CurrentNeighborhood Health Plan of Rhode IslandPolicy N/A

Zepzelca (lurbinectedin) — coverage and utilization guideline

Defines accepted indications, exclusions, coding, and evidence standards for authorization of lurbinectedin (Zepzelca) across applicable lines of business and describes when requests may be considered not approvable.

Policy Summary

PayerNeighborhood Health Plan of Rhode Island

PolicyZepzelca (lurbinectedin) — coverage and utilization guideline

Policy CodePolicy N/A

Change TypeClinical & Operational

Effective Date

Next Review Date

Key ActionPrior authorization is required for lurbinectedin (J9223); provide documentation of FDA labeling, CMS compendia or guideline/peer-reviewed evidence to support use.

SourceLink

POLICY UPDATE CHANGES

Updated exclusion criteria for Zepzelca (lurbinectedin).

Converted to new Evolent guideline template and replaced prior UM ONC_1408 Zepzelca (lurbinectedin) guideline.

J9223HCPCS code

3.2 mg/m2single dose max

Commercial, Medicaid, Exchangelines of business

No randomized OS benefitSCLC rationale

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Coverage stance and clinical criteria

Coverage and exclusion criteria

Covered when ALL of the following are met:

General evidence requirement: Use of Zepzelca (lurbinectedin) must be supported by FDA product labeling, CMS-approved compendia, NCCN or ASCO clinical guidelines, or peer-reviewed literature that meets CMS standards (Medicare Benefit Policy Manual Chapter 15).

See Purpose and References for acceptable evidence sources

Continuation requests exempt conditions: Continuation requests may be approved without full re-evaluation when ALL: the member has not experienced disease progression on the medication; the medication was used within the last year without a lapse greater than 30 days of authorization; and no additional medications are being added to the regimen.

From continuation clause

Exclusion — non-pulmonary neuroendocrine carcinomas: Zepzelca is excluded for any neuroendocrine carcinoma of non-lung (non-pulmonary) origin (for example, poorly differentiated neuroendocrine carcinoma of GI, GU, head and neck, or metastatic poorly differentiated neuroendocrine carcinoma of unknown primary).

Exclusion based on lack of clinical trial evidence

Exclusion — dosing limit: Requested dosing must not exceed a single dose limit of 3.2 mg/m2 for Zepzelca; requests exceeding this per-dose limit are excluded.<= 3.2 mg/m2

Single dose limit listed in Exclusion Criteria

Evidence sufficiency for off-label/ investigational use: Investigational or off-label use without sufficient evidence is excluded — sufficiency is defined by adequacy of patient and regimen representation in the published evidence, clinically meaningful outcomes (ASCO definitions, e.g., HR <0.80 or recommended survival benefit thresholds), and appropriate study design; non-randomized trials with substantial subject numbers may provide supportive evidence but case reports and meeting abstracts without full peer-reviewed articles are inadequate.

Details provided in Exclusion Criteria

SCLC policy position: Zepzelca use is not supported for metastatic/extensive stage small cell lung cancer (SCLC); the drug received accelerated approval based on a single-arm phase II trial using surrogate endpoints, and the randomized ATLANTIS phase III trial failed to demonstrate an overall survival benefit for lurbinectedin + doxorubicin versus standard second-line care (e.g., IV topotecan or CAV).

Providers should refer to Evolent Pathways for alternative agents/regimens

Exclusion criteria for lurbinectedin (Zepzelca) include any neuroendocrine carcinoma of non-pulmonary origin (for example, poorly differentiated neuroendocrine carcinoma of the GI tract, GU tract, head and neck, or metastatic poorly differentiated neuroendocrine carcinoma of unknown primary) because there is insufficient clinical trial evidence supporting use in these settings. Requests will also be excluded when the single dose exceeds 3.2 mg/m2.

Use considered investigational or off-label without sufficient evidence will be excluded. Evidence is considered insufficient when it is not supported by CMS-recognized compendia or acceptable peer-reviewed literature — for example, abstracts without full peer-reviewed articles — or when the available publications do not adequately represent the patient population, regimen, clinically meaningful outcomes (per ASCO thresholds such as HR < 0.80 or ≥3 months improvement in OS/PFS), or appropriate study design. Case reports alone are generally not adequate to establish accepted use.

Evolent does not support use of Zepzelca (lurbinectedin) for metastatic/extensive stage small cell lung cancer (SCLC). The FDA approval was accelerated and based on a single-arm phase II basket trial that used surrogate endpoints (overall response rate); there are no randomized data demonstrating superior survival over available standard second-line options such as intravenous topotecan or the CAV regimen.

The randomized phase III ATLANTIS trial evaluated lurbinectedin combined with doxorubicin and did not show an overall survival benefit versus standard-of-care regimens. Given the absence of confirmatory randomized evidence of improved survival, Zepzelca is not supported as a preferred second-line therapy for metastatic/extensive SCLC; providers should follow Evolent Pathways for recommended alternatives.

Billing codes and dose limits

Covered HCPCS CodesHCPCS

J9223

Injection, lurbinectedin, 0.1 mg

Single dose limit

Single dose maximum3.2 mg/m2 (requests exceeding this single dose limit are excluded)

Applicable billing codeJ9223 — Injection, lurbinectedin, 0.1 mg

Exclusion consequenceDosing that exceeds the single dose limit (3.2 mg/m2) may lead to denial of the request

Authorization, documentation, and decision triggers

Prior Authorization

Authorization and continuation rules for lurbinectedin

Prior authorization is required for lurbinectedin (HCPCS J9223). Continuation (re-authorization) requests may be approved without full review when ALL of the following are met: the member has not experienced disease progression on the medication; the medication was used within the last year without a lapse of more than 30 days of active authorization; and no additional medications are being added to the continuation request.

Drug/code: lurbinectedin (J9223)
Continuation exemption conditions: no progression; used within last year without >30‑day lapse; no new agents added

Step Therapy

Preferred alternatives for SCLC — follow Evolent Pathways

Evolent does not support use of Zepzelca for metastatic/extensive stage small cell lung cancer as a preferred second-line agent; providers should follow Evolent Pathways for alternative recommended regimens such as intravenous topotecan or the CAV regimen.

Zepzelca is not supported for metastatic/extensive SCLC second-line therapy
Refer to Evolent Pathways for recommended alternatives (e.g., IV topotecan, CAV)

Documentation Required

Required supporting evidence and documentation

Submit documentation demonstrating the request is supported by one of: FDA product labeling, CMS‑approved compendia, NCCN or ASCO clinical guidelines, or peer‑reviewed literature that meets CMS standards; when relying on non-randomized evidence include relevant clinical characteristics, regimen details, and reported outcomes.

Acceptable evidence: FDA labeling, CMS compendia, NCCN, ASCO, or peer‑reviewed literature meeting CMS Medicare Benefit Policy Manual Chapter 15
If citing non-randomized studies, include patient/population representation, regimen representation, and clinically meaningful outcomes per ASCO definitions

Denial Risk

Triggers for denial

Requests may be denied if the use is not supported by the guideline — including off‑label indications lacking CMS‑recognized compendia or adequate peer‑reviewed evidence, use for non‑pulmonary poorly differentiated neuroendocrine carcinomas, or dosing that exceeds the single dose limit of 3.2 mg/m2.

Excluded indications: neuroendocrine carcinomas of non‑lung origin (GI, GU, head & neck, unknown primary)
Dose limit trigger: single dose > 3.2 mg/m2
Evidence trigger: investigational/off‑label use without CMS compendia or acceptable peer‑reviewed support

Clinical and regulatory background

Lurbinectedin (Zepzelca) received accelerated FDA approval based on data from a phase II basket trial that used surrogate endpoints such as overall response rate rather than randomized survival outcomes. This approval pathway reflects provisional approval pending confirmatory evidence.

A subsequent randomized phase III study (ATLANTIS) comparing lurbinectedin plus doxorubicin to physician’s choice second-line regimens in relapsed SCLC failed to demonstrate an overall survival benefit. For authorization, Evolent requires supporting evidence from FDA labeling, CMS-recognized compendia, NCCN/ASCO guidelines, or acceptable peer-reviewed literature meeting CMS clinical evidence standards.

Regulatory terms and approvals

Accelerated approval — FDA context

DefinitionFDA accelerated approval based on surrogate endpoints (e.g., overall response rate) granted without confirmatory randomized evidence of superior survival

Clinical implicationAccelerated approval for lurbinectedin was based on a phase II single-arm basket trial using ORR as a surrogate; confirmatory randomized data showing overall survival benefit are lacking

Regulatory contextATLANTIS, a randomized phase III trial, failed to show an overall survival benefit for lurbinectedin + doxorubicin versus standard care in relapsed SCLC

Evidence expectationUse should be supported by FDA labeling, CMS-recognized compendia, NCCN/ASCO guidelines, or acceptable peer-reviewed literature meeting CMS standards

Permitted lines of therapy

Second-line (SCLC) criteria

Second-line therapy position for SCLC:

Second-line SCLC: Zepzelca (with or without doxorubicin as studied in ATLANTIS) is not supported for second-line treatment of metastatic/extensive‑stage small cell lung cancer because the ATLANTIS randomized phase III trial did not show an overall survival benefit versus standard second‑line regimens (e.g., IV topotecan or CAV).

Referenced ATLANTIS phase III trial

Regimen-level guidance

Regimen	Indication	Coverage Stance	Rationale / Evidence
Lurbinectedin (Zepzelca) +/- doxorubicin (as studied in ATLANTIS)	Second-line therapy for extensive-stage (metastatic) small cell lung cancer	Not Covered	The randomized phase III ATLANTIS trial failed to show an overall survival benefit for lurbinectedin + doxorubicin versus standard of care (e.g., IV topotecan or the CAV regimen); no randomized data demonstrate superior survival compared to standard second-line options. Evolent directs providers to alternative regimens per Evolent Pathways.