FDA Approves Radiopharmaceutical for Rare Gastrointestinal Cancers

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On January 26, 2018, the U.S. Food and Drug Administration (FDA) approved lutetium Lu-177 dotatate (Lutathera) for the treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The drug is indicated for adult patients with somatostatin receptor–positive GEP-NETs.

GEP-NETs can be present in the pancreas and in different parts of the gastrointestinal tract such as the stomach, intestines, colon, and rectum. It is estimated that approximately 1 out of 27,000 people are diagnosed with GEP-NETs per year.

Clinical Trials

LU-177 dotatate is a radioactive drug that works by binding to a somatostatin receptor, which may be present on the cells of certain tumors. After binding to the receptor, the drug enters the cell, allowing radiation to cause damage to the tumor cells.

The approval of Lu-177 dotatate was supported by two studies.1,2 The first study, NETTER-1, was 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 in the trial either received Lu-177 dotatate in combination with octreotide acetate (Sandostatin LAR) or octreotide alone. The study measured the duration of progression-free survival. Patients were randomized (1:1) to receive either 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). Lu-177 dotatate was coadministered with an amino acid solution as a renal protectant. In the United States, patients enrolled in NETTER-1 received Aminosyn II 10%, a commercially available solution of amino acids.

This approval provides another treatment choice for patients with these rare cancers [and] demonstrates how the FDA may consider data from therapies used in an expanded access program to support approval for a new treatment.
— Richard Pazdur, MD

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The major efficacy outcome measure was progression-free survival determined by a blinded independent radiology committee using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. The median progression-free survival was not reached for Lu-177 dotatate and was 8.5 months in the high-dose long-acting octreotide arm (hazard ratio = 0.21, 95% confidence interval = 0.13–0.32, P < .0001).

The efficacy of 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 assessed according to RECIST criteria. Lu-177 dotatate was initially provided through expanded access under a general peptide receptor radionuclide therapy protocol at a single site in the Netherlands. The drug was administered at a dose of 7.4 GBq [200 mCi]) every 6 to 13 weeks for up to 4 doses. The overall response rate was 16% (n = 58), including 3 complete responses.

Safety and Toxicity

Common side effects of Lu-177 dotatate included lymphopenia, increased levels of gamma-glutamyltransferase, aspartate aminotransferase, and/or alanine aminotransferase; vomiting; nausea; hyperglycemia; and hypokalemia. Serious side effects of Lu-177 dotatate included myelosuppression, secondary myelodysplastic syndrome and leukemia, renal toxicity, hepatotoxicity, neuroendocrine hormonal crises, and infertility.

Lu-177 dotatate can cause harm to a developing fetus; women should be advised of the potential risk to the fetus and to use effective contraception. Patients taking Lu-177 dotatate are exposed to radiation. Exposure of other patients, medical personnel, and household members should be limited in accordance with radiation safety practices.

“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 used in an expanded access program to support approval for a new treatment.”

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1. Strosberg J, El-Haddad G, Wolin E, et al: Phase 3 trial of 177Lu-Dotatate for midgut neuroendocrine tumors. N Engl J Med 376:125–135, 2017.

2. Van der Zwan WA, Bodei L, Mueller-Brand J, et al: GEPNETs update: Radionuclide therapy in neuroendocrine tumors. Eur J Endocrinol 172:R1–R8, 2015.