CurrentPremera BluecrossPolicy 5.01.589

BRAF and MEK Inhibitors

Pharmacy benefit policy defining medical necessity coverage criteria for listed BRAF and MEK inhibitors (combination and monotherapy) across multiple tumor types (melanoma, colorectal cancer, NSCLC, ovarian cancer, NF1 plexiform neurofibromas, pediatric low-grade glioma, histiocytic neoplasms, Erdheim-Chester disease, etc.), documentation requirements, length of approval, and investigational/exclusion statements.

Policy Summary

PayerPremera Bluecross

PolicyBRAF and MEK Inhibitors

Policy CodePolicy 5.01.589

Change TypeMultiple interim and annual updates (evidence, new indications, administrative edits)

Effective DateMay 1, 2026

Next Review Date

Key ActionSubmit chart notes demonstrating the individual meets stated criteria for medical necessity and include BRAF V600 test results for BRAF inhibitors.

SourceLink

POLICY UPDATE CHANGES

05/01/26 interim review updated initial authorization for all other reviews for oral drugs from 3 months to 6 months; changed Braftovi combination with Erbitux and mFOLFOX6 to Braftovi with Erbitux and fluorouracil-based chemotherapy.

Added coverage for Avmapki (avutometinib) + Fakzynja (defactinib) for KRAS-mutated recurrent LGSOC (09/01/25).

Added coverage for Ojemda (tovorafenib) for relapsed/refractory pediatric LGG (12/01/24).

Added Braftovi + Erbitux and mFOLFOX6 for metastatic colorectal cancer (05/01/25).

Clarified drugs are subject to FDA dosage and administration prescribing information and non-formulary exception reviews may be approved up to 12 months (05/01/25).

Added Gomekli (mirdametinib) coverage for NF1 and requirement to try Koselugo first (05/01/25 and updated 01/01/26).

MultipleCovered Indications

12+

Regimens/drugs referenced

Wild-type BRAFNot medically necessary

Coverage Summary & Scope

Scope: Pharmacy benefit policy defining medical necessity coverage criteria for listed BRAF and MEK inhibitors (combination and monotherapy) across multiple tumor types including melanoma, metastatic colorectal cancer, non-small cell lung cancer (NSCLC), ovarian cancer (KRAS‑mutated recurrent low‑grade serous ovarian cancer), neurofibromatosis type 1 (plexiform neurofibromas), pediatric low‑grade glioma (LGG), histiocytic neoplasms, Erdheim‑Chester disease, and others, plus documentation requirements, length of approval, and investigational/exclusion statements. Policy number: 5.01.589; Subject: BRAF and MEK inhibitors.

Coverage stance (policy level): Mixed — specific combination and monotherapy regimens listed in the policy are considered medically necessary when indication‑specific criteria are met (examples: Braftovi+Mektovi, Tafinlar+Mekinist, Zelboraf+Cotellic for BRAF V600E/V600K melanoma; Braftovi+Erbitux ± fluorouracil‑based chemotherapy for BRAF V600E metastatic colorectal cancer; Braftovi+Mektovi for BRAF V600E NSCLC; Avmapki+Fakzynja for KRAS‑mutated recurrent LGSOC; Ojemda for pediatric LGG; Gomekli and Koselugo for NF1 with specific requirements). Use in individuals with wild‑type BRAF is not medically necessary. All other uses not specifically listed are considered investigational. Documentation requirements and authorization lengths (including non‑formulary exception allowances) apply as stated in the policy.

Key Thresholds

Age limits - NSCLC and CRCIndividual must be aged ≥ 18 years

Age limits - Ojemda (tovorafenib)6 months to 17 years

Age limits - Koselugo (selumetinib)Individual aged ≥ 1 year

Age limits - Gomekli (mirdametinib)Individual aged ≥ 2 years

Gomekli dose limitDose limited to 4 mg twice daily

Authorization length / initial review (oral drugs)Initial authorization for oral drugs updated from 3 months to 6 months

Policy last review2026-04-14

Policy effective/updated dateEffective May 1, 2026 (Last revised Apr. 14, 2026)

Initial Therapy Criteria

Combination therapy for melanoma

ALL of the following

The individual has unresectable or metastatic melanoma with a documented BRAF V600E or V600K mutation (test results must be provided).
- ANY of the following
  - Braftovi (encorafenib) + Mektovi (binimetinib)
  - Tafinlar (dabrafenib) + Mekinist (trametinib)
  - Zelboraf (vemurafenib) + Cotellic (cobimetinib)

Other Combination Indications

Not Medically Necessary & Investigational Uses

Provider Actions & Prior Authorization Requirements

Documentation Required

Medical record documentation

Submit chart notes demonstrating that the individual meets the stated criteria for medical necessity. Include relevant diagnostic and treatment documentation in the medical record (e.g., clinical notes, prior therapies, age, dosing) to support the request.

Chart notes demonstrating that the individual meets stated criteria for medical necessity
Include prior therapy and clinical details as applicable

Documentation Required

BRAF testing requirement

For requests for BRAF inhibitors, include test results demonstrating the presence of a BRAF V600 mutation (e.g., V600E or V600K) with the submitted records. Testing for BRAF V600 mutations is covered whenever use of BRAF inhibitors is contemplated.

Applicable Codes

Codingmixed

No codes listed

Clinical Evidence Summary

14.9COLUMBUS: median PFS (encorafenib+binimetinib) 14.9 months vs 7.3 with vemurafenib

11.4COMBI-d/COMBI-v: PFS with dabrafenib+trametinib 11.4 months vs 7.3 with vemurafenib

12.3Vemurafenib+cobimetinib: median PFS 12.3 months vs 7.2 with vemurafenib

51%FIREFLY-1 (tovorafenib): ORR 51% in pediatric LGG evaluable population; median DoR 13.8 months

Background: BRAF and MEK are components of the MAPK signaling pathway; activating alterations (commonly BRAF V600 mutations) lead to constitutive MAPK‑ERK signaling and tumor growth, and BRAF and MEK inhibitors block this pathway. The policy lists indications supported by clinical trials and NCCN guidance and notes that the medications slow growth in BRAF‑mutant cancers and are considered medically necessary when criteria are met.

Definition: BRAF V600 mutation — an activating substitution at amino acid 600 (e.g., V600E or V600K) in the BRAF gene; per policy, testing is required when BRAF inhibitor therapy is contemplated.

Key trials summarized in the brief/evidence: COLUMBUS (encorafenib+binimetinib) showing median PFS 14.9 months vs 7.3 months with vemurafenib; COMBI‑d/COMBI‑v (dabrafenib+trametinib) showing PFS 11.4 months vs 7.3 months; the vemurafenib+cobimetinib trial showing median PFS 12.3 months vs 7.2 months; RAMP 201 (avutometinib+defactinib) with confirmed ORR 44% in KRAS‑mutated recurrent LGSOC; FIREFLY‑1 (tovorafenib) with ORR 51% and median DoR 13.8 months in pediatric LGG.

Background & Definitions

Background and definitions: BRAF and MEK inhibitors target aberrant MAPK pathway signaling driven by BRAF mutations; the policy describes when these agents may be considered medically necessary across multiple malignancies and refers providers to the specific coverage criteria. An activating substitution at amino acid 600 in the BRAF gene (for example, V600E or V600K) constitutes a BRAF V600 mutation, and testing for this mutation is required when BRAF inhibitors are being considered.

The policy includes indication‑specific coverage statements and age/other thresholds (for example, NSCLC and colorectal cancer regimens require age ≥ 18 years; Ojemda for pediatric LGG applies to ages 6 months to 17 years; Gomekli dosing and prior‑therapy requirements are specified). Provider documentation must include chart notes demonstrating criteria are met and, for BRAF inhibitors, test results showing presence of a BRAF V600 mutation.

Revision History

05/01/26revisedLatest

Interim review approved Apr 14, 2026: updated initial authorization for all other reviews for oral drugs from 3 months to 6 months; changed Braftovi combination for metastatic colorectal cancer wording from Braftovi with Erbitux and mFOLFOX6 to Braftovi with Erbitux and fluorouracil‑based chemotherapy.

09/01/25added

Interim review approved Aug 12, 2025: added coverage for Avmapki (avutometinib) plus Fakzynja (defactinib) for KRAS‑mutated recurrent low‑grade serous ovarian cancer (LGSOC).

12/01/24added

Policy Summary

PayerPremera Bluecross

PolicyBRAF and MEK Inhibitors

Policy CodePolicy 5.01.589

Change TypeMultiple interim and annual updates (evidence, new indications, administrative edits)

Effective DateMay 1, 2026

Next Review Date

Key ActionSubmit chart notes demonstrating the individual meets stated criteria for medical necessity and include BRAF V600 test results for BRAF inhibitors.

SourceLink

On This Page

Use is consistent with FDA-approved dosing and administration or supported by clinical evidence when used off-label.

Combination therapy for metastatic colorectal cancer

ALL of the following

The individual is aged 18 years or older.
The individual has metastatic colorectal cancer with a documented BRAF V600E mutation (test results must be provided).
- ANY of the following
  - Braftovi (encorafenib) + Erbitux (cetuximab), after prior therapy
  - Braftovi (encorafenib) in combination with Erbitux (cetuximab) and fluorouracil-based chemotherapy
Use is consistent with FDA-approved dosing and administration or supported by clinical evidence when used off-label.

Combination therapy for metastatic NSCLC

ALL of the following

The individual is aged 18 years or older.
The individual has metastatic non-small cell lung cancer (NSCLC) with a documented BRAF V600E mutation (test results must be provided).
Braftovi (encorafenib) + Mektovi (binimetinib) is prescribed.
Use is consistent with FDA-approved dosing and administration or supported by clinical evidence when used off-label.

Combination therapy for ovarian cancer (KRAS-mutated recurrent LGSOC)

ALL of the following

The individual is aged 18 years or older.
The individual has recurrent low-grade serous ovarian cancer (LGSOC) with a documented KRAS mutation (test results must be provided).
The individual has received at least one prior platinum-based regimen.
Avmapki (avutometinib) + Fakzynja (defactinib) is prescribed.

Monotherapy: Cotellic (cobimetinib)

ALL of the following

The individual is aged 18 years or older.
The individual has a histiocytic neoplasm requiring systemic therapy.
Cotellic (cobimetinib) as single agent is prescribed.
Use is consistent with FDA-approved dosing and administration or supported by clinical evidence when used off-label.

Monotherapy: Tafinlar (dabrafenib)

ALL of the following

The individual has unresectable or metastatic melanoma with a documented BRAF V600E or V600K mutation (test results must be provided).
Tafinlar (dabrafenib) monotherapy is prescribed.
Use is consistent with FDA-approved dosing and administration.

Monotherapy: Zelboraf (vemurafenib)

ANY of the following

Treatment of unresectable or metastatic melanoma with a documented BRAF V600E mutation (test results must be provided).
Treatment of Erdheim-Chester Disease with a documented BRAF V600 mutation (test results must be provided).

Ojemda (tovorafenib) for pediatric LGG (FIREFLY-1 supportive data)

ALL of the following

The individual is aged 6 months to 17 years.
The individual has relapsed or refractory pediatric low-grade glioma (LGG) with either a BRAF fusion or rearrangement, or a BRAF V600 mutation (appropriate molecular testing results must be provided).
Ojemda (tovorafenib) is prescribed for treatment of relapsed or refractory pediatric LGG.
Use is consistent with FDA-approved dosing and administration for the pediatric LGG indication (FDA approval supports use in 6 months to 17 years).
Clinical documentation demonstrates relapsed or refractory disease and prior therapy as appropriate.
Supportive evidence includes FIREFLY-1 trial data for tovorafenib in pediatric LGG with BRAF fusions/rearrangements or V600 mutations; include relevant clinical notes and response assessments in the chart.

Additional coverage notes

ALL of the following

The individual has a BRAF V600 mutation test result when required by the specific drug indication; test results must be included in the medical record.
Prescriptions are consistent with FDA dosing and administration or with documented clinical rationale when used off-label and supported by evidence.

Provide BRAF V600 test results (e.g., V600E or V600K)
Include with chart notes when BRAF inhibitor therapy is being requested

Prior Authorization

Authorization length and approvals

Initial authorization length: non‑formulary exception reviews for all drugs may be approved up to 12 months. Per the 05/01/26 interim update, initial authorization for all other reviews of oral drugs listed in the policy has been changed from 3 months to 6 months. Re‑authorization may be approved up to 12 months if drug‑specific criteria are met and records show continued clinical benefit.

Non‑formulary exception reviews: up to 12 months
Initial authorization for other oral drug reviews: updated from 3 to 6 months (05/01/26)
Re‑authorization: may be approved up to 12 months with documentation of continued benefit

Documentation Required

Specialty prescribing requirement for Gomekli

Gomekli (mirdametinib) must be prescribed by, or in consultation with, an oncologist or neurologist. Also ensure criteria for Gomekli (age ≥2 years, symptomatic inoperable plexiform neurofibromas, prior trial/intolerance of Koselugo or inability to swallow Koselugo capsules, and dose limit) are documented.

Prescribed by or in consultation with an oncologist or neurologist
Document trial/intolerance of Koselugo (selumetinib) or inability to swallow capsules
Document age and dose limitation (4 mg twice daily)

Testing requirement: The policy explicitly states that testing for BRAF V600 mutations is covered and required whenever use of BRAF inhibitors is contemplated, and provider documentation must include BRAF V600 test results when requesting BRAF inhibitor therapy.

Interim review approved Nov 12, 2024: added coverage for Ojemda (tovorafenib) for relapsed/refractory pediatric low‑grade glioma (LGG) in patients ≥6 months to <18 years with BRAF fusion/rearrangement or V600 mutation.

05/01/25added

Annual review approved Apr 8, 2025: added Braftovi (encorafenib) in combination with Erbitux (cetuximab) and mFOLFOX6 (later revised wording to fluorouracil‑based chemotherapy on 05/01/26) for metastatic colorectal cancer; added coverage for Gomekli (mirdametinib) for NF1.

01/01/26added

Interim review approved Dec 9, 2025 (effective 01/01/26 update): updated Gomekli (mirdametinib) coverage criteria to require prior trial/intolerance to Koselugo (selumetinib) before Gomekli.

04/14/26revised

Policy last reviewed Apr 14, 2026: evidence update and administrative wording changes approved; policy statements otherwise unchanged.

BRAF and MEK Inhibitors

Coverage Summary & Scope

Initial Therapy Criteria

Other Combination Indications

NF1 & Pediatric LGG Specific Criteria

Not Medically Necessary & Investigational Uses

Provider Actions & Prior Authorization Requirements

Applicable Codes

Clinical Evidence Summary

Background & Definitions

Revision History