Premera Bluecross BRAF/MEK Coverage Update

Coverage Criteria and Policy Scope

Medical necessity criteria by indication and drug

Covered when ALL of the following are met per listed indication and drug:

Melanoma combination therapy: Braftovi (encorafenib) + Mektovi (binimetinib); Tafinlar (dabrafenib) + Mekinist (trametinib); or Zelboraf (vemurafenib) + Cotellic (cobimetinib) may be considered medically necessary for unresectable or metastatic melanoma with a BRAF V600E or V600K mutation.

BRAF V600 testing is covered whenever use of BRAF inhibitors is contemplated

Metastatic colorectal cancer: Braftovi (encorafenib) in combination with Erbitux (cetuximab) may be considered medically necessary for metastatic colorectal cancer with a BRAF V600E mutation in individuals aged 18 years or older after prior therapy; encorafenib may also be used with cetuximab and mFOLFOX6 per criteria.age >= 18

NSCLC: Braftovi (encorafenib) plus Mektovi (binimetinib) may be considered medically necessary for metastatic non–small cell lung cancer (NSCLC) with a BRAF V600E mutation in individuals 18 years or older.age >= 18

Ovarian cancer: Avmapki (avutometinib) plus Fakzynja (defactinib) may be considered medically necessary for KRAS‑mutated recurrent low‑grade serous ovarian cancer (LGSOC) who have received at least one prior platinum‑based regimen in individuals 18 years or older.age >= 18

Other covered combination uses for dabrafenib + trametinib: Tafinlar (dabrafenib) + Mekinist (trametinib) may be considered medically necessary for: adjuvant melanoma with lymph node involvement after resection; metastatic NSCLC with BRAF V600E; locally advanced/metastatic anaplastic thyroid cancer with BRAF V600E and no satisfactory locoregional options; unresectable or metastatic solid tumors (adults and pediatrics ≥1 year) with BRAF V600E who progressed following prior treatment and have no satisfactory alternatives; pediatric low‑grade glioma (ages 1–17) with BRAF V600E requiring systemic therapy.age varies by indication

BRAF testing covered when using BRAF inhibitors

Monotherapy uses: Cotellic (cobimetinib) monotherapy may be considered medically necessary for histiocytic neoplasms (≥18 years). Dabrafenib (Tafinlar) monotherapy may be considered medically necessary for unresectable or metastatic melanoma with BRAF V600E or V600K. Vemurafenib (Zelboraf) monotherapy may be considered medically necessary for unresectable or metastatic melanoma with BRAF V600E and for Erdheim‑Chester disease with BRAF V600 mutation.age >= 18 for specified indications

BRAF testing required when using BRAF inhibitors

Pediatric‑specific agents: Selumetinib (Koselugo) may be medically necessary for pediatric NF1 (ages 2–17) with symptomatic, inoperable plexiform neurofibromas. Tovorafenib (Ojemda) may be medically necessary for pediatric relapsed/refractory low‑grade glioma (6 months–17 years) with BRAF fusion or rearrangement (or BRAF V600 mutation where applicable). Mirdametinib (Gomekli) may be considered medically necessary for NF1 (≥2 years) with symptomatic inoperable plexiform neurofibromas when criteria are met, including for ages 2–17 prior selumetinib failure or inability to swallow selumetinib and prescribed by or in consultation with an oncologist or neurologist with dose ≤ 4 mg twice daily.age thresholds per drug

Covered Indications (added/clarified across updates)

Policy additions and covered indications added or clarified in updates through 2025 include:

melanoma_first_line: Combination BRAF/MEK inhibitor therapy is recommended for metastatic or unresectable melanoma with a BRAF V600 activating mutation; specific first‑line combinations listed include dabrafenib/trametinib, vemurafenib/cobimetinib, and encorafenib/binimetinib (NCCN categories cited).

see NCCN guidance (chunk 22)

Tafinlar_Mekinist_solid_tumors: Tafinlar (dabrafenib) in combination with Mekinist (trametinib) was added for treatment of BRAF V600E mutation–positive unresectable or metastatic solid tumors (update noted in 2022/2023).

chunks 26,27

pediatric_LGG: Tafinlar + Mekinist coverage was added for pediatric individuals ≥1 year with low‑grade glioma (LGG) harboring BRAF V600E who require systemic therapy (2023 update).

chunk 27

Use of BRAF and/or MEK inhibitors for treatment of individuals with wild-type BRAF is considered not medically necessary. This policy therefore requires documentation of a qualifying BRAF mutation (e.g., BRAF V600 variants where applicable) when coverage for a BRAF or MEK inhibitor is requested.

This medical policy does not apply to Medicare Advantage members. Coverage of services described in this policy is subject to the limits and conditions of the member benefit plan; providers and members should consult the member benefit booklet or contact customer service to determine whether benefit limitations apply.

All other uses of the medications listed in this policy that are not specified as medically necessary in the criteria above are considered investigational. Requests for indications or uses outside those listed will be reviewed as investigational and are not covered under this policy.

Initial Therapy Coverage

Initial therapy — coverage by regimen

Initial therapy coverage by regimen

Melanoma combinations initial: Encorafenib + binimetinib; dabrafenib + trametinib; and vemurafenib + cobimetinib are covered for unresectable or metastatic melanoma with BRAF V600E or V600K mutations.

Initial therapy for melanoma — NCCN first-line recommendations

First‑line recommendations per NCCN for melanoma with BRAF V600 mutation:

first_line_options_melanoma: Preferred first‑line combination regimens per NCCN include dabrafenib/trametinib (category 1), vemurafenib/cobimetinib (category 1), and encorafenib/binimetinib (category 1); combination targeted therapy ± immunotherapy are also listed as options.

NCCN guidance (chunk 22)

Continuation and Re-induction

Continuation therapy — re-authorization criteria

Re-authorization

Re-authorization length and criteria: Re‑authorization for drugs listed may be approved up to 12 months provided drug‑specific coverage criteria are met and medical records/chart notes demonstrate continued positive clinical response to therapy (e.g., ongoing disease control).up to 12 months

Re-induction guidance per NCCN

Re‑induction guidance per NCCN:

reinduction_criteria: Re‑induction therapy may be considered for individuals who previously achieved disease control (complete response, partial response, or stable disease), had no residual toxicity, and subsequently experienced disease progression/relapse more than three months after treatment discontinuation.

NCCN guidance (chunk 22)

Provider Requirements, Prior Authorization, and Documentation

Prior Authorization

Prior Authorization Required

Prior authorization and non-formulary exception reviews are required for all drugs listed in this policy. Requests should follow the FDA-approved dosing and administration for the specific product. Non-formulary exception reviews and prior authorization approvals may be issued for up to 12 months when the drug-specific coverage criteria are met. Verify member benefits and any plan-specific limits prior to submission.

Drugs managed through the pharmacy benefit — submit pharmacy prior authorization
Approvals (including non-formulary exceptions) may be granted up to 12 months when criteria are met
Follow FDA dosing and administration as listed in each product's prescribing information

Note

NCCN Sequencing Guidance

NCCN guidelines recommend combination BRAF/MEK inhibitor therapy as first-line treatment for metastatic or unresectable melanoma with an activating BRAF V600 mutation. Preferred first-line combinations include dabrafenib/trametinib, vemurafenib/cobimetinib, and encorafenib/binimetinib (category 1). If combination BRAF/MEK therapy is contraindicated, BRAF inhibitor monotherapy is an option.

Step Therapy Requirements

Step	Requirement / Rationale	Applies to (age)
1	Prior selumetinib (Koselugo) required unless documentation provided that the individual is unable to swallow selumetinib capsules; requirement applies to pediatric NF1 patients prior to use of mirdametinib (Gomekli).	Ages 2–17

Step	Sequencing requirement	Coverage note / exception
1	Combination BRAF + MEK inhibitor therapy is the preferred first-line approach for metastatic or unresectable melanoma (examples: dabrafenib + trametinib; vemurafenib + cobimetinib; encorafenib + binimetinib).	Preferred first-line per NCCN; category designations vary by regimen
1	BRAF inhibitor monotherapy may be used when combination BRAF/MEK therapy is contraindicated or the individual is not an appropriate candidate for combination therapy or checkpoint immunotherapy.	Monotherapy allowed when combination contraindicated

Site of Care and Benefit Handling

Billing Rule

Pharmacy management of listed drugs

Drugs in this policy are dispensed and managed under the pharmacy benefit (site of care determined by pharmacy dispensing).

Note

Follow FDA dosing/plan rules across site settings

Medications are subject to the product’s FDA dosing and administration; site‑of‑care (office, infusion center, hospital outpatient, home) should follow product labeling and any plan‑specific benefit rules.

Background and Rationale

BRAF and MEK are components of the MAPK/ERK signaling pathway. Activating BRAF mutations (most commonly the V600 substitutions such as V600E) produce constitutive pathway signaling that can drive tumor growth. Targeted agents that inhibit BRAF and/or MEK interrupt this pathway and have demonstrated clinical activity in multiple tumor types; therefore, therapy is limited to indications and molecular contexts where a pathogenic BRAF alteration is present and supported by the policy criteria.

Key Definitions

BRAF V600E mutation

DefinitionSubstitution of glutamic acid for valine at amino acid position 600 (V600E) leading to constitutive activation of the MAPK‑ERK signaling pathway; accounts for approximately 90–95% of BRAF mutations in cancer.

Biologic consequenceMutated BRAF (V600E) causes constitutive MAPK‑ERK pathway signaling resulting in tumor maintenance and progression.

Clinical relevanceBRAF V600E may be a negative prognostic indicator in metastatic melanoma.

Testing implicationPresence of BRAF V600E is required to support use of BRAF inhibitor therapy per policy coverage criteria.

Overall response rate (ORR) definition

ORR (overall response rate)Proportion (percentage) of patients with a complete response (CR), partial response (PR), or minor response (MR) as assessed per the trial‑specified response criteria (e.g., RAPNO‑LGG, RANO‑LGG, or RECIST v1.1).

OpenPayer

BRAF and MEK Inhibitors (pharmacy coverage)