PO.CT01.02 · 临床试验
一种首创的HER2靶向放射性药物疗法：177Lu-RAD202治疗HER2+晚期实体瘤的0/1期HEAT试验的初步结果
A first-in-class HER2-targeted radiopharmaceutical therapy: Initial findings from the Phase 0/1 HEAT trial of 177Lu-RAD202 in HER2+ advanced solid tumors
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：HER2靶向疗法已改变了HER2表达实体瘤的结局，改善了乳腺癌、肺癌和胃癌的生存，并在胆道癌、膀胱癌和结肠癌中获得加速批准。然而，原发性和获得性耐药仍是主要挑战。177Lu-RAD202是一种镥-177标记的骆驼源单域抗体（sdAb），靶向HER2，用于治疗HER2阳性（HER2+）实体瘤。小分子sdAb可实现肿瘤深度穿透和快速清除，而177Lu发射细胞毒性β射线，产生不依赖受体密度的旁观者效应。一项采用99mTc-RAD202的I期诊断研究在10例HER2+乳腺癌患者中证明了其安全性以及良好的生物分布和显像特征（肿瘤靶向）。177Lu-RAD202可能克服对单克隆抗体、酪氨酸激酶抑制剂和抗体药物偶联物（ADC）疗法的耐药，支持进一步临床评价。
方法：HEAT试验（NCT06824155）是一项首次人体、开放标签、多中心的0/1期多剂量研究，评估177Lu-RAD202治疗HER2+晚期实体瘤。0期为单次10 mCi（0.37 GBq）静脉给药，并进行连续SPECT/CT显像以评估生物分布、剂量学和肿瘤摄取。1期包括递增的治疗剂量，起始为30 mCi（约1.1 GBq；剂量水平[DL]1），并按贝叶斯最优设计计划递增。该试验目前正在以75 mCi的治疗剂量入组患者。将探索更多剂量水平。主要目的是评估安全性、临床活性、肿瘤靶向性并确定推荐治疗剂量。
结果：截至2025年11月，3例HER2+实体瘤受试者接受了30 mCi治疗。病灶剂量学显示177Lu-RAD202在多个转移部位靶向摄取，包括内脏、皮下、乳腺、淋巴结和皮肤病灶。30 mCi时每个病灶的吸收剂量最高达3.6 Gy。未发生严重治疗相关不良事件（AE）。1例受试者报告2项治疗相关1级AE（味觉障碍、胸腔积液）。总体安全性良好，仅有少数低级别（1-2级）治疗中出现的AE。
结论：这些早期首次人体数据显示177Lu-RAD202具有高肿瘤摄取和良好安全性，支持继续剂量递增。这种HER2靶向放射治疗药物有望为HER2+实体瘤（包括乳腺癌、非小细胞肺癌和胃癌）提供一种新型治疗方法。DL2（75 mCi）及更高剂量的最新结果将在大会上公布。
查看英文原文 English abstract
Background: HER2-targeted therapies have transformed outcomes for HER2-expressing solid tumors, improving survival in breast, lung, and gastric cancers and gaining accelerated approval in biliary tract, bladder, and colon cancers. Nonetheless, primary and acquired resistance remain major challenges. 177Lu-RAD202 is a Lutetium-177-labeled camelid single-domain antibody (sdAb) targeting HER2, developed for treating HER2-positive (HER2+) solid tumors. The small sdAb enables deep tumor penetration and rapid clearance, while 177Lu emits cytotoxic beta-radiation producing a bystander effect independent of receptor density. A Phase I diagnostic study with 99mTc-RAD202 demonstrated safety, as well as favorable biodistribution and imaging characteristics (tumor targeting) in 10 patients with HER2+ breast cancer. 177Lu-RAD202 may overcome resistance to monoclonal antibody, tyrosine kinase inhibitor, and antibody-drug conjugate (ADC) therapies, supporting further clinical evaluation.
Methods: The HEAT Trial (NCT06824155) is a first-in-human, open-label, multicenter Phase 0/1 multiple dosing study of 177Lu-RAD202 in HER2+ advanced solid tumors. Phase 0 involves a single 10 mCi (0.37 GBq) intravenous dose with serial SPECT/CT imaging for biodistribution, dosimetry, and tumor uptake. Phase 1 includes escalating therapeutic doses, commencing at 30 mCi (~1.1 GBq; Dose Level [DL] 1) with planned increases as per Bayesian Optimal Design. The trial is currently enrolling patients at a therapeutic dose of 75 mCi. Additional dose levels will be explored. Primary objectives are to evaluate safety, clinical activity, tumor targeting and determine the recommended therapeutic dose(s).
Results: As of November 2025, three participants with HER2+ solid tumors have been treated at 30 mCi. Lesion dosimetry demonstrated targeted 177Lu-RAD202 uptake across multiple metastatic sites, including visceral, subcutaneous, breast, lymph node, and skin lesions. Absorbed doses reached up to 3.6 Gy per lesion at 30mCi. No serious treatment-related adverse events (AEs) occurred. Two treatment-related Grade 1 AEs (dysgeusia, pleural effusion) were reported in one participant. Overall safety has been favorable, with few low-grade (Grade 1-2) treatment-emergent AEs.
Conclusion: These early first-in-human data demonstrate high tumor uptake and favorable safety of 177Lu-RAD202, supporting continued dose escalation. This HER2-targeted radiotherapeutic potentially offers a novel treatment approach for HER2+ solid tumors, including breast, non-small cell lung and gastric cancer. Updated results from DL2 (75 mCi) and higher will be presented at the congress.
利益披露 Disclosure
A. Singh, None..
U. Nindra, None..
I. Swainson, None.
D. Voliotis,
Radiopharm Theranostics Employment.
V. Wong, None.