FDA Approves LUTATHERA® for the Treatment of Somatostatin Receptor-Positive GastroEnteroPancreatic Neuroendocrine Tumors

SUMMARY: The FDA on January 26, 2018 approved LUTATHERA® (Lutetium Lu 177 dotatate), 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. The most common type of malignant gastrointestinal NeuroEndocrine Tumors (NET) originate in the midgut (jejunoileum and the proximal colon) and often metastasize to the mesentery, peritoneum and liver. These patients frequently present with Carcinoid syndrome and are treated with Somatostatin analogue for control of tumor growth, as well as symptoms related to hormonal secretion. For patients who progress with functional neuroendocrine tumors, there are currently no standard second-line systemic treatment options available. A majority of advanced, well-differentiated neuroendocrine tumors express high levels of Somatostatin receptors and radiolabeled Somatostatin analogue therapy, also known as Peptide Receptor Radionuclide Therapy (PRRT) has been studied since the early 1990’s, with promising results. The radiolabeled Somatostatin analogues bind to the Somatostatin receptors expressed on the surface of the tumor cells and deliver targeted radiation, with a high therapeutic index, directly to the tumor cells.

LUTATHERA® is a radioconjugate consisting of the Somatostatin analog Octreotide conjugated with Lutetium-177 (177Lu), a beta and gamma-emitting radionuclide, using the chelator DOTA. In a study involving 310 patients with GastroEnteroPancreatic, NeuroEndocrine Tumors, treatment with LUTATHERA® resulted in an Objective Response Rate of 30%, and a median Progression Free Survival of 33 months.

The approval of LUTATHERA® was based on NETTER-1, a phase III, randomized, multicenter, open-label, active-controlled trial, which compared LUTATHERA® with high-dose Octreotide LAR (Long Acting), for patients with grade I or II metastatic midgut NeuroEndocrine Tumors. In this study, 229 patients (N=229) with progressive, well differentiated, locally advanced/inoperable or metastatic Somatostatin receptor-positive midgut Carcinoid tumors were randomized in a 1:1 ratio to receive either LUTATHERA® (7.4 GBq [200 mCi] every 8 weeks for up to 4 administrations along with Octreotide LAR 30 mg by IM injection every 4 weeks (N=116) or control group which received high dose Octreotide LAR 60 mg by IM injection every 4 weeks (N=113). LUTATHERA® was co-administered with an amino acid solution as a renal protectant, and in the US, patients received Aminosyn II 10%, a commercially available solution of amino acids. Well-differentiated tumors were defined as those with a Ki-67 by immunostaining of 20% or less. Tumors were assessed as low grade if they had a Ki-67 of 0-2%, intermediate grade if they had a Ki-67 of 3-20%, or high grade if they had a Ki-67 of greater than 20%, with a lower grade indicating a lower rate of cell proliferation. Baseline characteristics were well balanced between the two treatment groups. Enrolled patients had Somatostatin receptor-positive tumors and the primary site of the tumor was the ileum in 74% of the patients and the most common sites of metastasis were the liver (84%) and lymph nodes (66%). The Primary endpoint was Progression Free Survival (PFS) and Secondary endpoints included Objective Response Rates (ORR), Overall Survival (OS), and safety.

At the time of the primary analysis, it was noted that the median PFS was not reached for the LUTATHERA® group and was 8.5 months in the high-dose Octreotide LAR group (HR=0.21; P<0.001). This meant a 79% reduction in the risk of progression or death with LUTATHERA® compared with high dose Octreotide LAR. The estimated rate of PFS at month 20 was 65.2% in the LUTATHERA® group and 10.8% in the control group. The ORR with LUTATHERA® was 18% versus 3% with high dose Octreotide (P<0.001). The OS at the planned interim analysis showed a 60% reduction in the risk of death in favor of LUTATHERA® (HR=0.40; P=0.004). The most common grade 3/4 adverse reactions among patients receiving LUTATHERA® along with Octreotide LAR were nausea, vomiting, cytopenias, liver function abnormalities, hyperglycemia and hypokalemia.

It was concluded that treatment with LUTATHERA® resulted in significantly longer Progression Free Survival and a significantly higher Response Rate, when compared with high-dose Octreotide LAR, among patients with advanced midgut neuroendocrine tumors. Preliminary evidence suggests that there is an Overall Survival benefit as well. Phase 3 Trial of 177Lu-Dotatate for Midgut Neuroendocrine Tumors. Strosberg J, El-Haddad G, Wolin E, et al. for the NETTER-1 Trial Investigators. N Engl J Med 2017; 376:125-135