Department of Nuclear Medicine and Minnan PET Center, Xiamen Key Laboratory of Radiopharmaceuticals, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Department of Diagnostic Radiology, Yong Loo Lin School of Medicine and Faculty of Engineering, National University of Singapore, Singapore.
Clin Cancer Res. 2023 Dec 1;29(23):4740-4750. doi: 10.1158/1078-0432.CCR-23-1983.
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, 177Lu-EB-FAPI (177Lu-LNC1004), in patients with metastatic radioiodine-refractory thyroid cancer (mRAIR-TC).
This open-label, non-randomized, first-in-human, dose-escalation, investigator-initiated trial had a 3+3 design and involved a 6-week 177Lu-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.
177Lu-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 177Lu-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.
FAP-targeted radioligand therapy with 177Lu-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.
成纤维细胞激活蛋白（FAP）是肿瘤治疗的一个有前途的靶点。本研究旨在探讨放射性核素 177Lu 标记的白蛋白结合物偶联 FAP 靶向放射性药物 177Lu-EB-FAPI（177Lu-LNC1004）在转移性碘难治性甲状腺癌（mRAIR-TC）患者中的安全性和疗效。
这是一项开放标签、非随机、首次人体、剂量递增、研究者发起的试验，采用 3+3 设计，mRAIR-TC 患者最初接受 2.22GBq 的 177Lu-LNC1004 治疗周期，随后的队列接受递增 50%的剂量增加，直到观察到剂量限制性毒性（DLT）。
177Lu-LNC1004 给药耐受性良好，未观察到危及生命的不良事件。A 组（2.22GBq/周期）无患者发生 DLT。B 组（3.33GBq/周期）1 例患者发生 4 级血小板减少症；因此，又入组了 3 例患者，均未发生 DLT。C 组（4.99GBq/周期）2 例患者发生 3 级和 4 级血液毒性。平均全身有效剂量为 0.17±0.04mSv/MBq。177Lu-LNC1004 摄取强烈，肿瘤滞留时间延长，导致平均吸收肿瘤剂量高（8.50±12.36Gy/GBq）。全身和肿瘤病变的平均有效半衰期分别为 90.20±7.68 小时和 92.46±9.66 小时。根据 RECIST，3 例（25%）患者观察到部分缓解，7 例（58%）患者观察到疾病稳定，2 例（17%）患者观察到疾病进展。客观缓解率和疾病控制率分别为 25%和 83%。
在晚期 mRAIR-TC 患者中，3.33GBq/周期的 FAP 靶向放射性配体治疗 177Lu-LNC1004 耐受性良好，肿瘤病变有较高的辐射剂量传递，具有令人鼓舞的治疗效果和可接受的副作用。
