Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide and accounts for approximately 80% of all lung cancer cases. Despite advances in chemotherapy, radiotherapy, and immunotherapy, the prognosis of patients with advanced-stage metastatic NSCLC remains poor, with limited therapeutic options after the development of treatment resistance.

Fibroblast Activation Protein (FAP) is highly expressed in cancer-associated fibroblasts in a wide range of solid tumors and represents a promising target for tumor-specific theranostic approaches. Gallium-68-labeled FAPI (Ga-68 FAPI) PET/CT has recently demonstrated high sensitivity in imaging primary lung tumors and metastatic lesions.

This Phase II study aims to evaluate the safety, feasibility, dosimetry, and therapeutic efficacy of Yttrium-90-labeled FAPI (Y-90 FAPI) radionuclide therapy in patients with chemotherapy-resistant metastatic NSCLC showing significant FAP expression on Ga-68 FAPI PET/CT imaging.

Lung cancer remains the most common cause of cancer-related death globally, and non-small cell lung cancer (NSCLC) constitutes approximately 80% of all lung cancer cases. Patients with advanced or metastatic NSCLC have a particularly poor prognosis, with a 5-year survival rate of less than 10%, even among those who initially respond to systemic therapies. In patients with widespread metastatic disease, the addition of immune checkpoint inhibitors to chemotherapy and external beam radiotherapy provides only a limited survival benefit.

Fibroblast Activation Protein (FAP) is a cell surface protein expressed in up to 90% of cancer-associated fibroblasts and has emerged as a novel tumor-specific therapeutic target. Recent clinical studies have demonstrated that Ga-68 FAPI PET/CT is highly effective in visualizing primary NSCLC lesions as well as pleural, nodal, adrenal, and brain metastases.

Yttrium-90 (Y-90) is a beta-emitting radionuclide with a physical half-life of approximately 64 hours and favorable radiation characteristics for radionuclide therapy. Based on the high tumor uptake observed on Ga-68 FAPI PET/CT imaging, Y-90 FAPI is expected to selectively target FAP-expressing tumor lesions while minimizing radiation exposure to healthy tissues.

Although large-scale clinical trials investigating Y-90 FAPI therapy are currently lacking, limited case-based applications have been reported in other solid tumors, including breast cancer and osteosarcoma. This Phase II study aims to address this gap by systematically evaluating Y-90 FAPI therapy in patients with chemotherapy-resistant metastatic NSCLC.

Eligible patients will undergo Ga-68 FAPI PET/CT imaging prior to treatment. Patients demonstrating significant FAP expression in primary and metastatic tumor lesions will be selected for Y-90 FAPI radionuclide therapy. The radiolabeling of Y-90 FAPI will be performed under appropriate quality control conditions, including assessment of radiochemical purity and stability, prior to clinical administration.

Y-90 FAPI will be administered intravenously to selected patients. Patients will be followed with clinical assessments, laboratory tests, and radiological imaging. Post-therapy imaging and dosimetric evaluations will be performed using Single Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) to assess organ and tumor radiation doses. Safety and tolerability will be monitored throughout the study, and adverse events will be recorded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

This study aims to establish a novel nuclear medicine-based theranostic treatment approach for patients with metastatic NSCLC who have exhausted standard therapeutic options and to evaluate the potential of Y-90 FAPI as a safe and effective targeted radionuclide therapy.

Inclusion Criteria:

• Age ≥18 years
• Histologically confirmed diagnosis of non-small cell lung cancer (NSCLC)
• Metastatic disease
• Prior staging with F-18 FDG PET/CT
• Ga-68 FAPI PET/CT demonstrating increased tracer uptake in tumor lesions (SUVmax ≥10 in more than 50% of metastatic lesions)
• Disease progression or resistance after all standard approved therapies as determined by a multidisciplinary tumor board
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Adequate organ function:
• Serum creatinine ≤150 μmol/L
• Hemoglobin ≥8.0 g/dL
• White blood cell count ≥2.0 × 10⁹/L
• Platelet count ≥50 × 10⁹/L
• Total bilirubin ≤3 × upper limit of normal
• Serum albumin ≥2.0 g/dL
• Ability to understand and willingness to sign written informed consent

Exclusion Criteria:

• Age <18 years
• Diagnosis of small cell lung cancer
• History of another active malignancy
• Pregnancy or breastfeeding
• Severe uncontrolled medical illness that would interfere with study participation
• Refusal or inability to provide written informed consent