Medicare Advantage

Medical Policy

Notification

Lurbinectedin (Zepzelca®)

Notification Issue Date:

This version of the policy will become effective

XX/XX/2020

The following new policy has been developed to communicate the Company's coverage criteria for lurbinectedin (Zepzelca

^TM

Title:

Lurbinectedin (Zepzelca®)

Policy #:

MA08.125d

Policy

In the absence of coverage criteria from applicable Medicare statutes, regulations, NCDs, LCDs, CMS manuals, or other Medicare coverage documents, this policy uses internal coverage criteria developed by the Company in consideration of peer-reviewed medical literature, clinical practice guidelines, and/or regulatory status.

The Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition.

MEDICALLY NECESSARY

Lurbinectedin (Zepzelca^®) is considered medically necessary and, therefore, covered for the treatment of adult individuals with small cell lung cancer (SCLC) in ANY of the following scenarios:

For National Comprehensive Cancer Network (NCCN)-preferred primary treatment*, in combination with atezolizumab (or atezolizumab and hyaluronidase-tqjs), as maintenance following carboplatin, etoposide, and atezolizumab (or atezolizumab and hyaluronidase-tqjs) for extensive disease in ONE of the following:

Without localized symptomatic sites or brain metastases
With localized symptomatic sites (used with radiation therapy [typically sequential]) if spinal cord compression

For subsequent systemic therapy, as a single agent (NCCN preferred), for disease progression on or after platinum-based chemotherapy, if BOTH of the following exist:

Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2
Lurbinectedin (Zepzelca) not previously used for progression or relapse

For subsequent systemic therapy**, in combination with atezolizumab (or atezolizumab and hyaluronidase-tqjs), as maintenance treatment following treatment with carboplatin, etoposide, and atezolizumab (or atezolizumab and hyaluronidase-tqjs) if ALL of the following exist:

Prolonged disease-free time
PS 0-1
For progression or relapse

*Consider adding lurbinectedin (Zepzelca) to maintenance atezolizumab (or atezolizumab and hyaluronidase-tqjs) if at least stable disease following four cycles of carboplatin, etoposide, and atezolizumab (or atezolizumab and hyaluronidase-tqjs), ECOG PS 0-1, and no history of brain metastases.

**Consider adding lurbinectedin (Zepzelca) to maintenance atezolizumab (or atezolizumab and hyaluronidase-tqjs) if at least stable disease following four cycles of carboplatin, etoposide, and atezolizumab (or atezolizumab and hyaluronidase-tqjs) if no history of brain metastases, and if lurbinectedin (Zepzelca) has not been used previously.

EXPERIMENTAL/INVESTIGATIONAL

All other uses for lurbinectedin (Zepzelca) are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the service.

Guidelines

There is no Medicare coverage determination addressing lurbinectedin (Zepzelca); therefore, the Company policy is applicable.

BENEFIT APPLICATION

Subject to the applicable Evidence of Coverage, lurbinectedin (Zepzelca) is covered under the medical benefits of the Company’s Medicare Advantage products when the medical necessity criteria listed in this medical policy are met.

For Medicare Advantage members, certain drugs are available through either the member's medical benefit (Part B benefit) or pharmacy benefit (Part D benefit), depending on how the drug is prescribed, dispensed, or administered. This medical policy only addresses instances when lurbinectedin (Zepzelca) is covered under a member's medical benefit (Part B benefit). It does not address instances when lurbinectedin (Zepzelca) is covered under a member’s pharmacy benefit (Part D benefit).

THE EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS

The Eastern Cooperative Oncology Group (ECOG) has developed the ECOG Performance Status. It was originally published in 1982 in the American Journal of Clinical Oncology*. ECOG states, "These scales and criteria are used by doctors and researchers to assess how a patient's disease is progressing, assess how the disease affects the daily living abilities of the patient, and determine appropriate treatment and prognosis. They are included here for health care professionals to access."

ECOG Performance Status
Grade	ECOG
0	Fully active, able to carry on all pre-disease performance without restriction
1	Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work
2	Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50 percent of waking hours
3	Capable of only limited self-care, confined to bed or chair more than 50 percent of waking hours
4	Completely disabled. Cannot carry on any self-care: Totally confined to bed or chair
5	Dead

*Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol.1982;5(6):649-655.

US FOOD AND DRUG ADMINISTRATION STATUS

Lurbinectedin (Zepzelca) was approved by the US Food and Drug Administration (FDA) on June 15, 2020, for the treatment of adults 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. Supplemental approvals for lurbinectedin (Zepzelca) have since been issued by the FDA.

From the product's prescribing information: The recommended dosage of lurbinectedin (Zepzelca) for SCLC is 3.2 mg/m² by intravenous infusion over 60 minutes every 21 days until disease progression or unacceptable toxicity. Initiate treatment with lurbinectedin (Zepzelca) only if absolute neutrophil count (ANC) is at least 1500 cells/mm³ and platelet count is at least 100,000/mm³.

PEDIATRIC USE

The safety and effectiveness of lurbinectedin (Zepzelca) in pediatric individuals have not been established.

Description

SMALL CELL LUNG CANCER

Lung cancer is the second most common cancer and the leading cause of cancer death among women and men in the United States. Small cell lung cancer (SCLC) accounts for 10 percent to 15 percent of all lung cancers. SCLC is distinguished from non-small cell lung cancer (NSCLC) by its rapid doubling time, high growth fraction, and the early development of widespread metastases. SCLC is diagnosed almost exclusively in individuals who smoke.

LURBINECTEDIN (ZEPZELCA)

Lurbinectedin (Zepzelca) was approved by the US Food and Drug Administration (FDA) on June 15, 2020, for the treatment of adults with metastatic SCLC who had disease progression on or after platinum-based chemotherapy.

Lurbinectedin (Zepzelca) is an alkylating drug and a selective inhibitor of oncogenic transcription that preferentially binds to guanine residues in the DNA and affects the activity of DNA-binding proteins, resulting in the disruption of the tumor cell cycle and eventual tumor cell death (apoptosis). Tumors can prevent macrophages from performing their immune response. Lurbinectedin (Zepzelca) inhibits the transcription of tumor-associated macrophages, further affecting the tumor microenvironment landscape.

PEER-REVIEWED LITERATURE
Summary

The safety and efficacy of lurbinectedin (Zepzelca) as a single agent was evaluated in a multicenter, open-label, multicohort trial (NCT02454972) in individuals with advanced or metastatic solid tumors. Trigo et al. (2020) assessed a cohort of 105 individuals with SCLC with disease progression on or after platinum-based chemotherapy. The individuals in the cohort received lurbinectedin (Zepzelca) 3.2 mg/m² by intravenous infusion every 21 days until disease progression or unacceptable toxicity. Tumor assessments (computed tomography [CT] scans or magnetic resonance imaging [MRI]) were conducted every 6 weeks for the first 18 weeks and every 9 weeks thereafter. Baseline characteristics included: 92 percent had Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, 92 percent were former/current smokers, and 100 percent of individuals received at least one line of platinum-based chemotherapy. Prior radiotherapy had been administered to 71 percent of patients and eight percent had prior immunotherapy in addition to platinum-based chemotherapy. The major efficacy outcome measure was confirmed investigator-assessed overall response rate (ORR).

At the median follow-up period of 17.1 months, the investigator-assessed ORR was 35 percent (complete response, 0 percent; partial response, 35 percent) and the median duration of response was 5.3 months. In the assessment of overall survival, 63 percent of individuals had died and the median overall survival was 9.3 months. Serious treatment-related adverse events included neutropenia (46 percent), leucopenia (29 percent), and febrile neutropenia (5 percent).

In October 2025, the FDA approved lurbinectedin (Zepzelca), in combination with atezolizumab, as maintenance treatment of adult individuals with ES-SCLC whose disease has not progressed after first-line induction therapy with atezolizumab administered along with carboplatin and etoposide. This approval was based on a phase III randomized, multicenter, open-label clinical trial (NCT05091567; IMforte) in 483 individuals. The individuals were randomly assigned in a 1:1 ratio to two cohorts: lurbinectedin (Zepzelca) plus atezolizumab (n = 242) or atezolizumab alone (n = 241) as maintenance therapy. The primary endpoints were PFS and OS. Key secondary endpoints included ORR, DOR, and 12‑ and 24‑month survival rates. Safety was also characterized.

PFS favored lurbinectedin (Zepzelca) plus atezolizumab with a hazard ratio (HR) of 0.54 (95 percent CI, 0.43–0.67; P<0.0001), and a median of 5.4 months in the combination cohort versus 2.1 months with atezolizumab alone. At the preplanned interim analysis, OS favored the combination regimen. Median OS was 13.2 months (95 percent CI, 11.9–16.4 months) in the combination cohort versus 10.6 months (95 percent CI, 9.5–12.2 months) in the atezolizumab-alone cohort (HR, 0.73; 95 percent CI, 0.57–0.95; P=0.017). The 12‑month median OS rates were 56.3 percent in the combination cohort versus 44.1 percent in the atezolizumab-alone cohort. Among participants with measurable disease at maintenance baseline, confirmed ORR was 19 percent with the combination regimen versus 10 percent with atezolizumab alone. Median DOR was 9.0 months with the combination regimen versus 5.6 months with atezolizumab alone. Serious adverse reactions occurred in 31 percent of individuals in the combination cohort versus 17 percent in the atezolizumab alone cohort. Grade 3–4 laboratory hematologic abnormalities were more frequent than with atezolizumab alone. Fatal adverse reactions occurred in five percent of individuals in the combination cohort versus three percent of individuals in the atezolizumab-alone cohort. The safety profile was consistent with the known profiles of the agents, and no new safety signals were identified.

OFF-LABEL INDICATION

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.

References

American Cancer Society (ACS). Key statistics for lung cancer. [ACS Web site]. 01/13/2026. Available at: https://www.cancer.org/cancer/lung-cancer/about/key-statistics.html. Accessed January 30, 2026.

American Cancer Society (ACS). What is lung cancer? [ACS Web site]. 01/29/2024. Available at: https://www.cancer.org/cancer/lung-cancer/about/what-is.html. Accessed January 30, 2026.

American Hospital Formulary Service (AHFS). Lurbinectedin (Zepzelca^®). AHFS Drug Information. [UpToDate LexiDrug Web site]. 01/21/2026. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed January 30, 2026.

Byers LA, Gay CM. Pathobiology and staging of small cell carcinoma of the lung. [UpToDate Web site]. 01/17/2025. Available at: https://www.uptodate.com/contents/pathobiology-and-staging-of-small-cell-carcinoma-of-the-lung?search=Pathobiology and staging of small cell carcinoma of the lung&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1 [via subscription only]. Accessed January 30, 2026.

ClinicalTrials.gov. A phase III, open-label study of maintenance lurbinectedin in combination with atezolizumab compared with atezolizumab in participants with extensive-stage small-cell lung cancer (IMforte). ClinicalTrials.gov Identifier: NCT05091567. First Posted: October 25, 2021. Last Update Posted: December 29, 2025. Available at: https://clinicaltrials.gov/. Accessed January 30, 2026.

ClinicalTrials.gov. Clinical trial of lurbinectedin (PM01183) in selected advanced solid tumors. ClinicalTrials.gov Identifier: NCT02454972. First Posted: May 27, 2015. Last Update Posted: March 2, 2023. Available at: https://clinicaltrials.gov/. Accessed January 30, 2026.

Elsevier's Clinical Pharmacology Compendium. Lurbinectedin (Zepzelca^®). 01/14/2026. [Clinical Key Web site]. Available at: https://www.clinicalkey.com/#!/ [via subscription only]. Accessed January 30, 2026.

Merative Micromedex^® DRUGDEX^® (electronic version). Lurbinectedin (Zepzelca^®). [Micromedex Web site]. 12/22/2025. Available at: https://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed January 30, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology^®. Small cell lung cancer, V2.2026. [NCCN Web site]. 09/16/2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf [via free subscription only]. Accessed January 30, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium^®. [NCCN Web site]. Lurbinectedin (Zepzelca®). Available at: http://www.nccn.org/professionals/drug_compendium/content/ [via subscription only]. Accessed January 30, 2026.

Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol.1982;5(6):649-655.

Paz-Ares L, Borghaei H, Liu SV, et al. Efficacy and safety of first-line maintenance therapy with lurbinectedin plus atezolizumab in extensive-stage small-cell lung cancer (IMforte): a randomised, multicentre, open-label, phase 3 trial. Lancet. 2025;405(10495):2129-2143.

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(5):645-654.

UpToDate^® Lexidrug^TM. Lurbinectedin (Zepzelca^®). [UpToDate Lexidrug Web site]. 01/29/2026. Available at: https://online.lexi.com/lco/action/home [via subscription only]. Accessed January 30, 2026.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Lurbinectedin (Zepzelca^®). Prescribing information. [FDA Web site]. 10/02/2025. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. Accessed January 30, 2026.

Coding

CPT Procedure Code Number(s)

N/A

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

Report the most appropriate diagnosis code in support of medically necessary criteria as listed in the policy.

HCPCS Level II Code Number(s)

J9223 Injection, lurbinectedin, 0.1 mg

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

Cross Reference

Policy History

Revisions From MA08.125d:

06/01/2026

This version of the policy will become effective 06/01/2026.

The following policy criteria have been revised in accordance with the US Food and Drug Administration (FDA) and National Comprehensive Cancer Network (NCCN):

Small cell lung cancer

The following ICD-10 codes have been removed from the policy:

C33, C34.00, C34.01, C34,02, C34.10, C34.11, C34.12, C34.2, C34.30, C34.31, C34.32, C34.80, C34.81, C34.82, C34.90, C34.91, C34.92

The following statement has been added into the policy:

Report the most appropriate diagnosis code in support of medically necessary criteria as listed in the policy.

Revisions From MA08.125c:

05/28/2025	This policy has been reviewed and reissued to communicate the Company’s continuing position on lurbinectedin (Zepzelca^®).
10/30/2024	This policy has been reviewed and reissued to communicate the Company’s continuing position on lurbinectedin (Zepzelca^®).
01/01/2024	Effective 01/01/2024 this policy applies to New Jersey Medicare Advantage (MA) lines of business.
05/08/2023	This version of the policy will become effective 05/08/2023. This policy has been updated to communicate the Company's coverage position for lurbinectedin (Zepzelca), in alignment with US Food and Drug Administration (FDA) and National Comprehensive Cancer Network (NCCN). The options for subsequent therapy are now recommended regardless of the time since relapse.

Revisions From MA08.125b:

04/20/2022	This policy has been reissued in accordance with the Company's annual review process.
05/24/2021	This version of the policy will become effective 05/24/2021. This policy has been updated to communicate the Company's coverage position for lurbinectedin (Zepzelca), in alignment with US Food and Drug Administration (FDA) and National Comprehensive Cancer Network (NCCN).

Revisions From MA08.125a:

01/01/2021

This policy has been identified for the HCPCS code update, effective 01/01/2021.

The following NOC codes have been removed from this policy and are replaced by the following HCPCS code:

REMOVED:

C9399 Unclassified drugs or biologicals
J3490 Unclassified drugs
REPLACED WITH: J9223 Injection, lurbinectedin, 0.1 mg

Revisions From MA08.125:

09/14/2020

The following new policy has been developed to communicate the Company's coverage criteria for lurbinectedin (Zepzelca^TM).

Version Effective Date:

6/1/2026

Version Issued Date:

6/1/2026

Version Reissued Date: