Peptide receptor radiotherapy with somatostatin analogs has been successfully used for years as a treatment for somatostatin-overexpressing tumors. Treatment of neuroendocrine tumors (NETs) with the β-particle emitter ¹⁷⁷Lu-DOTATATE is currently considered the standard of care for subjects with gastroenteropancreatic NETs. Despite the success of ¹⁷⁷Lu-DOTATATE, there remains significant room for improvement in terms of both safety and efficacy. Targeted α-emitter therapy with isotopes such as ²¹²Pb has the potential to improve both. Here, we present the preliminary results of the phase 1 first-in-humans dose-escalation trial evaluating ²¹²Pb-DOTAMTATE (a bifunctional metal chelator [DOTAM] and the SSTR-targeting peptide [TATE]) in patients with somatostatin receptor–positive NETs. Methods: Twenty subjects with histologically confirmed NETs, prior positive somatostatin analog scans, and no prior history of ¹⁷⁷Lu/⁹⁰Y/¹¹¹In peptide receptor radiotherapy, with different primary sites of the disease, were enrolled. Treatment began with single ascending doses of ²¹²Pb-DOTAMTATE, with subsequent cohorts receiving an incremental 30% dose increase, which was continued until a tumor response or a dose-limiting toxicity was observed. This was followed by a multiple ascending dose regimen. The recommended phase 2 dose regimen consisted of 4 cycles of 2.50 MBq/kg (67.6 μCi/kg) of ²¹²Pb-DOTAMTATE administered at 8-wk intervals, intravenously. Results: Ten subjects received the highest dose, 2.50 MBq/kg/cycle (67.6 μCi/kg/cycle). Treatment was well tolerated, with the most common treatment-emergent adverse events being nausea, fatigue, and alopecia. No serious treatment-emergent adverse events were related to the study drug, and no subjects required treatment delay or a dose reduction. An objective radiologic response of 80% was observed for the first 10 subjects treated at the recommended phase 2 dose. Conclusion: Targeted α-therapy with ²¹²Pb-DOTAMTATE has been shown to be well tolerated. Preliminary efficacy results are highly promising. If these results are confirmed in a larger, multicenter clinical trial, ²¹²Pb-DOTAMTATE would provide a substantial benefit over currently Food and Drug Administration–approved therapies for patients with metastatic or inoperable SSTR-expressing NETs regardless of the grade and location of the primary tumor.

使用生长抑素类似物的肽受体放疗已成功用于治疗生长抑素过度表达的肿瘤多年。使用 β 粒子发射器¹⁷⁷ Lu-DOTATATE 治疗神经内分泌肿瘤 (NETs) 目前被认为是胃肠胰腺 NETs 受试者的护理标准。^尽管177 Lu-DOTATATE取得了成功，但在安全性和有效性方面仍有很大的改进空间。^使用212 Pb等同位素进行靶向 α 发射体治疗有可能改善这两者。^{在这里，我们展示了评估212}的第一阶段人体剂量递增试验的初步结果Pb-DOTAMTATE（一种双功能金属螯合剂 [DOTAM] 和 SSTR 靶向肽 [TATE]）用于生长抑素受体阳性 NETs 患者。方法：纳入了 20 名具有组织学证实的 NETs、既往生长抑素类似物扫描呈阳性且既往无¹⁷⁷ Lu/ ⁹⁰ Y/ ¹¹¹ In 肽受体放疗史且疾病原发部位不同的受试者。治疗开始于单次递增剂量²¹²Pb-DOTAMTATE，随后的队列接受了 30% 的增量剂量增加，一直持续到观察到肿瘤反应或剂量限制性毒性。随后是多次递增剂量方案。推荐的 2 期剂量方案包括 4 个周期的 2.50 MBq/kg (67.6 μCi/kg) ²¹² Pb-DOTAMTATE，间隔 8 周，静脉内给药。结果：十名受试者接受了最高剂量，2.50 MBq/kg/周期（67.6 μCi/kg/周期）。治疗耐受性良好，最常见的治疗紧急不良事件是恶心、疲劳和脱发。没有严重的治疗紧急不良事件与研究药物相关，并且没有受试者需要延迟治疗或减少剂量。在推荐的 2 期剂量下治疗的前 10 名受试者观察到 80% 的客观放射学反应。结论：已证明使用²¹² Pb-DOTAMTATE的靶向 α 疗法具有良好的耐受性。初步疗效结果非常有希望。如果这些结果在更大规模的多中心临床试验中得到证实，²¹²无论原发肿瘤的等级和位置如何，Pb-DOTAMTATE 都将比目前食品和药物管理局批准的治疗转移性或不能手术的 SSTR 表达 NETs 的患者提供实质性益处。