Zanubrutinib (Brukinsa) Form

Zanubrutinib (Brukinsa®) is a Bruton tyrosine kinase (BTK) inhibitor.
FDA Approved Indication(s) Brukinsa is indicated for the treatment of adult patients with: • Mantle cell lymphoma (MCL) who have received at least one prior therapy • Waldenström’s macroglobulinemia (WM) • Relapsed or refractory marginal zone lymphoma (MZL) who have received at least one anti- CD20-based regimen • Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) _ *This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
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.
It is the policy of health plans affiliated with Centene Corporation® that Brukinsa is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Mantle Cell Lymphoma (must meet all):

1. Diagnosis of MCL;
   2. Prescribed by or in consultation with an oncologist or hematologist;
   3. Age ≥ 18 years;
   4. Prescribed as single agent therapy;
   5. For brand Brukinsa requests, member must use generic zanubrutinib, if available, unless contraindicated or clinically significant adverse effects are experienced;
2. Member has received ≥ 1 prior therapy (see Appendix B);
   7. If disease is positive for BTK C481S mutation: Member has not had previous disease progression on Imbruvica®;

3. Request meets one of the following (a, b, or c):* a. Dose does not exceed 320 mg (4 capsules) per day; b. If co-administered with a moderate CYP3A4 inducer (e.g., bosentan, efavirenz, phenobarbital, primidone), dose does not exceed 640 mg (8 capsules) per day; Page 1 of 9

   CLINICAL POLICY Zanubrutinib c. 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. Waldenström’s Macroglobulinemia/Lymphoplasmacytic Lymphoma (must meet all):

   1. Diagnosis of WM or lymphoplasmacytic lymphoma (LPL, off-label);
   2. Prescribed by or in consultation with an oncologist or hematologist;
   3. Age ≥ 18 years;
   4. For brand Brukinsa requests, member must use generic zanubrutinib, if available, unless contraindicated or clinically significant adverse effects are experienced;
4. Brukinsa is not prescribed concurrently with Imbruvica® or Calquence®;
   6. Request meets one of the following (a, b, or c): a. Dose does not exceed 320 mg (4 capsules) per day; b. If co-administered with a moderate CYP3A4 inducer (e.g., bosentan, efavirenz, phenobarbital, primidone), dose does not exceed 640 mg (8 capsules) per day; c. 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. Marginal Zone Lymphoma (B-cell lymphoma subtype) (must meet all):
5. Diagnosis of one of the following MZL subtypes (a, b, c, or d): a. Gastric MALT lymphoma; b. Nongastric MALT lymphoma (noncutaneous); c. Nodal MZL; d. Splenic MZL;
6. Prescribed by or in consultation with an oncologist or hematologist;
   3. Age ≥ 18 years;
   4. Prescribed as single agent therapy;
   5. For brand Brukinsa requests, member must use generic zanubrutinib, if available, unless contraindicated or clinically significant adverse effects are experienced;
7. Member has received ≥ 1 line of systemic therapy including an anti-CD20 agent (e.g., rituximab/rituximab biosimilar) (see Appendix B); Prior authorization may be required

8. Request meets one of the following (a, b, or c): a. Dose does not exceed 320 mg (4 capsules) per day; b. If co-administered with a moderate CYP3A4 inducer (e.g., bosentan, efavirenz, phenobarbital, primidone), dose does not exceed 640 mg (8 capsules) per day; c. 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 Page 2 of 9

   CLINICAL POLICY Zanubrutinib Approval duration:
   Medicaid/HIM – 6 months
   Commercial – 12 months or duration of request, whichever is less D. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (must meet all):

9. Diagnosis of CLL/SLL;
   2. Prescribed by or in consultation with an oncologist or hematologist;
   3. Age ≥ 18 years;
   4. Prescribed as single agent therapy;
   5. If disease is positive for BTK C481S mutation: Member has not had previous disease progression on Imbruvica;
10. For brand Brukinsa requests, member must use generic zanubrutinib, if available, unless contraindicated or clinically significant adverse effects are experienced;
11. Request meets one of the following (a, b, or c): a. Dose does not exceed 320 mg (4 capsules) per day; b. If co-administered with a moderate CYP3A4 inducer (e.g., bosentan, efavirenz, phenobarbital, primidone), dose does not exceed 640 mg (8 capsules) per day; c. 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 E. Hairy Cell Leukemia (off-label) (must meet all):
12. Diagnosis Hairy Cell Leukemia;
    2. Prescribed by or in consultation with an oncologist or hematologist;
    3. Age ≥ 18 years;
    4. Prescribed as single agent therapy;
    5. For brand Brukinsa requests, member must use generic zanubrutinib, if available, unless contraindicated or clinically significant adverse effects are experienced;
13. Dose is within FDA maximum limit for any FDA-approved indication or 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. Other diagnoses/indications (must meet 1 or 2):

14. 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 3 of 9

    CLINICAL POLICY Zanubrutinib 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

15. 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):
16. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Brukinsa for a covered indication and has received this medication for at least 30 days;
17. Member is responding positively to therapy;
    3. For brand Brukinsa requests, member must use generic zanubrutinib, if available, unless contraindicated or clinically significant adverse effects are experienced;
    4. If request is for a dose increase, request meets one of the following (a, b, or c): a. New dose does not exceed 320 mg (4 capsules) per day; b. If co-administered with a moderate CYP3A4 inducer (e.g., bosentan, efavirenz, phenobarbital, primidone), dose does not exceed 640 mg (8 capsules) per day; c. 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):
18. 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 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

19. 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 Page 4 of 9

    CLINICAL POLICY Zanubrutinib 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 BTK: Bruton tyrosine kinase CLL: chronic lymphocytic leukemia FDA: Food and Drug Administration LPL: lymphoplasmacytic lymphoma MCL: mantle cell lymphoma MZL: marginal zone lymphoma NCCN: National Comprehensive Cancer Network SLL: small lymphocytic lymphoma WM: Waldenström’s macroglobulinemia Appendix B: Therapeutic Alternatives
    This table provides a listing of preferred alternative therapy recommended in the approval criteria. The drugs listed here may not be a formulary agent for all relevant lines of business and may require prior authorization.
    Drug Name Dosing Regimen Dose Limit/ Maximum Dose Varies Varies Varies MCL RDHA/RCHOP (rituximab, dexamethasone, cytarabine) + platinum (carboplatin, cisplatin, or oxaliplatin)/(rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) HyperCVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone/methotrexate/ cytarabine) + rituximab NORDIC (rituximab + cyclophosphamide, vincristine, doxorubicin, prednisone/rituximab + cytarabine) RCHOP/RDHAP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)/(rituximab, dexamethasone, cisplatin, cytarabine) Bendeka® (bendamustine) + Rituxan® (rituximab) Varies Varies VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, prednisone) RCHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) + Rituxan® (rituximab) Revlimid® (lenalidomide) + Rituxan® (rituximab) Varies MZL Bendeka® (bendamustine) + Rituxan® (rituximab) Varies Varies CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) + Rituxan® (rituximab) Varies Varies Page 5 of 9 Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies

    CLINICAL POLICY Zanubrutinib Drug Name Dosing Regimen Dose Limit/ CVP (cyclophosphamide, vincristine, prednisone)

    • Rituxan® (rituximab) Rituxan® (rituximab) Therapeutic alternatives are listed as Brand name® (generic) when the drug is available by brand name only and generic (Brand name®) when the drug is available by both brand and generic. Appendix C: Contraindications/Boxed Warnings None reported Varies Varies Varies Maximum Dose Varies V. Dosage and Administration
      Indication Dosing Regimen MCL, WM, MZL, CLL, SLL 160 mg PO BID or 320 mg PO QD Maximum Dose 320 mg/day 640 mg/day when used with a moderate CYP3A4 inducer VI. Product Availability
      Capsule: 80 mg VII.