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).

Inclusion criteriaExclusion criteria
  • Patients with midgut NET that had metastasized or were locally advanced, that were inoperable, and had progressed during treatment with long-acting octreotide
  • Karnofsky performance score ≥60 (median score: 90)1
  • Tumor with well-differentiated histologic features (Ki67 index ≤20%)
  • Confirmed presence of somatostatin receptors on all target lesions (somatostatin receptor scintigraphy uptake ≥normal liver)
  • Patients must have progressive disease based on RECIST criteria, version 1.1 while receiving an uninterrupted fixed dose of octreotide LAR (20-30 mg/3-4 weeks)
  • CrCl ≥50 mL/min
  • No prior treatment with PRRT
  • No prior external radiation therapy to >25% of the bone marrow
  • Serum creatinine level >150 μmol/L or CrCl <50 mL/min
  • Hemoglobin level <8.0 g/dL
  • White-cell count <2,000/mm3
  • Platelet count <75,000/mm3
  • Total bilirubin level >3x ULN
  • Serum albumin ≤3.0 g/dL, unless the prothrombin time value was within normal range
  • Treatment with >30 mg long-acting octreotide within 12 weeks before randomization
  • PRRT at any time before randomization
  • Any surgery, liver-directed transarterial therapy, or chemotherapy within 12 weeks before randomization
Inclusion criteria
  • Patients with midgut NET that had metastasized or were locally advanced, that were inoperable, and had progressed during treatment with long-acting octreotide
  • Karnofsky performance score ≥60 (median score: 90)1
  • Tumor with well-differentiated histologic features (Ki67 index ≤20%)
  • Confirmed presence of somatostatin receptors on all target lesions (somatostatin receptor scintigraphy uptake ≥normal liver)
  • Patients must have progressive disease based on RECIST criteria, version 1.1 while receiving an uninterrupted fixed dose of octreotide LAR (20-30 mg/3-4 weeks)
  • CrCl ≥50 mL/min
  • No prior treatment with PRRT
  • No prior external radiation therapy to >25% of the bone marrow
Exclusion criteria
  • Serum creatinine level >150 μmol/L or CrCl <50 mL/min
  • Hemoglobin level <8.0 g/dL
  • White-cell count <2,000/mm3
  • Platelet count <75,000/mm3
  • Total bilirubin level >3x ULN
  • Serum albumin ≤3.0 g/dL, unless the prothrombin time value was within normal range
  • Treatment with >30 mg long-acting octreotide within 12 weeks before randomization
  • PRRT at any time before randomization
  • Any surgery, liver-directed transarterial therapy, or chemotherapy within 12 weeks before randomization

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.

Progression-Free Survival in NETTER-1
PFSLUTATHERA Plus Long-Acting
Octreotide (30mg) (n=116)		Long-Acting Octreotide (60 mg)
(n=113)
Events, n (%)27 (23%)78 (69%)
Progressive disease, n (%)15 (13%)61 (54%)
Deaths, n (%)12 (10%)17 (15%)
Progression-Free Survival in NETTER-1
PFSLUTATHERA Plus Long-Acting
Octreotide (30mg) (n=116)		Long-Acting Octreotide (60 mg)
(n=113)
Events, n (%)27 (23%)78 (69%)
Progressive disease, n (%)15 (13%)61 (54%)
Deaths, n (%)12 (10%)17 (15%)
aAt time of prespecified analysis

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.; 2020. 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 INFORMATION

WARNINGS AND PRECAUTIONS

  • Radiation Exposure: Treatment with LUTATHERA contributes to a patient’s overall long-term cumulative radiation exposure and is associated with an increased risk for cancer. Radiation can be detected in the urine for up to 30 days following LUTATHERA administration. Minimize radiation exposure to patients, medical personnel, and household contacts during and after treatment with LUTATHERA consistent with institutional good radiation safety practices, patient management procedures, Nuclear Regulatory Commission patient-release guidance, and instructions to the patient for follow-up radiation protection at home.
  • Myelosuppression: In NETTER-1 clinical trial, myelosuppression occurred more frequently in patients receiving LUTATHERA with long acting octreotide at the following rates (all grades/grade 3 or 4): anemia (81%/0), thrombocytopenia (53%/1%), and neutropenia (26%/3%). Blood cell counts must be monitored prior to, during, and after treatment. Withhold, reduce dose, or permanently discontinue based on severity of myelosuppression.
  • Secondary Myelodysplastic Syndrome and Leukemia: In NETTER-1, with a median follow-up time of 24 months, myelodysplastic syndrome (MDS) was reported in 2.7% of patients receiving LUTATHERA with long-acting octreotide. In ERASMUS, a Phase II clinical study, 16 patients (2%) developed MDS and 4 (0.5%) developed acute leukemia. The median time to the development of MDS was 28 months (9 to 41 months) and 55 months (32 to 155 months) for acute leukemia.
  • Renal Toxicity: Treatment with LUTATHERA will expose kidneys to radiation, which may impair renal function. In ERASMUS <1% of patients developed renal failure 3 to 36 months following LUTATHERA. Monitor serum creatinine and creatinine clearance to assess changes in renal function. Advise patients to urinate frequently during and after administration of LUTATHERA. A concomitant intravenous infusion of amino acids before, during, and after LUTATHERA administration is mandatory for renal protection. Patients with baseline renal impairment may be at greater risk of toxicity. Perform more frequent assessments of renal function in patients with mild or moderate impairment. Withhold, reduce dose, or permanently discontinue based on severity of renal toxicity. Do not decrease the dose of amino acid solution if the dose of LUTATHERA is reduced. LUTATHERA has not been studied in patients with severe renal impairment (CrCL < 30 mL/min).
  • Hepatotoxicity: In ERASMUS, <1% of patients were reported to have hepatic tumor hemorrhage, edema, or necrosis, with one patient experiencing intrahepatic congestion and cholestasis. Patients with hepatic metastasis may be at increased risk of hepatotoxicity due to radiation exposure. Monitor transaminases, bilirubin, and serum albumin during treatment. Withhold, reduce dose, or permanently discontinue based on severity of hepatic impairment.
  • Neuroendocrine hormonal crisis: Manifesting with flushing, diarrhea, bronchospasm and hypotension, neuroendocrine hormonal crisis occurred in <1% of patients in ERASMUS and typically occurred during or within 24 hours following the initial LUTATHERA dose. Monitor patients for flushing, diarrhea, hypotension, bronchoconstriction or other signs and symptoms of tumor-related hormonal release. Administer intravenous somatostatin analogs, fluids, corticosteroids, and electrolytes as indicated.
  • Embryo-Fetal Toxicity: LUTATHERA can cause fetal harm. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 7 months after the final dose. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 months after the final dose. Verify pregnancy status of females of reproductive potential prior to initiating LUTATHERA.
  • Risk of Infertility: LUTATHERA may cause infertility in males and females. Radiation absorbed by testes and ovaries from the recommended cumulative LUTATHERA dose falls within the range in which temporary or permanent infertility can be expected following external beam radiotherapy.

ADVERSE REACTIONS

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.

DRUG INTERACTIONS

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.

Corticosteroids can induce down-regulation of subtype 2 somatostatin receptors (SSTR2). Avoid repeated administration of high doses of glucocorticosteroids during treatment with LUTATHERA.

SPECIFIC POPULATIONS

  • Lactation: Because of the potential risk for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment with LUTATHERA and for 2.5 months after the final dose.

To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or www.report.novartis.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

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