Yittrium-90(Y-90) Fibroblast Activation Protein Inhibitor (FAPI) Therapy in Patients With Non-Small Cell Lung Cancer (Phase II)

Official title

A Novel Therapeutic Target in Non-Small Cell Lung Cancer: Evaluation of the Efficacy of Yttrium-90 (Y-90) Fibroblast Activation Protein Inhibitor (FAPI) - A Phase II Study

Overview

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.

Detailed description

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.

Interventions

• Drug Yttrium-90-Labeled Fibroblast Activation Protein Inhibitor (Y-90 FAPI)
  Yttrium-90-labeled Fibroblast Activation Protein inhibitor (Y-90 FAPI) administered intravenously as targeted radionuclide therapy in patients with chemotherapy-resistant metastatic non-small cell lung cancer demonstrating significant FAP expression on Ga-68 FAPI PET/CT imaging.

Primary outcome measures

• 1. Safety and Tolerability [Time frame: From first dose of Y-90 FAPI up to 6 months]
• Objective Tumor Response [Time frame: Baseline to 3 months after treatment]

Secondary outcome measures (5)

• Dosimetry [Time frame: Within 7 days after Y-90 FAPI administration]
• Disease Control Rate [Time frame: Up to 6 months]
• Progression-Free Survival (PFS) [Time frame: Up to 12 months]
• Overall Survival (OS) [Time frame: Up to 12 months]
• Correlation of FAP Expression With Treatment Response [Time frame: Baseline to 3 months]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Turkey (Türkiye) · 2 centers

• Prof. Dr. Cemil Taşcıoğlu City Hospital — Istanbul
• Prof. Dr. Cemil Taşçıoğlu City Hospital — Istanbul

Publications

• Rathke H, Fuxius S, Giesel FL, Lindner T, Debus J, Haberkorn U, Kratochwil C. Two Tumors, One Target: Preliminary Experience With 90Y-FAPI Therapy in a Patient With Metastasized Breast and Colorectal Cancer. Clin Nucl Med. 2021 Oct 1;46(10):842-844. doi: 10.1097/RLU.0000000000003842. PMID 34392291
• Fendler WP, Pabst KM, Kessler L, Fragoso Costa P, Ferdinandus J, Weber M, Lippert M, Lueckerath K, Umutlu L, Kostbade K, Mavroeidi IA, Schuler M, Ahrens M, Rischpler C, Bauer S, Herrmann K, Siveke JT, Hamacher R. Safety and Efficacy of 90Y-FAPI-46 Radioligand Therapy in Patients with Advanced Sarcoma and Other Cancer Entities. Clin Cancer Res. 2022 Oct 3;28(19):4346-4353. doi: 10.1158/1078-0432.CC PMID 35833949
• Prive BM, Boussihmad MA, Timmermans B, van Gemert WA, Peters SMB, Derks YHW, van Lith SAM, Mehra N, Nagarajah J, Heskamp S, Westdorp H. Fibroblast activation protein-targeted radionuclide therapy: background, opportunities, and challenges of first (pre)clinical studies. Eur J Nucl Med Mol Imaging. 2023 Jun;50(7):1906-1918. doi: 10.1007/s00259-023-06144-0. Epub 2023 Feb 23. PMID 36813980

Identifiers

NCT: NCT07500285 · 49724 · 49724

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗