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The FDA has approved the new drug application (NDA) for lutetium Lu 177 dotatate for the treatment of somatostatin receptor positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults.

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Lutetium Lu 177 dotatate, which received orphan drug designation from the FDA, is a first-in-class drug and the first available FDA-approved Peptide Receptor Radionuclide Therapy, a form of targeted treatment comprising a targeting molecule that carries a radioactive component.


NETs are rare tumors originating in the neuroendocrine cells of numerous organs, including the gastrointestinal tract, pancreas, and lung. Some patients develop symptoms arising from the excessive production of hormones by neuroendocrine tumor cells, while others remain clinically silent for years. The estimated incidence, or rate of new cases of NETs, in the U.S. is approximately 6.98/100,000 per year, while the estimated prevalence for 2014, based on the NCI's SEER database, was 171,321. Patient survival with advanced GEP-NETs depends on stage and histology. Patients with well-differentiated and moderately differentiated tumors and distant metastases have a 5-year survival probability of 35 percent.


The approval of lutetium Lu 177 dotatate is based on results of the randomized, pivotal, phase III NETTER-1 study that compared treatment using lutetium Lu 177 dotatate plus best standard of care (octreotide LAR 30mg every 4 weeks) to 60 mg of octreotide LAR alone (also dosed every 4 weeks) in patients with inoperable midgut NETs progressing under standard dose octreotide LAR treatment and overexpressing somatostatin receptors, as well as a subset of efficacy and safety data from an international, single-institution, single-arm, open-label trial conducted by Erasmus Medical Center in Rotterdam, Netherlands, in more than 1,200 patients with somatostatin receptor positive tumors.


Jonathan Strosberg, MD, Associate Professor, Section Head, Neuroendocrine Tumor Program at Moffitt Cancer Center, Tampa, Fla., and NETTER-1 lead investigator, commented, "There are very few effective treatment options for patients with inoperable, advanced GEP-NETs who are progressive on somatostatin analogues. As a medical oncologist seeing more than 500 patients with NETs each year, I am grateful to have another tool in my arsenal."


The NETTER-1 study met its primary endpoint, showing a 79 percent reduction in risk of disease progression or death in the lutetium Lu 177 dotatate arm compared to the 60 mg octreotide LAR arm (HR 0.21, 95% CI: 0.13-0.32; p<0.0001). Median PFS was not reached in the lutetium Lu 177 dotatate arm compared to 8.5 months for the 60 mg octreotide LAR arm. A pre-planned interim overall survival analysis determined that lutetium Lu 177 dotatate treatment lead to a 48 percen reduction in the estimated risk of death (hazard ratio 0.52, 95% CI: 0.32-0.84) compared to treatment with 60 mg octreotide LAR. The objective response rate, composed of complete and partial responses, was 13 percent for the lutetium Lu 177 dotatate arm compared to 4 percent in the octreotide LAR 60mg arm (p<0.0148).


The most common grade 3/4 adverse reactions occurring with a greater frequency among patients in the NETTER-1 study receiving lutetium Lu 177 dotatate with octreotide compared to patients receiving high-dose octreotide include lymphopenia (44%); increased gamma-glutamyl transferase (20%); vomiting (7%); nausea and elevated aspartate aminotransferase (5% each); and increased alanine aminotransferase, hyperglycemia, and hypokalemia (4% each).


"GEP-NETs are a rare group of cancers with limited treatment options after initial therapy fails to keep the cancer from growing," said Richard Pazdur, MD, Director of the FDA's Oncology Center of Excellence and Acting Director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research. "This approval provides another treatment choice for patients with these rare cancers. It also demonstrates how the FDA may consider data from therapies that are used in an expanded access program to support approval for a new treatment."