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

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Non-Small Cell Lung Cancer; Metastatic Lung Carcinoma
• Intervention / Treatment: Drug: Yttrium-90-Labeled Fibroblast Activation Protein Inhibitor (Y-90 FAPI)

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.

• Study Type: Interventional
• Enrollment (Estimated): 10
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Muge O. Tamam, Professor; Phone Number: +90532402376; Email: mugetamam@yahoo.com
• Study Contact Backup: Name: Merve N Acar tayyar; Phone Number: +905532079693; Email: nurmacar13@gmail.com

Study Locations

• Turkey (Türkiye)
  • Istanbul, Turkey (Türkiye), 34384
    • Prof. Dr. Cemil Taşcıoğlu City Hospital
    • Contact: Muge Oner Tamam, Proffesor; Phone Number: 905324082376; Email: mugetamam@yahoo.com
    • Contact: Merve Nur Acar Tayyar, MD; Phone Number: 905532079693; Email: nurmacar13@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Y-90 FAPI Radionuclide Therapy; This single-arm study includes patients with histopathologically confirmed advanced non-small cell lung cancer (NSCLC) who are eligible for radioligand therapy. All enrolled participants will receive Yttrium-90-labeled FAPI (90Y-FAPI) administered intravenously according to the study protocol. Treatment will be performed under standardized radiation safety conditions. Patients will undergo baseline clinical and imaging evaluation prior to therapy and will be followed prospectively with clinical assessment, laboratory tests, and serial imaging (including FAPI PET/CT and/or conventional imaging) to evaluate treatment response, biodistribution, dosimetry, safety, and tolerability. Adverse events will be monitored and recorded throughout the study period in accordance with CTCAE criteria.

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.; Other Names: Y-90-labeled FAPI; Y-90 FAPI Radioligand Therapy; FAP-Targeted Radionuclide Therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
1. Safety and Tolerability	Safety and Tolerability Measure Description: Incidence and severity of treatment-related adverse events following Y-90 FAPI therapy, graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.	From first dose of Y-90 FAPI up to 6 months
Objective Tumor Response	Proportion of patients achieving complete or partial metabolic response on FDG PET/CT according to PERCIST criteria.	Baseline to 3 months after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dosimetry	Absorbed radiation dose to tumor lesions and critical organs calculated using post-therapy SPECT/CT imaging.	Within 7 days after Y-90 FAPI administration
Disease Control Rate	Proportion of patients achieving complete response, partial response, or stable disease after Y-90 FAPI therapy.	Up to 6 months
Progression-Free Survival (PFS)	Time from Y-90 FAPI administration to documented disease progression or death from any cause.	Up to 12 months
Overall Survival (OS)	Time from Y-90 FAPI therapy to death from any cause.	Up to 12 months
Correlation of FAP Expression With Treatment Response	Relationship between baseline Ga-68 FAPI PET/CT uptake values and post-treatment response outcomes.	Baseline to 3 months

Collaborators and Investigators

• Sponsor: Prof. Dr. Cemil Tascıoglu Education and Research Hospital Organization
• Collaborators: Health Institutes of Turkey

Publications and helpful links

General 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.
• 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.CCR-22-1432
• Privé 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.

Study record dates

Study Major Dates

• Study Start (Estimated): April 10, 2026
• Primary Completion (Estimated): June 15, 2027
• Study Completion (Estimated): November 15, 2027

Study Registration Dates

• First Submitted: February 28, 2026
• First Submitted That Met QC Criteria: March 24, 2026
• First Posted (Actual): March 30, 2026

Study Record Updates

• Last Update Posted (Actual): March 31, 2026
• Last Update Submitted That Met QC Criteria: March 28, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: non-small cell lung cancer; Fibroblast Activation Protein; Phase II Clinical Trial; Targeted Radionuclide Therapy; Yttrium-90 FAPI; 90Y-FAPI Radioligand Therapy
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: 49724 (Other Grant/Funding Number: Turkish Health Institutes Presidency)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No