The First FDA-approved Peptide Receptor Radionuclide Therapy (PRRT)1,2
LUTATHERA® (lutetium Lu 177 dotatate) is a radiolabeled somatostatin analog1
LUTATHERA is a radiopharmaceutical created by linking a radionuclide to a peptide that binds somatostatin receptors on the surface of GEP-NET tumor cells.1,2
Mechanism of action of LUTATHERA1
LUTATHERA binds to somatostatin receptors, with highest affinity for subtype 2 receptors, that are expressed on the surface of GEP-NET cells.1,3 Upon binding to somatostatin receptor-expressing cells, LUTATHERA is internalized.1 The beta emission from LUTATHERA induces cellular damage by formation of free radicals in somatostatin receptor-positive cells and in neighboring cells.1
Efficacy and safety of LUTATHERA was demonstrated in NETTER-1, a randomized, multicenter, open-label, active-controlled Phase 3 trial1,2
Design of the NETTER-1 trial1,2
The primary endpoint was progression-free survival (PFS), defined as the time from randomization to documented disease progression (as evaluated per RECIST v1.1 by independent central review by radiologists who were unaware of the treatment) and death from any cause. Secondary endpoints were overall response rate (ORR), duration of response, and overall survival (OS).
Markedly longer progression-free survival (PFS) in the LUTATHERA arm vs the active control arm1,2
There was a 79% reduction in the risk of disease progression and death compared with high-dose, long-acting octreotide 60 mg (HR=0.21 [95% CI 0.13, 0.32], P<0.0001). Median PFS for the LUTATHERA arm was not reached, compared with 8.5 months with long-acting octreotide 60 mg.
PFS was defined as the time from randomization to documented disease progression (as evaluated per RECIST v1.1 by independent central review by radiologists who were unaware of the treatment) and death from any cause.
Three times greater overall response rate (ORR) in LUTATHERA arm vs active control arm1,2
There was a 13% ORR for LUTATHERA plus long-acting octreotide 30 mg compared with 4% ORR for high-dose, long-acting octreotide 60 mg (P=0.0148)—a 3-fold increase.
Complete response (CR) was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response (PR) was defined as ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Interim analysis of overall survival (OS)1
Results of an updated 2016 interim analysis: HR 0.52 (95% CI: 0.32, 0.84). The P-value did not meet the pre-specified threshold for significance in the interim analysis. The final analysis of OS is planned after 158 cumulative deaths or 5 years from first patient randomization.
Consistent efficacy across the following subgroups2
The progression-free survival benefit in the LUTATHERA arm was seen across the following pre-specified subpopulations when compared with high-dose, long-acting octreotide 60 mg.
5-HIAA, 5-hydroxyindoleacetic acid; CrCl, creatinine clearance; ENETS, European Neuroendocrine Tumor Society; IM, intramuscular; IV, intravenous; PFS, progression-free survival; ORR, overall response rate; OS, interim survival; RECIST, Response Evaluation Criteria in Solid Tumors; ULN, upper limit of normal.
References: 1. LUTATHERA® [prescribing information]. Millburn, NJ: Advanced Accelerator Applications USA, Inc.; July 2018. 2. Strosberg J, El-Haddad G, Wolin E, et al. Phase 3 trial of 177Lu-dotatate for midgut neuroendocrine tumors. N Engl J Med. 2017;376(2):125-135. 3. Delaunoit T, Rubin J, Neczyporenko F, Erlichman C, Hobday TJ. Somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine tumors. Mayo Clin Proc. 2005;80(4):502-506.
IMPORTANT SAFETY INFORMATION1
WARNINGS AND PRECAUTIONS
The most common Grade 3-4 adverse reactions (≥ 4% with a higher incidence in LUTATHERA arm) observed in NETTER-1 were lymphopenia (44%), increased GGT (20%), vomiting (7%), nausea (5%), elevated AST (5%), increased ALT (4%), hyperglycemia (4%), and hypokalemia (4%).
In ERASMUS, the following serious adverse reactions have been observed with a median follow-up time of more than 4 years after treatment with LUTATHERA: myelodysplastic syndrome (2%), acute leukemia (1%), renal failure (2%), hypotension (1%), cardiac failure (2%), myocardial infarction (1%), and neuroendocrine hormonal crisis (1%). Patients should be counseled and monitored in accordance with the LUTATHERA Prescribing Information.
Somatostatin and its analogs competitively bind to somatostatin receptors and may interfere with the efficacy of LUTATHERA. Discontinue long-acting somatostatin analogs at least 4 weeks and short-acting octreotide at least 24 hours prior to each LUTATHERA dose. Administer short- and long-acting octreotide during LUTATHERA treatment as recommended.
To report SUSPECTED ADVERSE REACTIONS, contact Advanced Accelerator Applications USA, Inc. at 1-844-863-19301-844-863-1930, or email@example.com, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Please see full Prescribing Information.
Distributed by: Advanced Accelerator Applications USA, Inc., NJ 07041
References: 1. LUTATHERA® [prescribing information]. Millburn, NJ: Advanced Accelerator Applications USA, Inc.; July 2018.