D-BACE in Combination With Chemotherapy and Camrelizumab for Resectable II-IIIA or Potentially Resectable T3-4N2 Stage IIIB NSCLC

This study is a single-arm prospective single-center phase II study. Forty-six patients with untreated resectable stage II-IIIA or potentially resectable T3-4N2 stage IIIB NSCLC will be included in this prospective study, using a Simon two-stage optimal design. The aim of this study is to evaluate the major pathological response (MPR) rate and safety of D-BACE combined with neoadjuvant chemotherapy and camrelizumab in patients with resectable stage II-IIIA or potentially resectable T3-4N2 stage IIIB NSCLC. MPR is defined as no more than 10% residual viable tumor cells in the primary tumor bed upon comprehensive pathological assessment. The treatment regimen is 3 cycles of D-BACE (epirubicin 50 mg loaded on DCB microspheres) combined with chemotherapy and camrelizumab (the specific chemotherapy regimen is determined by the investigator, and generally platinum-based doublet chemotherapy is used, such as pemetrexed [500 mg/m²] plus carboplatin [AUC=5] for non-squamous carcinoma, or albumin-bound paclitaxel [260 mg/m²] plus carboplatin [AUC=5]). Adverse events will be monitored throughout the trial and their severity will be graded according to the NCI CTCAE, version 5.0. At the same time, tissue and blood samples will be dynamically collected during the treatment for related translational research exploration.

Patients could discontinue the regimen if:

• Having comorbidities that significantly affect the assessment of clinical status or require discontinuation of protocol treatment (investigator's discretion);
• Unacceptable treatment toxicity;
• Disease recurrence or new primary invasive malignancy;
• At patient's request.

4.1 Screening

Subjects will complete whole-body PET-CT and contrast-enhanced brain MR before enrollment to determine stage II-IIIB NSCLC. Patients are required to obtain adequate tissue or cell pathological diagnosis, relevant immunohistochemistry, PD-L1 protein immunohistochemistry and NGS testing before enrollment. At the same time, peripheral blood will be collected before treatment for exploratory clinical research. Tumor tissue is provided in newly obtained formalin-fixed specimens (preferred) or in old formalin-fixed paraffin-embedded specimens from sites not irradiated prior to biopsy. Tumor tissue must be archived before treatment (tissue blocks, slides ≤6 months old, or recently fresh tumor biopsy slides submitted to the local study center). PD-L1 status is determined as follows:

PD-L1 positive: defined as ≥1% tumor cell membrane staining positive in at least 100 evaluable tumor cells.

PD-L1 negative: defined as <1% tumor cell membrane staining positive in at least 100 evaluable tumor cells.

PD-L1 nonevaluable/ambiguous: defined as subjects with insufficient sample quantity or quality to determine PD-L1 status by staining, or subjects with adequate tissue sample but still unable to determine PD-L1 status, who are classified together with PD-L1-negative subjects.

Screening (baseline) assessments are to be performed within 28 days before the first D-BACE.

4.2 Neoadjuvant therapy: D-BACE should be administered within 28 days of baseline screening, adopting the "watershed vascular embolization" concept. This concept defines the complete blood supply unit nourishing the lesion as the "watershed vessel," emphasizing that the therapeutic target should shift from embolizing a single vessel to managing the entire dynamic blood supply network. It is a lesion-centered, universal interventional concept that, after completing structural anatomical assessment and functional blood supply analysis, achieves layered and zonal embolization of feeding arteries in the core and peripheral watersheds to reshape the hemodynamic balance of the lesion, thereby improving treatment thoroughness, safety, and long-term efficacy.

Specific operative steps:

One vial of 300-500 μm DC Bead is loaded with 50 mg epirubicin. After full drug loading, 10-20 mL of non-ionic contrast agent is added. Under digital subtraction angiography (DSA) monitoring, femoral artery puncture is performed according to the Seldinger technique. Combined with preoperative CTA assessment of the thoracic watershed vessels supplying the tumor, the systemic circulation blood supply includes four sub-watersheds (cervical, thoracic, axillary, and abdominal regions). Cobra, MIK, single-curve, or similar angiographic catheters are used to explore the openings of tumor-feeding arteries in each sub-watershed and perform angiography to understand the distribution of feeding arteries and tumor vasculature. Microcatheter superselective cannulation into the tumor-feeding artery is recommended. During angiography, embolization, and post-embolization, the dynamic balance concept of "watershed vascular embolization" is emphasized. If systemic artery-to-pulmonary artery/pulmonary vein shunting is observed during angiography, blank microspheres, PVA, or microcoils may be used first to occlude the shunt tract. After angiography, blood supply analysis is performed, followed by layered and zonal embolization of feeding arteries in the core and peripheral watersheds. After confirming avoidance of the spinal artery, drug-loaded microspheres are injected into the tumor-feeding artery through the microcatheter for chemoembolization at a rate of 1 mL/min. Antegrade blood flow in the target embolized vessel must be maintained. If "near-stasis" is observed during injection (i.e., the columnar contrast material in the vessel disappears after 2-5 heartbeats), injection must be stopped regardless of the actual amount of microspheres injected, to avoid reflux of the embolic agent. Conversely, if "near-stasis" does not occur after the full target dose is infused, no additional embolic agents are administered. After completing embolization of all target vessels, repeat angiography of the main arterial trunk in the embolized region is performed for watershed boundary confirmation and endpoint determination. After the procedure, the arterial catheter and sheath are removed, the arterial puncture site is compressed and bandaged, and the hip joint is immobilized for more than 6 hours.

Neoadjuvant chemotherapy and camrelizumab should be administered within 7 days after D-BACE. The chemotherapy regimen is determined by the investigator, generally platinum-based doublet chemotherapy, such as pemetrexed (500 mg/m²) plus carboplatin (AUC=5) (non-squamous carcinoma), or albumin-bound paclitaxel (260 mg/m²) combined with carboplatin (AUC=5).

4.3 Local treatment (surgery, SBRT, ablation, particle or D-BACE treatment): After 3 cycles of D-BACE combined with chemotherapy and camrelizumab, PET-CT and contrast-enhanced brain MRI are performed. The subsequent treatment strategy is evaluated by a multidisciplinary team. If surgical resection is considered feasible, the specific surgical plan is determined by the surgeon. Accepted types of resection (negative margin) include lobectomy, sleeve lobectomy, bilateral lobectomy, or pneumonectomy. If the lesion cannot be completely resected or the patient cannot tolerate surgery after treatment, the radiotherapy and interventional departments will evaluate local radiotherapy, ablation, brachytherapy seeds, or D-BACE as alternative treatment options.

4.4 Adjuvant therapy after local treatment: For this study, adjuvant therapy after local treatment is determined by the investigator. The main regimens include standard 3-4 cycles of adjuvant chemotherapy or immunotherapy maintenance.

4.5 Follow-up Each subject will be monitored for adverse events for at least 30 days after the end of treatment (serious adverse events will be collected for a maximum of 90 days after the end of treatment). Tumor assessments must continue according to the protocol, and the subject will undergo post-treatment follow-up for disease status until one of the following events occurs: (1) disease progression; (2) initiation of non-investigational cancer treatment; (3) withdrawal of consent; (4) loss of follow-up; or (5) death. Before treatment, after neoadjuvant therapy, and after surgery, lung cancer early screening (SHOX2/RASSF1A/PTGER4 gene methylation detection), CAC detection, and MRD detection (at the patient's own expense) will be performed. PBMC blood tests will be completed before treatment and before neoadjuvant therapy. Evaluation is performed by computed tomography (CT) of the chest and total abdomen (with intravenous contrast enhancement, including the liver and adrenal glands and sites of suspected/known disease). Imaging evaluation is performed before each interventional embolization procedure. Postoperative baseline imaging is performed 3 months after local treatment, and then every 12 weeks (±7 days) for up to 2 years, with primary chest (contrast-enhanced) CT. It is recommended to perform head contrast-enhanced MR at least once a year. If obvious neurological symptoms occur, head contrast-enhanced MR should be performed promptly. Whole-body PET-CT is recommended once in the second postoperative year.

4.6 Postoperative Radiotherapy Postoperative radiotherapy (PORT) will be administered at the discretion of the treating oncologist according to standard of care. Based on current international and domestic phase III randomized controlled trials of postoperative radiotherapy, postoperative adjuvant radiotherapy is not routinely performed for patients with complete resection. For patients with non-R0 resection, postoperative adjuvant radiotherapy is not recommended.

4.7 Definition of end of study The start of the trial is defined as the first visit of the first subject. After 3 cycles of D-BACE combined with chemotherapy and camrelizumab, local intervention is performed within 6 weeks after assessment by imaging PET-CT and brain contrast-enhanced MRI, and subsequent adjuvant therapy is determined by the investigator. Survival follow-up continues for 5 years. The study is closed once survival follow-up is completed.