectious pneumonitis requiring corticosteroids, or a history of ILD/non-infectious pneumonitis requiring corticosteroid treatment; Any comorbidity or other condition that, in the investigator's judgment, may affect protocol compliance or render the patient unsuitable for participation; Severe cardiovascular disease, including but not limited to: myocardial infarction, unstable angina, cerebrovascular accident (cerebral infarction or hemorrhage), or transient ischemic attack within 6 months prior to enrollment; New York Heart Association (NYHA) class ≥2 congestive heart failure; severe arrhythmia requiring medication (e.g., sustained ventricular tachycardia, or atrial fibrillation with rapid ventricular rate poorly controlled by medication); uncontrolled hypertension (systolic ≥150 mmHg and/or diastolic ≥95 mmHg) despite standard antihypertensive treatment; congenital long QT syndrome, or prolonged Fridericia-corrected QT interval (QTcF) on screening (males >450 ms, females >470 ms); Clinically significant bleeding risk or coagulation abnormality, including: known bleeding diathesis (e.g., hemophilia, von Willebrand disease) or hereditary coagulation disorders; grade ≥2 hemoptysis (single episode ≥2.5 mL) or grade ≥3 bleeding at other sites within 3 months prior to enrollment; clinically significant gastrointestinal bleeding within 4 weeks prior to enrollment; ongoing full-dose anticoagulation (e.g., warfarin, heparins, direct oral anticoagulants) that cannot be suspended or bridged to low-molecular-weight heparin during the study (patients on prophylactic low-dose anticoagulation may be eligible per investigator judgment); use of aspirin (>325 mg/day) or other platelet-inhibiting nonsteroidal anti-inflammatory drugs (NSAIDs) within 10 days prior to enrollment; imaging showing tumor invasion of or proximity to a major vessel with investigator-assessed bleeding risk; Inability or unwillingness to provide signed informed consent; Pregnancy or breastfeeding.

ClinicalTrials.gov NCT07885709