ModifiedPremera BluecrossPolicy N/A

Multikinase (receptor tyrosine kinase) inhibitor pharmacy coverage

Defines medical necessity and pharmacy benefit management for multiple oral and select targeted kinase inhibitor drugs used in oncology and related indications; applies to Premera-managed pharmacy benefit.

Policy Summary

PayerPremera Bluecross

PolicyMultikinase (receptor tyrosine kinase) inhibitor pharmacy coverage

Policy CodePolicy N/A

Change TypeMultiple additions and formulary sequencing updates

Effective DateJul 8, 2025

Next Review DateN/A

Key ActionRequest initial authorization for listed oral oncology drugs for 3 months and provide documentation of objective response for continuation.

SourceLink

POLICY UPDATE CHANGES

Added coverage criteria for Ibtrozi (taletrectinib).

Added coverage criteria for Augtyro (repotrectinib).

Added coverage criteria for Vanflyta (quizartinib) for newly diagnosed FLT3-ITD positive AML in adults.

Clarified non-formulary exception review authorizations may be approved up to 12 months and that listed medications are subject to FDA dosing/administration.

Updated multiple drug criteria to require trial with generic formulations first for select agents (pazopanib, sorafenib, sunitinib).

Added coverage criteria for generic sorafenib and generic sunitinib and required trial with generic before brand Nexavar/Sutent/Votrient in some indications.

~30+listed multikinase and targeted oral oncology drugs

3 monthsinitial approval period for oral drugs

pharmacy

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benefit application managed through

new agentsrecent drug additions (2023-2025)

2011-2025policy history revisions logged

Drug-Specific Coverage Criteria

New/Updated Drug Indications

New and updated drug indications and coverage clarifications added to the policy.

ALL of the following

Augtyro (repotrectinib) — added coverage for: (1) adults (age ≥18 years) with locally advanced or metastatic ROS1-positive non–small cell lung cancer (NSCLC) when ALL criteria are met, including dose limited to 160 mg twice daily; and (2) individuals aged ≥12 years with NTRK fusion–positive solid tumors that are locally advanced or metastatic or for which surgical resection is likely to result in severe morbidity, and who have progressed following treatment or have no satisfactory alternative therapy.
Generic pazopanib — added to policy as a required first-line trial for pazopanib-containing indications; updated Votrient (pazopanib) criteria to require trial with the generic formulation prior to branded product consideration.
Generic sorafenib — added to policy; updated Nexavar (sorafenib) criteria to clarify coverage is medically necessary in adults only per FDA prescribing information; updated Nexavar coverage to include treatment of certain individuals with desmoid tumors and to require trial with generic sorafenib first.
Sutent (sunitinib) / Generic sunitinib — clarified that indications for gastrointestinal stromal tumor (GIST), renal cell carcinoma (RCC), and pancreatic neuroendocrine tumors (pNET) are medically necessary in adults only per FDA label; added coverage criteria for generic sunitinib and updated Sutent criteria to require trial with the generic first where applicable.
Lenvima (lenvatinib) — clarified that lenvatinib may be used as first-line treatment for individuals with unresectable hepatocellular carcinoma (HCC) per updated prescribing information; removed reference to MSI-H and dMMR from Lenvima criteria (2023 update).
Ayvakit (avapritinib) — added coverage for adult individuals with advanced systemic mastocytosis (AdvSM) and updated to include indolent systemic mastocytosis (ISM) where criteria are met.
Vanflyta (quizartinib) — added coverage criteria for treatment of adults with newly diagnosed acute myeloid leukemia (AML) that is FLT3 internal tandem duplication (ITD)-positive, used in combination with standard induction (per policy criteria).
Ibtrozi (taletrectinib) — added coverage criteria for treatment of adults with locally advanced or metastatic ROS1-positive NSCLC when all policy criteria are met.
Cabometyx (cabozantinib) — updated criteria to include coverage for pancreatic neuroendocrine tumors (pNET) and extra-pancreatic neuroendocrine tumors (epNET).
General policy-level clarifications: non-formulary exception review authorizations for all drugs listed in this policy may be approved up to 12 months; medications are subject to the product's FDA dosage and administration prescribing information; initial approval period for listed oral drugs is 3 months with continuation requiring documentation of objective response to therapy.

Coding and Dose Limits

Dose limits examples

Repotrectinib (Augtyro)Dose limited to 160 mg twice daily

Fotivda (tivozanib)1.34 mg orally once daily for 21 days on/7 days off per 28-day cycle

Tepmetko (tepotinib)Dose limited to 450 mg per day

Qinlock (ripretinib)Dose limited to 150 mg once daily

Prior Authorization, Documentation, and Provider Requirements

Prior Authorization

Prior Authorization, Initial Approval Period, and Exception Duration

Prior Authorization Required. Initial approvals for oral drugs listed in this policy are generally limited to 3 months; continuation beyond the initial approval requires documentation of objective response to therapy. Non-formulary exception reviews may be approved up to 12 months when drug‑specific coverage criteria are met and chart notes demonstrate continued positive clinical response. All drugs are subject to the product's FDA dosage and administration prescribing information.

Initial approval period for oral drugs = 3 months; continued approval requires documented objective response
Non-formulary exception reviews may be approved up to 12 months
All drugs must follow FDA dosing/administration

Documentation Required

Required Clinical Documentation and Molecular Testing Confirmation

Documentation is required to support medical necessity and continuation of therapy. Submit office visit notes that include diagnosis, relevant history, physical examination, and comprehensive medication history. For agents with molecularly-defined indications, documentation of the specific molecular test result from an FDA‑approved or validated assay (eg, METex14, FLT3, NTRK, ROS1) must be provided. Where trial eligibility or label indications require measurable disease, include RECIST assessments or other objective measures of tumor burden and response.

Initial Authorization Rules and Evidence by Line

Initial authorization

Initial authorization — rules for oral oncology drugs listed in this policy:

Initial authorization duration: Initial authorization for oral drugs listed in this policy is for 3 months3 months

Per policy coverage criteria header; continued approval requires documented objective response

Documentation to obtain initial approval: Medical records submitted should document diagnosis, relevant history, and prior therapies as applicable to the drug‑specific criteriaoffice visit notes with diagnosis/history

See documentation requirements section for specifics

Line-specific evidence

Line‑specific evidence — examples of trial‑supported, line‑specific use:

Continuation and Reauthorization Criteria

Continuation criteria

Continuation beyond initial approval — requirements for ongoing therapy:

Objective response requirement: Continued approval beyond the initial 3‑month authorization requires documentation showing objective response to therapy and chart notes demonstrating continued positive clinical responseobjective response

Lack of documented objective response may preclude continued authorization

Non‑formulary exception duration: Non‑formulary exception reviews may be approved for up to 12 months when drug‑specific criteria and documentation are metup to 12 months

Per policy updates clarifying exception durations

Reauthorization

Reauthorization — ongoing monitoring and documentation expectations:

Step Therapy and Prior Treatment Tables

Drug / Example	Prior therapy requirement
Qinlock (ripretinib)	Received prior treatment with 3 or more kinase inhibitors, including imatinib (dose limited to 150 mg once daily)
Fotivda (tivozanib)	Received prior treatment with 2 or more systemic therapies (used in relapsed or refractory advanced RCC); therapy per TIVO-3 required 2–3 prior systemic treatments including at least one VEGFR inhibitor

Scenario	Policy expectation / documentation
Prior exposure required before later-line agent (example: regorafenib)	Documented progression following prior sorafenib is required for regorafenib use per RESORCE; individuals who permanently discontinued sorafenib for toxicity and could not tolerate 400 mg daily were ineligible for the trial
Prior exposure required before later-line agent (example: tivozanib)	Tivozanib evaluated in individuals who had received 2 or 3 prior systemic treatments including at least one VEGFR kinase inhibitor other than sorafenib or tivozanib (trial eligibility expectation)

Update date	Relevant policy change (high-level)
2019	Added coverage criteria for Turalio (pexidartinib); reviewed prescribing information and updated Lenvima criteria
2020	Updated Inlyta (axitinib) coverage criteria and added two first-line combination indications for advanced RCC (with avelumab or pembrolizumab)
2024	Added Augtyro (repotrectinib) and generic pazopanib; updated pazopanib, sunitinib, and sorafenib criteria to require trial with generic first and clarified adult-only labeling for some agents
2025	Clarified non‑formulary exception duration (may be approved up to 12 months); added pNET/epNET indication for Cabometyx (July 2025) and added Ibtrozi (taletrectinib) (Aug 2025)

Agent	Generic-first trial requirement
Pazopanib (Votrient / generic pazopanib)	Policy updated to require trial with generic pazopanib prior to branded Votrient in certain indications (2024 update added generic pazopanib and required trial with generic first)
Sorafenib (Nexavar / generic sorafenib)	Coverage criteria updated to require trial with generic sorafenib prior to Nexavar in specified indications (updates noted 2024 history and interim reviews)
Sunitinib (Sutent / generic sunitinib)	Policy added generic sunitinib and updated Sutent coverage criteria to require trial with the generic formulation first in applicable indications

Benefit Application and Site of Care

Billing Rule

Benefit managed through pharmacy (outpatient dispensing)

This benefit is managed through the pharmacy benefit; oral agents are dispensed via outpatient pharmacy and authorization requests should be directed to the pharmacy prior authorization process.

Requests for outpatient oral oncology agents follow pharmacy benefit prior authorization procedures.
Ensure pharmacy benefit identifiers and dispensing details are included with the request.

Note

Oral agents administered outpatient; continue until progression/toxicity

Oral agents are typically administered and monitored in outpatient settings (office, infusion center, or hospital outpatient) and trials continued until progression or unacceptable toxicity; document ongoing monitoring and toxicity management in the record.

Key Definitions

Multikinase inhibitor definition

DefinitionSmall-molecule targeted therapies designed to inhibit multiple receptor tyrosine kinases implicated in tumor growth; interfere with more than one tyrosine kinase protein to preferentially inhibit tumor cell signaling and proliferation

Typical usesUsed across a range of solid tumors and hematologic malignancies (examples in policy include agents for NSCLC, RCC, HCC, GIST, AML, TGCT)

Therapeutic rationaleBroader therapeutic index compared with cytotoxic chemotherapy and may be combined with other modalities to produce additive or synergistic activity

Child-Pugh Score

PurposeScoring system to measure severity of chronic liver disease (including cirrhosis) to objectively describe liver function

Components

Background and Clinical Context

Multikinase (receptor tyrosine kinase) inhibitors are small‑molecule targeted therapies that interfere with multiple tyrosine kinase proteins implicated in tumor growth and progression. These agents act on several kinase targets (for example, VEGFR, MET, PDGFRA, KIT, BRAF) to inhibit signaling pathways driving malignancy; their use is indication‑dependent with specific diagnostic confirmation, age limits, dose limits, and prior‑therapy requirements documented in the drug-specific sections of the policy.

Policy Revision History

2011-05-10addition

Policy added to Prescription Drug section as a new pharmacy policy.

2013-04-09revision

Added regorafenib (Stivarga) as medically necessary for metastatic colorectal cancer and GIST with prior therapy or intolerance to specified agents.

2019-06-01interim_review

Interim review approved; added criteria for Xospata (gilteritinib) and later in 2019 added criteria for Turalio (pexidartinib) and updated Lenvima criteria.

Policy Summary

PayerPremera Bluecross

PolicyMultikinase (receptor tyrosine kinase) inhibitor pharmacy coverage

Policy CodePolicy N/A

Change TypeMultiple additions and formulary sequencing updates

Effective DateJul 8, 2025

Next Review DateN/A

Key ActionRequest initial authorization for listed oral oncology drugs for 3 months and provide documentation of objective response for continuation.

SourceLink

On This Page

Office visit notes with diagnosis, history, physical, and medication history required
Molecular testing documentation required for molecularly defined populations (eg, FLT3, METex14, NTRK, ROS1)
RECIST measurable disease and objective response documentation where applicable

Prior Authorization

Prior Authorization and Coverage Criteria Exist for Listed Agents

Prior authorization and coverage criteria exist for the specific agents listed in this policy. Providers must demonstrate that all drug‑specific coverage criteria are met (age, diagnosis, prior treatments, dosing limits, molecular status when applicable) at the time of request. If required prior lines of therapy or specific agents are not documented, authorization may be denied or delayed.

Coverage criteria include age, diagnosis, required prior therapies, dose limits, and molecular status when applicable
Lack of documented prior therapy or intolerance may affect eligibility and trigger denial

Step Therapy

Prior Authorization with Generic-First Trial / Step Therapy

Generic‑first requirement / Step therapy. For select agents (for example pazopanib, sorafenib, sunitinib, and other drugs updated in recent reviews), the policy requires trial of the generic formulation prior to coverage of the branded product unless there is documented intolerance, contraindication, or other medical reason. Failure to document a trial of the generic when required may result in denial or necessitate a non‑formulary exception.

Updated Votrient (pazopanib) criteria require trial with the generic first
Nexavar (sorafenib) and Sutent (sunitinib) criteria updated to require generic-first trials where specified
If generic-first trial not completed, submit non‑formulary exception justification

Denial Risk

Objective Response Required for Continuation

Objective Response Required for Continuation. Continued authorization beyond the initial 3‑month period requires documentation of objective clinical benefit (for example tumor response or disease stabilization as appropriate per agent and indication). Absence of documented objective response may preclude continued authorization.

Continuation beyond initial approval requires objective response documentation (eg, RECIST, clinician assessment)
Lack of objective response can lead to denial of continued therapy

Prior Authorization

Prior Therapy Requirements and Line‑of‑Therapy Considerations

Prior Therapy and Line‑of‑Therapy Considerations. Many agents require prior lines of therapy or specific prior agents (eg, ripretinib after ≥3 kinase inhibitors including imatinib; tivozanib after 2–3 prior systemic treatments including a VEGFR inhibitor). Providers must document prior treatment history, dates, responses, and tolerability. Line‑of‑therapy eligibility (first‑line vs later lines) must align with the drug‑specific coverage criteria.

Document prior treatments, number of lines, and reason for discontinuation
Adhere to drug‑specific line‑of‑therapy requirements in coverage criteria

Documentation Required

Reauthorization and Documentation Requirements

Reauthorization and Documentation Updates. Reauthorization criteria and documentation requirements have been added and updated in recent policy revisions (2018–2025). When requesting reauthorization, include updated clinical notes demonstrating ongoing benefit, dosing administered per FDA labeling, and any new molecular testing or imaging supporting continued use.

2018–2025 updates added reauthorization criteria and documentation expectations
Reauthorization requests should include current chart notes, evidence of continued benefit, and adherence to FDA dosing

Denial Risk

Exception Duration, Dosing Documentation, and Denial Risk

Operational notes and denial risk. If a required generic trial, prior therapy, or molecular test is not documented, the request may be denied or require a non‑formulary exception with supporting justification. Ensure dosing, duration, and administration conform to FDA prescribing information; exceptions should document rationale and may be limited in duration.

Failure to document generic-first trial when required may trigger denial or need for exception
Exceptions to FDA dosing/administration must be justified; non‑formulary exceptions limited to 12 months where approved

Axitinib (AXIS trial): Axitinib demonstrated improved median progression‑free survival (6.7 vs 4.7 months) versus sorafenib in second‑line metastatic RCC (AXIS Phase III)

Supports axitinib as a second‑line option in mRCC

First-line therapy evidence

First‑line therapy evidence — randomized trial findings supporting first‑line uses where applicable:

First‑line RCC evidence: Sunitinib demonstrated higher objective response rate and longer time to progression versus interferon in first‑line advanced clear‑cell RCC

See randomized Phase III sunitinib vs interferon trial (chunk 38)

Pazopanib non‑inferiority: Pazopanib was non‑inferior to sunitinib for progression‑free survival in a Phase III trial comparing the two agents in clear‑cell metastatic RCC

See chunk 44

First‑line HCC evidence: Sorafenib demonstrated overall survival benefit versus placebo in advanced HCC (median OS 10.7 vs 7.9 months) and is the basis for its use in first‑line advanced HCC

See chunk 40

Reauthorization statement: The policy includes a reauthorization criteria statement and requires documentation at reauthorization (added in 2018), with specific clinical continuation criteria detailed in drug‑specific sections

Providers must supply chart notes documenting clinical benefit

Documentation elements: Medical record documentation for reauthorization should include office visit notes with diagnosis, relevant history, physical exam, and medication history; for molecularly targeted agents include confirmatory test results and evidence of measurable disease where applicable

See documentation and molecular testing confirmation sections

Include notes on toxicity management, dose interruptions, or dose reductions as applicable.

Document clinical rationale for continuing therapy between reauthorization periods.

Note

No explicit site‑of‑care limits; document monitoring and dose interruptions

No explicit site‑of‑care limitations are provided in the excerpt; when infusion or monitoring is required, document the need for observation and any dose interruptions or adjustments.

Document safety monitoring and any dose interruptions/reductions required for adverse events.
If a higher‑acuity site of care is requested, include clinical justification and monitoring needs.

Total bilirubin, serum albumin, INR, presence/degree of ascites, and presence/degree of hepatic encephalopathy

ClassificationTotal points summed and classified as Class A (5–6), Class B (7–9), or Class C (10–15)

MET exon 14 skipping

DefinitionA genomic alteration that results in skipping of exon 14 in the MET gene, removing a regulatory domain and leading to increased downstream MET signaling

Clinical implicationAssociated with sensitivity to MET inhibitors such as capmatinib and tepotinib

TestingDetected by stand-alone tests for MET exon 14 skipping or targeted panels that include MET exon 14 skipping

PDGFRA D842V

DefinitionAn activating mutation in PDGFRA (D842V) associated with constitutive activation of the receptor and resistance to some kinase inhibitors

Therapeutic relevanceTargeted by avapritinib which inhibits PDGFRA D842V and certain KIT mutants

Preclinical activityAvapritinib inhibited autophosphorylation of PDGFRA D842V in cellular assays with low nM IC50s

Progression-free survival (PFS)

DefinitionTime from randomization or treatment start until objective tumor progression or death; used as a primary or secondary endpoint in multiple trials summarized in the policy

Usage examplesReported as median PFS in randomized trials (e.g., axitinib vs sorafenib PFS 6.7 vs 4.7 months; sorafenib TTP/PFS improvements in HCC trials)

InterpretationLonger PFS indicates delayed tumor progression but must be considered alongside overall survival and safety data

Objective response rate (ORR)

DefinitionProportion of patients with a pre-specified partial or complete tumor response as assessed in clinical trials (e.g., investigator-assessed ORR)

ExamplesDabrafenib showed ORR up to 59% in BRAF V600E metastatic melanoma; sunitinib achieved 31% vs 6% interferon in first-line RCC trials

Role in authorizationObjective response documentation is required for continuation beyond initial authorization for oral agents per policy

Prescribing information

Reference sourceFDA prescribing information for individual agents (policy references multiple PIs including Augtyro, Tepmetko, Ayvakit, Fotivda)

Policy practiceProviders should document FDA-recommended dosing and administration per the product's prescribing information for non-formulary exception reviews

Cited documentsPolicy references specific prescribing information entries (examples in references: Sutent, Nexavar, Augtyro, Tepmetko, Ayvakit, Turalio, Vanflyta)

2020-04-01interim_review

Added criteria for Ayvakit (avapritinib) for treatment of GIST and later Qinlock (ripretinib) and other agent updates through 2020.

2021-05-01interim_review

Multiple 2021 updates including adding Fotivda (tivozanib), Tepmetko (tepotinib), and new indications for Cabometyx and Ayvakit (AdvSM), among others.

2023-01-01annual_update

2023 update reviewed prescribing information and added Vanflyta (quizartinib) coverage for newly diagnosed FLT3-ITD positive AML and updated Ayvakit criteria.

2024-01-01update

2024 update added coverage criteria for Augtyro (repotrectinib), generic pazopanib, generic sorafenib and generic sunitinib, and required trial of generics first for select agents.

2025-04-01annual_review

2025 annual review clarified non-formulary exception review authorizations may be approved up to 12 months and affirmed medications are subject to FDA dosing/administration.

2025-07-08interim_reviewLatest

Added coverage criteria for Ibtrozi (taletrectinib) and updated Cabometyx to include pNET and epNET; logged as the most recent revision.

2023addition

Added coverage criteria for Vanflyta (quizartinib) for newly diagnosed FLT3-ITD positive AML and updated Ayvakit (avapritinib) criteria.

2024addition

Added coverage criteria for Augtyro (repotrectinib) and added/required generic-first sequencing for pazopanib, sorafenib and sunitinib; added generic pazopanib and generic sorafenib coverage criteria.

2025additionLatest

Added coverage criteria for Ibtrozi (taletrectinib); clarified non-formulary exception durations and affirmed FDA dosing/administration applicability.