Lin Frank I, Del Rivero Jaydira, Carrasquillo Jorge A, Jha Abhishek, Zou Joy, Shamis Inna, Talvacchio Sara, Turkbey Baris, Huang Erich P, Shih Joanna, Klubo-Gwiezdzinska Joanna, Mena Esther, Lindenberg Liza, Teng Yating, Escorcia Freddy E, Chen Clara, Herscovitch Peter, Millo Corina, Choyke Peter L, Pacak Karel
Molecular Imaging Branch, National Institutes of Health, National Cancer Institute, Center for Cancer Research, Bethesda, MD.
Developmental Therapeutics Branch, National Institutes of Health, National Cancer Institute, Center for Cancer Research, Bethesda, MD.
J Clin Oncol. 2025 Aug 19:JCO2500791. doi: 10.1200/JCO-25-00791.
Lu-DOTA(0)-Tyr(3)-octreotate (Lu-DOTATATE) is a somatostatin receptor (SSTR)-targeting radiopharmaceutical that shows promise for treating metastatic pheochromocytomas/paragangliomas (PPGLs), a rare SSTR-expressing tumor.
In the first stage of this two-stage Simon phase II trial, 36 PPGL patients with RECIST 1.1 progression within 12 months were prospectively recruited into two genetic cohorts (succinate dehydrogenase []-mutated apparent sporadic, 18 per cohort) and treated with four cycles of Lu-DOTATATE. The primary end point was progression-free survival (PFS) rate at 6 months (from initiation of treatment). Secondary end points included safety, overall survival (OS), response rate, imaging/serum biomarkers, and antihypertensive medication reduction. Computed tomography/magnetic resonance imaging (CT/MRIs) and positron emission tomography (PET)-CTs (Ga-DOTATATE and F-labeled fluorodeoxyglucose) were obtained after two and four cycles, then every 3 (CT/MRIs) to 6 months (PET/CTs). Patients with systolic blood pressure (SBP) > 200 mmHg despite medical management were treated in the intensive care unit (ICU).
Six-month PFS rate for all patients was 0.861 (95% CI, 0.755 to 0.982), which was significantly lower ( = .009) for at 0.72 (95% CI, 0.542 to 0.962) versus sporadic at 1.00 (95% CI, 1.0 to 1.0). Median PFS was 19.9 months (12.9 months 24.3 months sporadic) and median OS was 51.7 months (31.2 months not reached in sporadic). Best response was achieved on average 11.0 months after completing Lu-DOTATATE. A 17% incidence of grade 3+ catecholamine release syndrome (CRS) was noted, which may benefit from preemptive ICU admission. Plasma chromogranin A and normetanephrine were the best tumor-marker surrogates and correlated well with changes in RECIST sum and total tumor lesion uptake on serial Ga-DOTATATE PET-CT scans.
Lu-DOTATATE demonstrated effectiveness and acceptable safety profile for progressive, metastatic PPGL. CRS may occur but can be mitigated through pretreatment with antihypertensives, and, when appropriate, intensified monitoring in the ICU with intravenous antihypertensives.
镥 - 多胺基多乙酸（0） - 酪胺酸（3） - 奥曲肽（Lu - DOTATATE）是一种靶向生长抑素受体（SSTR）的放射性药物，在治疗转移性嗜铬细胞瘤/副神经节瘤（PPGL）方面显示出前景，PPGL是一种罕见的表达SSTR的肿瘤。
在这项两阶段西蒙二期试验的第一阶段，前瞻性招募了36例在12个月内出现RECIST 1.1标准进展的PPGL患者，分为两个基因队列（琥珀酸脱氢酶[]突变型与明显散发型，每组18例），并接受四个周期的Lu - DOTATATE治疗。主要终点是6个月（从治疗开始）时的无进展生存率（PFS）。次要终点包括安全性、总生存期（OS）、缓解率、影像/血清生物标志物以及降压药物的减少。在两个和四个周期后进行计算机断层扫描/磁共振成像（CT/MRI）和正电子发射断层扫描（PET） - CT（镓 - DOTATATE和F标记的氟脱氧葡萄糖）检查，然后每3个月（CT/MRI）至6个月（PET/CT）检查一次。尽管进行了药物治疗但收缩压（SBP）> 200 mmHg的患者在重症监护病房（ICU）接受治疗。
所有患者的6个月PFS率为0.861（95%CI，0.755至0.982），其中突变型患者的PFS率为0.72（95%CI，0.542至0.962），明显低于散发型患者的1.00（95%CI，1.0至1.0）（P = 0.009）。中位PFS为19.9个月（突变型为12.9个月，散发型为24.3个月），中位OS为51.7个月（突变型为31.2个月，散发型未达到）。完成Lu - DOTATATE治疗后平均11.0个月达到最佳缓解。观察到3级及以上儿茶酚胺释放综合征（CRS）的发生率为17%，提前入住ICU可能有益。血浆嗜铬粒蛋白A和去甲变肾上腺素是最佳的肿瘤标志物替代指标，与系列镓 - DOTATATE PET - CT扫描上RECIST总和及总肿瘤病灶摄取的变化相关性良好。
Lu - DOTATATE对进展性转移性PPGL显示出有效性和可接受的安全性。CRS可能发生，但可通过术前使用降压药缓解，并且在适当情况下，在ICU加强监测并静脉使用降压药。
