lutetium Lu 177 rofapitide tetraxetan (AAA614) / Clovis, 3B Pharma, Novartis - LARVOL DELTA

Plenary 1 : THERANOSTICS: The Next Level (EANM 2026) - "Appreciate the current clinical trial evidence, spanning both novel-target monotherapy and combination strategies (UpFrontPSMA, PRINCE, PEACE-3, PROQURE, FAP-2286 phase II, and others), across disease stages...Discuss practical challenges (toxicity, sequencing, patient selection) common to both novel-target and combination approaches. After attending this session, participants will be able to:"

Heterobivalent fibroblast activation protein-targeted Radiotheranostic ligands integrating cyclic peptide and small-molecule motifs for enhanced tumor retention. (PubMed, Bioorg Chem) - "Notably, the therapeutic analog [177Lu]Lu-5 displayed the most favorable tumor-to-kidney area under the curve ratio and achieved significantly improved tumor growth inhibition compared with [177Lu]Lu-FAP-2286. Overall, ligand 5 shows promise as an FAP-targeted radiotheranostic agent and demonstrates potential for further translational development."

Journal • Oncology

Combined 177Lu-FAP-2286 Therapy and Chemotherapy in Extraskeletal Ewing Sarcoma With Multiple Metastases. (PubMed, Clin Nucl Med) - "A 23-year-old man with metastatic extraskeletal Ewing sarcoma, who was unable to tolerate standard-dose chemotherapy, received 1 cycle of 177Lu-FAP-2286, followed by 2 cycles of reduced-dose ifosfamide/epirubicin/mesna chemotherapy. The patient remained symptom-free at 2 months. This case suggests that 177Lu-FAP-2286 combined with chemotherapy may have clinical utility in advanced Ewing sarcoma."

Journal • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor

177Lu-FAP-2286 Targeted Radionuclide Therapy in Advanced Pancreatic Cancer: A Real-World Retrospective Salvage Study. (PubMed, Clin Nucl Med) - "177Lu-FAP-2286 demonstrated favorable safety and meaningful symptom palliation in refractory pancreatic cancer, supporting further clinical investigation as a salvage therapeutic option."

Journal • Real-world evidence • Retrospective data • Hematological Disorders • Oncology • Pain • Pancreatic Cancer • Solid Tumor

Combined 177Lu-FAP-2286 Therapy and Immunotherapy in Metastatic Esophageal Squamous Cell Carcinoma. (PubMed, Clin Nucl Med) - "The patient then received two cycles of 177Lu‑FAP‑2286 in combination with camrelizumab. The 68Ga-FAP-2286 PET/CT imaging demonstrated significant diminution of the lesions, with no severe adverse reactions observed."

Journal • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma

177Lu-FAP-2286 Therapy in a Patient of Advanced Metastatic Malignant Solitary Fibrous Tumor. (PubMed, Clin Nucl Med) - "This case report describes a 22-year-old man with an intracranial malignant solitary fibrous tumor. After 3 courses of 177Lu-FAP-2286 therapy, 68Ga-FAP-2286 PET/CT revealed partial tumor regression, with the patient reporting no adverse reactions."

Journal • Oncology

Head-to-Head Comparison of Monomeric, Homodimeric, and Heterodimeric Fibroblast Activation Protein-Targeting Radioligands Based on Small Molecule Inhibitor and Cyclic Peptide. (PubMed, ACS Pharmacol Transl Sci) - "Among these, a small molecule FAP inhibitor (FAPI), [68Ga]-Ga-FAPI-46, and a cyclic peptide-based FAP-targeting radioligand, [177Lu]-Lu-FAP-2286, are recognized as promising agents...Furthermore, [111In]-In-FAP-PID allowed clear visualization of tumors in the SPECT/CT studies. In conclusion, [111In]-In-FAP-PID achieved a favorable tumor-to-background ratio and higher tumor accumulation than homodimers, suggesting the utility of the heterodimeric structure based on both small molecule FAPI and cyclic peptide for FAP-targeting radioligands in tumor imaging and therapy."

Head-to-Head • Journal • Oncology

Preclinical Theranostic Study of 68Ga/177Lu/225Ac-Labeled Bicyclic Peptides Targeting Nectin‑4 in Lung Cancer. (PubMed, ACS Omega) - "[177Lu]-Lu-6 showed superior tumor retention (13% uptake) and internalization (3.5%) compared to [177Lu]-Lu-FAP-2286/N188, with sustained tumor growth suppression in xenograft models. PET/SPECT imaging revealed high tumor-to-background ratios and favorable pharmacokinetics, highlighting the potential of these agents for clinical application."

Journal • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • NECTIN4

A fibroblast activation protein degrader enhances cisplatin sensitivity in non‑small cell lung cancer. (PubMed, Oncol Rep) - "In the present study, a fibroblast activation protein (FAP) degrader (Pomalidomide‑PEG2‑FAP2286: FAP‑D) was utilized to enhance cisplatin sensitivity in NSCLC. In conclusion, the study demonstrated that FAP‑D can enhance the cisplatin sensitivity of H1299 cells and NSCLC tumors. The present findings shed new light into promising treatment strategies and demonstrated the potential clinical utility of cisplatin + FAP‑D for NSCLC treatment."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CASP3 • DPP4

Targeting Fibroblast Activation Protein with [177Lu]Lu-FAP-2286 in Patients with Advanced Solid Tumors in the Phase I LuMIERE Trial. (PubMed, Clin Cancer Res) - P1/2 | "177Lu-FAP-2286 was well tolerated in patients with advanced solid tumors. The safety and preliminary efficacy findings support its continued development in phase II."

Clinical • Journal • P1 data • Oncology • Solid Tumor

From animal to human: pros and cons of different translational dosimetry methodologies to predict human dosimetry and select first-in-human (FiH) escalation starting activity (SNMMI 2026) - "Of the methods evaluated in this study, PBPK modeling relies on information about species-specific physiology and compound properties and provides the most-informed AD projection. The PBPK approach yielded the best human AD estimates for red marrow with all three compounds and for kidneys in most cases. When preclinical bioD showed single‑organ uptake (e.g., mouse kidney uptake for 177 Lu‑PSMA‑617), PBPK leveraged human protein IHC data to assign appropriate organ target concentrations and generated more accurate organ AD predictions."

First-in-human • P1 data • FOLH1

From animal to human: pros and cons of different translational dosimetry methodologies to predict human dosimetry and select first-in-human (FiH) escalation starting activity (SNMMI 2026) - "Of the methods evaluated in this study, PBPK modeling relies on information about species-specific physiology and compound properties and provides the most-informed AD projection. The PBPK approach yielded the best human AD estimates for red marrow with all three compounds and for kidneys in most cases. When preclinical bioD showed single‑organ uptake (e.g., mouse kidney uptake for 177 Lu‑PSMA‑617), PBPK leveraged human protein IHC data to assign appropriate organ target concentrations and generated more accurate organ AD predictions."

First-in-human • P1 data • FOLH1

From animal to human: pros and cons of different translational dosimetry methodologies to predict human dosimetry and select first-in-human (FiH) escalation starting activity (SNMMI 2026) - "Of the methods evaluated in this study, PBPK modeling relies on information about species-specific physiology and compound properties and provides the most-informed AD projection. The PBPK approach yielded the best human AD estimates for red marrow with all three compounds and for kidneys in most cases. When preclinical bioD showed single‑organ uptake (e.g., mouse kidney uptake for 177 Lu‑PSMA‑617), PBPK leveraged human protein IHC data to assign appropriate organ target concentrations and generated more accurate organ AD predictions."

First-in-human • P1 data • FOLH1

A Phase 1a/1b Dose-Escalation and Expansion Study of [¹77Lu]Lu-FAP-2286 Radioligand Therapy in Combination with Dual Immune Checkpoint Blockade (Nivolumab and Ipilimumab) in Patients with Unresectable or Advanced Malignant Pleural Mesothelioma (MPM) (ANZCTR) - P1 | N=50 | Not yet recruiting | Sponsor: South Metropolitan Health Service

Checkpoint inhibition • New P1 trial • Malignant Pleural Mesothelioma • Mesothelioma • Neutropenia • Oncology • Pleural Mesothelioma • Solid Tumor • FAP

The evolving role of targeted radioligand therapy in small cell and non-small cell lung cancer: a systematic review. (PubMed, Explor Target Antitumor Ther) - "In NSCLC, fibroblast activation protein (FAP)-targeted agents such as [177Lu]Lu-FAP-2286 demonstrated partial metabolic responses, including a 44.4% response rate and 78% disease control in a mixed cohort...Early efficacy signals exist for strong somatostatin receptor (SSTR)-targeted therapy in SCLC and FAP-targeted therapy in NSCLC, but evidence remains limited. Prospective trials with standardized protocols and dosimetry are needed to define TRT's role in lung cancer treatment."

Journal • Review • Genito-urinary Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Prostate Cancer • Small Cell Lung Cancer • Solid Tumor • SSTR

Novel Covalent FAP-Targeted [68Ga]Ga-DOTA-mFS-KERERG-FAP-2286 for Improved Pharmacokinetics and Enhanced Tumor Uptake. (PubMed, Mol Pharm) - "The potential diagnostic value of [68Ga]Ga-DOTA-mFS-KERERG-FAP-2286 lies in its design as a derivative of the DOTA-FAP-2286 scaffold, incorporating a sulfur(VI) fluoride exchange (SuFEx)-based covalent warhead and a hydrophilic polypeptide. This modification is anticipated to alter the pharmacokinetic profile, leading to enhanced tumor uptake and retention, thereby improving clinical diagnostic accuracy."

Journal • PK/PD data • Oncology • FAP

Validation of a panel of fibroblast activation protein expressing cell line derived xenograft models as a platform for the development of targeted radioligand therapeutics (AACR 2026) - "In this study, we evaluate target expression and compare the anti-tumor efficacy of 177Lu-FAP-2286 across multiple immunocompromised mouse models bearing subcutaneous, cell line-derived tumors. Our findings underscore the critical role of model selection in preclinical development and highlight its importance for rational decision-making in RLT programs."

Preclinical • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

Cyclotron production of 67Ga using electroplated 68Zn targets on gold and gold-coated aluminum backings. (PubMed, Appl Radiat Isot) - "The suitability of the produced [67Ga]GaCl3 for radiopharmaceutical applications was further validated by the successful synthesis of six 67Ga-labelled radioligands, namely [67Ga]Ga-PSMA-11, [67Ga]Ga-PSMA-I&T, [67Ga]Ga-FAPI-46, [67Ga]Ga-FAP-2286, [67Ga]Ga-DOTA-TATE, and [67Ga]Ga-DPI-4452. Gold-coated aluminum backings demonstrated good irradiation stability, although further optimization is required to improve reusability."

Journal

Application of ⁶⁸Ga-FXX489 (NNS309) PET/CT Imaging in Diagnosis of Tumor Diseases. (clinicaltrials.gov) - P1 | N=30 | Recruiting | Sponsor: Yi Tian | Not yet recruiting ➔ Recruiting | N=80 ➔ 30

Enrollment change • Enrollment open • Oncology

Preclinical evaluation, and clinical translation of 68Ga/177Lu-JH04, a novel FAP-targeting radiolabeled agent (AACR 2025) - "The objective of this study is to evaluate the specificity, biodistribution, pharmacokinetics, and dosimetry of 68Ga/177Lu-JH04 through preclinical and preliminary clinical investigations, and to compare these findings with those of 68Ga/177Lu-FAP-2286. The FAP-positive cell line HT1080-FAP was employed in in vitro and in vivo studies. 68Ga/177Lu-JH04, novel FAP-targeting agent with excellent binding affinity, high tumor uptake, prolonged retention, and robust tumor-suppressive effects. These promising results encourage us to conduct further clinical research."

Preclinical • Oncology • FAP

18F-FDG Uptake Outperforms 68Ga-FAP-2286 in Metaplastic Breast Carcinoma. (PubMed, Clin Nucl Med) - "Metaplastic breast carcinoma is a rare, aggressive malignancy that most commonly exhibits a triple-negative phenotype; its clinical, pathologic, and imaging diagnosis can be challenging, and treatment outcomes and prognosis are generally poor. Here, we report the discrepant imaging findings on 18F-FDG PET/CT and 68Ga-FAP-2286 PET/CT in a 47-year-old woman with metaplastic carcinoma of the breast with mesenchymal differentiation and pulmonary and lymph node metastases: tracer uptake in both the primary lesion and metastatic sites was markedly higher on 18F-FDG PET/CT than on the corresponding 68Ga-FAP-2286 PET/CT."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer

Efficacy of 177Lu-FAP-2286 and 225Ac-FAP-2286 in Treating Pancreatic Adenocarcinoma With Lymph Node Metastasis. (PubMed, Clin Nucl Med) - "Here is a case of a 37-year-old woman with poorly differentiated pancreatic adenocarcinoma with lymph node metastasis who received 1 cycle of gemcitabine plus nab-paclitaxel, but relapsed a year ago. After that, the patient received an additional 2 cycles of 225Ac-FAP-2286 treatment. A follow-up 68Ga-FAP-2286 PET/CT scan revealed complete metabolic response of the lesions, and no severe adverse reactions were reported."

Journal • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer

Revisiting the segmentation threshold for Lu-177 SPECT. (PubMed, Med Phys) - "An optimal 177Lu-specific threshold (∼50%) was derived and clinically validated, differing from the conventional 42% threshold used for 99mTc. The new threshold improved segmentation accuracy across different therapeutic radiopharmaceutical distributions."

Journal • Oncology

Dual-tracer PET/CT and cocktail therapy with [177Lu]Lu-FAP2286 and [177Lu]Lu-DOTATATE in G3 Neuroendocrine Tumors (NET). (PubMed, Eur J Nucl Med Mol Imaging) - No abstract available

Journal • Neuroendocrine Tumor • Oncology • Solid Tumor

Fibroblast Activation Protein Inhibitor Theranostics in Sarcoma: Current Evidence and Future Directions. (PubMed, Clin Nucl Med) - "Various FAPI radiotracers, including FAPI-04, FAPI-46, and FAP-2286, offer unique pharmacokinetic properties...However, challenges remain, including FAP expression heterogeneity and the need for optimized treatment protocols. The aim of this review is to provide a comprehensive overview of the current evidence and future directions of FAPI-based theranostics in sarcoma management, highlighting its potential to improve patient outcomes."

Journal • Oncology • Sarcoma • Solid Tumor • FAP