FDA Approves ZEPZELCA (Lurbinectedin) for Adult Patients with Metastatic Small Cell Lung Cancer with Disease Progression on or after Platinum-Based Chemotherapy

On June 15, 2020, the U.S. Food and Drug Administration (FDA) approved ZEPZELCA (lurbinectedin) for the treatment of adult patients with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

The recommended dosage of ZEPZELCA is 3.2 mg/m2 by intravenous (IV) infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity. Initiate treatment with ZEPZELCA only if absolute neutrophil count (ANC) is at least 1,500 cells/mm3 and platelet count is at least 100,000/mm3. Additional information regarding dosage and administration, including dosage modifications for adverse reactions, as well as important warnings and precautions about myelosuppression, hepatotoxicity, and embryo-fetal toxicity can be found in the full prescribing information linked below.

Mechanism of Action (MOA) and Pharmacokinetics (PK)

MOA: Lurbinectedin is an alkylating drug.

General PK: Following the approved recommended dosage, geometric means (%CV) of plasma Cmax and AUC0-inf, were 107 μg/L (79%) and 551 μg•h/L (94%), respectively. No accumulation of lurbinectedin in plasma is observed upon repeated administrations every 3 weeks.

Distribution: The volume of distribution of lurbinectedin at steady state is 504 L (39%). Plasma protein binding is approximately 99%, to both albumin and α-1-acid glycoprotein.

Elimination: The terminal half-life of lurbinectedin is 51 hours. Total plasma clearance of lurbinectedin is 11 L/h (50%).

Metabolism: Lurbinectedin is metabolized by CYP3A4, in vitro.

Excretion: After a single dose of radiolabeled lurbinectedin administration, 89% of the radioactivity was recovered in feces (< 0.2% unchanged) and 6% in urine (1% unchanged).

Drug Interactions

Strong and Moderate CYP3A Inhibitors: Avoid coadministration of ZEPZELCA with strong or moderate CYP3A inhibitors. If the coadministration with a moderate CYP3A inhibitor cannot be avoided, consider dose reduction of ZEPZELCA as recommended, if clinically indicated. Coadministration with a strong or a moderate CYP3A inhibitor increases lurbinectedin systemic exposure, which may increase the incidence and severity of adverse reactions to ZEPZELCA.

Strong and Moderate CYP3A Inducers: Avoid coadministration of ZEPZELCA with strong or moderate CYP3A inducers. Coadministration with a strong CYP3A inducer decreases lurbinectedin systemic exposure,which may reduce ZEPZELCA efficacy.

Use in Specific Populations

No clinically significant differences in the pharmacokinetics of lurbinectedin were identified based on age (18-85 years), sex, body weight (39-154 kg), or mild to moderate renal impairment (CLcr 30 to 89 mL/min). The effects of severe renal impairment (CLcr < 30 mL/min) on the pharmacokinetics of lurbinectedin have not been studied.

Hepatic Impairment: No dose adjustment of ZEPZELCA is recommended for patients with mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1.0-1.5 × ULN and any AST). The effect of moderate or severe hepatic impairment (total bilirubin > 1.5 × ULN and any AST) on the pharmacokinetics of lurbinectedin has not been studied.

Efficacy and Safety

Efficacy of ZEPZELCA was demonstrated in a multicenter, open-label, multi-cohort trial evaluating ZEPZELCA as a single agent in patients with advanced or metastatic solid tumors. A cohort of patients with SCLC with disease progression on or after platinum-based chemotherapy received the approved recommended dosage of ZEPZELCA by IV infusion every 21 days until disease progression or unacceptable toxicity. The major efficacy outcome measure was confirmed investigator-assessed overall response rate (ORR). Additional information regarding the efficacy trial can be found in the full prescribing information linked below.

The most common adverse reactions (≥ 20%), including laboratory abnormalities, are leukopenia, lymphopenia, fatigue, anemia, neutropenia, increased creatinine, increased alanine aminotransferase, increased glucose, thrombocytopenia, nausea, decreased appetite, musculoskeletal pain, decreased albumin, constipation, dyspnea, decreased sodium, increased aspartate aminotransferase, vomiting, cough, decreased magnesium, and diarrhea.

Full prescribing information is available at https://go.usa.gov/xwMGx.

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This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.