Fibroblast Activation Protein-Targeted Radioligand Therapy with 177Lu-EB-FAPI for Metastatic Radioiodine-Refractory Thyroid Cancer: First-in-Human, Dose-Escalation Study

被引：58

作者：

Fu, Hao ^{[1
,2
]}

Huang, Jingxiong ^{[1
,2
]}

Zhao, Tianzhi ^{[3
,4
,5
,6
,7
,8
,9
]}

Wang, Hongjian ^{[10
]}

Chen, Yuhang ^{[10
]}

Xu, Weizhi ^{[1
,2
]}

Pang, Yizhen ^{[1
,2
]}

Guo, Wei ^{[1
,2
]}

Sun, Long ^{[1
,2
]}

Wu, Hua ^{[1
,2
]}

Xu, Pengfei ^{[3
,4
,5
,6
,7
,8
,9
]}

Su, Bishan ^{[1
,2
]}

Zhang, Jingjing ^{[3
,4
,5
,6
,7
,8
,9
]}

Chen, Xiaoyuan ^{[3
,4
,5
,6
,7
,8
,9
]}

Chen, Haoju ^{[1
,2
]}

机构：

[1] Xiamen Univ, Sch Med, Dept Nucl Med, Affiliated Hosp 1, Xiamen, Peoples R China

[2] Xiamen Univ, Affiliated Hosp 1, Minnan PET Ctr, Sch Med,Xiamen Key Lab Radiopharmaceut, Xiamen, Peoples R China

[3] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Diagnost Radiol, Singapore, Singapore

[4] Natl Univ Singapore, Fac Engn, Singapore, Singapore

[5] Natl Univ Singapore, Dept Surg, Yong Loo Lin Sch Med, Singapore 117597, Singapore

[6] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Chem & Biomol Engn, Singapore, Singapore

[7] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biomed Engn, Singapore 119074, Singapore

[8] Natl Univ Singapore, Clin Imaging Res Ctr, Ctr Translat Med, Yong Loo Lin Sch Med, Singapore, Singapore

[9] Natl Univ Singapore, NUS Ctr Nanomed, Yong Loo Lin Sch Med, Nanomed Translat Res Program, Singapore, Singapore

[10] Fujian Med Univ, Sch Clin Med, Fuzhou, Peoples R China

来源：

CLINICAL CANCER RESEARCH | 2023年 / 29卷 / 23期

基金：

中国国家自然科学基金;

关键词：

RECEPTOR RADIONUCLIDE THERAPY;

D O I：

10.1158/1078-0432.CCR-23-1983

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose: Fibroblast activation protein (FAP) is a promising target for tumor treatment. In this study, we aimed to investigate the safety and efficacy of the albumin binder-conjugated FAP-targeted radiopharmaceutical, Lu-177-EB-FAPI (Lu-177-LNC1004), in patients with metastatic radioiodine-refractory thyroid cancer (mRAIR-TC). Patients and Methods: This open-label, non-randomized, first-in-human, dose-escalation, investigator-initiated trial had a 3+3 design and involved a 6-week Lu-177-LNC1004 treatment cycle in patients with mRAIR-TC at 2.22 GBq initially, with subsequent cohorts receiving an incremental 50% dose increase until dose-limiting toxicity (DLT) was observed. Results: Lu-177-LNC1004 administration was well tolerated, with no life-threatening adverse events observed. No patients experienced DLT in Group A (2.22 GBq/cycle). One patient experienced grade 4 thrombocytopenia in Group B (3.33 GBq/cycle); hence, another three patients were enrolled, none of whom experienced DLT. Two patients experienced grade 3 and 4 hematotoxicity in Group C (4.99 GBq/cycle). The mean whole-body effective dose was 0.17 +/- 0.04 mSv/MBq. Intense Lu-177-LNC1004 uptake and prolonged tumor retention resulted in high mean absorbed tumor doses (8.50 +/- 12.36 Gy/GBq). The mean effective half-lives for the whole-body and tumor lesions were 90.20 +/- 7.68 and 92.46 +/- 9.66 hours, respectively. According to RECIST, partial response, stable disease, and progressive disease were observed in 3 (25%), 7 (58%), and 2 (17%) patients, respectively. The objective response and disease control rates were 25% and 83%, respectively. Conclusions: FAP-targeted radioligand therapy with Lu-177-LNC1004 at 3.33 GBq/cycle was well tolerated in patients with advanced mRAIR-TC, with high radiation dose delivery to the tumor lesions, encouraging therapeutic efficacy, and acceptable side effects.

引用

页码：4740 / 4750

页数：11

共 40 条

[1] Radioiodine-Refractory Thyroid Cancer: Molecular Basis of Redifferentiation Therapies, Management, and Novel Therapies [J].

Aashiq, Mohamed ;

Silverman, Deborah A. ;

Na'ara, Shorook ;

Takahashi, Hideaki ;

Amit, Moran .

CANCERS, 2019, 11 (09)

[2]

[Anonymous], U.S. Nuclear Regulatory Commission. Regulatory guide 8.39: release of patients administered radioactive materials. 1997

[3] Feasibility and Therapeutic Potential of 177Lu-Fibroblast Activation Protein Inhibitor-46 for Patients With Relapsed or Refractory Cancers A Preliminary Study [J].

Assadi, Majid ;

Rekabpour, Seyed Javad ;

Jafari, Esmail ;

Divband, GhasemAli ;

Nikkholgh, Babak ;

Amini, Hamidreza ;

Kamali, Hassan ;

Ebrahimi, Sakineh ;

Shakibazad, Nader ;

Jokar, Narges ;

Nabipour, Iraj ;

Ahmadzadehfar, Hojjat .

CLINICAL NUCLEAR MEDICINE, 2021, 46 (11) :E523-E530

[4] A theranostic approach of [68Ga]Ga-DOTA.SA.FAPi PET/CT-guided [177Lu]Lu-DOTA.SA.FAPi radionuclide therapy in an end-stage breast cancer patient: new frontier in targeted radionuclide therapy [J].

Ballal, Sanjana ;

Yadav, Madhav Prasad ;

Kramer, Vasko ;

Moon, Euy Sung ;

Roesch, Frank ;

Tripathi, Madhav ;

Mallick, Soumyaranjan ;

ArunRaj, Sreedharan Thankarajan ;

Bal, Chandrasekhar .

EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING, 2021, 48 (03) :942-944

[5] Feasibility, Biodistribution, and Preliminary Dosimetry in Peptide-Targeted Radionuclide Therapy of Diverse Adenocarcinomas Using 177Lu-FAP-2286: First-in-Humans Results [J].

Baum, Richard P. ;

Schuchardt, Christiane ;

Singh, Aviral ;

Chantadisai, Maythinee ;

Robiller, Franz C. ;

Zhang, Jingjing ;

Mueller, Dirk ;

Eismant, Alexander ;

Almaguel, Frankis ;

Zboralski, Dirk ;

Osterkamp, Frank ;

Hoehne, Aileen ;

Reineke, Ulrich ;

Smerling, Christiane ;

Kulkarni, Harshad R. .

JOURNAL OF NUCLEAR MEDICINE, 2022, 63 (03) :415-423

[6] Targeted Therapy for Advanced Thyroid Cancer: Kinase Inhibitors and Beyond [J].

Cabanillas, Maria E. ;

Ryder, Mabel ;

Jimenez, Camilo .

ENDOCRINE REVIEWS, 2019, 40 (06) :1573-1604

[7] Medullary thyroid carcinoma beyond surgery: advances, challenges, and perspectives [J].

Ceolin, Lucieli ;

da Silveira Duval, Marta Amaro ;

Benini, Antonio Felippe ;

Ferreira, Carla Vaz ;

Maia, Ana Luiza .

[8] Usefulness of [68Ga]Ga-DOTA-FAPI-04 PET/CT in patients presenting with inconclusive [18F]FDG PET/CT findings [J].

Chen, Haojun ;

Zhao, Liang ;

Ruan, Dan ;

Pang, Yizhen ;

Hao, Bing ;

Dai, Yaqing ;

Wu, Xiurong ;

Guo, Wei ;

Fan, Chunlei ;

Wu, Jingxun ;

Huang, Weipeng ;

Lin, Qin ;

Sun, Long ;

Wu, Hua .

EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING, 2021, 48 (01) :73-86

[9] Clinical and therapeutic relevance of cancer-associated fibroblasts [J].

Chen, Yang ;

McAndrews, Kathleen M. ;

Kalluri, Raghu .

NATURE REVIEWS CLINICAL ONCOLOGY, 2021, 18 (12) :792-804

[10] Safety and Efficacy of 90Y-FAPI-46 Radioligand Therapy in Patients with Advanced Sarcoma and Other Cancer Entities [J].

Fendler, Wolfgang P. ;

Pabst, Kim M. ;

Kessler, Lukas ;

Costa, Pedro Fragoso ;

Ferdinandus, Justin ;

Weber, Manuel ;

Lippert, Maria ;

Lueckerath, Katharina ;

Umutlu, Lale ;

Kostbade, Karina ;

Mavroeidi, Ilektra A. ;

Schuler, Martin ;

Ahrens, Marit ;

Rischpler, Christoph ;

Bauer, Sebastian ;

Herrmann, Ken ;

Siveke, Jens T. ;

Hamacher, Rainer .

CLINICAL CANCER RESEARCH, 2022, 28 (19) :4346-4353

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