1.1 Extensive-Stage Small Cell Lung Cancer

ZEPZELCA, in combination with atezolizumab or atezolizumab and hyaluronidase-tqjs, is indicated for the maintenance treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC) whose disease has not progressed after first-line induction therapy with atezolizumab or atezolizumab and hyaluronidase-tqjs, carboplatin and etoposide.

2.1 Recommended Dosage

The recommended dosage of ZEPZELCA in combination with atezolizumab or atezolizumab and hyaluronidase-tqjs is 3.2 mg/m2 by 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/mm3 and platelet count is at least 100,000/mm3 [see Warnings and Precautions (5.1)].

When 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. If immune toxicity does not resolve or recurs despite discontinuation of atezolizumab, permanently discontinue ZEPZELCA.

2.2 Dosage Modifications for Adverse Reactions

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 the second dose reduction.

Dosage modifications for ZEPZELCA for adverse reactions are presented in Table 2.

2.3 Dosage Modifications for Use with Strong or Moderate CYP3A Inhibitors

Avoid coadministration of ZEPZELCA with strong or moderate CYP3A inhibitors. If coadministration of ZEPZELCA with a strong or moderate CYP3A inhibitor cannot be avoided, reduce the dose of ZEPZELCA by 50% [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)]. After discontinuation of a strong or moderate CYP3A inhibitor for 5 half-lives of the inhibitor, increase the ZEPZELCA dose to the dose used before starting the inhibitor.

2.4 Dosage Modifications for Patients with Severe or Moderate Hepatic Impairment

Avoid administration of ZEPZELCA in patients with severe hepatic impairment (total bilirubin > 3 × Upper Limit of Normal (ULN)). If administration of ZEPZELCA cannot be avoided, the recommended dosage is 1.6 mg/m2 by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity [see Use In Specific Populations (8.6) and Clinical Pharmacology (12.3)].

In patients with moderate hepatic impairment (total bilirubin > 1.5 to ≤ 3 × ULN and any AST), the recommended dosage of ZEPZELCA is 1.6 mg/m2 by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity.

For patients with baseline severe or moderate hepatic impairment who experience intolerable adverse reactions at the 1.6 mg/m2 recommended dosage, permanently discontinue ZEPZELCA.

2.5 Recommended Prophylactic Medications

Consider administering the following pre-infusion medications [see Adverse Reactions (6.1)]:

•

To reduce the risk of febrile neutropenia, 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:

 

        ⸰    Corticosteroids (dexamethasone 8 mg or equivalent intravenously)

 

        ⸰    Serotonin antagonists (ondansetron 8 mg or equivalent intravenously)

2.6 Preparation, Administration and Storage

ZEPZELCA is a hazardous drug. Follow applicable special handling and disposal procedures1.

Preparation

•

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

•

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.

Storage of Infusion Solution

•

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.

5.1 Myelosuppression

ZEPZELCA can cause severe and fatal myelosuppression including febrile neutropenia and sepsis, thrombocytopenia and anemia.

Administer ZEPZELCA only to patients with baseline neutrophil count of at least 1,500 cells/mm3 and platelet count of at least 100,000/mm3. To reduce the risk of febrile neutropenia administer granulocyte colony-stimulating factor (G-CSF) [refer to Prescribing Information].

Monitor blood counts including neutrophils, red blood cells and platelets prior to each ZEPZELCA administration. For neutrophil count less than 500 cells/mm3 or any value less than lower limit of normal, administer G-CSF. Withhold, reduce the dose, or permanently discontinue ZEPZELCA based on severity [see Dosage and Administration (2.2)].

In the IMforte study [see Adverse Reactions (6.1)], primary prophylaxis of G-CSF was administered to 84% of patients. Based on laboratory values, decreased neutrophils occurred in 36%, including 18% Grade 3 or Grade 4 in patients who received ZEPZELCA in combination with atezolizumab. The median time to onset of Grade 3 and 4 decreased neutrophil cells was 31 days and a median duration of 10 days. Febrile neutropenia occurred in 1.7%. Sepsis occurred in 1%. There were 7 fatal infections: pneumonia (n=3), sepsis (n=3), and febrile neutropenia (n=1).

Based on laboratory values, decreased platelets occurred in 54%, including 15% Grade 3 or Grade 4 in patients who received ZEPZELCA in combination with atezolizumab. The median time to onset of Grade 3 and 4 decreased platelet cells was 31 days and a median duration of 12 days.

Based on laboratory values, decreased hemoglobin occurred in 51%, including 13% Grade 3 or Grade 4 in patients who received ZEPZELCA in combination with atezolizumab. The median time to onset of Grade 3 and 4 decreased hemoglobin was 64 days and a median duration of 8 days.

5.2 Hepatotoxicity

ZEPZELCA can cause hepatotoxicity which may be severe.

Monitor liver function tests prior to initiating ZEPZELCA and periodically during treatment as clinically indicated. Withhold, reduce the dose, or permanently discontinue ZEPZELCA based on severity [see Dosage and Administration (2.2)].

In the IMforte study [see Adverse Reactions (6.1)], based on laboratory values, increased alanine aminotransferase (ALT) occurred in 25%, including 3% Grade 3 or Grade 4 in patients who received ZEPZELCA in combination with atezolizumab. Increased aspartate aminotransferase (AST) occurred in 24% including 3% Grade 3 or Grade 4. The median time to onset of Grade ≥ 3 elevation in transaminases was 52 days (range: 6 to 337).

5.3 Extravasation Resulting in Tissue Necrosis

Extravasation of ZEPZELCA can cause skin and soft tissue injury, including necrosis requiring debridement. Consider use of a central venous catheter to reduce the risk of extravasation, particularly in patients with limited venous access. Monitor patients for signs and symptoms of extravasation during the ZEPZELCA infusion. If extravasation occurs, immediately discontinue the infusion, remove the infusion catheter, and monitor for signs and symptoms of tissue necrosis. The time to onset of necrosis after extravasation may vary.

In the IMforte study [see Adverse Reactions (6.1)], extravasation resulting in skin necrosis occurred in one patient who received ZEPZELCA in combination with atezolizumab.

Administer supportive care and consult with an appropriate medical specialist as needed for signs and symptoms of extravasation. Administer subsequent infusions at a site that was not affected by extravasation.

5.4 Rhabdomyolysis

Rhabdomyolysis has been reported in patients treated with ZEPZELCA.

Monitor creatine phosphokinase (CPK) prior to initiating ZEPZELCA and periodically during treatment as clinically indicated. Withhold or reduce the dose based on severity [see Dosage and Administration (2.2)].

In the IMforte study [see Adverse Reactions (6.1)], among 235 patients who had a creatine phosphokinase laboratory evaluation, increased creatine phosphokinase occurred in 9% who received ZEPZELCA in combination with atezolizumab.

5.5 Embryo-Fetal Toxicity

Based on animal data and its mechanism of action [see Clinical Pharmacology (12.1)] ZEPZELCA can cause fetal harm when administered to a pregnant woman. Intravenous administration of a single dose of lurbinectedin (approximately 0.2 times the 3.2 mg/m2 clinical dose) to pregnant animals during the period of organogenesis caused 100% embryo lethality in rats. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to use effective contraception during treatment with ZEPZELCA and for 7 months after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ZEPZELCA and for 4 months after the last dose [see Use in Specific Populations (8.1, 8.3)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety population described in the WARNINGS AND PRECAUTIONS reflects exposure to ZEPZELCA in combination with intravenous atezolizumab in the IMforte study [see Clinical Studies (14.1)], in 242 patients with extensive stage small cell lung cancer (ES-SCLC) whose disease had not progressed after initial therapy with atezolizumab, carboplatin, and etoposide. Patients received ZEPZELCA 3.2 mg/m2 intravenously (IV) in combination with atezolizumab 1,200 mg IV every 21 days until disease progression or unacceptable toxicity. Among 242 patients who received ZEPZELCA in combination with intravenous atezolizumab, 34% were exposed for 6 months or longer and 8% were exposed for greater than one year. The most common adverse reactions (≥ 15%), including laboratory abnormalities, in patients who received ZEPZELCA with atezolizumab were decreased lymphocytes, decreased platelets, decreased hemoglobin, decreased neutrophils, nausea, fatigue, increased alkaline phosphatase, decreased sodium, increased ALT, increased AST, decreased calcium, increased creatinine, musculoskeletal pain, decreased appetite and diarrhea.

Extensive-Stage Small Cell Lung Cancer (IMforte)

The safety of ZEPZELCA in combination with intravenous (IV) atezolizumab was evaluated in IMforte [see Clinical Studies (14)]. Patients received intravenous ZEPZELCA 3.2 mg/m2 in combination with intravenous atezolizumab 1,200 mg on Day 1 of each 21-day cycle until disease progression or unacceptable toxicity. Primary prophylaxis of G-CSF was administered to 84% of patients. Among 242 patients who received ZEPZELCA with atezolizumab, the median duration of exposure to lurbinectedin was 4.1 months, 33% were exposed for 6 months or longer and 8% were exposed for greater than one year.

The median age of patients who received ZEPZELCA in combination with intravenous atezolizumab was 66 years (range: 35 to 85); 62% male; 82% White, 13% Asian, and 0.8% Black or African American.

Serious adverse reactions occurred in 31% of patients receiving ZEPZELCA in combination with atezolizumab. Serious adverse reactions occurring in > 2% were pneumonia (2.5%), respiratory tract infection (2.1%), dyspnea (2.1%), and decreased platelet count (2.1%). Fatal adverse reactions occurred in 5% of patients receiving ZEPZELCA with atezolizumab including pneumonia (3 patients), sepsis (3 patients), cardio-respiratory arrest (2 patients), myocardial infarction (2 patients), and febrile neutropenia (1 patient).

Permanent discontinuation of ZEPZELCA due to an adverse reaction occurred in 5% of patients. The adverse reaction resulting in permanent discontinuation in ≥ 1% of patients who received ZEPZELCA was decreased neutrophil count.

Dosage interruptions of ZEPZELCA due to an adverse reaction occurred in 25%. Adverse reactions which required dosage interruption in ≥ 2% of patients included anemia, fatigue, decreased neutrophil count, and decreased platelet count.

Dose reductions of ZEPZELCA due to an adverse reaction occurred in 15% of patients. Adverse reactions which required dosage reduction in ≥ 2% of patients included decreased platelet count, fatigue, nausea, and vomiting.

Table 3 summarizes the adverse reactions in IMforte.

Clinically relevant adverse reactions in < 10% of patients who received ZEPZELCA in combination with intravenous atezolizumab included pneumonia, phlebitis, extravasation resulting in skin necrosis, hypersensitivity, and increased creatine phosphokinase.

Table 4 summarizes the laboratory abnormalities in IMforte.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ZEPZELCA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

General disorders and administration site conditions: Extravasation including tissue necrosis requiring debridement.

Musculoskeletal and connective tissue disorders: Rhabdomyolysis.

Metabolism and nutrition disorders: Tumor lysis syndrome.

7.1 Effect of Other Drugs on ZEPZELCA

Strong and Moderate CYP3A Inhibitors

Coadministration of ZEPZELCA with a strong or a moderate CYP3A inhibitor increases lurbinectedin systemic exposure [see Clinical Pharmacology (12.3)], which may increase the incidence and severity of adverse reactions to ZEPZELCA.

Avoid grapefruit and Seville oranges during ZEPZELCA treatment, as these contain strong or moderate inhibitors of CYP3A.

Avoid coadministration of ZEPZELCA with strong or moderate CYP3A inhibitors. If coadministration cannot be avoided, reduce the dose of ZEPZELCA [see Dosage and Administration (2.3)].

Strong CYP3A Inducers

Avoid coadministration of ZEPZELCA with strong CYP3A inducers. Coadministration of ZEPZELCA with a strong CYP3A inducer may decrease lurbinectedin systemic exposure, which may decrease the efficacy of ZEPZELCA [see Clinical Pharmacology (12.3)].

8.1 Pregnancy

Risk Summary

Based on animal data and its mechanism of action [see Clinical Pharmacology (12.1)], ZEPZELCA can cause fetal harm when administered to a pregnant woman. There are no available data to inform the risk of ZEPZELCA use in pregnant women. Intravenous administration of a single lurbinectedin dose (approximately 0.2 times the 3.2 mg/m2 clinical dose) to pregnant rats during the period of organogenesis caused embryolethality (see Data).

Advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

In a reproductive toxicity study, administration of a single lurbinectedin dose of 0.6 mg/m2 (approximately 0.2 times of the human dose of 3.2 mg/m2) to pregnant rats on Gestation Day 10 resulted in 100% post-implantation loss.

8.2 Lactation

Risk Summary

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.

8.3 Females and Males of Reproductive Potential

ZEPZELCA can cause embryolethality at doses lower than the human dose of 3.2 mg/m2 [see Use in Specific Populations (8.1)].

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating ZEPZELCA.

Contraception

Females

Advise female patients of reproductive potential to use effective contraception during treatment with ZEPZELCA and for 7 months after the last dose.

Males

Advise males with a female sexual partner of reproductive potential to use effective contraception during treatment with ZEPZELCA and for 4 months after the last dose.

8.4 Pediatric Use

The safety and effectiveness of ZEPZELCA in pediatric patients have not been established.

8.5 Geriatric Use

Of the 242 patients with ES-SCLC treated with ZEPZELCA and atezolizumab in IMforte, 124 (51%) patients were 65 years of age and older, while 29 (12%) patients were 75 years of age and older. No overall differences in effectiveness were observed between older and younger patients. There was no overall difference in the incidence of serious adverse reactions in patients ≥ 65 years of age and patients < 65 years of age (33% vs. 29%, respectively). There was a higher incidence of Grade 3 or 4 adverse reactions in patients ≥ 65 years of age compared to younger patients (45% vs. 31%, respectively).

8.6 Hepatic Impairment

Avoid administration of ZEPZELCA in patients with severe hepatic impairment (total bilirubin > 3 × ULN). If administration of ZEPZELCA cannot be avoided, reduce the dose [see Dosage and Administration (2.4)]. Monitor for increased adverse reactions in patients with severe hepatic impairment.

Reduce the dose of ZEPZELCA in patients with moderate hepatic impairment (total bilirubin > 1.5 to 3 × ULN and any AST) [see Dosage and Administration (2.4)]. Monitor for increased adverse reactions in patients with moderate 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 to ≤ 1.5 × ULN and any AST) [see Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Lurbinectedin is an alkylating drug that binds guanine residues in the minor groove of DNA, forming adducts and resulting in a bending of the DNA helix towards the major groove. Adduct formation triggers a cascade of events that can affect the subsequent activity of DNA binding proteins, including some transcription factors, and DNA repair pathways, resulting in perturbation of the cell cycle and eventual cell death.

Lurbinectedin inhibited human monocyte activity in vitro and reduced macrophage infiltration in implanted tumors in mice.

12.2 Pharmacodynamics

Lurbinectedin exposure-response relationships and the pharmacodynamic time-course for efficacy have not been fully characterized.

Increased incidence of Grade 4 neutropenia and Grade ≥ 3 thrombocytopenia were observed with increased lurbinectedin exposure.

Cardiac Electrophysiology

No large mean increase in QTc (i.e., > 20 ms) was detected at the recommended dose of 3.2 mg/m2.

12.3 Pharmacokinetics

Following the approved recommended dosage, geometric mean (%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 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 CYP3A in vitro.

Excretion

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

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 clinically significant differences in the pharmacokinetics of lurbinectedin were identified for patients with mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN or total bilirubin 1 to 1.5 × ULN and any AST) compared to that of patients with normal hepatic function.

No clinically significant differences in the pharmacokinetics of lurbinectedin were identified for patients with moderate hepatic impairment (total bilirubin > 1.5 to 3 × ULN and any AST) who received a lurbinectedin dose of 1.6 mg/m2 compared to that of patients with mild hepatic impairment who received a dose of 3.2 mg/m2.

No clinically significant differences in the pharmacokinetics of lurbinectedin were identified for patients with severe hepatic impairment (total bilirubin > 3 × ULN) who received a lurbinectedin dose of 1.6 mg/m2 compared to that of patients with mild hepatic impairment who received a dose of 3.2 mg/m2.

Drug Interactions Studies

Clinical Studies and Model-Informed Approaches

Effects of CYP3A Inhibitors on Lurbinectedin

Strong CYP3A inhibitors: Coadministration of itraconazole (200 mg once daily) increased the systemic exposure (AUC) of total lurbinectedin by 2.7-fold and unbound lurbinectedin by 2.4‑fold.

Moderate CYP3A inhibitors: Coadministration of verapamil (80 mg every 8 hours) and erythromycin (500 mg every 6 hours) is predicted to increase lurbinectedin AUC by 2.3-fold and 2.1-fold, respectively.

Weak CYP3A inhibitors: Coadministration of fluvoxamine (150 mg every 12 hours) is predicted to increase lurbinectedin AUC by 1.3-fold.

Effects of CYP3A Inducers on Lurbinectedin

Coadministration of bosentan (a moderate CYP3A inducer) decreased systemic exposure (AUC) of total lurbinectedin by 20% and unbound lurbinectedin by 19%. These changes are not considered clinically relevant.

In Vitro Studies

Cytochrome P450 (CYP) enzymes: Lurbinectedin is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4.

Lurbinectedin is not an inducer of CYP1A2 or CYP3A4.

Transporter systems: Lurbinectedin is a substrate of MDR1, but is not a substrate of OATB1P1, OATP1B3, OCT1, or MATE1.

Lurbinectedin inhibits MDR1, OATP1B1, OATP1B3, and OCT1 but not BCRP, BSEP, MATE1, OAT1, OAT3, or OCT2.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity testing of lurbinectedin has not been performed. Lurbinectedin is genotoxic to mammalian cells in the presence and absence of metabolic activation. Lurbinectedin was not mutagenic in vitro in a bacterial reverse mutation (Ames) assay.

Fertility studies with lurbinectedin were not performed. There were no findings in reproductive organs in general toxicology studies in rats, dogs, or monkeys; however, the highest doses and exposures in these studies were all at levels lower than those at the human dose of 3.2 mg/m2.

14.1 Extensive-Stage Small Cell Lung Cancer

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/m2 IV with atezolizumab 1,200 mg IV once every 3 weeks until disease progression or unacceptable toxicity, or

•

Atezolizumab 1,200 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 5 and Figures 1 and 2.

Figure 1: Progression Free Survival Curve in IMforte

Figure 2: Kaplan-Meier Plot of Overall Survival in IMforte