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Date Printed: December 18, 2017: 03:26 PM

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This medical policy (medical coverage guideline) is Copyright 2017, Blue Cross and Blue Shield of Florida (BCBSF). All Rights Reserved. You may not copy or use this document or disclose its contents without the express written permission of BCBSF. The medical codes referenced in this document may be proprietary and owned by others. BCBSF makes no claim of ownership of such codes. Our use of such codes in this document is for explanation and guidance and should not be construed as a license for their use by you. Before utilizing the codes, please be sure that to the extent required, you have secured any appropriate licenses for such use. Current Procedural Terminology (CPT) is copyright 2017 American Medical Association. All Rights Reserved. No fee schedules, basic units, relative values, or related listings are included in CPT. The AMA assumes no liability for the data contained herein. Applicable FARS/DFARS restrictions apply to government use. CPT® is a trademark of the American Medical Association. The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

09-J1000-99

Original Effective Date: 09/15/13

Reviewed: 11/08/17

Revised: 12/15/17

Subject: Trametinib (Mekinist™) Tablets

THIS MEDICAL COVERAGE GUIDELINE IS NOT AN AUTHORIZATION, CERTIFICATION, EXPLANATION OF BENEFITS, OR A GUARANTEE OF PAYMENT, NOR DOES IT SUBSTITUTE FOR OR CONSTITUTE MEDICAL ADVICE. ALL MEDICAL DECISIONS ARE SOLELY THE RESPONSIBILITY OF THE PATIENT AND PHYSICIAN. BENEFITS ARE DETERMINED BY THE GROUP CONTRACT, MEMBER BENEFIT BOOKLET, AND/OR INDIVIDUAL SUBSCRIBER CERTIFICATE IN EFFECT AT THE TIME SERVICES WERE RENDERED. THIS MEDICAL COVERAGE GUIDELINE APPLIES TO ALL LINES OF BUSINESS UNLESS OTHERWISE NOTED IN THE PROGRAM EXCEPTIONS SECTION.

           
Dosage/ Administration Position Statement Billing/Coding Reimbursement Program Exceptions Definitions
           
Related Guidelines Other References Updates  
           

DESCRIPTION:

An estimated 50% of patients with metastatic melanoma have a mutation of the intracellular signaling kinase, BRAF. Targeted BRAF mutation therapies currently FDA-approved for the treatment of unresectable or metastatic melanoma which include vemurafenib, dabrafenib, trametinib, and cobimetinib.

Trametinib (Mekinist), a MEK1 and MEK2 kinase inhibitor, was approved by the U.S. Food and Drug Administration (FDA) on May 29, 2013 for the treatment of unresectable or metastatic melanoma in patients whose tumors express the BRAF V600E or V600K mutation. Importantly, trametinib is not indicated for treatment of BRAF V600 mutation positive melanoma in a population that was previously treated with a BRAF inhibitor. MEK 1 and MEK2 occur downstream of BRAF in the MAP kinase signal transduction pathway. Trametinib is also FDA approved in combination with dabrafenib for the treatment of metastatic non-small cell lung cancer with BRAF V600E mutation.

The safety and efficacy of trametinib were evaluated in subjects with previously untreated or treated, unresectable (stage IIIC) or metastatic (stage IV) melanoma determined to be BRAF V600E or V600K mutation positive in a randomized, open-label, active-controlled Phase III study (also known as METRIC). Subjects were randomized 2:1 to receive trametinib (dose: 2 mg by mouth) daily (n=214) or chemotherapy (n=108) with either dacarbazine (dose: 1,000 mg/m2 IV) or paclitaxel (dose: 175 mg/m2 IV) every three weeks. The primary endpoint was progression free survival, defined as the time from randomization until the earliest date of radiological disease progression or death from any cause.

The primary endpoint of progression free survival was statistically significant with a 53% reduction in the hazard rate of progression of disease or death with a hazard ratio of 0.47 (95% CI: 0.34, 0.65; p<0.0001) in the trametinib group compared to the chemotherapy group. The median progression free survival was 4.8 months (95%CI: 4.3, 4.9) in the trametinib group compared to 1.5 months (95%CI: 1.4, 2.7) in the chemotherapy arm. The 6-month overall survival was also improved in the trametinib group at 81% as compared to 67% in the chemotherapy group (HR, 0.54; 95% CI 0.32-0.92). The primary safety risk of trametinib was cardiomyopathy, interstitial lung disease, and ocular toxicity. The risk of cardiomyopathy requires routine monitoring of left ventricular ejection fraction. The most frequent (≥ 20%) adverse reactions of trametinib included rash, diarrhea, and peripheral edema.

Targeted therapies have shown high initial response rates, although about 50% of patients treated with monotherapy relapse around 6 months. An open-label, phase I/II trial was conducted in 247 patients to evaluate combination therapy with dabrafenib plus trametinib as compared to dabrafenib alone. Combination therapy resulted in an improved response rate as compared to monotherapy (76% vs 54%; p = 0.03). In addition, progression-free survival was also improved (9.4 vs 5.8 months; p <.001). The incidence of pyrexia was more common with the combination (76% vs 26%) although secondary squamous cell skin carcinoma was lower (7% vs 26%, respectively).

THxID BRAF Mutation Kit was approved with trametinib for use as a diagnostic assay to detect BRAF V600 (E or K) mutations in melanoma and to aid in the selection of patients for treatment with trametinib.

National Comprehensive Cancer Network (NCCN) Guidelines for Melanoma currently recommend trametinib in combination with dabrafenib for treatment of melanoma in patients with V600 mutation of the BRAF gene. In addition, the NCCN guidelines for the treatment of Non-Small Cell Lung Cancer (NSCLC) recommend trametinib in combination with dabrafenib for BRAF V600E mutations.

POSITION STATEMENT:

Comparative Effectiveness

The Food and Drug Administration has deemed the drug(s) or biological product(s) in this coverage policy to be appropriate for self-administration or administration by a caregiver (i.e., not a healthcare professional). Therefore, coverage (i.e., administration) in a provider-administered setting such as an outpatient hospital, ambulatory surgical suite, physician office, or emergency facility is not considered medically necessary.

I. Initiation of trametinib (Mekinist) meets the definition of medical necessity when ALL of the following criteria are met:

A. Unresectable or metastatic melanoma

1. Member has a BRAF V600E or V600K mutation as detected by an FDA‐approved test

2. Member meets ONE of the following:

a. Trametinib will be used as first line therapy in combination with dabrafenib (Tafinlar)

b. Trametinib will be used as second-line or subsequent therapy in combination with dabrafenib (Tafinlar) if the combination was not previously used

c. Trametinib is used as reinduction therapy in combination with dabrafenib (Tafinlar) and ALL of the following:

i.Member’s disease relapsed or progressed greater than 3 months after initial clinical response or stable disease with previous trametinib treatment

ii.Member does not have any remaining toxicity from previous trametinib treatment

3. The dose does not exceed 2 mg daily – dosage will be achieved using the fewest number of tablets per day

B. Adjuvant treatment of melanoma

1. Member has a BRAF V600E or V600K mutation as detected by an FDAapproved test

2. Member meets ONE of the following:

a. Member has Stage III disease

b. Member had complete lymph node dissection

c. Member underwent surgery for disease recurrence and has no evidence of disease following surgery

3. Trametinib is used in combination with dabrafenib (Tafinlar)

4. The dose does not exceed 2 mg daily – dosage will be achieved using the fewest number of tablets per day

C. Non-small cell lung cancer (NSCLC) with BRAF V600E mutation

1. BRAF V600E mutation is detected by an FDA-approved test

2. Trametinib is used in combination with dabrafenib (Tafinlar)

3. Dose does not exceed 2 mg daily – dosage will be achieved using the fewest number of tablets per day

Duration of approval: 180 days

II. Trametinib (Mekinist) meets the definition of medical necessity when used in combination with dabrafenib (Tafinlar) for the following designated Orphan Drug indications (http://www.fda.gov/orphan/designat/list.htm) when the dose does not exceed the maximum FDA-approved dose:

A. Treatment of anaplastic thyroid carcinoma and advanced papillary thyroid cancer whose tumors harbor a BRAF V600 mutation

Duration of approval: 1 year

III. Continuation of trametinib (Mekinist) meets the definition of medical necessity for the treatment of melanoma, NSCLC, and orphan indications when used in combination with dabrafenib(Tafinlar) and the following criteria are met:

A. The member’s disease has not progressed while receiving treatment with trametinib

B. The member has been previously approved by Florida Blue or another health plan in the past 2 years, OR the member has previously met all indication-specific criteria for coverage

C. The dose does not exceed 2 mg daily and dosage will be achieved using the fewest number of tablets per day

Duration of approval: 1 year

DOSAGE/ADMINISTRATION:

THIS INFORMATION IS PROVIDED FOR INFORMATIONAL PURPOSES ONLY AND SHOULD NOT BE USED AS A SOURCE FOR MAKING PRESCRIBING OR OTHER MEDICAL DETERMINATIONS. PROVIDERS SHOULD REFER TO THE MANUFACTURER’S FULL PRESCRIBING INFORMATION FOR DOSAGE GUIDELINES AND OTHER INFORMATION RELATED TO THIS MEDICATION BEFORE MAKING ANY CLINICAL DECISIONS REGARDING ITS USAGE.

FDA-approved

Unresectable or metastatic melanoma with BRAF V600E or V600K mutation: 2 mg orally once daily until disease progression

Metastatic NSCLC with BRAF V600E mutation: 2 mg orally in combination with dabrafenib once daily until disease progression

Trametinib is not indicated for treatment of patients with melanoma who have received prior BRAF-inhibitor therapy.

Continue treatment until disease progression or unacceptable toxicity occurs. Take at least 1 hour before or 2 hours after a meal. Do not take a missed dose within 12 hours of the next dose. When used in combination with dabrafenib, take at the same time each day with either the morning or evening dose of dabrafenib.

Dose Adjustments

Refer to product label for management of treatment-related toxicity. Dosing may be reduced by 0.5 mg to 1.5 mg daily and 1 mg daily. If unable to tolerate 1 mg daily, discontinue.

Drug Availability

0.5 mg and 2 mg tablets

PRECAUTIONS:

Boxed Warning

None

Contraindications

None

Precautions/Warnings

• New primary malignancies, cutaneous and non-cutaneous, may occur when used in combination with dabrafenib. Monitor for new malignancies before, during and after treatment.

• Hemorrhage: Major hemorrhagic events can occur when used in combination with dabrafenib. Monitor for bleeding.

Colitis and gastrointestinal perforations have occurred.

• Venous Thromboembolism: Deep vein thrombosis and pulmonary embolism can occur when used in combination with dabrafenib.

• Cardiomyopathy: Assess LVEF before treatment, after one month of treatment, and evaluate approximately every 2 to 3 months thereafter.

• Ocular Toxicities: Perform ophthalmologic evaluation for any visual disturbances. Permanently discontinue for Retinal Vein Occlusion (RVO).

• Interstitial Lung Disease (ILD): Withhold trametinib for new or progressive unexplained pulmonary symptoms or findings, such as cough, dyspnea, hypoxia, or infiltrates; permanently discontinue for treatment-related ILD or pneumonitis.

• Serious Febrile Reactions can occur when used in combination with dabrafenib.

• Serious Skin Toxicity: Monitor for skin toxicities and for secondary infections. Discontinue for Common Terminology Criteria Adverse Events (CTCAE) intolerant Grade 2, or Grade 3 or 4 rash not improving within 3 weeks despite interruption of therapy.

• Hyperglycemia: Monitor serum glucose levels in patients with pre-existing diabetes or hyperglycemia.

• Embryofetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to the fetus.

BILLING/CODING INFORMATION:

The following codes may be used to describe:

HCPCS Coding:

C9399

Unclassified drugs or biologicals

J8999

Prescription drug, oral, chemotherapeutic, Not Otherwise Specified

ICD-10 Diagnoses Codes That Support Medical Necessity:

C33

Malignant neoplasm of trachea

C34.00 – C34.02

Malignant neoplasm of unspecified main bronchus

C34.10 – C34.12

Malignant neoplasm of upper lobe, unspecified bronchus or lung

C34.2

Malignant neoplasm of middle lobe, unspecified bronchus or lung

C34.30 – C34.32

Malignant neoplasm of lower lobe, unspecified bronchus or lung

C34.80 – C34.82

Malignant neoplasm of overlapping sites of unspecified bronchus and lung

C34.90 – C34.92

Malignant neoplasm of unspecified part of unspecified bronchus or lung

C43.0

Malignant melanoma of lip

C43.10

Malignant melanoma of unspecified eyelid, including canthus

C43.11

Malignant melanoma of right eyelid, including canthus

C43.12

Malignant melanoma of left eyelid, including canthus

C43.20

Malignant melanoma of unspecified ear and external auricular canal

C43.21

Malignant melanoma of right ear and external auricular canal

C43.22

Malignant melanoma of left ear and external auricular canal

C43.30

Malignant melanoma of unspecified part of face

C43.31

Malignant melanoma of nose

C43.39

Malignant melanoma of other parts of face

C43.4

Malignant melanoma of scalp and neck

C43.51

Malignant melanoma of anal skin

C43.52

Malignant melanoma of skin of breast

C43.59

Malignant melanoma of other part of trunk

C43.60

Malignant melanoma of unspecified upper limb, including shoulder

C43.61

Malignant melanoma of right upper limb, including shoulder

C43.62

Malignant melanoma of left upper limb, including shoulder

C43.70

Malignant melanoma of unspecified lower limb, including hip

C43.71

Malignant melanoma of right lower limb, including hip

C43.72

Malignant melanoma of left lower limb, including hip

C43.8

Malignant melanoma of overlapping sites of skin

C43.9

Malignant melanoma of skin, unspecified

C73

Malignant neoplasm of thyroid gland

C79.31

Secondary malignant neoplasm of brain

C80.0

Disseminated malignant neoplasm, unspecified

C80.1

Malignant (primary) neoplasm, unspecified

REIMBURSEMENT INFORMATION:

Refer to section entitled POSITION STATEMENT.

PROGRAM EXCEPTIONS:

Federal Employee Program (FEP): Follow FEP guidelines.

State Account Organization (SAO): Follow SAO guidelines.

Medicare Part D: BCBSF has delegated to Prime Therapeutics authority to make coverage determinations for the Medicare Part D services referenced in this guideline.

Medicare Advantage: No National Coverage Determination (NCD) and/or Local Coverage Determination (LCD) were found at the time of the last guideline revised date.

DEFINITIONS:

Table 1: Eastern Cooperative Oncology Group (ECOG) Performance Status

Grade

Description

0

Fully active, able to carry on all pre-disease performance without restriction

1

Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work

2

Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours

3

Capable of only limited self-care, confined to bed or chair more than 50% of waking hours

4

Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair

5

Dead

RELATED GUIDELINES:

Dabrafenib (Tafinlar®) Capsules - 09-J2000-00

OTHER:

Table 2: Common Terminology Criteria for Adverse Events v4.0 (CTCAE)

Grade

Description

1

Mild; asymptomatic or mild symptoms; clinical diagnostic observations only; intervention not indicated

2

Moderate; minimal, local or noninvasive intervention indicated; limited age-appropriate instrumental activities of daily living

3

Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living

4

Life-threatening consequences; urgent intervention indicated

5

Death related to adverse event

REFERENCES:

  1. AHFS Drug Information. Bethesda (MD): American Society of Health-System Pharmacists, Inc; 2016 [cited 2016 Aug 25]. In: STAT!Ref Online Electronic Medical Library [Internet]. Available from: http://online.statref.com/.
  2. American Cancer Society: Cancer Facts and Figures 2015. Available at http://www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf. Accessed Sept 24, 2015.
  3. Clinical Pharmacology [Internet]. Tampa (FL): Gold Standard, Inc.; 2017 [cited 2017 Oct 23]. Available from: http://www.clinicalpharmacology.com/.
  4. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine; 2017- [cited 2017 Oct 25]. Available from: http://clinicaltrials.gov/.
  5. DRUGDEX® System [Internet]. Greenwood Village (CO): Thomson Micromedex; Updated periodically [cited 2017 Oct 23]. Available from: http://www.thomsonhc.com/.
  6. Mekinist (trametinib) tablet [package insert]. GlaxoSmithKline LLC. Research Triangle Park, NC. June 2017
  7. National Cancer Institute. Common Terminology Criteria for Adverse Events. Available at: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf. Accessed 9/24/15.
  8. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology. Version 1.2018 Melanoma. Available at http://www.nccn.org/professionals/physician_gls/PDF/melanoma.pdf. Accessed 10/25/17
  9. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology. Version 9.2017. Non-Small Cell Lung Cancer. Available at http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed 10/25/17.
  10. National Comprehensive Cancer Network (NCCN) Drugs & Biologics Compendium [Internet]. Fort Washington (PA): National Comprehensive Cancer Network; 2017 [cited 2017 Oct 23]. Available from: http://www.nccn.org/professionals/drug_compendium/content/contents.asp/.
  11. Orphan Drug Designations and Approval [Internet]. Silver Spring (MD): US Food and Drug Administration; 2017 [cited 2017 Oct 23]. Available from: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm/.

COMMITTEE APPROVAL:

This Medical Coverage Guideline (MCG) was approved by the BCBSF Pharmacy Coverage Committee on 11/8/17

GUIDELINE UPDATE INFORMATION:

09/15/13

New Medical Coverage Guideline.

11/15/14

Review and revision to guideline; consisting of position statement, coding, references

11/15/15

Review and revision to guideline; consisting of updating position statement, description, dosing/administration, warnings/precautions, definitions, coding, references

12/15/15

Revision to guideline; consisting of updating position statement, coding, references.

10/15/16

Revision to guideline; consisting of updating position statement, description, coding, and references.

12/15/17

Revision to guideline; consisting of updating position statement, dosing, warnings, coding, and references.

Date Printed: December 18, 2017: 03:26 PM