Safety and Efficacy of Lu-177-DOTATATE in Metastatic or Inoperable Pheochromocytoma/Paraganglioma – An Interim Analysis

Introduction: Pheochromocytoma/Paraganglioma (PPGL) are rare neuroendocrine tumors that express somatostatin receptors (SSTR) on their surface and can be treated with radiolabeled somatostatin analogues such as Lu-177-DOTATATE. We report on the planned interim analysis of the safety and efficacy of Lu-177-DOTATATE in the treatment of metastatic or inoperable PPGL in a prospective phase 2 clinical trial.

Methods: This is an open-label, single-arm phase 2 study conducted at the National Institutes of Health to evaluate the efficacy and safety of Lu-177-DOTATATE in patients with PPGL (NCT03206060). Patients are divided into 2 cohorts: those with no genetic mutations known to be associated with PPGL (sporadic), and those with mutations in the succinate dehydrogenase complex (SDHx), which may be associated with more aggressive disease. The primary endpoint is progression free surival (PFS) at 6 months post initiation of treatment. Eligibility criteria include: histologically-confirmed PPGL, SSTR+ tumor as determined by a Ga-68-DOTATATE PET scan, and evidence of progression by RECIST 1.1 within 12 months before study enrollment. CT and/or MRIs, as well as both F-18-FDG and Ga-68-DOTATATE PET scans, are acquired at baseline, 4 weeks after the second cycle of Lu-177-DOTATATE, 8 weeks after the fourth cycle, and then every 3 months (anatomic scans) to 6 months (PET scans). Lu-177-DOTATATE is administered per the FDA-approved regimen for GI-neuroendocrine tumors, which is 200 mCi (7.4 GBq) every 8 weeks x 4 cycles with amino acid renal blocking. The study opened for enrollment in August 2017 and is conducted using a Simon two-stage optimal design. An interim analysis is built-in for both the sporadic and SDHx cohorts when each has reaches 18 participants, and the study will continue onto the second stage for each cohort if 11 or more out of 18 patients meet the primary endpoint. Full accrual for the study will be 90 patients, 45 per cohort.

Results: For the interim analysis, 36 patients (18 per cohort) were evaluated for safety and efficacy. For the sporadic cohort, 16 (89%) patients achieved stable disease (SD) while 2 (11%) had partial response (PR) by RECIST 1.1 at 6 months. In the SDHx (SDHA=2, SDHB=15, SDHD=1) cohort, 10 (55%) patients had SD, 3 (17%) patients had PR, and 5 (28%) patients had progression at 6 months. In total, 31/36 (86%) met the primary study end point, and the mean PFS is 19.1 months. Patients in the sporadic cohort had longer average PFS of 22.7 months vs 15.4 months in the SDHx cohort. Rates of adverse and serious adverse events (SAE) attributable to Lu-177-DOTATATE were similar to those previously reported in other studies such as NETTER-1, with hematologic SAEs being the most common and in the 5 to 10% range. Adverse events unique to the PPGL population included increased catecholamine-related symptoms such as flushing, hypertension, and tachycardia starting as early as during the Lu-177-DOTATATE infusion and persisting for days to weeks after treatment. Serum catecholamine levels often surged quickly, which likely accounts for the increase in symptoms, and on average peaked at 24 hours post-administration (median increase = 60%, max increase 10x baseline). In a few patients with baseline severe hypertension, systolic blood pressure went as high as 260 mm with heart rate > 160/min, requiring ICU intervention for intravenous anti-hypertensives. Despite these acute increases and associated symptoms, catecholamine levels in most patients returned approximately to baseline by Day 28.

Conclusions: Our interim analysis demonstrates that Lu-177-DOTATATE has high efficacy and a good safety profile for metastatic PPGL in both the sporadic and SDHx cohorts, although the PFS in the spordaic group (24.6 months) is longer than in the SDHx (13.2 months) group. While catecholamine crisis related to surging serum catecholamine levels occurs, levels usually return to near baseline and patients can be safety treated, though ICU care is sometimes needed.

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