Premera Bluecross ALK Inhibitor Coverage Update

Drug-specific Medical Necessity and Indications

Alecensa (alectinib) — NSCLC and iMT

Alecensa (alectinib) may be considered medically necessary when ALL of the following are met:

Alecensa (alectinib) initial criteria: The individual is aged 18 years or older AND Diagnosed with anaplastic lymphoma kinase (ALK)-positive NSCLC AND Meets one of: Diagnosed with advanced or metastatic disease OR Requires adjuvant treatment following tumor resection with tumors at least 4 cm or node positive AND The dose is limited to 1,200 mg dailyage >= 18; dose <= 1200 mg/day

Also may be considered medically necessary for metastatic or recurrent inflammatory myofibroblastic tumor (iMT) with ALK translocation when the individual has had treatment failure on prior Xalkori

Alunbrig (brigatinib) — NSCLC and iMT

Alunbrig (brigatinib) may be considered medically necessary when ALL of the following are met:

Alunbrig (brigatinib) criteria: The individual is aged 18 years or older AND Diagnosed with advanced or metastatic NSCLC that is anaplastic lymphoma kinase (ALK)-positive AND The dose is limited to 180 mg dailyage >= 18; dose = 180 mg/day

Also may be considered medically necessary for metastatic or recurrent inflammatory myofibroblastic tumor (iMT) with ALK translocation when the individual has had treatment failure on prior Xalkori (crizotinib)

Ensacove (ensartinib) — NSCLC (limited uses)

Ensacove (ensartinib) may be considered medically necessary when ALL of the following are met:

Ensacove (ensartinib) criteria: The individual is aged 18 years or older AND Diagnosed with advanced or metastatic NSCLC that is anaplastic lymphoma kinase (ALK)-positive AND Meets one of: Has not previously received an ALK inhibitor OR Is changing ALK inhibitor due to documented side effects (not due to failure of ALK inhibitor therapy) AND There is a documented contraindication to the use of Alecensa (alectinib)age >= 18

Dose and quantity limits per product labeling

Lorbrena (lorlatinib) — NSCLC and iMT

Lorbrena (lorlatinib) may be considered medically necessary when ALL of the following are met:

Lorbrena (lorlatinib) criteria: The individual is aged 18 years or older AND Diagnosed with advanced or metastatic NSCLC that is anaplastic lymphoma kinase (ALK)-positive AND The dose is limited to 100 mg daily AND Quantity limits: 25 mg tablets: 90 tablets per 30 days; 100 mg tablets: 30 tablets per 30 daysage >= 18; dose = 100 mg/day; quantity limits as specified

Xalkori (crizotinib) — NSCLC, ROS1, ALCL, iMT

Xalkori (crizotinib) may be considered medically necessary when ALL of the following are met:

Xalkori (crizotinib) NSCLC criteria: The individual is aged 18 years or older AND Diagnosed with advanced or metastatic NSCLC that is anaplastic lymphoma kinase (ALK)-positive OR ROS1-positive AND The dose is limited to 500 mg dailyage >= 18; dose <= 500 mg/day

Also may be considered medically necessary for anaplastic large cell lymphoma (ALCL) in ages 1–21 and for inflammatory myofibroblastic tumor (iMT) in ages >=1 with ALK-positive tumors

Zykadia (ceritinib) — NSCLC and iMT

Zykadia (ceritinib) may be considered medically necessary when ALL of the following are met:

Zykadia (ceritinib) criteria: The individual is aged 18 years or older AND Diagnosed with advanced or metastatic NSCLC that is anaplastic lymphoma kinase (ALK)-positive AND The dose is limited to 450 mg per dayage >= 18; dose = 450 mg/day

Inflammatory myofibroblastic tumor (iMT) — agent-specific criteria

Policy history and recent coverage modifications relevant to clinical criteria

iMT coverage for certain ALK inhibitors (2021/2026 updates): Coverage for Alunbrig (brigatinib), Xalkori (crizotinib), and Zykadia (ceritinib) was expanded for treatment of inflammatory myofibroblastic tumor (iMT) with ALK translocation (NCCN category 2A). In 2026, coverage for Alunbrig and Zykadia for iMT was clarified to be limited to metastatic or recurrent disease and requires prior treatment failure on Xalkori (crizotinib). Alecensa (alectinib) and Lorbrena (lorlatinib) were added for metastatic or recurrent iMT with ALK translocation when the individual has had treatment failure on prior Xalkori (crizotinib).

NCCN guidance cited; changes applied in 2021 and 2026 updates.

Ceritinib (Zykadia) clinical summary

Evidence summary for ceritinib

ceritinib evidence: Ceritinib approval was based on a single-arm Phase I study (n=130 ALK-mutated tumors, mostly NSCLC) showing 41.1% partial response (BIRC), 2.5% complete response, and median progression-free survival of approximately 7 months. Common adverse events included nausea, elevated LFTs, diarrhea, and vomiting; uncommon but serious events included interstitial lung disease, hyperglycemia, dyspnea, and prolonged QT; fatal reactions occurred in 5% of patients.

Supports coverage decisions and safety monitoring.

Authorization and quantity limits

Administrative coverage stipulations

authorization and limits: Quantity limits were added to drugs for NSCLC following prescribing information (2021); nonformulary exception authorizations for drugs listed in this policy may be approved up to 12 months (clarified 2025). Lorbrena (lorlatinib) has a prescribed quantity limit per 30 days (added 2026). Initial authorization duration for drugs listed in the policy was updated to 6 months (effective 2026).

Operational limits per agent and year-specific updates.

Recent coverage revisions and new indications

Recent additions and revisions to coverage criteria include:

Ensartinib for NSCLC: Ensacove (ensartinib) was added as covered for treatment of advanced or metastatic NSCLC (2025 update).

Reference: Prescribing information and 2025 update.

iMT agents after crizotinib: Coverage for Alunbrig (brigatinib) and Zykadia (ceritinib) for iMT was limited to metastatic or recurrent disease and requires prior treatment failure on Xalkori (crizotinib); Alecensa and Lorbrena were added for metastatic/recurrent iMT after prior crizotinib failure.

Changes applied in 2026 updates.

Authorization duration: Initial authorization period for all drugs in the policy is 6 months (changed from 3 months).6 months

Updated in 2026.

All other uses of the medications listed in this policy are considered investigational. Coverage and approvals are limited to uses that meet the drug‑specific medical necessity criteria and the product's FDA dosing and administration prescribing information; uses outside those specified criteria will not be approved.

For requests involving Alunbrig (brigatinib) and Zykadia (ceritinib) for inflammatory myofibroblastic tumor (iMT), coverage is limited to metastatic or recurrent disease and requires documentation that the individual has had treatment failure on prior Xalkori (crizotinib) therapy.

This medical policy is a guide for determining medical necessity and does not apply to Medicare Advantage; member benefits may vary and providers should consult the member benefit booklet or customer service for plan‑specific coverage.

Uses of the listed medications that are outside the drug‑specific coverage criteria described in this policy are considered investigational and are not medically necessary for coverage.

In the 2018 policy update there were no changes to coverage; the update noted policy review and added reauthorization and documentation language but did not alter coverage determinations.

Dosing, Regimens and Agent Listings

Drug	Dose (daily)	Indication (covered)	Special limits / quantity
Zykadia (ceritinib)
450 mg daily
ALK‑positive advanced or metastatic NSCLC; metastatic or recurrent inflammatory myofibroblastic tumor (iMT) with ALK translocation after prior crizotinib (Xalkori) failure
Dose limited to 450 mg per day

Agent	Covered Indications	Prior therapy requirement (if any)
Zykadia (ceritinib)
ALK‑positive advanced or metastatic NSCLC; metastatic or recurrent iMT with ALK translocation
For iMT: coverage requires prior treatment failure on Xalkori (crizotinib)

Source	FDA-approved indication (brief)
Ensacove (ensartinib) Prescribing Information (referenced)
Treatment of adults with ALK‑positive advanced or metastatic non‑small cell lung cancer (NSCLC); added to policy for adults who have not previously received an ALK‑inhibitor

Biomarker and Diagnostic Requirements

ALK (anaplastic lymphoma kinase)

MarkerAnaplastic lymphoma kinase (ALK)

Required forCoverage of ALK inhibitors for ALK-positive NSCLC and other ALK-translocated tumors per policy

Evidence basisALK activation is via chromosomal rearrangement (eg, EML4-ALK) driving ~2–7% of NSCLC

ROS1

MarkerROS1 (ROS proto-oncogene 1 receptor tyrosine kinase)

Required forXalkori (crizotinib) coverage in NSCLC when tumor is ROS1-positive

Policy note

Indication by Line of Therapy

first-line | second-line

Line-of-therapy distinctions:

first-line | second-line: Ensacove (ensartinib) coverage was added for adults who have not previously received an ALK inhibitor (first-line, per 2025 update). Lorbrena (lorlatinib) has approvals for both first-line (CROWN study) and for later-line use after progression on other ALK inhibitors; other agents have adult-only NSCLC indications and may be used based on prior ALK-inhibitor exposure per agent-specific criteria.

first-line | second-line (trial-specific)

Trial-specific line-of-therapy notes:

first-line | second-line (trial-specific): The eXalt3 Phase III trial evaluated ensartinib versus crizotinib in adults with advanced or recurrent/metastatic ALK-positive NSCLC; the trial excluded prior ALK TKIs and allowed up to one prior chemotherapy for metastatic disease, supporting first-line use of ensartinib in individuals without prior ALK inhibitor exposure.

first-line

Billing and Administrative Codes

Codingmixed

No codes listed

Administrative coding notemixed

managed through pharmacy benefit

Policy clarification that these medications are managed through the member's pharmacy benefit (historical note).

Prior Authorization, Documentation, and Provider Requirements

Prior Authorization

Prior Authorization Required

This policy is managed through the pharmacy benefit. Prior authorization is required for ALK inhibitors and related agents listed in this policy. Non‑formulary exception reviews may be approved for up to 12 months; other reviews may be approved for initial and reauthorization periods when criteria are met (see note on initial authorization duration). Lack of required documentation or failure to meet prior‑therapy requirements may result in denial.

Non‑formulary exception review authorizations may be approved up to 12 months.
Initial authorization for other reviews updated to 6 months (effective 05/01/26).
Reauthorizations may be approved up to 12 months if drug‑specific criteria and positive clinical response are documented.

Documentation Required

Required Clinical Documentation

Medical records submitted must document that medical necessity criteria are met. Acceptable documentation includes office visit notes with diagnosis, relevant history, physical exam, medication history, imaging and pathology reports as applicable, and documentation of prior therapies and treatment response.

Key Definitions and Terms

ALK-positive NSCLC definition

DefinitionALK-positive NSCLC: non-small cell lung cancer driven by ALK gene rearrangements (commonly EML4-ALK)

Clinical featuresAssociated with younger age, minimal smoking history, and adenocarcinoma histology

Coverage implicationALK positivity is required for coverage of listed ALK inhibitors for NSCLC indications

inflammatory myofibroblastic tumor (iMT) with ALK translocation

DefinitionInflammatory myofibroblastic tumor (iMT) with ALK translocation: a soft tissue tumor subtype harboring ALK fusions that may respond to ALK inhibitors

Guideline supportNCCN lists ALK inhibitors as category 2A options for iMT with ALK translocation

Clinical Background and Rationale

Rearrangements of the anaplastic lymphoma kinase (ALK) gene produce oncogenic fusion proteins (for example, EML4‑ALK) that drive tumor growth in a subset of non‑small cell lung cancers (NSCLC).

ALK‑positive NSCLC represents a distinct molecular subtype often seen in younger patients with little or no smoking history; ALK tyrosine kinase inhibitors target ALK signaling and are indicated for ALK‑positive advanced or metastatic NSCLC and, in selected circumstances, for other ALK‑translocated tumors such as inflammatory myofibroblastic tumor (iMT).

Document Changes and Update Log

2025-04-01addition

Added coverage for Ensacove (ensartinib) for treatment of advanced or metastatic ALK-positive NSCLC and clarified non‑formulary exception authorizations may be approved up to 12 months; medications subject to FDA dosing and administration guidance.

2026-03-01revision

Updated Lorbrena (lorlatinib) coverage to add a prescribed quantity limit per 30 days and revised iMT coverage for Alunbrig (brigatinib) and Zykadia (ceritinib) to be limited to metastatic or recurrent disease with documented treatment failure on prior Xalkori (crizotinib); added Alecensa (alectinib) and Lorbrena for metastatic/recurrent iMT after prior crizotinib failure.

2026-05-01

OpenPayer

ALK Tyrosine Kinase Inhibitors