Lurbinectedin

Approved Indication:

• Metastatic Small Cell Lung Cancer (SCLC):
  Indicated for the treatment of adult patients with metastatic SCLC whose disease has progressed on or after platinum-based chemotherapy.

Clinically Accepted Off-label Uses (Under Clinical Evaluation):

• Recurrent ovarian cancer (particularly platinum-resistant cases)
• Ewing sarcoma
• Malignant pleural mesothelioma
• Endometrial cancer
• Breast cancer (triple-negative subtype)

Note: These off-label uses are under investigation in clinical trials and not yet part of routine clinical practice.

Adults (Metastatic SCLC):

• Dose: 3.2 mg/m²
• Route: Intravenous (IV) infusion over 60 minutes
• Frequency: Once every 21 days (every 3 weeks)
• Premedication: Recommended use of antiemetics (e.g., dexamethasone, 5-HT3 antagonist) before infusion.

Special Populations:

• Renal Impairment:
• Mild to Moderate: No dose adjustment required.
• Severe (CrCl <30 mL/min): Not studied; avoid use.
• Hepatic Impairment:
• Mild (Child-Pugh A): Use with caution.
• Moderate to Severe (Child-Pugh B/C): Not recommended.
• Geriatrics (≥65 years):
  No specific dose adjustment required, but monitor closely due to increased risk of adverse effects.
• Pediatrics:
  Safety and efficacy not established in individuals under 18 years of age.

Dose Adjustments:

• Hematologic Toxicities (e.g., Grade 3–4 neutropenia, thrombocytopenia):
• Withhold or delay dose until recovery.
• Resume at a reduced dose: 2.6 mg/m² or 2.0 mg/m² depending on severity.
• Non-Hematologic Toxicities (e.g., liver enzyme elevation):
• Temporarily discontinue or reduce the dose accordingly.

Lurbinectedin is a selective inhibitor of oncogenic transcription. It binds to guanine residues in the minor groove of DNA, forming adducts that cause DNA strand breaks and inhibit RNA polymerase II activity. This leads to inhibition of active transcription in tumor cells and promotes apoptosis. Additionally, Lurbinectedin alters the tumor microenvironment by reducing the infiltration of tumor-associated macrophages, which are known to support tumor progression and immune evasion.

• Absorption: Administered intravenously; complete systemic availability.
• Distribution: Extensive tissue distribution; volume of distribution ~504 L. Plasma protein binding: >99%.
• Metabolism: Primarily metabolized by hepatic CYP3A4 enzymes.
• Active Metabolites: No known clinically significant active metabolites.
• Elimination:
• Fecal excretion: ~89%
• Renal excretion: ~6%
• Half-life: Approximately 51 hours
• Time to Peak Concentration (Tmax): At the end of the 1-hour infusion

• Pregnancy:
• Not assigned to an FDA category under the new PLLR labeling.
• Based on mechanism of action and animal studies, Lurbinectedin may cause fetal harm.
• Contraindicated during pregnancy.
• Women of reproductive potential should use effective contraception during treatment and for at least 6 months after the last dose.
• Male patients with female partners should use contraception during treatment and for 4 months after the last dose.
• Lactation:
• Unknown if excreted in human breast milk.
• Due to potential for serious adverse reactions in infants, breastfeeding is not recommended during treatment and for at least 2 weeks after the last dose.

• Primary Class: Antineoplastic Agent
• Subclass: Selective Transcription Inhibitor
• Chemical Family: Tetrahydroisoquinoline alkaloid derivative

• Known hypersensitivity to Lurbinectedin or any component of the formulation
• Severe hepatic impairment (Child-Pugh B or C)
• Pregnancy
• Breastfeeding
• Concurrent use with strong CYP3A4 inhibitors or inducers without appropriate monitoring or adjustment

• Myelosuppression: High risk of severe neutropenia, leukopenia, and thrombocytopenia.
• Monitor complete blood counts (CBC) prior to each dose.
• Consider prophylactic G-CSF in patients with high neutropenic risk.
• Hepatotoxicity:
• Transient elevations in liver enzymes (AST/ALT) are common.
• Monitor LFTs regularly.
• Infections:
• Due to immunosuppression, monitor for signs of sepsis or other infections.
• Prompt treatment is essential.
• Tumor Lysis Syndrome (TLS):
• Rare but possible in high tumor burden cases; monitor electrolytes and renal function.
• Drug Interactions:
• Avoid use with strong CYP3A4 inhibitors/inducers.
• Consider dose modifications if interaction is unavoidable.
• Embryo-Fetal Toxicity:
• Can cause fetal harm; contraindicated in pregnancy.

Common Adverse Effects (>20%):

• Hematologic: Neutropenia, anemia, thrombocytopenia
• Gastrointestinal: Nausea, vomiting, constipation, decreased appetite
• General: Fatigue, musculoskeletal pain
• Hepatic: Elevated AST/ALT

Less Common (<10%):

• Peripheral edema
• Febrile neutropenia
• Infections (e.g., pneumonia, urinary tract infections)

Serious Adverse Effects:

• Grade 3–4 neutropenia and thrombocytopenia
• Sepsis or septic shock
• Hypersensitivity reactions (rare)
• Pneumonitis or respiratory distress (rare)

Note: Hematologic toxicities are typically dose-dependent and peak around 10–15 days after administration.

• Strong CYP3A4 Inhibitors (e.g., ketoconazole, clarithromycin):
  ↑ Lurbinectedin levels → ↑ risk of toxicity
  → Avoid or monitor and consider dose reduction.
• Strong CYP3A4 Inducers (e.g., rifampin, phenytoin):
  ↓ Efficacy due to reduced drug exposure
  → Avoid use.
• Grapefruit Juice:
  May inhibit CYP3A4 → ↑ plasma concentration → Avoid.
• Alcohol:
  No direct interaction, but may increase risk of hepatotoxicity.

• FDA Accelerated Approval:
• Approved in June 2020 for metastatic SCLC based on response rate and duration.
• Continued approval may be contingent upon confirmatory trials.
• NCCN Guidelines:
• Lists Lurbinectedin as a second-line option for metastatic SCLC.
• EMA & NICE Status:
• Conditional review status in the EU and UK; subject to more trial data.
• Ongoing Clinical Trials:
• Being evaluated in combination with immune checkpoint inhibitors and other chemotherapies in various solid tumors.

• Unopened Vials:
• Store at 2°C to 8°C (refrigerated)
• Keep in the original carton to protect from light
• Do not freeze
• Reconstituted/Prepared Solution:
• Should be used immediately or stored at 2°C to 8°C for up to 24 hours
• Do not shake
• Inspect visually for particulates or discoloration before use