MRD and Imaging Guided Adaptive Neoadjuvant Therapy for Resectable NSCLC

• PD-1 inhibitor (Drug), also known as Nivolumab (Opdivo), Pembrolizumab (Keytruda), Toripalimab (Tuoyi), Tislelizumab (Tevimbra): One of four PD-1 inhibitors selected per patient: nivolumab 360 mg, pembrolizumab 200 mg, toripalimab 240 mg, or tislelizumab 200 mg, administered by intravenous infusion once every 3 weeks
• Carboplatin (Drug): AUC 5 by intravenous infusion on day 1 of each 21-day cycle
• Nab-paclitaxel (Drug): 100 mg/m² by intravenous infusion on days 1 and 5 of each 21-day cycle. Used for squamous histology throughout all cycles, and for non-squamous histology in the treatment-escalation group (cycles 3-4), where it replaces pemetrexed
• Pemetrexed (Drug): 500 mg/m² by intravenous infusion on day 1 of each 21-day cycle (non-squamous histology). In the treatment-escalation group, pemetrexed is replaced by nab-paclitaxel during cycles 3-4
• Anlotinib (Drug): 12 mg orally once daily on days 1-14 of each 21-day cycle; added during cycles 3-4 in the treatment-escalation group

Primary outcomes

• Pathological complete response (pCR) rate in the treatment-escalation population [At the time of definitive surgery, approximately 13 to 18 weeks after initiation of neoadjuvant therapy]: pCR is defined as the absence of residual viable tumor cells in the primary lung tumor and all sampled regional lymph nodes upon systematic pathological review of the surgical specimen, per the IASLC 2020 pathological evaluation criteria. The treatment-escalation population comprises patients with ctDNA non-clearance and radiological stable disease (SD) after two cycles of neoadjuvant therapy.

Secondary outcomes

• Major pathological response (MPR) rate in the treatment-escalation population [At the time of definitive surgery, approximately 13 to 18 weeks after initiation of neoadjuvant therapy]: MPR is defined as ≤10% residual viable tumor cells in the primary lung tumor and regional lymph nodes upon pathological review of the surgical specimen; carcinoma in situ is excluded from the MPR calculation. The treatment-escalation population comprises patients with ctDNA non-clearance and radiological stable disease (SD) after two cycles of neoadjuvant therapy.
• Pathological complete response (pCR) rate in the intention-to-treat (ITT) population [At the time of definitive surgery, approximately 13 to 18 weeks after initiation of neoadjuvant therapy]: pCR is defined as the absence of residual viable tumor cells in the primary lung tumor and all sampled regional lymph nodes upon systematic pathological review of the surgical specimen, per the IASLC 2020 pathological evaluation criteria. The ITT population comprises all enrolled patients.
• Major pathological response (MPR) rate in the intention-to-treat (ITT) population [At the time of definitive surgery, approximately 13 to 18 weeks after initiation of neoadjuvant therapy]: MPR is defined as ≤10% residual viable tumor cells in the primary lung tumor and regional lymph nodes upon pathological review of the surgical specimen; carcinoma in situ is excluded from the MPR calculation. The ITT population comprises all enrolled patients.
• 2-year event-free survival (EFS) rate in the treatment-escalation and ITT populations [2 years]: EFS is defined as the time from initiation of neoadjuvant therapy to the first occurrence of any of the following, whichever occurs first: radiological disease progression per RECIST 1.1 precluding surgery, local or distant recurrence, or death from any cause
• 2-year overall survival (OS) rate in the treatment-escalation and ITT populations [2 years]: OS is defined as the time from initiation of neoadjuvant therapy to death from any cause.
• Objective response rate (ORR) in the treatment-escalation and ITT populations [After completion of neoadjuvant therapy (3-4 cycles; each cycle is 21 days), before definitive surgery]: Assessed per RECIST 1.1. ORR is defined as the proportion of patients achieving complete response (CR) or partial response (PR).
• Disease control rate (DCR) in the treatment-escalation and ITT populations [After completion of neoadjuvant therapy (3-4 cycles; each cycle is 21 days), before definitive surgery]: Assessed per RECIST 1.1. DCR is defined as the proportion of patients achieving complete response (CR), partial response (PR), or stable disease (SD).
• Incidence and severity of treatment-related adverse events (TRAEs) [From first dose through 90 days after the last dose of study treatment]: Adverse events graded and recorded according to NCI-CTCAE version 5.0.

Other outcomes

• ctDNA-MRD clearance rate (proportion of patients with undetectable ctDNA) at each assessment time point [At baseline (Cycle 1 Day 1), on Cycle 2 Day 14, and preoperatively on the day of surgery (each cycle is 21 days)]
• Correlation between ctDNA-MRD status (cleared vs. not cleared) and pathological response (pCR/MPR) [At the time of definitive surgery]
• Correlation between ctDNA-MRD dynamics (time to clearance, rate of decline) and EFS [From treatment initiation through follow-up, up to 2 years]

Sex: All, ages: 18 Years to any

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 <1.5× upper limit of normal (ULN), aspartate aminotransferase (AST) <3× ULN, and alanine aminotransferase (ALT) <3× ULN.
12. Presence of at least one measurable lesion per RECIST 1.1.
13. 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 Criteria:

1. 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.
2. 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.
3. Known allergy to carboplatin, paclitaxel, nab-paclitaxel, pemetrexed, or other chemotherapeutic agents.
4. History of allergy to monoclonal antibody drugs.
5. Known allergy to anlotinib or any of its excipients.
6. Prior allogeneic stem cell or solid organ transplantation.
7. 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).
8. Psychiatric disorders or any other condition that would preclude compliance with treatment.
9. Inability or unwillingness to provide signed informed consent.
10. 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).
11. 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.
12. 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.
13. Pregnancy or breastfeeding.
14. 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).
15. 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.
16. Receipt of a live or live-attenuated vaccine within 30 days prior to enrollment.
17. Any comorbidity or other condition that, in the investigator's judgment, may affect protocol compliance or render the patient unsuitable for participation.