Translate this page into:
Targeting the Untargetable: [161Tb]Tb-FAP-2286 in Young-Onset Refractory Cholangiocarcinoma
, Vindhya Malasani1, Rakhee Vatsa2, Majid Assadi3, Habibollah Dadgar4, Hossein Arabi5, Amit Verma, Dinesh Pendharkar7
*Corresponding author: Dr. Swagat Dash, Centre for Nuclear Medicine and Molecular Theranostics, Sarvodaya Healthcare, YMCA ROAD, SECTOR 8, Faridabad, 121006, India. swagatdash08@gmail.com
-
Received: ,
Accepted: ,
How to cite this article: Dash S, Malasani V, Vatsa R, Assadi M, Dadgar H, Arabi H, Verma A, Pendharkar D.et al. Targeting the Untargetable: [161Tb] Tb-FAP-2286 in Young-Onset Refractory Cholangiocarcinoma. Indian J Nucl Med. 2026;41:237-40. doi: 10.25259/IJNM_31_2026
Abstract
Paediatric and adolescent cholangiocarcinoma (CCC) is extremely rare, and an advanced-stage diagnosis precludes surgical intervention as a primary treatment. Therefore, early diagnosis and precise staging are critical for improving patient outcomes. A pronounced desmoplastic reaction is the hallmark of cholangiocarcinoma, positioning FAPI as a promising theragnostic approach for patients unresponsive to conventional therapies. We present a case of young-onset refractory cholangiocarcinoma, refractory to multiple treatment lines, administered [161Tb]Tb-FAP-2286, exhibiting a partial response.
Keywords
Auger therapy
Cholangiocarcinoma
FAP-2286
Targeted radionuclide therapy
Terbium-161
INTRODUCTION
Paediatric and adolescent cholangiocarcinoma (CCC) is extremely rare, with an incidence rate of 0.0036/1,00,000. These cases are typically diagnosed at an advanced stage with limited treatment options.[1] Cancer-associated fibroblasts (CAFs) have emerged as potential theragnostic targets in tumours that overexpress fibroblast activation protein (FAP).[2] Radiolabelled FAPIs show superior sensitivity compared to commonly used imaging modalities in CCC, representing a potential theragnostic alternative.[2-4]
[161Tb]Tb-FAP-2286 is a beta and Auger/conversion electron-emitting radiopharmaceutical targeting overexpressed FAP receptors. Clinical studies with [161Tb]Tb-FAP-2286 are still in the nascent stage.[5] Compared with 177Lu, 161Tb delivers approximately four times higher absorbed dose per unit activity.[6,7] We report the compassionate use of [161Tb]Tb-FAP-2286 in young-onset metastatic hilar cholangiocarcinoma refractory to multiple treatment lines.
CASE REPORT
A 16-year-old male presented with jaundice, deranged liver profile and multiple liver lesions with nodal involvement on [18F]FDG PET-CT. Liver lesion FNA cytology suggested metastatic adenocarcinoma. Immunohistochemistry results were negative for Her-2, PD-L1, and MMR protein. Magnetic resonance cholangiopancreatography revealed multiple liver metastases, a porta hepatic mass with necrotic lymphadenopathy. The case was confirmed as moderately differentiated adenocarcinoma likely originating from the pancreatic-biliary tree.
Treatment profile
The patient progressed on first-line chemo-immunotherapy with gemcitabine-cisplatin-durvalumab as observed on interim [18F]FDG PET-CT [Fig 1 and 2], and severe hepatotoxicity developed on second-line treatment with FOLFOX-ipilimumabolaparib [Table 1]. Supportive care with sacituzumab was complicated by febrile neutropenia (Absolute Neutrophil Count - 0.3 × 109/L & Total Leucocyte Count - 1700/µL).
| Blood parameter | Post 2nd-line treatment | Before [161Tb]TbFAP-2286 | Post [161Tb]TbFAP-2286 (3 wks) | Post [161Tb]TbFAP-2286 (6 wks) |
|---|---|---|---|---|
| HB (13-17 gm/dl) | 7.5 | 8.9 | 8.7 | 8.5 |
| TLC (4-10 x 103 cells/mm3) | 11.15 | 10.17 | 9.8 | 10.7 |
| Platelets (150-410 x 103 cells/mm3) | 110 | 112 | 118 | 114 |
| Total bilirubin (0-1 mg/dL) | 12.6 | 10.2 | 7.3 | 9.1 |
| Aspartate aminotransferase (0-50 µ/L) | 175 | 165 | 129 | 137 |
| Alanine aminotransferase (0-50 µ/L) | 86.7 | 92.6 | 81.7 | 84.3 |
| Alkaline phosphatase (82-331 µ/L) | 929 | 898 | 683 | 689 |
| Gamma-glutamyl transferase (10-71 µ/L) | 404 | 386 | 287 | 303 |
| Total protein (6-8 gm/dL) | 5.36 | 5.52 | 5.4 | 5.39 |
| Urea (16.6-48.5 mg/dL) | 27.4 | 30.3 | 32.1 | 39.7 |
| Creatinine (0.7-1.2 mg/dL) | 0.35 | 0.42 | 0.45 | 0.89 |
| Sodium (136-145 mmol/L) | 133.7 | 134.8 | 136.4 | 136.2 |
| Serum ammonia (16-60 µmol/L) | 46.4 | 39.6 | 28.9 | 30.5 |
| Carcinoembryonic antigen (ng/mL) | 134 (Pre-treatment) | 8 | ||
| Carbohydrate antigen 19-9 (U/mL) | 40.85 (Pre-treatment) | 31 |
TLC: Total leucocyte count HB: Haemoglobin
![Maximum intensity projection (MIP) image of (A) [18F]FDG, (B) [68Ga]Ga-FAP-2286, (C) Whole-body anterior-posterior [161Tb]TbFAP2286 images at 96 h, and (D) [68Ga]Ga-FAP-2286 MIP image 6-weeks post radionuclide therapy.](/content/210/2026/41/2/img/IJNM-41-237-g001.png)
- Maximum intensity projection (MIP) image of (A) [18F]FDG, (B) [68Ga]Ga-FAP-2286, (C) Whole-body anterior-posterior [161Tb]TbFAP2286 images at 96 h, and (D) [68Ga]Ga-FAP-2286 MIP image 6-weeks post radionuclide therapy.
![(A) The fused transaxial PET-CT images of [18F]FDG (upper row), (B) [68Ga]Ga-FAP-2286 baseline (middle row), and (C) response (bottom row). Multiple tracer avid hepatic lesions and retroperitoneal lymph nodes were noted on [18F]FDG (A, Column I, II, III) with SUVmax (Ibm) 10.70 (L1), 9.67 (L2), 11.23 (L3) and LN 11.20. Corresponding lesions were observed on baseline [68Ga] Ga-FAP-2286 (B) with SUVmax 9.11 (L1), 8.64 (L2), 10.26 (L3) and LN 7.85 respectively. Reduced intensity of FAPI uptake was noted in the response evaluation [68Ga]Ga-FAP-2286 (C) with SUVmax of hepatic lesions 6.85 (L1), 5.22 (L2), 8.43 (L3) and LN 3.37. FDG: Fluorodeoxy glucose; LN: lymph node; FAPI: Fibroblast activation protein inhibitor; SUV: Standardized uptake value](/content/210/2026/41/2/img/IJNM-41-237-g002.png)
- (A) The fused transaxial PET-CT images of [18F]FDG (upper row), (B) [68Ga]Ga-FAP-2286 baseline (middle row), and (C) response (bottom row). Multiple tracer avid hepatic lesions and retroperitoneal lymph nodes were noted on [18F]FDG (A, Column I, II, III) with SUVmax (Ibm) 10.70 (L1), 9.67 (L2), 11.23 (L3) and LN 11.20. Corresponding lesions were observed on baseline [68Ga] Ga-FAP-2286 (B) with SUVmax 9.11 (L1), 8.64 (L2), 10.26 (L3) and LN 7.85 respectively. Reduced intensity of FAPI uptake was noted in the response evaluation [68Ga]Ga-FAP-2286 (C) with SUVmax of hepatic lesions 6.85 (L1), 5.22 (L2), 8.43 (L3) and LN 3.37. FDG: Fluorodeoxy glucose; LN: lymph node; FAPI: Fibroblast activation protein inhibitor; SUV: Standardized uptake value
The depletion of all viable treatment option, lead to assessment of FAP avidity for possible FAP-2286 peptide targeted radionuclide therapy (PTRT). [68Ga]Ga-FAP-2286 PET-CT revealed extensive foci of abnormal uptake involving hepatic parenchyma (tumour to background ratio 7.54) on maximum intensity projection and trans axial fused images [Fig 1 ad 2]. Considering the disease burden and exhaustion of all conventional treatment options, PTRT was recommended by the tumour board on compassionate grounds. Because of the limited availability of 225Ac and higher tumour absorbed dose compared with 177Lu radiopharmaceuticals, [161Tb] TbFAP2286 was chosen.
[161Tb]Tb-FAP-2286 administration
After obtaining approvals from the Institutional Ethics Committee and written informed consent from the patient, in-house prepared [161Tb]Tb-FAP-2286 (5.55 GBq, RCP >99%) was administered via slow intravenous infusion.
Safety and biodistribution assessment
The patient remained hemodynamically stable during and after infusion. No treatment-related early or delayed adverse reactions or CTCAE v5. 0 adverse events were observed during 8 weeks follow-up. Detailed follow-up blood parameters are presented in Table 1. Post-therapy whole-body SPECT-CT imaging at different time points demonstrated appropriate distribution of [161Tb]Tb-FAP-2286 [Fig. 1] with adequate retention in pathological lesions.
Dosimetry
OLINDA/EXM-based dosimetry calculations were performed on SPECT-CT images at 2 h, 24 h, 48 h, and 96 h post-administration of [161Tb]Tb-FAP-2286. Organs at risk included the kidneys and liver, while target lesions comprised three hepatic lesions (baseline SUVmax 9.11, 8.64, 10.26) and one retroperitoneal lymph node (SUVmax 7.85). Targeted efficacy was confirmed by higher tumour-to -organ dose [Table 2], and the dose-limiting organ was the kidneys.
| Organs/Metastases | AD (Gy) | AD (Gy/GBq) |
|---|---|---|
| Kidneys | 1.475 | 0.295 |
| Liver | 0.424 | 0.0865 |
| Hepatic lesion-1 | 13.8 | 2.76 |
| Hepatic lesion-2 | 4.043 | 0.825 |
| Hepatic lesion-3 | 3.04 | 0.621 |
| Retroperitoneal lymph node | 2.1 | 0.42 |
AD:Absorbed dose, Gy: Gray, Gy/Bq: Gray/Becquerel
Response assessment
Improved appetite and severity of icterus indicated clinical improvement. Declining bilirubin, liver enzymes and serum tumour markers levels until week 3 indicated biochemical response [Table 1]. Follow-up FAP-2286 PET-CT at six weeks demonstrated >30% decrease in the sum of diameters of target lesions, indicating partial response as per RECIST 1.1 criteria [Fig. 1 and 2].
Second dose of [161Tb]Tb-FAP-2286 was delayed due to logistical reasons. At 8 weeks post-therapy, the patient developed sepsis, and mortality occurred 11 days later due to multi-organ failure. A direct causal association with radionuclide therapy was not established.
DISCUSSION
The present case demonstrated the feasibility and short-term safety of [161Tb]Tb-FAP-2286 PTRT in metastatic refractory cholangiocarcinoma.161Tb was preferred over 177Lu owing to its better anti-tumour effect and higher therapeutic index. [8-10] Based on the radio-equivalence modelling, 5.55 GBq of [161Tb]Tb-FAP-2286 was chosen.[7,10] [161Tb]Tb-FAP-2286 biodistribution was comparable to that of 68Ga/177Lu labelled FAP-2286.[11,12] High absorbed dose to liver lesions (3.04-13.8 Gy) and comparable renal absorbed dose with [177Lu]LuFAP-2286 suggested improved tumour dose delivery without increasing the radiation exposure to vital organs.[13] Despitedisease progression and exhaustion of all available treatment options, a single cycle of [161Tb]Tb-FAP-2286 showed a partial response. Although the patient could not be saved, this study provides the feasibility of FAP-targeted PTRT in CCC.
Limitations
Limitations include single-patient experience and short-term safety data. Nevertheless, the study opens doors for more prospective trials to establish the safety, optimal dose, patient selection, and efficacy for [161Tb]Tb-FAP-2286 PTRT.
CONCLUSION
FAP-targeted theranostics with [161Tb]Tb-FAP-2286 may offer a salvage treatment option for patients with cholangiocarcinoma who are ineligible for standard chemotherapy or immunotherapy, highlighting the translational potential of terbium-161 in precision oncology.
Author contributions:
All authors contributed to the study conception and design. MA, HD, and HA: Contributed in optimising acquisition parameters and dosimetry analysis; SD,VM, AV, DP: Part of treating team from multidisciplinary tumor board; SD, VM, and RV: Collected data and perform analysis. RV: Wrote the first draft of the manuscript and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Ethical approval:
The research/study was approved by the Institutional Review Board at Sarvodaya Hospital, number SHRC/IEC/08/2025, dated 20 January 2025.
Declaration of patient consent:
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients have given their consent for their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Financial support and sponsorship: Nil
References
- Cholangiocarcinoma among children and adolescents. J Pediatr Gastroenterol Nutr. 2018;66:e12-8.
- [CrossRef] [PubMed] [Google Scholar]
- The value of FAPI PET/CT in cholangiocarcinoma and pancreatic cancer: An update. Semin Nucl Med. 2025;55:701-9.
- [CrossRef] [PubMed] [Google Scholar]
- Comparative diagnostic performance of [68Ga]Ga-FAPI PET/CT and [18F]FDG PET/CT in biliary tract cancers: A systematic review and meta-analysis. Eur J Nucl Med Mol Imaging. 2025;52:4200-12.
- [CrossRef] [PubMed] [Google Scholar]
- Role of [18F]FAPI-04 in staging and therapeutic management of intrahepatic cholangiocarcinoma: Prospective comparison with [18F]FDG PET/CT. EJNMMI Res. 2024;14:81.
- [CrossRef] [PubMed] [Google Scholar]
- Targeting of fibroblast activation protein with [161Tb]TbFAP-2286 in treatment-refractory non-small cell lung cancer. Eur J Nucl Med Mol Imaging. 2025;53:1689-90.
- [CrossRef] [PubMed] [Google Scholar]
- Replacing Lu-177 with Tb-161 in DOTA-TATE and PSMA-617 therapy: Potential dosimetric implications for activity selection. EJNMMI Phys. 2023;10:69.
- [CrossRef] [PubMed] [Google Scholar]
- Comparison of the dosimetry and cell survival effect of 177Lu and 161Tb somatostatin analog radiopharmaceuticals in cancer cell clusters and micrometastases. EJNMMI Phys. 2024;11:94.
- [CrossRef] [PubMed] [Google Scholar]
- Terbium-161 in nuclear medicine: Preclinical and clinical progress in comparison with lutetium-177. Nucl Med Biol. 2025;144-145:108998.
- [CrossRef] [PubMed] [Google Scholar]
- Potentials and practical challenges of terbium-161 labeled radiopharmaceuticals. EJNMMI Radiopharm Chem. 2025;10:64.
- [CrossRef] [PubMed] [Google Scholar]
- [161Tb]Tb-PSMA-617 radioligand therapy in patients with mCRPC: Preliminary dosimetry results and intra-individual head-to-head comparison to [177Lu]LuPSMA-617. Theranostics. 2024;14:1829-40.
- [CrossRef] [PubMed] [Google Scholar]
- 671P LuMIERE: A phase I/II study evaluating safety, dosimetry, and preliminary activity of [177Lu]Lu-FAP-2286 in patients with advanced solid tumors. Ann Oncol. 2024;35(Suppl 2):S526.
- [CrossRef] [Google Scholar]
- 68Ga-FAP-2286 PET of solid tumors: Biodistribution, dosimetry, and comparison with 18F-FDG. J Nucl Med. 2024;65:938-43.
- [CrossRef] [PubMed] [Google Scholar]
- Feasibility, biodistribution, and preliminary dosimetry in peptide-targeted radionuclide therapy of diverse adenocarcinomas using 177Lu-FAP-2286: First-in-humans results. J Nucl Med. 2022;63:415-23.
- [CrossRef] [PubMed] [Google Scholar]