ModifiedmhnPolicy CP.PHAR.406

Clinical Policy: Lorlatinib (Lorbrena)

This policy defines medical necessity criteria, prior authorization requirements, dosing limits, and approved indications (FDA and selected NCCN off-label uses) for lorlatinib (Lorbrena) for members under the payer's commercial, HIM, and Medicaid lines of business.

Policy Summary

Payermhn

PolicyLorlatinib (Lorbrena) coverage for ALK-positive NSCLC and NCCN-recommended uses

Policy CodePolicy CP.PHAR.406

Change TypeMaterial updates to NCCN off-label indications and ROS1 failure options

Effective DateMar 1, 2019

Next Review Date

Key ActionSubmit prior authorization with diagnosis, ALK/ROS1 status, prescriber specialty, age, prior ROS1 agents tried (if ROS1+), and supporting clinical documentation.

SourceLink

POLICY UPDATE CHANGES

Added off-label NCCN-supported indications of diffuse large B-cell lymphoma, Erdheim-Chester disease, inflammatory myofibroblastic tumor (IMT), and uterine sarcoma.

Added Augtyro as a failure option for ROS1-positive disease and added anaplastic large cell lymphoma indication per NCCN; condensed uterine sarcoma IMT-specific criteria.

Removed Zykadia from list of ROS1-positive NSCLC failure agents per NCCN update; added pediatric diffuse high-grade glioma to NCCN-supported off-label indications.

100 mg/daymaximum dose (tablet limit)

Adults ≥18minimum age

6–12 moMedicaid/HIM approval

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Coverage Criteria for Lorlatinib (Lorbrena)

Initial Therapy - NSCLC

Covered when ALL of the following are met for Initial Approval — Non-Small Cell Lung Cancer:

Initial Approval - NSCLC: 1. Diagnosis of recurrent, advanced, or metastatic non-small cell lung cancer (NSCLC). 2. Prescribed by or in consultation with an oncologist. 3. Age ≥ 18 years. 4. Tumor is ALK-positive or ROS1-positive. 5. If ROS1-positive: documented failure of Augtyro, Rozlytrek, and Xalkori unless clinically significant adverse effects or all are contraindicated. 6. Prescribed as a single agent. 7. Member must use generic lorlatinib if available unless contraindicated or clinically significant adverse effects are experienced. 8. Request meets one of the following: (a) dose does not exceed both i) 100 mg per day and ii) 1 tablet per day; OR (b) dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).dose <= 100 mg/day and <= 1 tablet/day

Prescribed regimen must be FDA-approved or recommended by NCCN

NCCN Recommended Off-Label Uses

Covered when ALL of the following are met for NCCN-recommended off-label uses:

Initial Approval - NCCN Off-Label: 1. Prescribed for one of the following diagnoses: a) relapsed or refractory anaplastic large cell lymphoma; b) relapsed or refractory diffuse large B-cell lymphoma; c) symptomatic or relapsed/refractory Erdheim-Chester disease; d) inflammatory myofibroblastic tumor (IMT); e) uterine IMT that is advanced, recurrent, metastatic, or inoperable; f) pediatric diffuse high-grade glioma. 2. Prescribed by or in consultation with an oncologist or hematologist. 3. Age meets one of the following: a) for pediatric diffuse high-grade glioma: < 18 years; b) for all other NCCN-recommended uses: ≥ 18 years. 4. Disease is ALK positive. 5. Prescribed as a single agent. 6. For pediatric diffuse high-grade glioma, prescribed as either a) adjuvant treatment (except diffuse midline glioma, H3 K27-altered or pontine location) or b) treatment of recurrent or progressive disease (with specified histologic exceptions). 7. Member must use generic lorlatinib if available unless contraindicated or clinically significant adverse effects are experienced. 8. Request meets one of the following: (a) dose does not exceed both i) 100 mg per day and ii) 1 tablet per day; OR (b) requested dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).dose <= 100 mg/day and <= 1 tablet/day

Prescribed regimen must be FDA-approved or recommended by NCCN

Continuation Therapy

Covered when ALL of the following are met for Continuation Therapy:

Continuation Therapy: 1. Member is currently receiving lorlatinib via the Centene benefit, or documentation supports that the member has been receiving lorlatinib for a covered indication for at least 30 days. 2. Member is responding positively to therapy. 3. Member must use generic lorlatinib if available unless contraindicated or clinically significant adverse effects are experienced. 4. If the request is for a dose increase, the new dose must meet one of the following: (a) new dose does not exceed both i) 100 mg per day and ii) 1 tablet per day; OR (b) new dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).dose <= 100 mg/day and <= 1 tablet/day

Prescribed regimen must be FDA-approved or recommended by NCCN

Non‑FDA approved indications that are not specifically addressed in this policy are not authorized unless the provider supplies sufficient documentation of efficacy and safety consistent with the payer's off‑label use requirements (see CP.CPA.09 for commercial, HIM.PA.154 for Health Insurance Marketplace, and CP.PMN.53 for Medicaid) or the member's evidence of coverage documents.

Coverage and coverage decisions under this clinical policy are subject to all applicable terms, conditions, exclusions, and limitations contained in the member's coverage documents (for example, evidence of coverage, certificate of coverage, policy, or contract of insurance), as well as applicable state and federal requirements and Health Plan administrative policies and procedures.

Uses that are non‑FDA approved and not specifically addressed in this policy are considered not authorized unless the prescriber provides adequate off‑label documentation demonstrating safety and efficacy in accordance with the referenced off‑label policies or the member's coverage terms.

Billing and Dose Coding

Prior authorization / billingmixed

affected codes

Document references prior authorization and affected billing codes but specific CPT/HCPCS/NDC codes are not listed in this portion of the policy.

Maximum dose

Maximum daily dose100 mg per day

Tablet limit1 tablet per day

Dosing regimen (NSCLC)100 mg PO QD as single-agent

Provider Requirements and Prior Authorization

Prior Authorization

Prior Authorization Required

Prior authorization is required. Providers must document the clinical rationale for therapy and submit supporting records to demonstrate the member meets all approval criteria. Failure to submit required documentation (office chart notes, laboratory results, pathology reports, molecular testing confirming ALK/ROS1 status, prior therapy history, or other clinical information) may result in denial of the request.

Documentation should include: diagnosis, ALK/ROS1 test results, prescriber specialty, age, prior ROS1 agents tried (if applicable), and supportive evidence for off-label dosing when relevant.
Prior authorization may be required for ROS1 agents listed as prior-failure options (Augtyro™, Rozlytrek®, Xalkori®).

Note

Coverage Document Compliance and Administrative Requirements

Providers must follow Health Plan-level administrative policies and ensure the request aligns with the member's coverage documents. Coverage decisions and administration of benefits are subject to all terms, conditions, exclusions, and limitations of the member's evidence of coverage, certificate of coverage, policy, or contract. This clinical policy is effective per the Health Plan and may be changed, amended, or withdrawn.

Key Definitions and Abbreviations

ALK

ALK (definition)Anaplastic lymphoma kinase

RelevanceRequired biomarker for FDA-approved ALK-positive NSCLC indication

Source test requirementDetected by an FDA-approved test per FDA indication

IMT

IMT (definition)Inflammatory myofibroblastic tumor

ClassificationDescribed in policy as a soft tissue sarcoma

Coverage contextListed among NCCN-recommended off-label indications for lorlatinib

Line of Therapy Specifications

first-line

Line of therapy: Per NCCN compendium and updated FDA indication, Lorbrena may be used as first-line therapy in ALK-positive NSCLC; prior requirement for disease progression on specific prior therapies has been removed.

See FDA indication and NCCN references

Approved Regimens and Dosing

Indication	Regimen / Dose	Notes
ALK-positive non-small cell lung cancer (NSCLC)
Lorlatinib 100 mg PO QD (1 tablet per day) as single-agent
Dose must not exceed both 100 mg/day and 1 tablet/day; prescribed regimen must be FDA‑approved or recommended by NCCN. Approval duration: Medicaid/HIM 6 months; Commercial 12 months or duration of request, whichever is less.

Indication	Regimen / Dose	Notes
NCCN-supported off-label indications (examples added/updated: diffuse large B-cell lymphoma; Erdheim‑Chester disease; inflammatory myofibroblastic tumor [IMT]; uterine sarcoma; anaplastic large cell lymphoma; pediatric diffuse high-grade glioma)
Lorlatinib per NCCN–recommended regimen; dose must not exceed both 100 mg/day and 1 tablet/day unless supported by practice guidelines or peer‑reviewed literature (prescriber must submit supporting evidence).
Use generic lorlatinib if available unless contraindicated; prescriber specialty and age requirements vary by indication (e.g., pediatric criteria for diffuse high‑grade glioma). Prescribed regimen must be recommended by NCCN. (Policy updates: 2Q2023–2Q2025 reflected additions/removals of listed indications and ROS1 failure agent updates.)

Background

Lorlatinib (Lorbrena) is a kinase inhibitor indicated for the treatment of adult patients with metastatic ALK‑positive non‑small cell lung cancer as detected by an FDA‑approved test; the policy also incorporates selected NCCN‑recommended off‑label uses.

Policy Revision History

2025-02-18annual reviewLatest

Removed Zykadia from the list of ROS1-positive NSCLC failure agents per NCCN update; added pediatric diffuse high-grade glioma to NCCN-supported off-label indications.

2024-01-11annual review

Added Augtyro as a failure option for ROS1-positive disease and added anaplastic large cell lymphoma as an NCCN-supported off-label indication; condensed uterine sarcoma/IMT-specific criteria.

2023-02-04annual review