MEKINIST, Trametinib Dimethyl Sulfoxide Form

Trametinib (Mekinist®) is a kinase inhibitor. FDA Approved Indication(s) Mekinist is indicated: • As a single agent for the treatment of BRAF-inhibitor treatment-naïve patients with • unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test In combination with dabrafenib (Tafinlar®): o For the treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test o For the adjuvant treatment of patients with melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test, and involvement of lymph node(s), following complete resection o For the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with BRAF V600E mutation as detected by an FDA-approved test o For the treatment of patients with locally advanced or metastatic anaplastic thyroid cancer (ATC) with BRAF V600E mutation and with no satisfactory locoregional treatment options o For the treatment of adult and pediatric patients 1 year of age and older with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options.* o For the treatment of pediatric patients 1 year of age and older with low-grade glioma (LGG) with a BRAF V600E mutation who require systemic therapy Limitation(s) of use: Mekinist is not indicated for treatment of patients with colorectal cancer because of known intrinsic resistance to BRAF inhibition. _

• This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). Policy/Criteria Provider must submit documentation (such as office chart notes, lab results or other clinical information) supporting that member has met all approval criteria. Page 1 of 12

  CLINICAL POLICY Trametinib It is the policy of health plans affiliated with Centene Corporation® that Mekinist is medically necessary when the following criteria are met:
  I. Initial Approval Criteria
  A. Melanoma (must meet all):

  1. Diagnosis of melanoma with BRAF V600E or V600K mutation;
  2. Disease meets one of the following (a or b): a. Unresectable, limited resectable, or metastatic; b. Presence of lymph node(s) involvement following complete resection;
  3. Prescribed by or in consultation with an oncologist;
  4. Age ≥ 18 years;
  5. For Mekinist requests, member must use generic trametinib, if available, unless contraindicated or clinically significant adverse effects are experienced;
  6. Request meets one of the following (a or b): a. Dose does not exceed both of the following (i and ii): i. 2 mg per day; ii. 1 tablet per day;
     b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN
     Approval duration:
     Medicaid/HIM – 6 months
     Commercial – 12 months or duration of request, whichever is less
     B. Non-Small Cell Lung Cancer (must meet all):
  7. Diagnosis of advanced, metastatic, or recurrent NSCLC;
  8. Prescribed by or in consultation with an oncologist;
  9. Age ≥ 18 years;
  10. Disease is positive for a BRAF V600E mutation;
  11. Prescribed in combination with Tafinlar;
  12. For Mekinist requests, member must use generic trametinib, if available, unless contraindicated or clinically significant adverse effects are experienced;
  13. Request meets one of the following (a or b): a. Dose does not exceed both of the following (i and ii):
      i. 2 mg per day; ii. 1 tablet per day;
      b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN
      Approval duration:
      Medicaid/HIM – 6 months Commercial – 12 months or duration of request, whichever is less
      C. Anaplastic Thyroid Cancer (must meet all):
  14. Diagnosis of advanced or metastatic ATC;
  15. Prescribed by or in consultation with an oncologist;
  16. Age ≥ 18 years; Page 2 of 12

  CLINICAL POLICY Trametinib

  4. Disease is positive for a BRAF V600E mutation;
  5. Prescribed in combination with Tafinlar;
  6. For Mekinist requests, member must use generic trametinib, if available, unless contraindicated or clinically significant adverse effects are experienced;
  7. Request meets one of the following (a or b): a. Dose does not exceed both of the following (i and ii):
     i. 2 mg per day; ii. 1 tablet per day;
     b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN
     Approval duration:
     Medicaid/HIM – 6 months Commercial – 12 months or duration of request, whichever is less
     D. BRAF V600E Mutation-Positive Solid Tumor (must meet all):
  8. Diagnosis of unresectable or metastatic solid tumor that is positive for a BRAF V600E mutation (see Appendix D for examples);
  9. Prescribed by or in consultation with an oncologist;
  10. Age ≥ 1 year;
  11. Request meets one of the following (a or b):
      a. Disease has progressed on prior treatment, and no satisfactory alternative treatment options are available;
      b. Prescribed for one of the following NCCN 2A or higher supported indications (i- vii):
      i. Ampullary adenocarcinoma, as subsequent therapy;
      ii. Salivary gland tumor;
      iii. Pancreatic adenocarcinoma;
      iv. One of the following thyroid carcinomas, as subsequent treatment in unresectable, recurrent, persistent, or metastatic disease (a, b, or c): a) Papillary;
      b) Follicular;
      c) Hürthle cell; iv. One of the following hepatobiliary cancers, as subsequent treatment in unresectable or metastatic disease (a, b, or c): a) Extrahepatic cholangiocarcinoma; b) Intrahepatic cholangiocarcinoma; c) Gallbladder cancer;
      v. One of the following central nervous system cancers (a - f): a) Adult low-grade (World Health Organization [WHO] grade 1) glioma; b) Recurrent adult isocitrate dehydrogenase (IDH) mutant oligodendroglioma (1p19q codeleted, WHO grade 2 or 3); c) Recurrent adult IDH mutant astrocytoma (WHO grade 2, 3, or 4);
      d) Recurrent adult glioblastoma; e) Brain metastases;
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  CLINICAL POLICY Trametinib f) Pediatric diffuse high-grade gliomas, as adjuvant treatment (except for diffuse midline glioma, H3 K27-altered or pontine location), or treatment for recurrent or progressive disease (except for oligodendroglioma, IDH- mutant and 1p/19q co-deleted or astrocytoma IDH-mutant);
  vi. One of the following for ovarian cancer, fallopian tube cancer, or peritoneal cancers (a-e): a) Carcinosarcoma (malignant mixed Müllerian tumors) of the ovary;
  b) Clear cell carcinoma of the ovary;
  c) Grade 1 endometrioid carcinoma;
  d) Mucinous carcinoma of ovary; e) Low-grade serous carcinoma; vii. Metastatic uveal melanoma;

  5. For ovarian cancer, fallopian tube cancer, or peritoneal cancer: Request is for recurrence therapy (e.g., previous treatment with a regimen containing carboplatin, cisplatin, or oxaliplatin);
  6. Request meets one of the following (a or b): a. For metastatic uveal melanoma, prescribed as a single agent; b. For all other indications, prescribed in combination with Tafinlar;
  7. For Mekinist requests, member must use generic trametinib, if available, unless contraindicated or clinically significant adverse effects are experienced;
  8. For pediatric members, documentation of member’s current body weight (in kg);
  9. Request meets one of the following (a or b): a. Dose does not exceed one of the following (i or ii):
     i. Adults: both of the following (a and b):
     a) 2 mg per day;
     b) 1 tablet per day; ii. Pediatric members: FDA approved maximum recommended dose (see Section V); b. Dose is supported by practice guidelines or peer-reviewed literature for relevant off-label use (prescriber must submit supporting evidence).
     *Prescribed regimen must be FDA-approved or recommended by NCCN Approval duration:
     Medicaid/HIM – 6 months Commercial – 12 months or duration of request, whichever is less E. Pediatric Low-Grade Glioma (must meet all):
  10. Diagnosis of LGG (WHO grade 1 or 2);
  11. Prescribed by or in consultation with an oncologist;
  12. Age is between 1 to < 18 years;
  13. Disease is positive for a BRAF V600E mutation;
  14. Prescribed in combination with Tafinlar;
  15. For Mekinist requests, member must use generic trametinib, if available, unless contraindicated or clinically significant adverse effects are experienced;
  16. Documentation of member’s current body weight (in kg);
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  CLINICAL POLICY Trametinib

  8. Request meets one of the following (a or b):
     a. Dose does not exceed the FDA approved maximum recommended dose (see Section V);
     b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence).
     Prescribed regimen must be FDA-approved or recommended by NCCN Approval duration:
     Medicaid/HIM – 6 months Commercial – 12 months or duration of request, whichever is less F. Off-Label NCCN Compendium Recommended Indication(s) (must meet all):
  9. Diagnosis of one of the following (a or b): a. Histiocytic neoplasms that are positive for a MAP kinase pathway mutation or have no detectable mutation, unless testing is not available (i, ii, or iii): i. Erdheim-Chester disease; ii. Langerhans Cell histiocytosis; iii. Rosai Dorfman disease; b. Recurrent low-grade serous carcinoma that is platinum-sensitive or platinum- resistant;
  10. Prescribed by or in consultation with one of the following (a or b): a. Histiocytic neoplasms: a hematologist or oncologist; b. Low-grade serous carcinoma: oncologist;
  11. Age ≥ 18 years;
  12. Disease is;
  13. Prescribed as a single agent;
  14. For Mekinist requests, member must use generic trametinib, if available, unless contraindicated or clinically significant adverse effects are experienced;
  15. Request meets one of the following (a or b): a. Dose does not exceed both of the following (i and ii): i. 2 mg per day; ii. 1 tablet per day;
      b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN
      Approval duration: Medicaid/HIM – 6 months Commercial – 12 months or duration of request, whichever is less
      G. Other diagnoses/indications (must meet 1 or 2):
  16. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or Page 5 of 12

  CLINICAL POLICY Trametinib b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

  2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
     II. Continued Therapy A. All Indications in Section I (must meet all):
  3. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Mekinist for a covered indication and has received this medication for at least 30 days;
  4. Member is responding positively to therapy;
  5. For Mekinist requests, member must use generic trametinib, if available, unless contraindicated or clinically significant adverse effects are experienced;
  6. For pediatric members, documentation of member’s current body weight (in kg);
  7. If request is for a dose increase, request meets one of the following (a or b): a. New dose does not exceed one of the following (i, ii or iii): i. BRAF V600E mutation-positive solid tumor (a or b): a) Adults: both of the following (1 and 2):
     1) 2 mg per day; 2) 1 tablet per day; b) Pediatric members: FDA approved maximum (see Section V); ii. Pediatric LGG: FDA approved maximum (see Section V);
     iii. All other indications: both of the following (a and b):
     a) 2 mg per day; b) 1 tablet per day;
     b. New dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Prescribed regimen must be FDA-approved or recommended by NCCN
     Approval duration:
     Medicaid/HIM – 12 months Commercial – 12 months or duration of request, whichever is less
     B. Other diagnoses/indications (must meet 1 or 2):
  8. If this drug has recently (within the last 6 months) undergone a label change (e.g., newly approved indication, age expansion, new dosing regimen) that is not yet reflected in this policy, refer to one of the following policies (a or b): a. For drugs on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the no coverage criteria policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.33 for health insurance marketplace, and CP.PMN.255 for Medicaid; or Page 6 of 12

  CLINICAL POLICY Trametinib b. For drugs NOT on the formulary (commercial, health insurance marketplace) or PDL (Medicaid), the non-formulary policy for the relevant line of business: CP.CPA.190 for commercial, HIM.PA.103 for health insurance marketplace, and CP.PMN.16 for Medicaid; or

  2. If the requested use (e.g., diagnosis, age, dosing regimen) is NOT specifically listed under section III (Diagnoses/Indications for which coverage is NOT authorized) AND criterion 1 above does not apply, refer to the off-label use policy for the relevant line of business: CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid.
     III. Diagnoses/Indications for which coverage is NOT authorized:
     A. Non-FDA approved indications, which are not addressed in this policy, unless there is sufficient documentation of efficacy and safety according to the off label use policies – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid or evidence of coverage documents.
     IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key ATC: anaplastic thyroid cancer BRAF: B-Raf proto-oncogene serine/threonine kinase FDA: Food and Drug Administration Appendix B: Therapeutic Alternatives
     Not applicable Appendix C: Contraindications/Boxed Warnings None reported IDH: isocitrate dehydrogenase MAP: mitogen-activated protein
     NSCLC: non-small cell lung cancer WHO: World Health Organization Appendix D: General Information • According to NCCN, Mekinist has category 2A recommendation for combination treatment with Tafinlar for brain metastases if active against primary tumor (melanoma) for recurrent disease. • Examples of solid tumors that may be BRAF V600E mutation-positive include, but are not limited to, the following: biliary tract cancer, high grade glioma (glioblastoma, anaplastic pleomorphic xanthoastrocytoma, anaplastic astrocytoma, astroblastoma, anaplastic ganglioglioma, and anaplastic oligodendroglioma), low grade glioma (astrocytoma, ganglioglioma, pleomorphic xanthoastrocytoma, pilocytic astrocytoma, choroid plexus papilloma, gangliocytoma/ganglioglioma), adenocarcinoma of small intestine, pancreas, or anus, mixed ductal/adenoneuroendocrine carcinoma, neuroendocrine carcinoma of colon, ameloblastoma of mandible, combined small cell- squamous carcinoma of lung, mucinous-papillary serous adenocarcinoma of peritoneum, gastrointestinal stromal tumor.
     Page 7 of 12

  CLINICAL POLICY Trametinib V. Dosage and Administration
  Indication Dosing Regimen Melanoma, NSCLC, ATC 2 mg (1 tablet) PO QD
  The recommended duration of treatment in the adjuvant melanoma setting is until disease recurrence or unacceptable toxicity for up to 1 year. The recommended duration of treatment for all other indications is until disease progression or unacceptable toxicity. Adults: 2 mg (1 tablet) PO QD Maximum Dose 2 mg/day 2 mg/day BRAF V600E mutation- positive solid tumors Pediatric patients: Tablets: • 26-37 kg: 1 mg (two 0.5 mg tablets) PO QD • 38-50 kg: 1.5 mg (three 0.5 mg tablets) PO QD • ≥ 51 kg: 2 mg (one 2 mg tablet) PO QD Oral solution:
  • 8 kg: 0.3 mg (6 mL) PO QD • 9 and 10 kg: 0.35 mg (7 mL) PO QD
  • 11 kg: 0.4 mg (8 mL) PO QD
  • 12 to 13 kg: 0.45 mg (9 mL) PO QD
  • 14 to 17 kg: 0.55 mg (11 mL) PO QD
  • 18 to 21 kg: 0.7 mg (14 mL) PO QD
  • 22 to 25 kg: 0.85 mg (17 mL) PO QD
  • 26 to 29 kg: 0.9 mg (18 mL) PO QD
  • 30 to 33 kg: 1 mg (20 mL) PO QD
  • 34 to 37 kg: 1.15 mg (23 mL) PO QD
  • 38 to 41 kg: 1.25 (25 mL) PO QD • 42 to 45 kg: 1.4 mg (28 mL) PO QD
  • 46 to 50 kg: 1.6 mg (32 mL) PO QD
  • ≥ 51 kg: 2 mg (40 mL) PO QD Pediatric LGG The recommended duration of treatment is until disease progression or unacceptable toxicity. Tablets: • 26-37 kg: 1 mg (two 0.5 mg tablets) PO QD • 38-50 kg: 1.5 mg (three 0.5 mg tablets) PO QD • ≥ 51 kg: 2 mg (one 2 mg tablet) PO QD See dosing regimen Oral solution:
  • 8 kg: 0.3 mg (6 mL) PO QD • 9 and 10 kg: 0.35 mg (7 mL) PO QD
  • 11 kg: 0.4 mg (8 mL) PO QD
  • 12 to 13 kg: 0.45 mg (9 mL) PO QD
  • 14 to 17 kg: 0.55 mg (11 mL) PO QD
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  CLINICAL POLICY Trametinib Indication Dosing Regimen Maximum Dose • 18 to 21 kg: 0.7 mg (14 mL) PO QD
  • 22 to 25 kg: 0.85 mg (17 mL) PO QD
  • 26 to 29 kg: 0.9 mg (18 mL) PO QD
  • 30 to 33 kg: 1 mg (20 mL) PO QD
  • 34 to 37 kg: 1.15 mg (23 mL) PO QD
  • 38 to 41 kg: 1.25 (25 mL) PO QD • 42 to 45 kg: 1.4 mg (28 mL) PO QD
  • 46 to 50 kg: 1.6 mg (32 mL) PO QD
  • ≥ 51 kg: 2 mg (40 mL) PO QD The recommended duration of treatment is until disease progression or unacceptable toxicity. VI. Product Availability
  • Tablets: 0.5 mg, 2 mg • Oral solution: 4.7 mg per bottle VII.