FDA Approves Lutetium Lu 177 Dotatate for Treatment of GEP-NETS
On January 26, 2018, the U.S. Food and Drug Administration (FDA) approved lutetium Lu 177 dotatate (Lutathera®) a radiolabeled somatostatin analog, for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors 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 eight weeks for up to four administrations; maximum cumulative dose of 29.6 GBq) with long-acting octreotide (30 mg by intramuscular injection every four weeks) or high-dose long-acting octreotide (60 mg by intramuscular injection every four weeks). Lutetium Lu 177 dotatate was co-administered with an amino acid solution as a renal protectant. In the United States, patients enrolled in NETTER-1 received 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 1.1. The median PFS was not reached for lutetium Lu 177 dotatate and was 8.5 months in the high-dose long-acting octreotide arm (hazard ratio = 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 (MC) study with GEP-NET tumors who were assessed according to RECIST criteria. At the ERASMUS MC, 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 6–13 weeks for up to four doses. The ORR was 16% (n = 58), including three 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 eight weeks for a total of four doses.
Full prescribing information is available (https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/208700s000lbl.pdf).
FDA granted priority review for this application and previously granted orphan drug designation to lutetium Lu 177 dotatate for treatment of GEP-NETs. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics (http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm358301.pdf).
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