ModifiedPremera BluecrossPolicy 5.01.534

Multiple receptor tyrosine kinase inhibitors (multikinase inhibitors) — pharmacy coverage

Pharmacy benefit policy describing medical necessity criteria, approvals, and documentation requirements for multiple receptor tyrosine kinase (multikinase) inhibitor oral drugs for specified oncologic indications; applies to Premera Blue Cross pharmacy benefit management.

Policy Summary

PayerPremera Bluecross

PolicyMultiple receptor tyrosine kinase inhibitors (multikinase inhibitors) — pharmacy coverage

Policy CodePolicy 5.01.534

Change TypeCriteria updates and authorization duration changes

Effective Date

Next Review Date

Key ActionSubmit prior authorization with documentation of diagnosis, prior therapies, and objective response for reauthorization.

SourceLink

POLICY UPDATE CHANGES

Updated initial authorization for all other reviews for all drugs listed in the policy from 3 months to 6 months.

Updated Cabometyx (cabozantinib) criteria to include coverage for the treatment of pancreatic neuroendocrine tumors (pNET) and extra-pancreatic neuroendocrine tumors (epNET).

Updated coverage criteria for Fotivda (tivozanib) adding a prescribed quantity limit per 28 days.

Updated coverage criteria for Tepmetko (tepotinib) adding a prescribed quantity limit per 30 days.

Clarified that non-formulary exception review authorizations for all drugs listed in this policy may be approved up to 12 months.

6 monthsnew default initial authorization

12 monthsnon-formulary exception max

3 monthsinitial approval period (legacy)

Trek Health ingests and normalizes Transparency in Coverage data and payer policy updates to give provider organizations a clear view of how commercial reimbursement behaves across markets, payers, and services. Our platform transforms raw payer disclosures into structured intelligence that supports contract evaluation, payer negotiations, and service line strategy. By combining market benchmarks with ongoing policy visibility, Trek helps teams identify variability, risk, and opportunity in commercial reimbursement. The result is faster insight, stronger negotiating positions, and more informed financial decisions.

2026-04-13last review

Medical Necessity and Drug-Specific Coverage Criteria

Augtyro (repotrectinib) — ROS1-positive NSCLC and NTRK fusion solid tumors

Augtyro (repotrectinib) may be considered medically necessary when ALL of the following are met

Augtyro ROS1 NSCLC: The individual is aged 18 years or older AND has been diagnosed with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC) AND dose is limited to 160 mg twice daily

Initial approval 3 months; continued approval requires objective response

Augtyro NTRK solid tumor: The individual is aged 12 years or older AND has a solid tumor with an NTRK gene fusion that is locally advanced or metastatic or where surgical resection is likely to result in severe morbidity AND the tumor has progressed following treatment or there is no satisfactory alternative therapy

Cabometyx / Cometriq (cabozantinib) — assorted indications

Cabometyx (cabozantinib) may be considered medically necessary for one of the following indications

Advanced RCC: Advanced renal cell carcinoma (RCC) in adults

Advanced RCC first-line combination: Advanced RCC in adults as a first-line treatment in combination with nivolumab (Opdivo)

HCC after sorafenib: Hepatocellular carcinoma (HCC) in adults who have been previously treated with sorafenib

DTC ≥12 years: Locally advanced or metastatic differentiated thyroid cancer (DTC) in individuals aged ≥12 years that has progressed following prior VEGFR‑targeted therapy and who are radioactive iodine‑refractory or ineligible

pNET/epNET ≥12 years: Unresectable, locally advanced or metastatic, well‑differentiated pancreatic neuroendocrine tumors (pNET) or extra‑pancreatic neuroendocrine tumors (epNET) in individuals aged ≥12 years previously treated with specified therapies (e.g., everolimus, sunitinib, or Lutathera as applicable)

Added coverage for pNET and epNET in 2025 update

Cometriq (MTC): Cometriq (cabozantinib) for treatment of adults with progressive, metastatic medullary thyroid carcinoma (MTC)

Other oral multikinase inhibitor specific criteria (selected examples)

Each listed drug may be considered medically necessary when the individual meets the drug-specific age, diagnostic, mutation/test, prior therapy, and dosing criteria shown

Fotivda (tivozanib): Individual aged ≥18 years AND has relapsed or refractory advanced renal cell carcinoma (RCC) AND has received prior treatment with 2 or more systemic therapies AND dose limited to 1.34 mg per day for 21 days on followed by 7 days off in a 28‑day cycle AND quantity limited to 21 capsules per 28 days

Ibtrozi (taletrectinib): Individual aged ≥18 years AND diagnosed with locally advanced or metastatic ROS1‑positive NSCLC

Qinlock (ripretinib): Individual aged ≥18 years AND has advanced gastrointestinal stromal tumor (GIST) AND has received prior treatment with 3 or more kinase inhibitors including imatinib AND dose limited to 150 mg per day

Tabrecta (capmatinib) / Tepmetko (tepotinib): Individual aged ≥18 years AND has metastatic NSCLC with MET exon 14 skipping confirmed by an appropriate stand‑alone test or targeted panel AND (for tepotinib) dose limited to 450 mg per day

Clinical evidence by drug/indication

Summaries of clinical trial evidence and FDA-approved uses for individual multikinase inhibitors:

Agent-specific evidence summaries: Individual agents have clinical trials supporting their FDA‑approved indications (examples: avapritinib showed high ORR for PDGFRA D842V mutant GIST; axitinib improved PFS vs sorafenib in second‑line mRCC in AXIS; cabozantinib improved PFS in progressive metastatic medullary thyroid cancer; regorafenib improved OS in third‑line metastatic colorectal cancer; lenvatinib improved PFS in radioactive iodine‑refractory differentiated thyroid cancer).

Summaries reflect trial endpoints such as PFS, OS, ORR and safety; approvals are often line‑of‑therapy specific and rely on prior therapy history.

Drug-level coverage criteria (aggregate)

Policy includes drug-specific medically necessary coverage criteria updated over time; coverage decisions reference FDA prescribing information and, where noted, require trials of generic agents first or specify age-limited use.

Drug-specific coverage summaries: The document contains multiple individualized coverage criteria and updates (examples: Inlyta combinations added for first‑line advanced RCC; Ayvakit expanded for AdvSM and ISM; Vanflyta added for FLT3‑ITD AML; Augtyro and generic pazopanib added; Cabometyx expanded to pNET and epNET; Fotivda and Tepmetko include prescribed quantity limits; generic‑first trial requirements for pazopanib, sorafenib, sunitinib; several agents limited to adults per FDA labeling).

Detailed, drug‑level criteria are available in the full policy sections and history updates.

All uses of the agents listed in this policy that are not specifically described in the drug‑specific coverage sections are considered investigational. The policy states: All other uses of the medications listed in this policy are considered investigational, and the medications are subject to the product's FDA dosage and administration prescribing information. Providers should ensure requested uses match an indication and criteria explicitly listed in this policy to avoid denial for investigational use.

Evidence supporting approval of sunitinib (Sutent) for advanced renal cell carcinoma is based on uncontrolled partial response rates and duration of response rather than randomized controlled trials demonstrating improvements in survival or disease‑related symptoms. The document notes that the Sutent approval was derived from uncontrolled response data and that randomized trials showing clinical benefit for outcomes such as survival were not cited for advanced RCC.

The policy clarifies that several indications for certain multikinase inhibitors are limited to adults per the FDA prescribing information. For example, the 2024 update specifies that use of Sutent (sunitinib), Nexavar (sorafenib), and Votrient (pazopanib) is considered medically necessary in adults only where indicated on the FDA label. Providers must follow age‑specific labeling when documenting medical necessity.

Uses that are not described among the policy's specified drug indications are treated as investigational and therefore are not considered medically necessary. The policy explicitly indicates that investigational uses (i.e., those not listed in the coverage criteria) may be denied and that the medications are reviewed against FDA‑approved dosing and administration guidance.

Coverage decisions under this policy are subject to the member's benefit plan limitations. The policy is a guide and notes that member contracts differ in their benefits; providers and members should consult the member benefit booklet or contact customer service to confirm coverage. Additionally, length of approval and any non‑formulary exceptions are governed by the policy and the member contract (the policy notes non‑formulary exception reviews may be approved up to 12 months, and initial approvals for other reviews were updated to 6 months).

Coding, Age and Dose Limits

Codingmixed

No codes listed

Age

Age requirement>= 18 years for many adult indications

Pediatric exceptionsSelected agents (e.g., repotrectinib for NTRK fusion solid tumors) have criteria starting at age 12

Reference contextAge thresholds are specified in individual drug criteria and align with FDA labeling

Dose limits — Augtyro (repotrectinib)

Augtyro (repotrectinib) dosing limitDose is limited to 160 mg twice daily

Indication linkLimit applies for ROS1-positive NSCLC adult indication as specified in criteria

Prior Authorization, Documentation and Reauthorization Requirements

Prior Authorization

Prior Authorization Required

Prior Authorization Required: Prior authorization is required for medications covered under this policy. Initial authorizations for oral drugs listed in this policy will be approved for up to 6 months; non-formulary exception requests may be approved up to 12 months. Continued approval (reauthorization) requires documentation of ongoing clinical benefit (objective response or clinical stability) and review of updated chart notes.

Initial approval period: up to 6 months for routine reviews; up to 12 months for non-formulary exceptions.
Reauthorization: may be approved up to 12 months if drug‑specific criteria are met and chart notes demonstrate continued positive clinical response.

Prior Authorization

Indication‑Specific Prior Authorization

Indication‑Specific Prior Authorization: Approvals are indication specific and must match the FDA‑approved indication or the specific coverage criteria in this policy (e.g., repotrectinib for ROS1‑positive NSCLC; lenvatinib combinations for RCC; agents listed in Table 1). Uses not meeting the drug‑specific coverage criteria are investigational and not covered.

Clinical Background and Policy Scope

Multikinase inhibitors are small‑molecule tyrosine kinase inhibitors that target multiple receptor tyrosine kinases to interrupt signaling pathways that drive tumor proliferation. The policy frames these agents as oral targeted therapies used across a range of tumor types and notes they are administered in ambulatory outpatient settings per prescribing information. Examples in the policy include agents with indications in RCC, HCC, GIST and other solid tumors, and the document describes trial contexts (line of therapy, response assessments) used to define coverage and continuation criteria.

Definitions and Scoring Systems

Child-Pugh Score

PurposeScoring system to measure severity of chronic liver disease (including cirrhosis) using bilirubin, albumin, INR, ascites, and hepatic encephalopathy

ComponentsTotal bilirubin, serum albumin, INR, presence/absence of ascites, and hepatic encephalopathy (points assigned per ranges)

ClassificationsTotal score classifies disease as Class A (5-6), Class B (7-9), or Class C (10-15)

Multikinase inhibitors — definition

DefinitionMultikinase inhibitors are small molecule agents designed to interfere with more than one tyrosine kinase protein to inhibit tumor cell growth

MechanismTarget receptor tyrosine kinases on cell membranes to inhibit intracellular signaling driving tumor proliferation

Initial Approval Conditions and Evidence

Initial therapy examples — initial approval conditions for select drugs

Initial approval conditions for select drugs

Augtyro initial: Age and diagnosis criteria as specified for ROS1 NSCLC; dose limited to 160 mg twice daily

Initial approval 3 months

Initial therapy evidence — line-of-therapy evidence examples

Line-of-therapy evidence examples

Second-line and first-line examples: Axitinib demonstrated improved progression‑free survival versus sorafenib in second‑line metastatic RCC (AXIS trial); approvals for agents such as sorafenib and sunitinib were supported by randomized or uncontrolled trials respectively — used to inform initial therapy positioning relative to prior treatments.

Initial therapy notes — some drugs may be used first-line per label

Reauthorization and Continuation Rules

Continuation therapy — continued approval beyond initial authorization requires evidence of clinical benefit

Continued approval beyond initial authorization requires evidence of clinical benefit.

Continuation requirement: Continued approval beyond the initial authorization period requires documentation showing objective response to therapy; reauthorization may be approved up to 12 months if drug‑specific criteria are met and chart notes demonstrate continued positive clinical response

Initial authorization previously 3 months (updated in history); see reauthorization rules for duration

Continuation rules from trials — trial and labeling context for continuation

Trial and labeling context for continuation

Continue until progression or toxicity: In clinical trials individuals continued therapy until radiographic or clinical progression or unacceptable toxicity; trial eligibility sometimes required prior exposure to specific agents and adequate tolerance, which has implications for continuation authorizations.

Step Therapy and Prior Treatment Requirements

Requirement	Details / Example
Documented prior therapy or intolerance when specified in individual drug criteria
Examples: Fotivda — prior treatment with 2 or more systemic therapies required; Qinlock (ripretinib) — prior treatment with 3 or more kinase inhibitors including imatinib; Tabrecta — inadequate response or intolerance to generic sunitinib

Practice	Policy / Trial Example
Prior exposure to specific agents may be required
Example from trials: RESORCE and other studies required prior sorafenib before subsequent agents; many approvals are line-of-therapy specific (e.g., axitinib shown as second-line in AXIS).

Update note	Implication for step therapy
Addition of first-line combination indications (Inlyta with avelumab or pembrolizumab)
May alter sequencing and step-therapy rules; reviewers should assess step requirements in full policy when first-line combinations are applicable

Generic-first requirement	Scope / Examples
Require trial with generic formulation first where specified
Policy updates specify generic-first trials for pazopanib (Votrient), sorafenib (Nexavar), and sunitinib (Sutent); coverage criteria note inadequate response or intolerance to generic agent is required before brand use.

Prescribed Quantity Limits and Cycle Quantities

Fotivda (tivozanib) — 21 capsules

Fotivda quantity21 capsules per 28 days

Dosing cycle1.34 mg per day for 21 days on, 7 days off (28-day cycle)

Policy updatePrescribed quantity limit per 28 days was added in the 02/01/26 and 04/01/26 history entries

Fotivda (tivozanib) — prescribed quantity limit (updated)

Fotivda prescribed quantity limitPolicy updated to add a prescribed quantity limit per 28 days for Fotivda (tivozanib)

Effective history noteUpdate recorded 02/01/26 and referenced in 05/01/26 history confirming quantity limit addition

Site of Care and Administration Setting

Note

Office or hospital outpatient administration per prescribing information

Oral small‑molecule multikinase inhibitors are administered in the outpatient setting per their prescribing information; clinical trials enrolled ambulatory individuals with ECOG performance status 0–1.

Plan administration and monitoring in office or hospital outpatient settings per the product labeling.
Consider ECOG PS recorded in the chart when it is relevant to the indication or trial evidence.

Note

Oral targeted agents are outpatient therapies

Oral targeted multikinase agents are outpatient therapies; specific site‑of‑care restrictions are not detailed in this policy segment.

Treat and monitor patients in an outpatient setting unless product labeling specifies otherwise.
Refer to product prescribing information for any site‑of‑care exceptions.

Policy Summary

PayerPremera Bluecross

PolicyMultiple receptor tyrosine kinase inhibitors (multikinase inhibitors) — pharmacy coverage

Policy CodePolicy 5.01.534

Change TypeCriteria updates and authorization duration changes

Effective Date

Next Review Date

Key ActionSubmit prior authorization with documentation of diagnosis, prior therapies, and objective response for reauthorization.

SourceLink

On This Page

Turalio (pexidartinib): Individual aged ≥18 years AND tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations

Vanflyta (quizartinib): Individual aged ≥18 years AND newly diagnosed acute myeloid leukemia (AML) AND FLT3‑ITD positive as detected by an FDA‑approved test AND used in combination with cytarabine and anthracycline induction and cytarabine consolidation

Initial approval previously 3 months; continued approval requires documentation of objective response

Dose limits — Tepmetko (tepotinib)

Tepmetko (tepotinib) dosing limitDose is limited to 450 mg per day

Indication linkApplied for adult metastatic NSCLC with MET exon 14 skipping confirmed by specified tests

Quantity updatePolicy history notes addition of a prescribed quantity limit per 30 days (see history)

Fotivda dosing cycle and quantity

Fotivda (tivozanib) dosing cycle1.34 mg per day for 21 days on treatment followed by 7 days off (28-day cycle)

Quantity limitQuantity limited to 21 capsules per 28 days (prescribed quantity limit added in updates)

Prior therapy requirementUsed in individuals aged >=18 years who have received prior treatment with 2 or more systemic therapies (per drug-specific criteria)

Initial authorization duration

Initial authorization duration6 months (updated from 3 months for all other reviews as of 05/01/26)

Prior wordingNote: initial approval period for oral drugs listed previously stated 3 months; continued approval requires objective response

Reauthorization implicationReauthorization requires documentation showing objective clinical benefit per policy sections

Non-formulary exception approval duration

Non-formulary exception approval durationMay be approved up to 12 months

Policy clarificationClarified in 2024 update that non-formulary exception review authorizations for all drugs listed may be approved up to 12 months

Reauthorization alignmentReauthorization durations of up to 12 months noted when criteria are met

Check the policy drug‑specific coverage criteria and FDA‑approved indication before submitting authorization.

All other uses of medications listed in this policy are considered investigational.

Documentation Required

Documentation Required with Submission

Required Documentation: Medical records submitted for review must demonstrate that medical necessity criteria are met.

Office visit notes documenting diagnosis, relevant history, physical exam and medication history.
Drug‑specific documentation (see drug criteria) such as mutation testing results (e.g., FLT3 for gilteritinib) or prior therapy history.

Documentation Required

Clinical Documentation for Trial‑Based or Line‑Specific Indications

Required Clinical Documentation in Trials and Certain Approvals: For indications supported by clinical trials or specific efficacy measures, include objective disease assessments and performance status.

Radiologic response assessments per RECIST 1.1 (or mRECIST for HCC) and investigator‑assessed ORR/PFS where applicable.
ECOG performance status and relevant liver function staging (e.g., Child‑Pugh) when required by the indication.
Detailed prior therapy history including number and type of prior kinase inhibitors or systemic therapies when line‑of‑therapy criteria apply.

Prior Authorization

Therapy Continuation and Eligibility

Therapy Continuation and Eligibility Considerations: Members may continue therapy until clinical or radiological disease progression or unacceptable toxicity, provided documentation demonstrates ongoing benefit and tolerability.

Continuation requires chart notes showing objective response, clinical benefit, or stability.
If disease progression or unacceptable toxicity occurs, treatment is not eligible for continuation.
Failure to meet continuation criteria may result in denial of reauthorization.

Prior Authorization

Prior Therapy and Line‑of‑Therapy Requirements

Prior Therapy and Line‑of‑Therapy Requirements: Some agents require prior treatments or are indicated for specific lines of therapy; authorization will be contingent on documented prior therapies.

Example: Ripretinib (Qinlock) requires prior treatment with ≥3 kinase inhibitors including imatinib for advanced GIST.
Example: Many RCC and HCC regimens specify prior anti‑angiogenic therapy or are first‑line combinations — verify the required line of therapy in the drug criteria.
Document the names, dates, durations, and reasons for discontinuation of prior systemic therapies.

Step Therapy

Step Therapy / Generic‑First Requirements

Step Therapy and Generic‑First Requirements: Where this policy specifies a generic‑first or step requirement, documentation must show trial and inadequate response or intolerance to the generic or prior agent before brand drug coverage will be approved.

Examples: Votrient (pazopanib) and Nexavar (sorafenib) criteria updated to require trial with the generic first where specified.
Documentation should include trial dates, doses, and reason for failure or intolerance to the generic agent.

Denial Risk

Denial Risk from Incomplete Documentation

Documentation and Reauthorization Risk: Failure to supply required documentation, or submission that does not meet the drug‑specific criteria, may result in denial of authorization or reauthorization.

Missing office visit notes, lack of mutation test results, or absent prior therapy documentation are common reasons for denial.
Reauthorization denials may occur if chart notes do not document objective response or ongoing clinical benefit.

Note

Verify Member Benefits and Plan Limits

Member Benefit Verification: Coverage is subject to the member's benefit plan limits. Always verify benefits before initiating therapy.

Consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to the service or supply.
This policy does not apply to Medicare Advantage — check plan type and benefits.

Clinical roleMay be used alone or in combination with chemotherapy, immunotherapy, or radiation for oncologic indications

NCCN Categories of Evidence and Consensus

Category 1Recommendation based on high-level evidence (e.g., randomized controlled trials) with uniform NCCN consensus

Category 2ARecommendation based on lower-level evidence with uniform NCCN consensus

Category 2BRecommendation based on lower-level evidence with nonuniform NCCN consensus (no major disagreement)

Category 3Recommendation based on any level of evidence but reflects major disagreement

RCC — definition

TermRenal cell carcinoma (RCC)

DescriptionMost common malignant kidney tumor; clear cell is the predominant histologic subtype; systemic therapy reserved for recurrent or metastatic disease

EpidemiologyOccurs most often in adults aged 50-70; 25-30% have metastases at diagnosis

HCC — definition

TermHepatocellular carcinoma (HCC)

DescriptionPrimary liver cancer with poor prognosis; surgical resection and transplant are curative options for a minority of patients

OutcomeMost cases are fatal within one year of diagnosis for advanced disease without curative options

K-Ras mutation — definition and relevance

DefinitionK-Ras mutation: genetic alteration downstream of EGFR associated with decreased response to EGFR-targeted tyrosine kinase inhibitors in many studies

Clinical relevanceK-Ras mutation status is associated with poorer response rates to certain TKIs (e.g., cetuximab) though it is not the sole determinant of response

Evidence summaryMultiple retrospective studies show lower response and sometimes worse PFS/OS in K-Ras mutants vs wild-type

Child-Pugh Scoring System (alternate)

PurposeChild-Pugh Scoring System (alternate reference) — used to classify liver function into Class A, B, or C based on laboratory and clinical parameters

ComponentsIncludes bilirubin, albumin, INR, ascites, and hepatic encephalopathy with point scoring and class thresholds

Use in trials/policyChild-Pugh status used in trial eligibility and to guide treatment decisions for hepatocellular carcinoma and other liver-involved conditions

Where specified, some drugs may be used first-line per label.

Example first-line uses: Lenvima (lenvatinib) can be used first‑line for unresectable hepatocellular carcinoma; Inlyta (axitinib) combinations were added for first‑line advanced RCC in combination with immunotherapies (avelumab, pembrolizumab).

See drug‑specific sections for full criteria.

Reauthorization / continuation — reauthorization criteria and documentation requirements were added

Reauthorization criteria and documentation requirements were added to the policy; continuation depends on meeting these criteria.

Reauthorization requirements: Reauthorization requires meeting drug‑specific coverage criteria and submission of documentation (chart notes) demonstrating continued clinical benefit; non‑formulary exception reviews may be approved up to 12 months and initial approvals for other reviews were updated to 6 months per history

Missing required documentation or failure to meet reauthorization criteria may trigger denial

1.34 mg daily for 21 days on, 7 days off per 28-day cycle (quantity limited to 21 capsules)

Tepmetko (tepotinib) — prescribed quantity limit (updated)

Tepmetko prescribed quantity limitPolicy updated to add a prescribed quantity limit per 30 days for Tepmetko (tepotinib)

Dose limitDose is limited to 450 mg per day for adult metastatic NSCLC with MET exon 14 skipping

History entryQuantity limit addition documented in the 02/01/26 history update