GAZYVA, Obinutuzumab Form

Obinutuzumab (Gazyva®) is a CD20-directed cytolytic antibody. FDA Approved Indication(s) Gazyva is indicated in combination with: • Chlorambucil, for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL) • Bendamustine followed by Gazyva monotherapy, for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab-containing regimen • Chemotherapy followed by Gazyva monotherapy in patients achieving at least a partial remission, for the treatment of adult patients with previously untreated stage II bulky, III or IV FL 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 Gazyva is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (must meet all):

1. Diagnosis of CLL or small lymphocytic lymphoma (SLL);
   2. Prescribed by or in consultation with an oncologist or hematologist;
   3. Age ≥ 18 years;
   4. If prescribed for second-line or subsequent therapy, both of the following (a and b): a. Prescribed as a single agent or in combination with Venclexta® (if combination previously used as first-line therapy); b. Disease does not have del(17p)/TP53 mutation;

2. Request meets one of the following (a or b): a. After initial loading doses, dose does not exceed 1,000 mg per 28-day cycle; 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: 6 months
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   CLINICAL POLICY Obinutuzumab B. Follicular and Other B-Cell Lymphomas (must meet all):

3. Diagnosis of one of the following B-cell lymphoma subtypes (a or b): a. FL; b. Other B-cell lymphomas (off-label): i. Marginal zone lymphoma (a, b, or c):
   a) Splenic marginal zone lymphoma; b) Nodal marginal zone lymphoma; c) Extranodal marginal zone lymphoma (1 or 2): 1) Gastric MALT lymphoma; 2) Nongastric MALT lymphoma; ii. Histologic transformation of marginal zone lymphoma to diffuse large B-cell lymphoma; iii. Diffuse large B-cell lymphoma; iv. High-grade B-cell lymphoma; v. Mantle cell lymphoma; vi. Castleman’s disease; vii. Post-transplant lymphoproliferative disorders; viii. HIV-related B-cell lymphoma; ix. Burkitt lymphoma;
4. Prescribed by or in consultation with an oncologist or hematologist;
   3. Age ≥ 18 years;
   4. For FL: Gazyva is requested for one of the following uses (a, b, c, or d): a. First line therapy in combination with chemotherapy; b. Second-line or subsequent therapy in combination with chemotherapy (see Appendix B for examples of prior therapy); c. Maintenance therapy as a single agent if disease is rituximab-refractory or following chemotherapy; d. As a substitute for rituximab in patients experiencing rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis; Re-challenge with the same anti-CD20 monoclonal antibody is not recommended and it is unclear if the use of an alternative anti-CD20 monoclonal antibody poses the same risk of recurrence.

5. For marginal zone lymphomas: Gazyva is requested for one of the following uses (a, b, c, or d): a. Maintenance therapy if disease is rituximab-refractory, recurrent, and has been treated with Gazyva and bendamustine;
   b. Second-line or subsequent therapy in combination with chemotherapy (see Appendix B for examples of prior therapy); c. As a substitute for rituximab in patients experiencing rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis; Re-challenge with the same anti-CD20 monoclonal antibody is not recommended and it is unclear if the use of an alternative anti-CD20 monoclonal antibody poses the same risk of recurrence. Page 2 of 8

   CLINICAL POLICY Obinutuzumab d. Nodal marginal zone lymphoma only: First line therapy in combination with chemotherapy;

6. For all subtypes other than FL and marginal zone lymphoma: Gazyva is requested as a substitute for rituximab in patients experiencing rare complications such as mucocutaneous reactions including paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis; Re-challenge with the same anti-CD20 monoclonal antibody is not recommended and it is unclear if the use of an alternative anti-CD20 monoclonal antibody poses the same risk of recurrence.
7. Request meets one of the following (a or b): a. After initial loading doses, dose does not exceed 1,000 mg per 28-day cycle; 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: 6 months C. Hairy Cell Leukemia (off-label) (must meet all):
8. Diagnosis of hairy cell leukemia;
   2. Prescribed by or in consultation with an oncologist or hematologist;
   3. Age ≥ 18 years;
   4. Prescribed as initial therapy in combination with Zelboraf® (vemurafenib);
   5. Member is either unable to tolerate purine analogs (e.g., cladribine, pentostatin) or has active infection;
9. 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: 6 months D. Other diagnoses/indications (must meet 1 or 2):

10. 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: 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: 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: HIM.PA.154 for health insurance marketplace and CP.PMN.53 for Medicaid.
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    CLINICAL POLICY Obinutuzumab II. Continued Therapy A. All Indications in Section I (must meet all):

11. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Gazyva for a covered indication and has received this medication for at least 30 days;
12. Member is responding positively to therapy;
    3. If request is for a dose increase, request meets one of the following (a or b): a. After initial loading doses, new dose does not exceed 1,000 mg per 28-day cycle; 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: 12 months
       B. Other diagnoses/indications (must meet 1 or 2):

13. 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: 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: 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: 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 – 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 CLL: chronic lymphocytic leukemia FDA: Food and Drug Administration FL: follicular lymphoma MALT: mucosa-associated lymphoid tissue
       NCCN: National Comprehensive Cancer Network NHL: non-Hodgkin lymphoma SLL: small lymphocytic lymphoma 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.
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    CLINICAL POLICY Obinutuzumab Drug Name FL and Marginal Zone Lymphomas
    Examples of first-line, second-line and subsequent therapies: • bendamustine + rituximab • RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) • RCVP (rituximab, cyclophosphamide, vincristine, prednisone) • Single-agent examples: rituximab; Leukeran® (chlorambucil) ± rituximab; cyclophosphamide ± rituximab; Revlimid® (lenalidomide) ± rituximab; Aliqopa® (copanlisib) Dosing Regimen Varies Dose Limit/ Maximum Dose Varies 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 • Contraindication(s): patients with known hypersensitivity reactions (e.g., anaphylaxis) to obinutuzumab or any of the excipients, including serum sickness with prior obinutuzumab use • Boxed warning(s): hepatitis B virus reactivation and progressive multifocal leukoencephalopathy
    V. Dosage and Administration
    Indication Dosing Regimen CLL/SLL Maximum Dose See regimen See regimen FL 100 mg IV on day 1, 900 mg IV on day 2 of cycle 1, then 1,000 mg IV on days 8 and 15 of cycle 1; begin the next cycle of therapy on day 29. For cycles 2 to 6, give obinutuzumab 1,000 mg IV on day 1 repeated every 28 days.
    1,000 mg IV on day 1, 8 and 15 of Cycle 1; 1,000 mg on day 1 of Cycles 2-6 or Cycles 2-8; and then 1,000 mg every 2 months for up to 2 years. For patients with relapsed or refractory FL, administer Gazyva in combination with bendamustine in six 28- day cycles. Patients who achieve stable disease, complete response, or partial response to the initial 6 cycles should continue on Gazyva 1,000 mg as monotherapy for up to two years. For patients with previously untreated FL, administer Gazyva with one of the following chemotherapy regimens: • Six 28-day cycles in combination with bendamustine Page 5 of 8

    CLINICAL POLICY Obinutuzumab Indication Dosing Regimen Maximum Dose • Six 21-day cycles in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), followed by 2 additional 21-day cycles of Gazyva alone • Eight 21-day cycles in combination with CVP (cyclophosphamide, vincristine, prednisone) Patients with previously untreated FL who achieve a complete response or partial response to the initial 6 or 8 cycles should continue on Gazyva 1,000 mg as monotherapy for up to two years. VI. Product Availability
    Single-dose vial: 1,000 mg/40 mL (25 mg/mL)
    VII.