Subject: Cobimetinib (Cotellic ) Tablet

09-J2000-53 Original Effective Date: 03/15/16 Reviewed: 11/14/18 Revised: 12/15/18 Subject: Cobimetinib (Cotellic ) Tablet 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, which results in activation of the mitogen-activated protein kinase pathway (MAPK). Targeted BRAF mutation therapies currently FDA-approved for the treatment of unresectable or metastatic melanoma which include vemurafenib, dabrafenib, trametinib, and cobimetinib. Cobimetinib (Cotellic) is a reversible inhibitor of MAPK/extracellular signal regulated kinase 1 (MEK1) and MEK2. MEK proteins are regulators of cellular proliferation that occur downstream of BRAF in the MAP kinase signal transduction pathway. Cobimetinib (Cotellic) was approved by the U.S. Food and Drug Administration (FDA) in November 2015 in combination with vemurafenib for the treatment of unresectable or metastatic melanoma in patients whose tumors express the BRAF V600E or V600K mutation. The safety and efficacy of cobimetinib was evaluated in combination with vemurafenib in subjects with previously untreated unresectable (stage IIIC) or metastatic (stage IV) melanoma determined to be BRAF V600E or V600K mutation positive in a multicenter, randomized, double-blinded, placebo-controlled Phase III study. Subjects were randomized 1:1 to receive cobimetinib 60 mg by mouth daily or matching placebo on days 21 of an every 28 day cycle in combination with vemurafenib 960 mg orally twice daily (every 28 days). Treatment continued until disease progression or unacceptable toxicity. The primary endpoint was progression free survival (PFS). The median PFS was 12.3 months in the cobimetinib group as compared to 7.2 months in the placebo group (hazard ratio 0.56; 95% CI 0.45 0.70; p<0.001). The objective response rate was 70% in the cobimetinib group as compared with 50% in the placebo group (p<0.001); rates of complete response were16% and 10%, respectively. The number of deaths was 32% in the cobimetinib group as compared to 44% in the placebo group. Evaluation of the median overall

survival has not been completed. There was a decrease in the number of secondary cutaneous cancers in the cobimetinib group. National Comprehensive Cancer Network (NCCN) Guidelines for Melanoma currently recommend cobimetinib in combination with vemurafenib for treatment of BRAF mutated unresectable or metastatic melanoma. NCCN also recommends cobimetinib in combination with vemurafenib for treatment of recurrent brain metastases due to melanoma. 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 cobimetinib (Cotellic) meets the definition of medical necessity when ALL of the following are met: 1. Melanoma A. Member is diagnosed with EITHER unresectable or metastatic melanoma B. Member has a BRAF V600E or V600K mutation as detected by an FDA approved test C. Member meets ONE of the following: a. Cobimetinib (Cotellic) will be used as first line therapy in combination with vemurafenib (Zelboraf) b. Cobimetinib (Cotellic) will be used as second-line or subsequent therapy in combination with vemurafenib (Zelboraf) if the combination was not previously used c. Cobimetinib is used as reinduction therapy in combination with vemurafenib (Zelboraf) 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 cobimetinib treatment ii. Member does not have any remaining toxicity from previous cobimetinib treatment D. The dose does not exceed 60 mg daily for 21 days of a 28 day cycle 2. Recurrent brain metastases from metastatic melanoma A. Cobimetinib is used in combination with vemurafenib (Zelboraf) B. Cobimetinib was active against the primary tumor (i.e., melanoma with BRAF V600 mutation) C. The dose does not exceed 60 mg daily for 21 days of a 28 day cycle Duration of approval: 180 days

II. Continuation of cobimetinib (Cotellic) meets the definition of medical necessity for the treatment of melanoma or recurrent brain metastases from melanoma when ALL of the following criteria are met: 1. The member s disease has not progressed while receiving treatment with cobimetinib (Cotellic) 2. 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 3. The dose does not exceed 60 mg daily for 21 days of a 28 day cycle 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 Cobimetinib is indicated for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, in combination with vemurafenib. Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to initiation of treatment. The recommended dosage is 60 mg (three 20 mg tablets) orally taken once daily for the first 21 days of each 28-day cycle until disease progression or unacceptable toxicity. Take with or without food. If a dose is missed or if vomiting occurs when the dose is taken, resume dosing with the next scheduled dose. Dose Adjustments Do not take strong or moderate CYP3A inhibitors while taking cobimetinib. If concurrent short term (14 days or less) use of moderate CYP3A inhibitors is unavoidable for patients who are taking cobimetinib 60 mg, reduce the dose to 20 mg. After discontinuation of a moderate CYP3A inhibitor, resume previous dose of 60 mg. Use an alternative to a strong or moderate CYP3A inhibitor in patients who are already taking a reduced dose of 40 or 20 mg daily. Dose reductions may be necessary. See prescribing information for details of adjustment in the setting of an adverse reaction by grade from the National Cancer Institute Common Terminology Criteria for Adverse Events. o o o First Dose Reduction 40 mg orally once daily Second Dose Reduction 20 mg orally once daily Subsequent Modification - Permanently discontinue if unable to tolerate 20 mg orally once daily Drug Availability 20 mg tablets

PRECAUTIONS: Boxed Warning None Contraindications None Precautions/Warnings New primary malignancies, cutaneous and non-cutaneous: Monitor patients for new malignancies prior to initiation of therapy, while on therapy, and for up to 6 months following the last dose Hemorrhage: Major hemorrhagic events can occur. Monitor for signs and symptoms of bleeding. Cardiomyopathy: The risk of cardiomyopathy is increased in patients receiving cobimetinib with vemurafenib compared with vemurafenib as a single agent. The safety of cobimetinib has not been established in patients with decreased left ventricular ejection fraction (LVEF). Evaluate LVEF before treatment, after one month of treatment, then every 3 months thereafter during treatment. Severe Dermatologic Reactions: Monitor for severe skin rashes. Interrupt, reduce, or discontinue. Serous Retinopathy and Retinal Vein Occlusion: Perform an ophthalmological evaluation at regular intervals and for any visual disturbances. Permanently discontinue for retinal vein occlusion (RVO). Hepatotoxicity: Monitor liver laboratory tests during treatment and as clinically indicated. Rhabdomyolysis: Monitor creatine phosphokinase periodically and as clinically indicated for signs and symptoms of rhabdomyolysis. Severe Photosensitivity: Advise patients to avoid sun exposure. Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. BILLING/CODING INFORMATION: The following codes may be used to describe: HCPCS Coding C9399 Unclassified drugs or biologicals J8999 Prescription drug, oral, chemotherapeutic, NOS ICD-10 Diagnoses Codes That Support Medical Necessity C43.0 C43.9 Malignant melanoma of skin C79.31 Secondary malignant neoplasm of brain C80.0 Disseminated malignant neoplasm, unspecified

C80.1 Malignant primary neoplasm, unspecified REIMBURSEMENT INFORMATION: 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 guideline creation. 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: Vemurafenib (Zelboraf ), 00-J2000-53

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. Clinical Pharmacology [Internet]. Tampa (FL): Gold Standard, Inc.; 2018 [cited 2018 Oct 29]. Available from: http://www.clinicalpharmacology.com/. 2. Cotellic (cobimetinib) prescribing information. Genentech, Inc. South San Francisco, CA. January 2018. 3. DRUGDEX System [Internet]. Greenwood Village (CO): Thomson Micromedex; Updated periodically [cited 2018 Oct 29]. Available from: http://www.thomsonhc.com/. 4. Larkin J, Ascierto PA, Dreno B et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014; 371: 1867-76. 5. 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 1/15/16. 6. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology. Version 1.2018 Central Nervous System Cancers. Available at http://www.nccn.org/professionals/physician_gls/pdf/cns.pdf. Accessed 10/29/18. 7. National Comprehensive Cancer Network (NCCN). Clinical practice guidelines in oncology. Version 1.2019. Cutaneous Melanoma. Available at http://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf. Accessed 10/29/18. 8. National Comprehensive Cancer Network (NCCN). Drugs & Biologics Compendium [Internet]. Fort Washington (PA): National Comprehensive Cancer Network; 2018 [cited 2018 Oct 29] Available from: http://www.nccn.org/professionals/drug_compendium/content/contents.asp/. 9. Orphan Drug Designations and Approval [Internet]. Silver Spring (MD): US Food and Drug Administration; 2018 [cited 2018 Oct 29]. Available from: http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm/.

COMMITTEE APPROVAL: This Medical Coverage Guideline (MCG) was approved by the Florida Blue Pharmacy Policy Committee on 11/14/18. GUIDELINE UPDATE INFORMATION: 03/15/16 New Medical Coverage Guideline. 05/15/16 Updated administration section. 10/15/16 Revision to guideline; consisting of updating description, position statement and references. 12/15/17 Revision to guideline; consisting of updating position statement and references. 06/15/18 Revision to guideline; consisting of updating position statement and references. 07/15/18 Update to coding. 12/15/18 Revision to guideline; consisting of updating references.