PURPOSE: 177Lu-DOTA(0)-Tyr(3)-octreotate (177Lu-DOTATATE) is a somatostatin receptor (SSTR)-targeting radiopharmaceutical that shows promise for treating metastatic pheochromocytomas/paragangliomas (PPGLs), a rare SSTR-expressing tumor. METHODS: 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 [SDHx]-mutated v apparent sporadic, 18 per cohort) and treated with four cycles of 177Lu-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 (68Ga-DOTATATE and 18F-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). RESULTS: Six-month PFS rate for all patients was 0.861 (95% CI, 0.755 to 0.982), which was significantly lower (P = .009) for SDHx 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 SDHx v 24.3 months sporadic) and median OS was 51.7 months (31.2 months SDHx v not reached in sporadic). Best response was achieved on average 11.0 months after completing 177Lu-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 68Ga-DOTATATE PET-CT scans. CONCLUSION: 177Lu-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.

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