Lurbinectedin - Indication, Mechanism, Adverse Effects, and Precaution

Overview

Lurbinectedin is an alkylating agent prescribed to treat adults with a type of lung cancer named small-cell lung cancer. So, it is used as a second-line treatment of small cell lung cancer (SSLC), which has been metastasized (spread) to variant parts of the system and in cases showing no improvements during or after platinum chemotherapy. The Lurbinectedin is available in power for solution form to be administered intravenously by direct supervision of doctors. The drug inhibits the tumor cells and their activity, modifying the tumor habitat.

Lurbinectedin gained food and drug administration (FDA) approval on June 15, 2020, for its medical use. The approval was significantly based on its clinical effects, such as duration of response, overall response rate, and safety profile. This is the first drug approved in the past twenty years as the second-line intervention in metastatic small-cell lung cancer. Moreover, the drug Lurbinectedin encompasses indications in people presenting platinum-resistance conditions.

How Does Lurbinectedin Work?

Lurbinectedin is an antineoplastic agent that functions by inhibiting the transcription of oncogenic activity. So, it holds two processes that result in this consequence. They promote tumor cell breaks and regulation of the tumor environment. First, Lurbinectedin inhibits and suppresses the active transcription process by a defined means. Transcriptase is the process in which distinct signals of the DNA are carried to the RNA via the RNA polymerase enzyme. So, the Lurbinectedin first binds to the DNA sequences. Then, the process of transfer through the enzyme is inhibited and degraded.

In addition, Lurbinectedin is vital in the tumor environment as it is the secondary process. Here, the Lurbinectedin influences the macrophages associated with the tumor since tumor cells can affect macrophages on its activation to the immune system, and macrophages, in turn, are attributable to the tumor progression.

Prescriptions -

• Lurbinectedin is prescribed for treating a metastatic form of small cell lung cancer (SCLC) with the progression of the disease. It is also used during or after chemotherapy or in cases where the therapeutic intervention doesn’t work effectively.

Drug and Its Dosage

Route of Administration.

The drug Lurbinectedin is administered using an intravenous injection.

Drug Form and Strengths.

• Lyophilized powder for injection.

• 4 mg in a single-dose vial.

Drug Dosage for Small Cell Lung Cancer.

The recommended dosage in adults is 3.2 mg/ IV q 21 days in people with metastatic small cell lung cancer. So, the recommended flat dose is 4 mg (milligram) in the integrated regimen. Nevertheless, drug therapy is initiated after monitoring specific blood counts that should include relevant and desired results.

• Platelet count greater than or equal to 100,000/mm³

• Absolute neutrophil count less than or equals 1,500 cells/mm³

The doctors might alter the dosage based on the severity of the condition, blood results, and adverse reactions. However, the medication therapy is generally carried on until the progression.

What Are the Precautions for Lurbinectedin in Specified Populations?

• Allergy - Cautions should be taken if one is allergic to Lurbinectedin or any ingredients in the prescribed panel. Also, consider allergies to food, preservatives, dyes, dust, or animals.

• Pregnancy - The mechanism of the drug based on the animal data prevails that the drug Lurbinectedin can harm the fetus but with no evidence elaborating the actual risks. So, the injection is not recommended for both parents considering pregnancy. The pregnancy status of women's reproductive potential is confirmed preceding the treatment. Effective contraception or birth control is recommended in men and women during the treatment and for certain months after the final dose.

• Breastfeeding - There prevail inadequate studies about the effects of Lurbinectedin on infants while breastfeeding. However, considering the adverse reactions, breastfeeding is not advised during and for several weeks after the last dose.

• Pediatrics - The safety and efficacy of the drug in the pediatric population are not yet established.

• Geriatrics - The studies and findings are less evidence describing the effects of Lurbinectedin in older adults, so the geriatric problems are not proven. Nevertheless, caution is to be taken into account as the drug might cause undesirable effects in them, including blood and bone marrow concerns.

• Hepatic Impairment - The interaction of the drug in cases of moderate and severe hepatic impairment is not yet completely established. However, dosage modifications are to be considered. And so, liver function must be monitored regularly. No dosage modification is required in midland forms of hepatic impairment.

For Patients

What Are the Effects of Small Cell Lung Cancer (SCLC)?

Small-cell lung cancer, also referred to as small-cell carcinoma, is a rare yet rapid-growing lung cancer. Small-cell lung cancer affects about 57 in 100,000 United States people. It can occur in anyone, but it seems more prevalent among tobacco smokers. Small-cell lung cancer results when the healthy cells in the lung transmute and multiply into tumor cells. Small cell carcinoma is generally seen in the central airways that influence and infiltrate the lung's submucosa lining.

Symptoms of Small Cell Lung Cancer -

Therefore, bronchial (breathing tube) narrowing results, presenting the following symptoms.

• Shortness of breath.

• Blood mucus from the lungs.

• Wheezing.

• Chest pain or discomfort.

• Persistent cough.

• Hoarse voice.

• Loss of appetite.

• Fatigue.

• Loss in weight.

• Swelling of neck veins.

How Does Small Cell Lung Cancer Metastasize?

The initial form of small cell lung cancer at the lung clumps and is carried through the blood and lymph pathways to the other parts of the system. So, this cancer is aggressive and usually begins in the bronchial tube. Then, it further multiplies, grows, and accumulates into large tumors, spreading all around the body. Common sites of small cell lung cancer metastasis include the liver, bones, brain, and adrenal glands. About 70% of minor cell lung cancer conditions develop into metastasis.

How Does Lurbinectedin Treat Metastatic Small Cell Lung Cancer?

Small-cell lung cancer is primarily suspected with chest X-ray, computed tomography (CT) scan, needle biopsy, and bronchoscopy. The treatment options include surgery, radiation therapy, chemotherapy, immunotherapy, and palliative care which is prescribed based on age and severity of the condition.

Lurbinectedin injection is prescribed and used to treat small cell lung cancer that has metastasized or spread and showing no improvement during and after platinum chemotherapy. Lurbinectedin is an alkylating agent that inhibits the active transcription genes. Consequently, it suppresses the tumor macrophages and their activity, thus modifying the tumor environment.

How Is the Drug Lurbinectedin Used?

• Doctors and other healthcare professionals administer the Lurbinectedin injection into the vein in medical or hospital settings.

• So, the powder is mixed with the liquid proportionally and injected intravenously over one hour.

• The Lurbinectedin injection is generally prescribed once every 21 days. But, the doctors modify the length of the therapy considering the person’s reaction toward the drug.

• A few medications in the form of tablets or infusions are given before the Lurbinectedin injection in an effort to prevent vomiting and nausea.

• The doctors generally advise blood and liver function tests before and during the treatment, as Lurbinectedin can cause fluctuations in blood count.

• The doctors might reduce the dose or advise discontinuing the treatment in accordance with the side effects.

Things to Consider and Inform the Doctor.

People receiving Lurbinectedin should precisely check the progress during the treatment to prevent adverse reactions.

• One should inform the doctor if one is allergic to Lurbinectedin or other ingredients.

• Also, allergies to other drugs should be informed formally.

• Convey the doctor about the additional medications, nutritional supplements, and vitamins one takes.

• Paramountly, inform the doctor about the present and past medical illnesses.

• Inform the doctor if one has or once had kidney and liver diseases.

• Also, concentrate on blood and urine tests per the doctor’s advice.

• Report to the doctor in times of pregnancy or plans of pregnancy, as the drug Lurbinectedin can harm the unborn child from either of the parents. So, one must show a negative pregnancy result before initial treatment.

• Women should not take Lurbinectedin injections while pregnant. In addition, women should prevent pregnancy with effective birth control aids for a minimum of six months following the final dose.

• Men should use birth control aids to prevent pregnancy with their partners. The aids are to be used for a minimum of four months following the final dose of Lurbinectedin.

• Call and inform the doctor if one or the partner gets pregnant during Lurbinectedin treatment.

• One should not breastfeed during and for at least two weeks with the injection therapy.

• No other medications are to be taken without the doctor’s consent whatsoever as prescription, non-prescription, or herbal drugs.

Dietetic Considerations:

One should avoid grapefruit, grape juice, or foodstuffs containing grapes, as it might interact with the drug Lurbinectedin and cause undesired reactions. In addition, a well-balanced, healthy diet paves the way for good physical, emotional, and social states.

What if One Misses the Dose of Lurbinectedin?

Call the doctor immediately and inform them if the appointment for a Lurbinectedin injection has been missed. The doctors will advise on withholding or rescheduling.

In Cases of Overdose of Lurbinectedin:

Overdosage is unlikely as the administration is given in hospital settings. However, reach out to the emergency helpline services in case of overdosage or emergency concerns like a seizure, collapse, and difficulty breathing.

How Effective Is Lurbinectedin?

Lurbinectedin, on appropriate dosage, yields an antitumor efficacy by inhibiting the oncogenic activity by inducing double-strand breaks and amending the tumor environment. So, the studies and clinical trials showed desirable outcomes on Lurbinectedin as a single drug in the second-line intervention of small-cell lung cancer, with or without the downgrade of first-line therapy. Hence, Lurbinectedin is considered a novel anti-cancer agent.

Side Effects:

Lurbinectedin is a safe and effective drug. Unfortunately, it might cause specific side effects, and one should convey to healthcare professionals if these symptoms seem not relieving.

• Nausea.

• Vomiting.

• Constipation.

• Diarrhea.

• Fatigue.

• Headache.

• Muscular pain.

• Reduced or loss of appetite.

• Cough.

• Loss of taste.

• Burning, numbness, or tingling sensations.

• A decline in blood cell counts.

• Increased urination.

• Abnormal blood results.

Serious Side Effects:

The drug might include serious side effects. In any of these cases, one must immediately contact the doctor or seek medical attention.

• Shortness of breath.

• Chest pain and discomfort.

• Easy bruising and unusual bleeding.

• Red or purple spots in the skin.

• Decreased white blood cell count shows skin sores, fever, cough, sore throat, and difficulty breathing.

• A decline in red blood cells shows signs of anemia - tiredness, pale skin, lightheadedness, and chill extremities.

• Signs of sepsis or infection include fever, chills, illnesses, dizziness, rapid heartbeat, and rapid breathing.

• Liver concerns- stomach pain, decreased or loss of appetite, jaundice, dark-colored urine, abnormal bowel movements, and clay-colored stools.

For Doctors

Clinical Data of Lurbinectedin.

Generic Name: Lurbinectedin.

Drug Class: Antineoplastic Agent.

Formula: C14H44N4O10S.

Molar Mass: 784.88 g.mol-1.

Indications

Lurbinectedin is indicated in treating metastatic phases of small cell lung cancer (SCLC) with the condition's progression during or after platinum-based chemotherapy.

What Is the Pharmacology of Lurbinectedin?

Chemistry:

The chemical structure of Lurbinectedin resembles the drug trabectedin in many ways. However, the tetrahydroisoquinoline of trabectedin is substituted with tetrahydro B-carboline in the Lurbinectedin.

Mechanism of Action:

Lurbinectedin belongs to the class of drugs called antineoplastic agents. So, it is a DNA alkylating drug that covalently binds to guanine residues in the minor grooves of DNA. This results in the formation of adducts, bending the DNA helix directed toward the major groove. This action, in turn, triggers a cascade of events that all influence the transcriptase factor's activities and deteriorate the DNA regeneration pathways. Finally, the process culminates in double-strand DNA breaks with cell death.

In addition, the following mechanisms also effectuate the therapy.

• Inhibition of RNA polymerase and its activity.

• Inactivation of EWS-FL11, Ewing sarcoma oncoprotein through nuclear redistribution.

• Inhibition of specific activities into the tumor tissue, including human monocyte and macrophage infiltration.

Pharmacodynamics:

• The pharmacodynamic course on the efficacy of Lurbinectedin is not yet completely defined.

• However, the incidence of a grade less than or equal to 3 thrombocytopenia and grade 4 neutropenia is increased with increased exposure to Lurbinectedin.

Absorption:

• The peak plasma concentration is 107 mcg/mL after intravenous administration.

• Whereas the AUC is 551 mcg hr/L.

• There has been no accumulation of the drug between the dosing intervals.

• No substantial differences are noticed in the absorption concerning distinct populations based on age, race, ethnicity, and sex.

Distribution:

• The volume of distribution at steady state is 504L.

• The protein binding of Lurbinectedin is about 99% towards albumin and A-1 acid glycoprotein, as it presents a high-protein binding potential in plasma.

Metabolism:

• CYP3A4 chiefly metabolizes Lurbinectedin in vitro.

Elimination:

• Following single-dose Lurbinectedin, approximately 89% in feces (<0.2% unchanged) and about 6% in urine (1 percent unchanged).

• The terminal half-life is 51 hours.

• The plasma clearance is about 11L/hr.

Adverse Effects:

• Leukopenia.

• Lymphopenia.

• Fatigue.

• Anemia.

• Neutropenia.

• Increased creatinine.

• Increased glucose.

• Increased alanine aminotransferase.

• Thrombocytopenia.

• Nausea.

• Decreased appetite.

• Decreased albumin.

• Musculoskeletal pain.

• Constipation.

• Dyspnea.

• Decreased sodium.

• Increased aspartate aminotransferase.

• Vomiting.

• Cough.

• Diarrhea.

• Decreased magnesium level.

Essential Considerations of Lurbinectedin Based on Adverse Effects.

Myelosuppression - The drug Lurbinectedin can cause myelosuppression. Findings from studies reveal the adverse reactions among patients with advanced tumors receiving the medication, including grade 3 or grade 4 neutropenia, febrile neutropenia, thrombocytopenia, grade 3 or 4 thrombocytopenia, and anemia. Therefore, monitoring the neutrophil and platelet count before each intravenous administration is significant. So, Lurbinectedin should be administered only to patients with baseline blood counts of 1,500 cells/mm3 for neutrophils and 100,000/mm3 for platelets. Hold, diminish the dosage or discontinue in cases of blood count less than the average measure.

Extravasation Precipitates Tissue Necrosis - Lurbinectedin can cause extravasation in the skin and soft tissue, precipitating tissue necrosis, and usually seeks debridement. So, the following consideration is to be taken.

• Central venous catheters can prevent extravasation, especially in people with limited infiltration.

• Stop the infusion and remove the catheter in case of extravasation. In addition, look for the signs of tissue necrosis.

• Supportive care and attention must be given as the means of extravasation.

• Also, the consequent dosage and infusion will be administered at the non-extravasation sites.

Hepatotoxicity - Hepatotoxicity can result from Lurbinectedin following grade 3 or 4 of ALT, AST, and transaminase. Therefore, liver function tests should be monitored before, during, or on clinical-based with Lurbinectedin therapy. Hold, diminish the dosage or discontinue in cases of severity.

Rhabdomyolysis - Studies present that rhabdomyolysis might result from Lurbinectedin therapy. So, the creatinine phosphatase measure should be tracked before, during, or on indication with Lurbinectedin therapy. Then, hold, diminish the dosage or discontinue in cases of severity.

Fetal Toxicity - Lurbinectedin can cause harm to the fetus during the administration of pregnancy. So, the potential risks and complications should be conveyed to pregnant women.

Lactation - Limited studies and data are enlightening the effects of Lurbinectedin in lactation. Nevertheless, cautions are to be taken by means of informing not to breastfeed during and for two weeks with Lurbinectedin administration.

What Are the Drug Interactions of Lurbinectedin?

Studies reveal the effects of other drugs on Lurbinectedin. They include the following.

• Potent and Moderate CYP3A Inhibitors - Lurbidectedin in co administration with strong and moderate CYP3A inhibitors results in increased systemic exposure to Lurbinectedin. Avoidance of such co-administration should be considered. In case of required coadministration, consider lowering the dosage of Lurbinectedin.

• Potent and Moderate CYP3A Inducers - The coadministration of Lurbinectedin and potent CYP3A inducers diminishes Lurbinectedin systemic exposure. This might culminate in decreased efficacy of Lurbinectedin. So, this co-administration should be avoided.

How Far Have Clinical Trials Proven the Safety and Efficacy of Lurbinectedin?

The clinical trial established and demonstrated the use of Lurbinectedin in second-line treatment for patients having small-cell lung cancer. The phase-2 study evaluated the safety and efficacy of Lurbinectedin in people with small-cell lung cancer who showed failures in the first line of platinum-based chemotherapy. The trial was on single-arm, and open-label matriculated patients from about twenty-six hospitals. The patients were pathologically determined with SCLC, as stated by the response criteria. The intervention constituted the one-hour intravenous administration of 3.2 mg/m2 of the drug Lurbinectedin up until the progression of the disease and unfavorable toxicity. Finally, all the patients were monitored for activity, efficacy, and safety.

Results

Lurbinectedin was considered a second-line intervention for small-cell lung cancer in terms of overall healthy responses. In addition, the favorable and manageable safety profile has been determined. The most common adverse effects studied were thrombocytopenia, anemia, neutropenia, and leukopenia. Therefore, it is concluded that Lurbinectedin could illustrate the potential monotherapy for metastatic small-cell lung cancer.