Lutetium Lu 177 Dotatate is a radio-conjugate consisting of the tyrosine-containing somatostatin analog Tyr3-octreotate (TATE) conjugated with the bifunctional, macrocyclic chelating agent tetra-azacyclododecanetetra-acetic acid (DOTA) and radiolabeled with the beta-emitting radioisotope lutetium Lu 177, with potential imaging and antineoplastic activities. Lutetium Lu 177 dotatate binds to somatostatin receptors (SSTRs), with high affinity to type 2 SSTR, present on the cell membranes of many types of neuroendocrine tumor (NET) cells. Upon binding and internalization, this radioconjugate specifically delivers a cytotoxic dose of beta radiation to SSTR-positive cells. Tyr3-octreotate (TATE) is an octreotide derivative in which phenylalanine at position 3 is substituted by tyrosine and at position 8 threoninol is replaced with threonine. SSTRs have been shown to be present in large numbers on NET and their metastases, while most other normal tissues express low levels of SSTRs.
Lutetium Lu 177–Edotreotide is a radio-conjugate consisting of the somatostatin analog edotreotide labeled with lutetium Lu 177 with potential antineoplastic activities. Lutetium Lu 177-edotreotide binds to somatostatin receptors (SSTRs), with high affinity to type 2 SSTR, present on the cell membranes of many types of neuroendocrine tumor cells. Upon binding and internalization, this radio-conjugate specifically delivers a cytotoxic dose of beta radiation to SSTR-positive cells. Edotreotide is produced by substituting tyrosine for phenylalanine at the 3 positions of the somatostatin analog octreotide (Tyr3-octreotide or TOC) and chelated by the bifunctional, macrocyclic chelating agent dodecane tetraacetic acid (DOTA).
A 177Lu-labeled somatostatin analog peptide, Lutetium Lu 177 dotatate belongs to an emerging form of treatment called Peptide Receptor Radionuclide Therapy (PRRT), which involves targeting tumours with molecules carrying radioactive particles that bind to specific receptors expressed by the tumour. Lutetium Lu 177 dotatate may also be referred to as 177Lu-DOTA-Tyr3-octreotate. Compared to the alternative somatostatin analogue DOTA-Tyr3-octreotide (dotatoc), Lutetium Lu 177 dotatate displays higher uptake of radioactivity in tumors and better residence times. In terms of biodistribution, Lutetium Lu 177 dotatate demonstrated lower whole-body retention, indicating a potentially lower risk for bone marrow toxicity. The presence of a radioligand allows monitoring of treatment response post-therapy and prior to the next fraction of the dose delivery which may be clinically beneficial in estimating the intensity of lesion uptakes or deciding the dose for subsequent administrations. Lutetium Lu 177 dotatate was approved by the FDA as Lutathera in January 2018 for intravenous injection. It is the first radiopharmaceutical agent to be approved for gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and is indicated for adult patients with somatostatin receptor-positive GEP-NETs. Targeting the pancreas and other parts of the gastrointestinal tract such as the intestines and colon, neuroendocrine tumors may commonly metastasize to the mesentery, peritoneum, and liver. Patients with GEP-NETs have limited second-line treatment options after the metastasis of tumors and inadequate therapeutic response from first-line therapies. In a clinical trial involving patients with advanced somatostatin receptor-positive GEP-NET, the treatment of Lutetium Lu 177 dotatate in combination with octreotide resulted in longer progression-free survival compared to patients receiving octreotide alone and there was evidence of an overall survival benefit.
Mechanism of Action
Somatostatin receptors (SSRT) are inhibitory G-protein coupled receptors that are ubiquitously expressed in normal and cancer cells. The natural ligand of SSRTs, somatostatin, is a potent inhibitory regulator of pituitary and gastrointestinal hormone release and proliferation. Advanced and well-differentiated neuroendocrine tumors express high levels of somatostatin receptors, especially somatostatin receptor type 2 (SSRT2), and have the ability to incorporate amines intracellularly and decarboxylate them. As an analog of somatostatin, Lutetium Lu 177 dotatate binds to somatostatin receptors with the highest binding affinity for SSRT2. Upon binding to SSRT-expressing cells, including malignant somatostatin receptor-positive tumors, the radiolabelled compound is internalized and the beta emission from the radioligand Lu 177 induces cellular damage by the formation of free radicals in somatostatin receptor-positive cells and in neighboring cells. As with other somatostatin analogs, Lu177 dotatate is expected to suppress the excessive secretion of amines and hormones, such as serotonin, from carcinoid tumors and certain types of endocrine pancreatic tumors (glucagonoma, VIPoma, and gastrinoma). The release of peptides and other gastrointestinal hormones important in tumor growth, including gastrin, cholecystokinin, and epidermal growth factor (EGF), may also be reduced through promoted somatostatin signaling pathways.
Clinically significant myelosuppression occurred in less than 10% of patients in the Lutetium Lu 177 dotatate (177Lu-Dotatate) group in one clinical trial. According to an open-label study involving 20 patients with somatostatin receptor-positive midgut carcinoid tumors, the treatment with did not result in any large changes in the mean QTc interval (i.e., >20 ms). Due to high expression of SSTR2, pancreas was the primary target in animal studies using a non-radioactive form of lutetium Lu 177 dotatate (lutetium Lu 175 dotatate).
Indications
- Indicated for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults.
- Lutathera is indicated for the treatment of unresectable or metastatic, progressive, well-differentiated (G1 and G2), somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP‑NETs) in adults.
- Gastroenteropancreatic Neuroendocrine Tumors
- It is a chelated complex of a radioisotope of the element lutetium with DOTA-TATE, used in peptide receptor radionuclide therapy (PRRT). Specifically, it is used in the treatment of cancers which express somatostatin receptors.[rx]
- Treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including foregut, midgut, and hindgut neuroendocrine tumors in adults.
Use in Cancer
Lutetium Lu 177-dotatate is approved to treat:
- Gastroenteropancreatic neuroendocrine tumors. It is used in adults whose cancer is somatostatin receptor positive.
Lutetium Lu 177-dotatate is also being studied in the treatment of other types of cancer.
Contraindications
- low amount of albumin proteins in the blood
- anemia
- decreased blood platelets
- low levels of a type of white blood cell called neutrophils
- high amount of bilirubin in the blood
- pregnancy
- a patient who is producing milk and breastfeeding
- chronic kidney disease stage 1 with mild signs of kidney damage
- chronic kidney disease stage 2 (mild)
- chronic kidney disease stage 3A (moderate)
- chronic kidney disease stage 3B (moderate)
- chronic kidney disease stage 4 (severe)
- chronic kidney disease stage 5 (failure)
- kidney disease with likely reduction in kidney function
Dosage
Strengths: 370 MBq/mL
Neuroendocrine Carcinoma
- Intravenous infusion: 7.4 GBq (200 mCi) every 8 weeks for a total of 4 doses.
- Discontinue long-acting somatostatin analogs (e.g., long-acting octreotide) for at least 4 weeks prior to initiating this drug. Administer short-acting octreotide as needed; discontinue at least 24 hours prior to initiating this drug.
- During treatment: Administer long-acting octreotide 30 mg intramuscularly 4 to 24 hours after each dose of this drug. Do not administer long-acting octreotide within 4 weeks of each subsequent dose. Short-acting octreotide may be given for symptomatic management during treatment with this drug, but must be withheld for at least 24 hours before each dose of this drug.
- Following treatment: Continue long-acting octreotide 30 mg intramuscularly every 4 weeks after completing this drug until disease progression or for up to 18 months following treatment initiation.
Antiemetic
- Administer antiemetics 30 minutes before the recommended amino acid solution.
Amino Acid Solution:
- Initiate an intravenous amino acid solution containing L-lysine and L-arginine 30 minutes before administering this drug.
- Use a three-way valve to administer amino acids using the same venous access as this drug or administer amino acids through a separate venous access in the patient’s other arm.
- Continue the infusion during, and for at least 3 hours after infusion of this drug.
- Do not decrease the dose of the amino acid solution if the dose of this drug is reduced.
- Dose modifications due to adverse reactions are provided in the dose adjustment section.
- Radiation Dosimetry: The maximum penetration in tissue is 2.2 mm and the mean penetration is 0.67 mm.
Renal Dose Adjustments
Mild to moderate renal dysfunction:
- No adjustment is recommended.
- Patients may be at greater risk of toxicity; frequent assessments of renal function should be performed.
Severe renal dysfunction (CrCl less than 30 mL/min) and ESRD: Safety has not been studied.
If creatinine clearance is less than 40 mL/min, 40% increase, or 40% decrease in baseline serum creatinine:
- Withhold dose until complete or partial resolution.
- Resume this drug at 3.7 GBq (100 mCi) in patients with complete resolution.
- If the reduced dose does not result in renal toxicity, administer this drug at 7.4 GBq (200 mCi) for the next dose.
- Permanently discontinue this drug for renal toxicity requiring a treatment delay of 16 weeks or longer.
- Recurrent renal toxicity: Permanently discontinue this drug.
Liver Dose Adjustments
Mild to moderate liver dysfunction: No adjustment is recommended.
Severe liver dysfunction (total bilirubin 3 times more the upper limit of normal and any AST): Safety has not been studied.
If bilirubinemia is greater than 3 times the upper limit of normal (Grades 3 or 4) or hypoalbuminemia is less than 30 g/L with a decreased prothrombin ratio of less than 70%:
- Withhold the dose until complete or partial resolution.
- Resume this drug at 3.7 GBq (100 mCi) in patients with complete resolution.
- If the reduced dose does not result in hepatotoxicity, administer this drug at 7.4 GBq (200 mCi) for next dose.
- Permanently discontinue this drug for hepatotoxicity requiring a treatment delay of 16 weeks or longer.
- Recurrent hepatotoxicity: Permanently discontinue this drug.
Dose Adjustments
Thrombocytopenia Grade 2, 3 or 4:
- Withhold dose until complete or partial resolution (Grade 0 to 1)
- Resume this drug at 3.7 GBq (100 mCi) in patients with complete or partial resolution.
- If the reduced dose does not result in Grade 2, 3 or 4 thrombocytopenia toxicity, administer this drug at 7.4 GBq (200 mCi) for the next dose.
- Permanently discontinue this drug for Grade 2 or higher toxicity requiring a treatment delay of 16 weeks or longer.
- Recurrent toxicity Grade 2, 3 or 4: Permanently discontinue this drug.
Anemia and Neutropenia Grade 3 or 4; Other Non-Hematologic Toxicity Grade 3 or 4:
- Withhold dose until complete or partial resolution: Anemia and Neutropenia (0, 1, or 2); Other Non-Hematologic Toxicity (0 to 2)
- Resume this drug at 3.7 GBq (100 mCi) in patients with complete or partial resolution.
- If the reduced dose does not result in Grade 3 or 4 toxicity, administer this drug at 7.4 GBq (200 mCi) for the next dose.
- Permanently discontinue this drug for Grade 3 or higher toxicity requiring a treatment delay of 16 weeks or longer.
- Recurrent Grade 3 or 4: Permanently discontinue this drug.
Administration advice:
- Handle appropriate safety measures to minimize radiation exposure.
- Use an aseptic technique, waterproof gloves, tongs, and radiation shielding when administering this drug.
- This drug should be used by or under the control of physicians qualified by specific training and experience in the safe use and handling of radiopharmaceuticals, and whose experience and training have been approved by the appropriate governmental agency authorized to license the use of radiopharmaceuticals.
- Do not administer as an intravenous bolus.
- During the infusion, ensure that the level of solution in the vial remains constant.
- The manufacturer’s product information should be consulted.
Reconstitution/preparation techniques:
- Do not inject directly into any other intravenous solution.
- Confirm the amount of radioactivity of this drug in the radiopharmaceutical vial with an appropriate dose calibrator prior to and after administration.
- Inspect the product visually for particulate matter and discoloration prior to administration under a shielded screen. Discard vial if particulates or discoloration are present.
- Dispose of any unused medicinal product or waste material in accordance with local and federal laws.
- The manufacturer’s product information should be consulted.
Patient advice:
- Patients should contact their healthcare provider for any signs or symptoms of myelosuppression or infection, such as fever, chills, dizziness, shortness of breath, or increased bleeding or bruising.
- There is a potential for secondary cancers, including myelodysplastic syndrome and acute leukemia.
- Patients should hydrate and urinate frequently during and after the administration of this drug.
- Periodic laboratory tests to monitor for hepatotoxicity is recommended.
- Patients should contact their healthcare provider for signs or symptoms that may occur following tumor-hormone release, including severe flushing, diarrhea, bronchospasm, and hypotension.
Side Effects
The Most Common
- dry mouth or throat
- nausea
- vomiting
- diarrhea
- constipation
- stomach pain
- decreased appetite
- decreased weight
- change in the ability to taste
- headache
- dry eye
- unusual tiredness or weakness, pale skin, dizziness, shortness of breath
- unusual bleeding or bruising
- fever, chills, sore throat, or other signs of infection
- mouth sores
- increased or decreased urination
- swelling of the arms, hands, feet, ankles, or lower legs
More common
- Agitation
- anxiety
- black, tarry stools
- bleeding gums
- blood in the urine or stools
- blurred vision
- chills
- cold sweats
- confusion
- cool, pale skin
- cough
- decreased urine output
- diarrhea
- difficulty in breathing
- dizziness
- dry mouth
- feeling of warmth
- fever
- flushed, dry skin
- fruit-like breath odor
- headache
- hoarseness
- hostility
- increased hunger
- increased thirst
- increased urination
- irritability
- joint pain, stiffness, or swelling
- loss of appetite
- loss of consciousness
- lower back, side, arm, leg, or stomach pain
- mood changes
- mood or mental changes
- muscle cramps in the hands, arms, feet, legs, or face
- muscle pain or twitching
- nausea
- nervousness
- nightmares
- numbness and tingling around the mouth, lips, hands, fingertips, or feet
- painful or difficult urination
- pale skin
- pinpoint red spots on the skin
- pounding in the ears
- rapid weight gain
- redness of the face, neck, arms, and occasionally, upper chest
- restlessness
- seizures
- shakiness
- slow, fast, or irregular heartbeat
- slurred speech
- sore throat
- sweating
- swelling of the face, feet, lower legs, ankles, or hands
- tremor
- troubled breathing
- troubled breathing with exertion
- ulcers, sores, or white spots in the mouth
- unexplained weight loss
- unusual bleeding or bruising
- unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness
- vomiting
- weakness or heaviness of the legs
Rare
- Bone pain
- chest pain or discomfort
- dilated neck veins
- dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
- extreme tiredness or weakness
- irregular breathing
- pain or discomfort in the arms, jaw, back, or neck
- swollen glands
- Constipation
- decreased appetite
- hair loss or thinning of the hair
- loss or change in taste
- Difficulty in moving
- neck pain
Drug Interactions
| DRUG | INTERACTION |
|---|---|
| Lanreotide | The therapeutic efficacy of Lutetium Lu 177 dotatate can be decreased when used in combination with Lanreotide. |
| Octreotide | The therapeutic efficacy of Lutetium Lu 177 dotatate can be decreased when used in combination with Octreotide. |
| Pasireotide | The therapeutic efficacy of Lutetium Lu 177 dotatate can be decreased when used in combination with Pasireotide. |
| Somatostatin | The therapeutic efficacy of Lutetium Lu 177 dotatate can be decreased when used in combination with Somatostatin. |
Pregnancy and Lactation
US FDA pregnancy category: Not assigned.
Pregnancy
The safety and efficacy of PLUVICTO have not been established in females. Based on its mechanism of action, PLUVICTO can cause fetal harm [see Clinical Pharmacology (12.1)]. There are no available data on PLUVICTO use in pregnant females. No animal studies using lutetium Lu 177 vipivotide tetraxetan have been conducted to evaluate its effect on female reproduction and embryo-fetal development; however, all radiopharmaceuticals, including PLUVICTO, have the potential to cause fetal harm
Lactation
Lutetium Lu 177 dotatate is a radiolabeled somatostatin analog indicated for the treatment of somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors. No information is available on the use of lutetium Lu 177 dotatate during breastfeeding. The manufacturer recommends that breastfeeding be discontinued during lutetium Lu 177 dotatate therapy and for 2.5 months following the last dose, which would usually mean permanently discontinuing breastfeeding of the current infant.
Why is this medication prescribed?
Lutetium Lu 177 vipivotide tetraxetan injection is used to treat a certain type of prostate cancer (cancer of a male reproductive gland) that has spread to other parts of the body and that has already been treated with other medications. Lutetium Lu 177 vipivotide tetraxetan is in a class of medications called radiopharmaceuticals. It works by targeting and delivering radiation directly to cancer cells which damages and kills these cells.
How should this medicine be used?
Lutetium Lu 177 vipivotide tetraxetan comes as a liquid to be given intravenously (into a vein) by a doctor or nurse in a hospital or clinic. It is usually injected slowly over 1 to 10 minutes or it may be infused slowly over up to 30 minutes. It may be given once every 6 weeks for up to 6 doses depending on how well your body responds to the medication and the side effects that you experience.
Your doctor will probably tell you to drink plenty of water before you receive lutetium Lu 177 vipivotide tetraxetan injection and to urinate as often as possible during the first hours after you receive a dose.
Your doctor may reduce your dose or temporarily or permanently stop your treatment. This depends on how well the medication works for you and the side effects you experience. Be sure to tell your doctor how you are feeling during your treatment with lutetium Lu 177 vipivotide tetraxetan. Ask your pharmacist or doctor for a copy of the manufacturer’s information for the patient. This medication may be prescribed for other uses; ask your doctor or pharmacist for more information.
What special precautions should I follow?
Before receiving lutetium Lu 177 vipivotide tetraxetan injection,
- tell your doctor and pharmacist if you are allergic to lutetium Lu 177 vipivotide tetraxetan, any other medications, or any of the ingredients in lutetium Lu 177 vipivotide tetraxetan injection. Ask your pharmacist for a list of the ingredients.
- tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
- tell your doctor if you often get any type of infection or if you think you may have any type of infection now. Also tell your doctor if have previously received radiation therapy or if you have or have ever had cancer; bleeding problems; anemia (a lower than normal number of red blood cells); abnormal blood levels of sodium, potassium, or calcium; or liver or kidney problems.
- you should know that lutetium Lu 177 vipivotide tetraxetan injection is for use only in men. If your female partner is not pregnant but could become pregnant, you and your partner must use birth control during your treatment and for 14 week after your final dose. If your partner becomes pregnant while you are receiving this medication, call your doctor. Lutetium Lu 177 vipivotide tetraxetan may harm the fetus.
- you should know that this medication may temporarily or permanently cause infertility in men. However, you should not assume that your female partner cannot become pregnant during your treatment.
- if you are having surgery, including dental surgery, tell the doctor or dentist that you are receiving lutetium Lu 177 vipivotide tetraxetan injection.
- you should minimize exposing other people to radiation after you receive a dose of lutetium Lu 177 vipivotide tetraxetan by limiting close contact with other people. Stay at least 3 feet away from household contacts for 2 days and from children and pregnant women for 7 days. You should also sleep in a separate bedroom apart from household contacts for 3 days, apart from children for 7 days, and apart from pregnant women for 15 days. You should also avoid sexual activity for 7 days after receiving a dose of lutetium Lu 177 vipivotide tetraxetan injection.
What special dietary instructions should I follow?
Make sure you drink plenty of water or other fluids while you are receiving lutetium Lu 177 vipivotide tetraxetan injection.
