Drug Therapy Guidelines Kisqali® (ribociclib), Kisqali® Femara® Co-Pack (ribociclib; letrozole)

Applicable Medical Benefit Effective: 8/30/21 Pharmacy- Formulary 1 x Next Review: 6/22 Pharmacy- Formulary 2 x Date of Origin: 7/17 Pharmacy- Formulary 3/Exclusive x Review Dates: 6/17, 6/18, 6/19, 6/20, 9/20, 6/21 Pharmacy- Formulary 4/AON X

I. Medication Description

Ribociclib is a cyclin-dependent kinase (CDK) 4 and 6 inhibitor. CDK 4 and 6 are activated when binding to D- cyclins. Cyclin D1 and CDK 4/6 are downstream of signaling pathways that lead to cellular proliferation; the cyclin D-CDK4/6 complex regulates cell cycle progression through phosphorylation of the retinoblastoma protein (pRb). In vitro, ribociclib decreased pRb phosphorylation leading to arrest in the G1 phase of the cell cycle, reducing cell proliferation in breast cancer cell lines. In a rat xenograft model with human tumor cells, inhibition of pRb phosphorylation by ribociclib monotherapy decreased tumor volumes.

Letrozole is a nonsteroidal inhibitor of aromatase, the enzyme that catalyzes the final step in estrogen production. In postmenopausal women, the primary source of circulating estrogen is from the conversion of adrenal estrogens (androstenedione and testosterone) to estrogens (estrone and estradiol) by aromatase; letrozole decreases plasma concentrations of estradiol, estrone, and estrone sulfate by 75% to 95% from baseline, with maximal suppression within 2 to 3 days. Letrozole competitively binds to the heme of the cytochrome P450 subunit of aromatase, decreasing estrogen biosynthesis in all tissues; it is highly specific, and does not impair adrenal steroidogenesis.

Using patient-derived estrogen receptor positive breast cancer xenograft models, the combination of ribociclib and letrozole increased tumor growth inhibition compared to each drug alone.

II. Position Statement

Coverage is determined through a prior authorization process with supporting clinical documentation for every request. Plan-preferred medications: Ibrance, Verzenio Non-preferred medication: Kisqali, Kisqali Femara Co-Pack

III. Policy

Coverage of Kisqali or Kisqali Femara Co-Pack is available when the following criteria have been met: • Member is at least 18 years of age AND • The medication is prescribed by a hematologist/oncologist AND • The requested use is supported by the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines (NCCN Guidelines®) and/or NCCN Drugs & Biologics Compendium (NCCN Compendium®) with a recommendation of category level 1 or 2A AND Page 1 of 3

Drug Therapy Guidelines Kisqali® (ribociclib), Kisqali® Femara® Last Review Date: 6/2021 Co-Pack (ribociclib; letrozole)

• Coverage of non-preferred medications, Kisqali and Kisqali Femara Co-Pack, will be provided if the member has experienced a therapeutic failure or intolerance with ONE plan-preferred medication (Ibrance or Verzenio) first OR at least ONE of the following criteria are met:  The plan-preferred medications are contraindicated or will likely cause an adverse reaction by or physical or mental harm to the member.  The plan-preferred medications are expected to be ineffective based on the known clinical history and conditions of the member and the member’s prescription drug regimen.  The member has tried the plan-preferred medications or another prescription drug in the same pharmacologic class or with the same mechanism of action and such prescription drug was discontinued due to lack of efficacy or effectiveness, diminished effect, or an adverse event.  The member is stable on the medication selected by their healthcare professional for the medical condition under consideration (where “stable” is defined as receiving the medication for an adequate period of time, have achieved optimal response, and continued favorable outcomes are expected UNLESS the medication was initially selected due to the availability of a drug sample or a coupon card and the member does not otherwise meet the definition of “stable”).  The plan-preferred medication is not in the best interest of the member because it will likely cause a significant barrier to the member’s adherence or to compliance with the member’s plan of care, will likely worsen a comorbid condition of the member, or will likely decrease the member’s ability to achieve or maintain reasonable functional ability in performing daily activities.

IV. Quantity Limitations

Coverage is available as follows:  Kisqali: one package (containing 21 doses) per each 28 days  KIsqali Femara Co-Pack: one package (containing 21 Kisqali doses and 28 Femara doses) per each 28 days

V. Coverage Duration

Coverage is available for 6 months and may be renewed.

VI. Coverage Renewal Criteria

Coverage can be renewed based upon the following criteria:  Stabilization of disease or in absence of disease progression AND  Absence of unacceptable toxicity from the drug.

VII. Billing/Coding Information

 Kisqali is available as follows: o Blister pack (21 tablets) – each blister pack contains 21 tablets (200 mg per tablet) (600 mg daily dose). Outer container -3 Blister packs per outer container

Page 2 of 3

Drug Therapy Guidelines Kisqali® (ribociclib), Kisqali® Femara® Last Review Date: 6/2021 Co-Pack (ribociclib; letrozole)

o Blister pack (14 tablets) – each blister pack contains 14 tablets (200 mg per tablet) (400 mg daily dose). Outer container -3 Blisters packs per outer container o Blister pack (21 tablets) – each blister pack contains 21 tablets (200 mg per tablet) (200 mg daily dose). Outer container – 1 Blister pack per outer container  Kisqali Femara Co-Pack is available as follows: o 3 Blister packs, containing 21 tablets (200 mg per tablet) (600 mg daily dose) of Kisqali plus one 28- tablet count bottle of Femara 2.5 mg tablets o 3 Blister packs, containing 14 tablets (200 mg per tablet) (400 mg daily dose) of Kisqali plus one 28- tablet count bottle of Femara 2.5 mg tablets o 1 Blister pack, containing 21 tablets (200 mg per tablet) (200 mg daily dose) of Kisqali plus one 28- tablet count bottle of Femara 2.5 mg tablets

VIII. Summary of Policy Changes

 7/1/17: new policy  6/15/18: no policy changes  8/15/19: no policy changes  8/1/20: no policy changes  1/1/21: added STEP to policy; preferred agents: Ibrance and Verzenio  8/30/21: no policy changes

IX. References

1. Kisqali [prescribing information]. East Hanover, NJ; Novartis Pharmaceuticals Corporation; Revised 7/2020. 2. Kisqali Femara Co-Pack [prescribing information]. East Hanover, NJ; Novartis Pharmaceuticals Corporation; Revised 5/2017. 3. Clinical Pharmacology. Gold Standard. www.clinicalkey.com. Kisqali monograph. Accessed 4/2021. 4. Clinical Pharmacology. Gold Standard. www.clinicalkey.com. Kisqali Femara Co-Pack monograph. Accessed 4/2021. 5. NCCN Drug & Biologics Compendium: ribociclib. Accessed 4/2021. 6. National Comprehensive Cancer Network Guidelines [database online]. Fort Washington, PA: National Comprehensive Cancer Network, Inc.; 2021. URL: https://www.nccn.org/professionals/physician_gls/default.aspx .Updated April, 2021.

The Plan fully expects that only appropriate and medically necessary services will be rendered. The Plan reserves the right to conduct pre-payment and post-payment reviews to assess the medical appropriateness of the above-referenced therapies.

The preceding policy applies only to members for whom the above named pharmacy benefit medications are included on their covered formulary. Members with closed formulary benefits are subject to trying all appropriate formulary alternatives before a coverage exception for a non-formulary medication will be considered.

The preceding policy is a guideline to allow for coverage of the pertinent medication/product, and is not meant to serve as a clinical practice guideline.

Page 3 of 3