On January 26, 2018, the US Food and Drug Administration (FDA) approved lutetium Lu 177 dotatate (LUTATHERA, Advanced Accelerator Applications USA, Inc), a radiolabeled somatostatin analogue, for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut NETs in adults.

Approval was based on data from NETTER-1 (NCT01578239), a randomized, multicenter, open-label, active-controlled trial in 229 patients with progressive, well-differentiated, locally advanced/inoperable, or metastatic somatostatin receptor-positive midgut carcinoid tumors. Patients were randomized (1:1) to receive either lutetium Lu 177 dotatate (7.4 GBq [200 mCi] every 8 weeks for up to 4 administrations; maximum cumulative dose of 29.6 GBq) with long-acting octreotide (30 mg by intramuscular injection every 4 weeks) or high-dose long-acting octreotide (60 mg by intramuscular injection every 4 weeks). Lutetium Lu 177 dotatate was co-administered with an amino acid solution as a renal protectant. In the US, patients enrolled in NETTER-1 received Aminosyn II 10%, a commercially available solution of amino acids.

The major efficacy outcome measure was progression-free survival (PFS) determined by a blinded independent radiology committee using RECIST v1.1. The median PFS was not reached for lutetium Lu 177 dotatate and was 8.5 months in the high-dose long-acting octreotide arm (HR, 0.21; 95% CI: 0.13, 0.32; p < 0.0001).

The efficacy of lutetium Lu 177 dotatate was also assessed in a subset (n=360) of 1,214 patients enrolled in the ERASMUS Medical Center study with GEP-NET tumors who were assessed according to RECIST criteria. At the ERASMUS Medical Center, lutetium Lu 177 dotatate was initially provided as expanded access under a general peptide receptor radionuclide therapy protocol at a single site in the Netherlands. Lutetium Lu 177 dotatate (7.4 GBq [200 mCi]) was administered every 6 to 13 weeks for up to 4 doses. The overall response rate was 16% (n=58), including 3 complete responses in this subset of 360 patients with GEP-NETs who were assessed according to RECIST criteria.

In the NETTER-1 study, the most common grade 3/4 adverse reactions occurring with a greater frequency (at least 4%) among patients receiving lutetium Lu 177 dotatate with long-acting octreotide, compared to patients receiving high-dose octreotide alone, included lymphopenia (44%), increased GGT (20%), vomiting (7%), nausea and elevated AST (5% each), and increased ALT, hyperglycemia, and hypokalemia (4% each). In NETTER-1, with a median follow-up of 24 months, myelodysplastic syndrome was reported in 2.7% of patients receiving lutetium Lu 177 dotatate with long-acting octreotide; no patients receiving high-dose octreotide LAR developed myelodysplastic syndrome.

The recommended dose of lutetium Lu 177 dotatate is 7.4 GBq (200 mCi) as an intravenous infusion over 30 minutes every 8 weeks for a total of 4 doses.

Full prescribing information is available here.

FDA granted priority review for this application and previously granted Orphan Drug designation to lutetium Lu 177 dotatate for treatment of GEP-NETs.