Lurbinectedin – Uses, Dosage, Side Effects, Interaction

Lurbinectedin exerts its chemotherapeutic activity by covalently binding to DNA, resulting in double-strand DNA breaks and subsequent cell death. Lurbinectedin has been associated with myelosuppression, and patients receiving therapy with this agent should be closely monitored for evidence of cytopenias. Prior to beginning therapy, ensure baseline? neutrophil? counts are >1,500 cells/mm³ and platelet? counts are >100,000/mm³. The supplementary use of granulocyte colony-stimulating factor (G-CSF) should be considered if the neutrophil count falls below 500 cells/mm³. Lurbinectedin has also been associated with hepatotoxicity. Monitor liver function tests at baseline and regular intervals throughout therapy, and consider holding, reducing, or permanently discontinuing therapy based on the severity of observed hepatotoxicity.

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According to PharmaMar,^[rx] lurbinectedin inhibits the active transcription of the encoding genes. This has two consequences. It promotes tumor cell death and normalizes the tumor microenvironment. Active transcription is the process by which there are specific signals where information contained in the DNA sequence is transferred to an RNA molecule. This activity depends on the activity of an enzyme called RNA polymerase II. Lurbinectedin inhibits transcription through a very precise mechanism. Firstly, lurbinectedin binds to specific DNA sequences. It is at these precise spots that slide down the DNA to produce RNA polymerase II that is blocked and degraded by lurbinectedin. Lurbinectedin also has an important role in the tumor microenvironment. The tumor cells act upon macrophages to avoid them from behaving like an activator of the immune system. Macrophages can contribute to tumor growth and progression by promoting tumor cell proliferation and invasion, fostering tumor angiogenesis, and suppressing antitumor immune cells.^[rx][rx] Attracted to oxygen-starved (hypoxic) and necrotic tumor cells they promote chronic inflammation?. So, not only that macrophages inhibit the immune system avoiding the destruction of tumor cells, but they also create tumor tissue that allows tumor growth. However, macrophages associated with tumors are cells that are addicted to the transcription process. Lurbinectedin acts specifically on the macrophages associated with tumors in two ways: firstly, by inhibiting the transcription of macrophages that leads to cell death, and secondly, by inhibiting the production of tumor growth factors. In this way, lurbinectedin normalizes the tumor microenvironment.

Use in Cancer

Lurbinectedin is approved to treat:

• Small cell lung cancer that is metastatic. It is used in adults whose disease has gotten worse during or after treatment with platinum chemotherapy.

This use is approved under FDA’s Accelerated Approval Program. As a condition of approval, a confirmatory trial(s) must show that lurbinectedin provides a clinical benefit in these patients.

Lurbinectedin is also being studied in the treatment of other types of cancer.

Contraindications

• an increased risk of bleeding
• decreased blood platelets
• low levels of a type of white blood cell called neutrophils
• liver problems
• abnormal liver function tests
• pregnancy
• a patient who is producing milk and breastfeeding
• increased creatine kinase levels

Dosage?

Strengths: 4 mg

Small Cell Lung Cancer

• 3.2 mg/m2 IV over 60 minutes every 21 days until disease progression or unacceptable toxicity
• Initiate this drug only if the absolute neutrophil count (ANC) is at least 1500 cells/mm3 and the platelet count is at least 100,000/mm3.
• Consider administering pre-infusion medications for antiemetic prophylaxis: Corticosteroids (e.g., dexamethasone 8 mg IV or equivalent) and serotonin antagonists (e.g., ondansetron 8 mg IV or equivalent). For the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy.

Dose Adjustments

DOSE REDUCTION:

• First dose reduction: 2.6 mg/m2 IV over 60 minutes every 21 days
• Second dose reduction: 2 mg/m2 IV over 60 minutes every 21 days

DOSE MODIFICATION FOR ADVERSE REACTIONS:
NEUTROPENIA? (patients with isolated Grade 4 neutropenia [neutrophil count less than 500 cells/mm3] may receive G-CSF prophylaxis rather than undergo dose reduction):

• Grade 4 or any Grade febrile neutropenia: Withhold therapy until resolved to Grade 1 or less; resume therapy at a reduced dose.

THROMBOCYTOPENIA?:

• Grade 3 with bleeding or Grade 4: Withhold therapy until platelet count is 100,000/mm3 or greater; resume therapy at a reduced dose.

HEPATOTOXICITY:

• Grade 2: Withhold therapy until Grade 1 or less; resume therapy at same dose.
• Grade 3 or greater: Withhold therapy until Grade 1 or greater; resume at reduced dose.

Administration advice:

• Advise patients to avoid grapefruit products during therapy with this drug.
• Read the approved patient labeling (Patient Information) before you receive this drug the first time and each subsequent dose.
• Do not become pregnant or breastfeed a child while taking this drug.
• Inform your healthcare providers of all concomitant medications, herbal. and dietary supplements.

Side Effects

The Most Common

• fatigue?
• nausea?
• vomiting?
• constipation?
• diarrhea?
• loss of appetite?
• muscle pain?
• headache?
• tingling, numbness, and pain in the hands and feet
• chest pain
• shortness of breath
• light-colored bowel movements, yellowing of the skin or eyes, loss of appetite, unusual bleeding or bruising, dark yellow or brown urine, or pain in the upper right part of the stomach
• fever, cough, chills, or other signs of infection
• tiredness or pale skin

More common

• Black, tarry stools
• bleeding gums
• bloody urine
• bone, joint, or muscle pain
• chest pain or tightness
• chills
• dark urine
• difficult or labored breathing
• fever
• the general feeling of discomfort or illness
• hoarseness
• loss of appetite
• lower back or side pain
• nausea
• painful or difficult urination
• pale skin
• pale stools
• pinpoint red spots on the skin
• sneezing
• sore throat
• stomach pain or tenderness
• thickening of bronchial secretions
• trouble breathing
• ulcers, sores, or white spots in the mouth
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting
• yellow eyes or skin

Rare

• Swelling of the feet or lower legs
• Muscle cramps, spasms, or stiffness
• pain, discomfort, itching, redness, or swelling at the injection site
• Burning, numbness, tingling, or painful sensations
• change in or loss of taste
• constipation
• diarrhea
• headache
• unsteadiness or awkwardness

Drug Interactions

Pregnancy and Lactation

Pregnancy

Based on animal data and its mechanism of action, ZEPZELCA can cause fetal harm when administered to a pregnant woman. There are no
available data to inform the risk of ZEPZELCA use in pregnant women. Intravenous administration of a single lurbinectedin dose (approximately 0.2 times the 3.2 mg/m2 clinical dose) to pregnant rats during the period of organogenesis caused embryo lethality. Advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth
defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Lactation

There are no data on the presence of lurbinectedin in human milk or its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions from ZEPZELCA in breastfed children, advise women not to breastfeed during treatment with
ZEPZELCA and for 2 weeks after the final dose.