On January 26, 2018, the radiolabeled somatostatin analog lutetium Lu-177 dotatate (Lutathera) was approved for the treatment of somatostatin receptor–positive gastroenteropancreatic neuroendocrine tumors, including foregut, midgut, and hindgut neuroendocrine tumors, in adults.^1,2

Supporting Efficacy Data

Approval was based on findings in the open-label phase III NETTER-1 trial, in which 229 patients with progressive, well-differentiated, locally advanced/inoperable or metastatic somatostatin receptor–positive midgut carcinoid tumors were randomized to receive lutetium Lu-177 dotatate at 7.4 GBq (200 mCi) every 8 weeks for up to 4 administrations (maximum cumulative dose of 29.6 GBq) with long-acting octreotide at 30 mg by intramuscular injection every 4 weeks (n = 116) or high-dose long-acting octreotide at 60 mg by intramuscular injection every 4 weeks (n = 113).^2,3 Lutetium 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.

Median progression-free survival on blinded independent radiology committee review using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 was not reached in the lutetium Lu-177 dotatate group vs 8.5 months in the high-dose long-acting octreotide group (hazard ratio [HR] = 0.21, P < .0001). Median overall survival in an updated analysis was not reached vs 27.4 months (HR = 0.52, 95% confidence interval [CI] = 0.32–0.84). Objective response rates were 13% vs 4% (P = .0148); median duration of response was not reached vs 1.9 months.

The efficacy of lutetium Lu-177 dotatate was also assessed in a subset of 360 patients (of a total of 1,214) in the ERASMUS Medical Center study; they had gastroenteropancreatic neuroendocrine tumors and were assessed according to RECIST. Lutetium Lu-177 dotatate was given at 7.4 GBq (200 mCi) every 6 to 13 weeks for up to 4 doses. The objective response rate was 16%.

How It Works

Lutetium Lu-177 dotatate binds to somatostatin receptors, with highest affinity for subtype 2 receptors. Upon binding to somatostatin receptor–expressing cells, including malignant somatostatin receptor–positive tumors, the compound is internalized. The beta emission from Lu-177 induces cellular damage by formation of free radicals in somatostatin receptor–positive cells and in neighboring cells.

How It Is Used

The recommended lutetium Lu-177 dotatate dose is 7.4 GBq (200 mCi) every 8 weeks for a total of 4 doses.

Long-acting somatostatin analogs should be discontinued for at least 4 weeks prior to starting lutetium Lu-177 dotatate. Short-acting octreotide can be given as needed but must be discontinued at least 24 hours prior to initiating treatment with lutetium Lu-177 dotatate.

During treatment, long-acting octreotide at 30 mg should be given intramuscularly between 4 to 24 hours after each lutetium Lu-177 dotatate dose. Long-acting octreotide should not be given within 4 weeks of each subsequent lutetium Lu-177 dotatate dose. Short-acting octreotide may be given for symptomatic management during treatment, but it must be withheld for at least 24 hours before each lutetium Lu-177 dotatate dose.

Following lutetium Lu-177 dotatate treatment, long-acting octreotide at 30 mg intramuscularly every 4 weeks should be continued until disease progression or for up to 18 months following treatment initiation. An intravenous amino acid solution containing L-lysine and L-arginine must be given 30 minutes before lutetium Lu-177 dotatate. Antiemetics should be given 30 minutes before the amino acid solution.

Product labeling provides detailed instructions for lutetium Lu-177 dotatate dose modification for thrombocytopenia, anemia, neutropenia, renal toxicity, hepatotoxicity, and other nonhematologic toxicity. Treatment should be permanently discontinued for grade ≥ 2 thrombocytopenia requiring a treatment delay of ≥ 16 weeks; recurrent grade 2, 3, or 4 thrombocytopenia; grade ≥ 3 anemia or neutropenia requiring a treatment delay of ≥ 16 weeks; recurrent grade 3 or 4 anemia or neutropenia; renal toxicity and hepatotoxicity requiring a treatment delay of ≥ 16 weeks; recurrent renal toxicity or hepatotoxicity; grade ≥ 3 nonhematologic toxicity requiring a treatment delay of ≥ 16 weeks; and recurrent grade ≥ 3 nonhematologic toxicity.

Safety Profile

In the NETTER-1 trial, the most common grade 3 or 4 adverse events occurring with greater frequency (at least 4%) among patients in the lutetium Lu-177 dotatate group vs the high-dose octreotide-alone group included lymphopenia (44% vs 4%), increased gamma-glutamyltransferase levels (20% vs 16%), vomiting (7% vs 0%), nausea (5% vs 2%), elevated aspartate transaminase levels (5% vs 0%), elevated alanine transaminase levels (4% vs 0%), hyperglycemia (4% vs 2%), and hypokalemia (4% vs 2%). Adverse events led to dose reduction in 6% of patients and treatment discontinuation in 13%, with discontinuation being due to renal events in five patients (4.5%) and hematologic toxicity in four patients (3.6%). Myelodysplastic syndrome was reported in 2.7% vs 0% of patients.

Lutetium Lu-177 dotatate carries warnings/precautions for risk from radiation exposure, myelosuppression, secondary myelodysplastic syndrome, and leukemia; renal toxicity; hepatotoxicity; neuroendocrine hormonal crisis; embryofetal toxicity; and risk for infertility. Blood cell counts must be monitored. Patients should be advised to urinate frequently during and after drug administration of lutetium Lu-177 dotatate, and serum creatinine and calculated creatinine clearance must be monitored. Liver transaminases, bilirubin, and albumin must be monitored. Patients should be monitored for flushing, diarrhea, hypotension, bronchoconstriction, and other signs/symptoms of neuroendocrine hormonal crisis.

Pregnancy status of females must be ascertained prior to treatment. Patients should be advised of the potential risk to a fetus and to use effective contraception. Patients should be advised not to breastfeed while receiving lutetium Lu-177 dotatate. ■

REFERENCES

1. U.S. Food and Drug Administration: FDA approves lutetium Lu 177 dotatate for treatment of GEP-NETS. Available at www.fda.gov/Drugs/-InformationOnDrugs/ApprovedDrugs/ucm594105.htm. Accessed February 27, 2018.

2. Lutathera (lutetium Lu 177 dotatate) injection prescribing information, Advanced Accelerator Applications USA, Inc, January 2018. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2018/208700s000lbl.pdf. Accessed February 27, 2018.

3. 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.