Zepzelca
(Lurbinectedin)Dosage & Administration
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Zepzelca Prescribing Information
Dosage and Administration 04/2025
ZEPZELCA is indicated 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
The efficacy of ZEPZELCA in combination with intravenous (IV) atezolizumab was evaluated in IMforte (NCT05091567), a randomized, multicenter, open-label study in patients with first-line extensive-stage small cell lung cancer (ES-SCLC). Patients were eligible if their disease had not progressed after completion of four cycles of atezolizumab, carboplatin and etoposide (induction treatment) and their Eastern Cooperative Oncology Group (ECOG) performance status was 0 or 1. The trial excluded patients with CNS metastases, history of autoimmune disease, or administration of systemic immunosuppressive medications within 1 week prior to enrollment. Unless contraindicated, primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) was mandated for patients assigned to the ZEPZELCA with atezolizumab arm.
The trial randomized 483 patients who had not experienced disease progression following the completion of 4 cycles of intravenous atezolizumab with carboplatin and etoposide 1:1 to one of the following treatment arms:
• ZEPZELCA 3.2 mg/m2IV with atezolizumab 1200 mg IV once every 3 weeks until disease progression or unacceptable toxicity, or• Atezolizumab 1200 mg IV once every 3 weeks until disease progression or unacceptable toxicity
Randomization was stratified by ECOG performance status prior to randomization (0 vs. 1), lactate dehydrogenase (LDH) (≤ ULN vs. > ULN) prior to randomization, presence of liver metastases prior to initial study enrollment (yes vs. no), and prior receipt of prophylactic cranial irradiation (yes vs. no).
The major efficacy outcome measures were overall survival (OS) and progression-free survival (PFS) by Independent Review Facility (IRF) per RECIST v1.1.
A total of 483 patients were randomized, including 242 to the ZEPZELCA with atezolizumab arm and 241 to the atezolizumab arm. The median age was 66 years (range 35 to 85); 63% male; 82% White, 13% Asian, 0.8% were Black or African American; 7% were of Hispanic or Latino ethnicity; and 98% were current or previous smokers. Baseline ECOG performance status was 0 (43%) or 1 (57%).
Efficacy results are presented in Table 7 and Figures 1 and 2.
| 1Measured from the time of randomization | ||
| 2Stratified by ECOG performance status, LDH level, presence of liver metastases and prior receipt of prophylactic cranial irradiation | ||
| 3Based on the two-sided stratified log-rank test | ||
| 4As determined by IRF | ||
| 5per RECIST v1.1 (Response Evaluation Criteria in Solid Tumors v1.1) | ||
| 6Compared to the allocated alpha of 0.0313 (two-sided) for this interim OS analysis. | ||
| 7Compared to the allocated alpha of 0.001 (two- sided) for this final PFS analysis. | ||
| CI=confidence interval | ||
ZEPZELCA with Atezolizumab N=242 | Atezolizumab N=241 | |
Overall Survival1 | ||
Deaths (%) | 113 (47%) | 136 (56%) |
Median, months | 13.2 | 10.6 |
(95% CI) | (11.9, 16.4) | (9.5, 12.2) |
Hazard ratio2(95% CI) | 0.73 (0.57, 0.95) | |
p-value3, 6 | 0.0174 | |
Progression-Free Survival1,4,5 | ||
Number of events (%) | 174 (72%) | 202 (84%) |
Median, months | 5.4 | 2.1 |
(95% CI) | (4.2, 5.8) | (1.6, 2.7) |
Hazard ratio2(95% CI) | 0.54 (0.43, 0.67) | |
p-value3, 7 | < 0.0001 | |
PM1183-B-005-14 (Study B-005; NCT02454972) is 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 small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy received ZEPZELCA 3.2 mg/m2by intravenous infusion every 21 days (one cycle). Patients received a median of 4 cycles of ZEPZELCA (range 1 to 24 cycles). The trial excluded patients with central nervous system (CNS) involvement, grade ≥ 3 dyspnea, daily intermittent oxygen requirement, hepatitis or cirrhosis, and immunocompromised patients. Tumor assessments were conducted every 6 weeks for the first 18 weeks and every 9 weeks thereafter. The major efficacy outcome measure was confirmed investigator-assessed overall response rate (ORR). Additional efficacy outcome measures included duration of response (DoR), and an Independent Review Committee (IRC) assessed ORR using Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
A total of 105 patients with SCLC who progressed on or after platinum-based chemotherapy were enrolled. The median age was 60 years (range: 40 to 83) with 65% of patients < 65 years and 35% of patients ≥ 65 years, and 60% were male. The majority (75%) of the patients were White, 1% were Asian, 1% were Black and 23% were not reported. Baseline ECOG performance status was 0 or 1 in 92% of patients, and 92% were former/current smokers. All patients received at least one line of platinum-based chemotherapy (range 1-2 lines), and prior radiotherapy had been administered to 71% of patients. Eight patients (8%) had prior immunotherapy in addition to platinum-based chemotherapy. Sixty patients (57%) had platinum-sensitive SCLC, defined as recurrence or progression ≥ 90 days after the last dose of platinum-containing therapy (chemotherapy free interval [CTFI] ≥ 90 days). The remaining 45 patients had platinum-resistant SCLC, defined as recurrence or progression < 90 days after the last dose of platinum-containing therapy (CTFI < 90 days).
Table 8 summarizes investigator-assessed and independent review committee assessed key efficacy measures in all patients and in platinum-resistant and platinum-sensitive subgroups.
| CI: confidence interval, CTFI: chemotherapy free interval. | |||
| aConfirmed overall response rate. | |||
| bBased on observed duration of response. | |||
Investigator Assessed Responsea | ZEPZELCA All Patients (n=105) | ZEPZELCA CTFI < 90 days (n=45) | ZEPZELCA CTFI ≥ 90 days (n=60) |
Overall Response Rate (95% CI) | 35% (26%, 45%) | 22% (11%, 37%) | 45% (32%, 58%) |
Complete response | 0% | 0% | 0% |
Partial response | 35% | 22% | 45% |
Duration of Response | |||
Median in months (95% CI) | 5.3 (4.1, 6.4) | 4.7 (2.6, 5.6) | 6.2 (3.5, 7.3) |
% with ≥ 6 monthsb | 35% | 10% | 44% |
Independent Review Committee Assessed Responsea | All Patients (n=105) | CTFI < 90 days (n=45) | CTFI ≥ 90 days (n=60) |
Overall Response Rate (95% CI) | 30% (22%, 40%) | 13% (5%, 27%) | 43% (31%, 57%) |
Complete response | 0% | 0% | 0% |
Partial response | 30% | 13% | 43% |
Duration of Response | |||
Median in months (95% CI) | 5.1 (4.9, 6.4) | 4.8 (2.4, 5.3) | 5.3 (4.9, 7.0) |
% with ≥ 6 monthsb | 25% | 0% | 31% |
• Recommended Dosage: 3.2 mg/m2 every 21 days until disease progression or unacceptable toxicity. ()2.1 Recommended DosageThe recommended dosage of ZEPZELCA as a single-agent and as a combination with atezolizumab or atezolizumab and hyaluronidase-tqjs is 3.2 mg/m2by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity
[see Dosage and Administration (2.4)].Initiate treatment with ZEPZELCA only if absolute neutrophil count (ANC) is at least 1,500 cells/mm3and platelet count is at least 100,000/mm3.
ZEPZELCA with Intravenous Atezolizumab or atezolizumab and hyaluronidase-tqjsWhen administering ZEPZELCA on the same day as atezolizumab or atezolizumab and hyaluronidase-tqjs, administer the chosen atezolizumab drug first. For the recommended dosage of atezolizumab or atezolizumab and hyaluronidase-tqjs refer to the respective Prescribing Information.If discontinuation of atezolizumab or atezolizumab and hyaluronidase-tqjs is required due to an immune-related severe adverse event, treatment with ZEPZELCA may be continued at the same dose as a single agent. If immune toxicity does not resolve or recurs despite discontinuation of atezolizumab, permanently discontinue ZEPZELCA.• Administer ZEPZELCA as an intravenous infusion over 60 minutes. ()2.1 Recommended DosageThe recommended dosage of ZEPZELCA as a single-agent and as a combination with atezolizumab or atezolizumab and hyaluronidase-tqjs is 3.2 mg/m2by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity
[see Dosage and Administration (2.4)].Initiate treatment with ZEPZELCA only if absolute neutrophil count (ANC) is at least 1,500 cells/mm3and platelet count is at least 100,000/mm3.
ZEPZELCA with Intravenous Atezolizumab or atezolizumab and hyaluronidase-tqjsWhen administering ZEPZELCA on the same day as atezolizumab or atezolizumab and hyaluronidase-tqjs, administer the chosen atezolizumab drug first. For the recommended dosage of atezolizumab or atezolizumab and hyaluronidase-tqjs refer to the respective Prescribing Information.If discontinuation of atezolizumab or atezolizumab and hyaluronidase-tqjs is required due to an immune-related severe adverse event, treatment with ZEPZELCA may be continued at the same dose as a single agent. If immune toxicity does not resolve or recurs despite discontinuation of atezolizumab, permanently discontinue ZEPZELCA.• Moderate Hepatic Impairment: Recommended dosage is 1.6 mg/m2 every 21 days until disease progression or unacceptable toxicity.
For injection: 4 mg of lurbinectedin as a sterile, preservative-free, white to off-white lyophilized powder in a single-dose vial for reconstitution prior to intravenous infusion.
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 last dose.
• Recommended Dosage: 3.2 mg/m2administered intravenously every 21 days until disease progression or unacceptable toxicity.• Administration via a central venous line is recommended to reduce the risk of extravasation that can cause tissue necrosis requiring debridement.• Administer ZEPZELCA as an intravenous infusion over 60 minutes.• To reduce the risk of nausea, administer corticosteroids and serotonin agonists prior to Cycle 1 and consider use for subsequent cycles.• To reduce the risk of febrile neutropenia during treatment with ZEPZELCA in combination with atezolizumab or atezolizumab and hyaluronidase-tqjs, administer granulocyte colony-stimulating factor (G-CSF) [Refer to Prescribing Information].• Moderate Hepatic Impairment: Recommended dosage is 1.6 mg/m2administered intravenously every 21 days until disease progression or unacceptable toxicity.• Severe Hepatic Impairment: Avoid use of ZEPZELCA. If use cannot be avoided, the recommended dosage is 1.6 mg/m2administered intravenously every 21 days until disease progression or unacceptable toxicity.
The recommended dosage of ZEPZELCA as a single-agent and as a combination with atezolizumab or atezolizumab and hyaluronidase-tqjs is 3.2 mg/m2by intravenous 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/mm3and platelet count is at least 100,000/mm3.
The recommended dose reductions for adverse reactions are listed in Table 1.
Permanently discontinue ZEPZELCA in patients who require a dose interruption of greater than two weeks and in patients who are unable to tolerate 2 mg/m2every 21 days.
Dose Reduction | Total Dose |
First Second | 2.6 mg/m2every 21 days 2 mg/m2every 21 days |
Dosage modifications for ZEPZELCA for adverse reactions are presented in Table 2.
| aNational Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0. | ||
| bPatients who have not received primary prophylaxis of G-CSF with isolated Grade 4 neutropenia (neutrophil count less than 500 cells/mm3) may receive G-CSF prophylaxis rather than undergo lurbinectedin dose reduction. | ||
Adverse Reaction | Severitya | Dosage Modification |
Neutropeniab [see Warnings and Precautions (5.1)] | Grade 4 or Any grade febrile neutropenia |
|
Thrombocytopenia [see Warnings and Precautions (5.1)] | Grade 3 with bleeding or Grade 4 |
|
Hepatotoxicity [see Warnings and Precautions (5.2)] | Grade 2 |
|
Grade ≥ 3 |
| |
Rhabdomyolysis [see Warnings and Precautions (5.4)] | Grade 2 |
|
Grade ≥ 3 |
| |
Other Adverse Reactions [see Adverse Reactions (6.1), Postmarketing (6.2)] | Grade 2 |
|
Grade ≥ 3 |
| |
Consider administering the following pre-infusion medications for antiemetic prophylaxis
• Corticosteroids (dexamethasone 8 mg intravenously or equivalent)• Serotonin antagonists (ondansetron 8 mg intravenously or equivalent)
• To reduce the risk of febrile neutropenia during treatment with ZEPZELCA in combination with atezolizumab or atezolizumab and hyaluronidase-tqjs, administer granulocyte colony-stimulating factor (G-CSF) [Refer to Prescribing Information].• To reduce the risk of nausea, administer the following pre-infusion medications for antiemetic prophylaxis prior to Cycle 1 and consider administering for subsequent cycles:[see Adverse Reactions (6.1)]- ⸰ Corticosteroids (dexamethasone 8 mg or equivalent intravenously)
- ⸰ Serotonin antagonists (ondansetron 8 mg or equivalent intravenously)
ZEPZELCA is a hazardous drug. Follow applicable special handling and disposal procedures1.
• Inject 8 mL of Sterile Water for Injection USP into the vial, yielding a solution containing 0.5 mg/mL lurbinectedin. Shake the vial until complete dissolution.• Visually inspect the solution for particulate matter and discoloration. The reconstituted solution is a clear, colorless or slightly yellowish solution, free of visible particles.• Calculate the required volume of reconstituted solution as follows:• For administration through a central venous line, withdraw the appropriate amount of reconstituted solution from the vial and add to an infusion container containing at least 100 mL of diluent (0.9% Sodium Chloride Injection USP or 5% Dextrose Injection USP).• For administration through a peripheral venous line, withdraw the appropriate amount of reconstituted solution from the vial and add to an infusion container containing at least 250 mL of diluent (0.9% Sodium Chloride Injection USP or 5% Dextrose Injection USP).
• Administration via a central venous line is recommended to reduce the risk of extravasation that can cause tissue necrosis requiring debridement[see Warnings and Precautions (5.3)].• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulate matter is observed, do not administer.• ZEPZELCA can be administered with or without an in-line filter. If infusion lines containing in-line filters are utilized for administration of ZEPZELCA, polyethersulfone (PES) in-line filters with pore sizes of 0.22 micron are recommended.o Do not use in-line nylon membrane filters when the reconstituted ZEPZELCA solution is diluted using 0.9% Sodium Chloride Injection, USP. Adsorption of ZEPZELCA to the Nylon membrane filters has been observed when 0.9% Sodium Chloride Injection, USP is used as the diluent.
• Compatibility with other intravenous administration materials and the diluted ZEPZELCA solution has been demonstrated in the following materials:o Containers: Polyolefin containers (polyethylene, polypropylene and mixtures).o Infusion sets: Polyvinyl Chloride (PVC) (non-DEHP-containing), polyurethane and polyolefin infusion sets (polyethylene, polypropylene and polybutadiene).o Implantable venous access systems: Implantable venous access systems with titanium and plastic resin ports and with polyurethane or silicone intravenous catheters.
• Do not co-administer ZEPZELCA and other intravenous drugs concurrently within the same intravenous line.
• Administer either atezolizumab or atezolizumab and hyaluronidase-tqjs first, then administer ZEPZELCA. For the recommended dosage of atezolizumab or atezolizumab and hyaluronidase-tqjs refer to the respective Prescribing Information.
• If not used immediately after reconstitution or dilution, the ZEPZELCA 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 2ºC to 8ºC (36ºF to 46ºF) conditions.
Avoid administration of ZEPZELCA in patients with severe hepatic impairment (total bilirubin > 3 × ULN). If administration of ZEPZELCA cannot be avoided, reduce the dose
Reduce the dose of ZEPZELCA in patients with moderate hepatic impairment (total bilirubin > 1.5 to 3 × ULN and any AST)
No dose adjustment of ZEPZELCA is recommended for patients with mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1 to ≤ 1.5 × ULN and any AST)
None.