Lurbinectedin, a synthetic tetrahydroisoquinoline alkaloid, is an alkylating antineoplastic agent.1, 2, 7, 8
Lurbinectedin is used for the treatment of metastatic small cell lung cancer (SCLC) that has progressed during or following chemotherapy with a platinum-based regimen.1 Lurbinectedin has been designated an orphan drug by the FDA for treatment of this cancer.5 The accelerated approval of lurbinectedin for this indication is based on overall response rate and duration of response.1 Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory studies.1
The current indication for lurbinectedin is based principally on the results from a cohort of patients with metastatic SCLC in a multicenter, open-label phase 2 study (Study B-005; NCT02454972) evaluating lurbinectedin monotherapy in patients with advanced or metastatic solid tumors.1 This cohort included 105 adults with metastatic SCLC that had progressed on or following chemotherapy with a platinum-based regimen.1, 2 Patients received lurbinectedin (3.2 mg/m2 administered by IV infusion every 21 days) until disease progression or unacceptable toxicity occurred.1, 2 The primary efficacy end point was confirmed investigator-assessed overall response rate; additional outcome measures included duration of response and overall response rate according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) as evaluated by an independent review committee.1 The median age of patients in the SCLC cohort was 60 years (range: 40-83 years); 75% of patients were white, 1% were Asian, and 1% were Black; 60% were male; 92% were former or current smokers; and 92% had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.1 All patients in the cohort had received at least 1 prior line of platinum-based chemotherapy and 71% had received prior radiation therapy; 57% of patients had platinum-sensitive disease (defined as disease progression or recurrence ≥90 days following the last dose of platinum-containing chemotherapy).1 Although baseline CNS involvement was an exclusion criterion for the study, 1 patient in the SCLC cohort had CNS metastasis at baseline;2 the study also excluded patients with grade ≥3 dyspnea, hepatitis, or cirrhosis, and those who were immunocompromised.1
At a median follow-up of 17.1 months, the overall response rate with lurbinectedin as assessed by the investigator in the SCLC cohort was 35% (45% in patients with platinum-sensitive disease and 22% in patients with platinum-resistant disease [defined as disease recurrence or progression <90 days following the last dose of platinum-containing chemotherapy]); there were no complete responses.1, 2 Overall, the median duration of response was 5.3 months (6.2 or 4.7 months in patients with platinum-sensitive or platinum-resistant disease, respectively).1 A durable response of at least 6 months was achieved in 35% of patients overall (44% of patients with platinum-sensitive disease and 10% of patients with platinum-resistant disease).1 These results were confirmed by blinded independent review; the overall response rate as assessed by the independent review committee was 30% (43 or 13% in patients with platinum-sensitive or platinum-resistant disease, respectively) and the median duration of response was 5.1 months (5.3 or 4.8 months in patients with platinum-sensitive or platinum-resistant disease, respectively).1, 3
Dispensing and Administration Precautions
Lurbinectedin is administered by IV infusion over 60 minutes via a central or peripheral venous line.1 The commercially available lyophilized drug must be reconstituted and diluted prior to administration.1
Store unopened vials of lurbinectedin powder for injection at 2-8°C.1
Prior to administration, lurbinectedin lyophilized powder for injection must be reconstituted and diluted using proper aseptic technique.1 Reconstitute the powder by adding 8 mL of sterile water for injection to a vial labeled as containing 4 mg of lurbinectedin to provide a solution containing 0.5 mg/mL.1 Shake the vial until complete dissolution of the powder, and visually inspect the solution for particulate matter and discoloration.1 The reconstituted solution should be clear, colorless or slightly yellowish, and essentially free of visible particulates.1
For administration through a peripheral venous line, withdraw the appropriate volume of reconstituted solution from the vial and add to an infusion container containing at least 250 mL of 0.9% sodium chloride injection or 5% dextrose injection.1
For administration through a central venous line, withdraw the appropriate volume of reconstituted solution from the vial and add to an infusion container containing at least 100 mL of 0.9% sodium chloride injection or 5% dextrose injection.1
Inspect the final diluted solution for particulate matter and discoloration prior to administration; do not administer if particulate matter is observed.1
If not used immediately after reconstitution or dilution, the solution can be stored prior to administration for up to 24 hours following reconstitution (including infusion time) at either room temperature/ambient light or under refrigeration at 2-8º C.1
Consult manufacturer's labeling for additional details on preparation and administration of the drug.1
For the treatment of metastatic small cell lung cancer (SCLC) that has progressed during or following therapy with platinum-based chemotherapy, the recommended adult dosage of lurbinectedin is 3.2 mg/m2 by IV infusion over 60 minutes once every 21 days.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Dosage Modification for Toxicity
If adverse reactions occur during lurbinectedin therapy, temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of the drug may be necessary.1 If dosage reduction is required, the dosage of lurbinectedin should be reduced as described in Table 1.1
Lurbinectedin should be permanently discontinued in patients who are unable to tolerate a dose of 2 mg/m2 or require a dose delay of more than 2 weeks.1
Toxicity Occurrence | Dosage Modification After Recovery from Toxicity |
|---|---|
First | 2.6 mg/m2 every 21 days |
Second | 2 mg/m2 every 21 days |
Third | Permanently discontinue therapy |
Recommended dosage modifications for neutropenia, thrombocytopenia, and hepatotoxicity are presented in Table 2.1
Toxicity | Dosage Modification |
|---|---|
Neutropenia | Grade 4 or any grade febrile neutropenia: Withhold therapy; when toxicity improves to grade ≤1, resume at reduced dosage (see Table 1) |
| In patients with isolated grade 4 neutropenia (neutrophil count <500/mm3), G-CSF prophylaxis may be administered rather than reducing dosage of lurbinectedin |
Thrombocytopenia | Grade 3 with bleeding or grade 4: Withhold therapy; when platelet count improves to ≥100,000/mm3, resume at reduced dosage (see Table 1) |
Hepatotoxicity | Grade 2: Withhold therapy; when toxicity improves to grade ≤1, resume at same dosage |
| Grade 3 or 4: Withhold therapy; when toxicity improves to grade ≤1, resume at reduced dosage (see Table 1) |
Dosage adjustment is not necessary in patients with mild hepatic impairment (total bilirubin concentration ≤ upper limit of normal [ULN] with AST concentration > ULN, or total bilirubin concentration 1-1.5 times the ULN with any AST concentration).1
The effect of moderate or severe hepatic impairment (total bilirubin concentration >1.5 times the ULN with any AST concentration) on the pharmacokinetics of lurbinectedin has not been established, and the manufacturer makes no specific dosage recommendations for such patients.1
Dosage adjustment is not necessary in patients with renal impairment.3
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Severe myelosuppression, including neutropenia, thrombocytopenia, and anemia may occur with lurbinectedin.1 In clinical studies of patients with advanced solid tumors receiving lurbinectedin, grade 3 or 4 neutropenia occurred in 41% of patients, with a median time to onset of 15 days and a median duration of 7 days.1 Febrile neutropenia and sepsis were reported in 7 and 2%, respectively, of patients receiving the drug.1, 3 Fatal sepsis occurred in 3 (0.54%) patients.6 All cases of sepsis occurred in patients with solid tumors other than small cell lung cancer (SCLC).3
Grade 3 or 4 thrombocytopenia occurred in 10% of patients, with a median time to onset of 10 days and a median duration of 7 days.1 Grade 3 or 4 anemia occurred in 17% of patients.1
Monitor blood counts, including neutrophil count and platelet count, prior to each dose of lurbinectedin.1 Temporary interruption, dosage reduction, or discontinuance of lurbinectedin may be necessary based on the severity of the findings.1 Lurbinectedin should not be administered to patients with absolute neutrophil count (ANC) <1500/mm3 or platelet count <100,000/mm3.1 Use of a granulocyte colony-stimulating factor (G-CSF) is recommended for neutrophil counts <500/mm3 or below the lower limit of normal.1
Hepatotoxicity may occur with lurbinectedin.1 In clinical studies of patients with advanced solid tumors receiving lurbinectedin, grade 3 elevations in serum ALT and AST concentrations were reported in 6 and 3% of patients, respectively, and grade 4 elevations were observed in 0.4 and 0.5% of patients, respectively.1 The median time to development of grade 3 or 4 elevations in serum ALT or AST concentrations was 8 days (range: 3-49 days), with a median duration of 7 days.1
Perform liver function tests prior to initiation of lurbinectedin, periodically during therapy with the drug, and as clinically indicated.1 Temporary interruption, dosage reduction, or discontinuance of lurbinectedin may be necessary based on the severity of the findings.1
Fetal/Neonatal Morbidity and Mortality
Lurbinectedin may cause fetal harm based on its mechanism of action and animal findings.1 There are no data regarding use of lurbinectedin in pregnant women.1 In rats, IV administration of a single dose of lurbinectedin at approximately 0.2 times the recommended human dose during the period of organogenesis resulted in 100% embryolethality.1
Avoid pregnancy during lurbinectedin therapy.1 (See Females and Males of Reproductive Potential under Cautions.)
Apprise patients of the potential hazard to the fetus if lurbinectedin is used during pregnancy.1
Lurbinectedin may cause fetal harm based on its mechanism of action and animal findings.1 Advise pregnant women of the potential risk to the fetus.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
It is not known whether lurbinectedin is distributed into human milk.1 The effects of the drug on breast-fed infants or on the production of milk are unknown.1 Because of the potential for serious adverse reactions to lurbinectedin in breast-fed infants, advise women not to breast-feed while receiving the drug and for 2 weeks after the last dose.1
Females and Males of Reproductive Potential
Verify pregnancy status in women of reproductive potential prior to initiation of therapy, and advise such women to use effective contraceptive methods while receiving lurbinectedin and for 6 months after the last dose of the drug.1 In addition, men with female partners of reproductive potential should use effective contraceptive methods while receiving lurbinectedin and for 4 months after the last dose of the drug.1
Safety and efficacy of lurbinectedin have not been established in pediatric patients.1
In the principal efficacy study in 105 patients receiving lurbinectedin for the treatment of SCLC, 35% of patients were ≥65 years of age and 9% were ≥75 years of age.1 No overall difference in efficacy was observed between geriatric patients and younger adults; however, serious adverse effects occurred more frequently in patients ≥65 years of age compared with younger adults (49% versus 26%).1
Serious adverse reactions most frequently reported in geriatric patients were related to myelosuppression (i.e., febrile neutropenia, neutropenia, thrombocytopenia, and anemia).1
Clinically important differences in the pharmacokinetics of lurbinectedin based on age (18-85 years) have not been observed.1
In population pharmacokinetic analyses, mild hepatic impairment (total bilirubin concentrations ≤ upper limit of normal [ULN] with AST concentration > ULN, or total bilirubin concentration 1-1.5 times the ULN with any AST concentration) did not have clinically important effects on the pharmacokinetics of lurbinectedin.1
The effect of moderate or severe hepatic impairment (total bilirubin concentrations >1.5 times the ULN with any AST concentration) on the pharmacokinetics of lurbinectedin has not been evaluated.1
Renal excretion of lurbinectedin is minimal.1, 3 In population pharmacokinetic analyses, mild to moderate renal impairment (creatinine clearance of 30-89 mL/minute) did not have clinically important effects on the pharmacokinetics of lurbinectedin.1
The effect of severe renal impairment (creatinine clearance <30 mL/minute) on the pharmacokinetics of lurbinectedin has not been evaluated.1
The most common adverse effects reported in ≥20% of patients receiving lurbinectedin in clinical studies include leukopenia, lymphopenia, fatigue, anemia, neutropenia, increased creatinine, increased ALT/AST, increased glucose, thrombocytopenia, nausea, decreased appetite, musculoskeletal pain, decreased albumin, constipation, dyspnea, decreased sodium, vomiting, cough, decreased magnesium concentrations, and diarrhea.1
Lurbinectedin is metabolized by cytochrome P-450 (CYP) isoenzyme 3A4.1
In vitro studies indicate that lurbinectedin does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4 and does not induce CYP1A2 or CYP3A4.1
Lurbinectedin is a substrate of P-glycoprotein (P-gp; multidrug resistance protein 1 [MDR1]) in vitro, but is not a substrate of organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, or multidrug and toxic compound extrusion protein (MATE) 1.1
Lurbinectedin inhibits P-gp, OATP1B1, OATP1B3, and OCT1, but not breast cancer resistance protein (BCRP), bile salt export pump (BSEP), MATE1, organic anion transporter (OAT) 1, OAT3, or OCT2.1
Drugs and Foods Affecting Hepatic Microsomal Enzymes
Formal drug interaction studies with lurbinectedin and drugs affecting CYP3A have not been conducted to date.1
Concomitant use of lurbinectedin and moderate or potent inhibitors of CYP3A may result in increased systemic exposure to lurbinectedin and increased risk of lurbinectedin toxicity.1
Avoid concomitant use of lurbinectedin and moderate or potent CYP3A inhibitors.1 If concomitant use of lurbinectedin and a moderate CYP3A inhibitor cannot be avoided, the manufacturer states that dosage reduction of lurbinectedin may be considered, if clinically indicated.1
Consumption of grapefruit juice, a CYP3A inhibitor, during lurbinectedin therapy may result in increased systemic exposure to lurbinectedin and increased risk of lurbinectedin toxicity.1, 10 Avoid consumption of grapefruit juice or products containing grapefruit during lurbinectedin therapy.1
Concomitant use of lurbinectedin with a potent CYP3A inducer may result in decreased systemic exposure to lurbinectedin and reduced lurbinectedin efficacy.1
Avoid concomitant use of lurbinectedin and moderate or potent CYP3A inducers.1
Lurbinectedin, a synthetic tetrahydroisoquinoline alkaloid, is an alkylating antineoplastic agent.1, 2, 7, 8 The drug is structurally similar to trabectedin which was originally isolated from the marine tunicate Ecteinascidia turbinata .7, 8 Lurbinectedin forms covalent adducts with guanine residues in the minor groove of DNA, which induces bending of the DNA helix toward the major groove.1, 3, 7, 8 This adduct formation triggers a cascade of events that can alter the subsequent actions of DNA binding proteins, including some transcription factors and DNA repair pathways, resulting in double-strand breaks, cell growth arrest, and apoptosis.1, 7, 8 Lurbinectedin demonstrated antiproliferative activity in vitro and in xenograft models of human cancers.3, 7, 8 The drug also inhibited human monocyte activity in vitro and reduced tumor macrophage infiltration in mouse xenograft models1, 9 which included a lurbinectedin-resistant cell line, indicating direct effects of lurbinectedin on the tumor microenvironment.9
Following repeated IV administration of lurbinectedin every 3 weeks, plasma accumulation is not observed.1 The drug is approximately 99% bound to plasma proteins (albumin and α1-acid glycoprotein).1 Lurbinectedin is metabolized by cytochrome P-450 (CYP) isoenzyme 3A4.1, 3 Following administration of a radiolabeled dose of lurbinectedin, 89% of total radioactivity was recovered in feces and 6% in urine (<0.2 and 1%, respectively, as unchanged drug).1 The terminal half-life of lurbinectedin is 51 hours.1
The pharmacokinetics of lurbinectedin do not appear to be affected substantially by age (18-85 years), sex, or body weight (39-154 kg).1
Additional Information
Overview® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Lurbinectedin is available through a specialty pharmacy network.4 Consult the Zepzelca® website for additional information ([Web]).4
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection, for IV infusion only | 4 mg | Zepzelca® | Jazz |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions March 31, 2022. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Jazz Pharmaceuticals, Inc. Zepzelca® (lurbinectedin) for injection prescribing information. Palo Alto, CA; 2021 Oct. [Web]
2. Trigo J, Subbiah V, Besse B et al. Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. Lancet Oncol . 2020; 21:645-654. [PubMed 32224306]
3. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 213702Orig1s000: Multi-discipline review. From FDA website. [Web]
4. Jazz Pharmaceuticals. Ordering Information for Zepzelca®. From Zepzelca website. Accessed 2021 Feb 24. [Web]
5. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2021 Feb 24. [Web]
6. Jazz Pharmaceuticals, Inc. Personal communication.
7. Leal JF, Martínez-Díez M, García-Hernández V et al. PM01183, a new DNA minor groove covalent binder with potent in vitro and in vivo anti-tumour activity. Br J Pharmacol . 2010; 161:1099-110. [PubMedCentral][PubMed 20977459]
8. Santamaría Nuñez G, Robles CM, Giraudon C et al. Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells. Mol Cancer Ther . 2016; 15:2399-2412. [PubMed 27630271]
9. Belgiovine C, Bello E, Liguori M et al. Lurbinectedin reduces tumour-associated macrophages and the inflammatory tumour microenvironment in preclinical models. Br J Cancer . 2017; 117:628-638. [PubMedCentral][PubMed 28683469]
10. Food and Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers. From FDA website. Accessed 2021 Mar 12. [Web]