YESCARTA, Axicabtagene Ciloleucel Form

Axicabtagene ciloleucel (Yescarta™) is a CD19-directed, genetically modified, autologous T cell immunotherapy. FDA Approved Indication(s) Yescarta is indicated for the treatment of adult patients with
• Relapsed or refractory large B-cell lymphoma (LBCL): o After two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma, and DLBCL arising from follicular lymphoma o That is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy o Limitation of use: Yescarta is not indicated for the treatment of patients with primary central nervous system (CNS) lymphoma. • Relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy o This indication is approved under accelerated approval based on response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s). ____ Efficacy of Yescarta has not been established in patients with a history of or current CNS lymphoma (see Appendix D) 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.
All requests reviewed under this policy require medical director review. It is the policy of health plans affiliated with Centene Corporation® that Yescarta is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Large B-Cell Lymphoma (must meet all): Only for initial treatment dose; subsequent doses will not be covered.

1. Diagnosis of one of the following LBCL (a–h ); a. DLBCL; b. Transformed follicular lymphoma (TFL) to DLBCL; c. Transformed nodal marginal zone lymphoma (MZL) to DLBCL; Page 1 of 10

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   Axicabtagene Ciloleucel d. High-grade B-cell lymphomas with translocations of MYC and BCL2 and/or BCL6 (double/triple hit lymphoma) or high-grade B-cell lymphomas, not otherwise specified; e. Monomorphic post-transplant lymphoproliferative disorders (B-cell type); f. HIV-related DLBCL, primary effusion lymphoma, and HHV8-positive DLBCL;
   g. Monomorphic post-transplant lymphoproliferative disorders (B-cell type); h. If request is for third line or later therapy, any of the following (i-vii): i. Primary mediastinal Large B-cell lymphoma (PMBCL); ii. Gastric MALT lymphoma; iii. Splenic marginal zone lymphoma; iv. Nongastric MALT lymphoma; v. Extranodal marginal zone lymphoma of the stomach; vi. Extranodal marginal zone lymphoma of nongastric sites (noncutaneous); vii. Nodal marginal zone lymphoma;

   2. Prescribed by or in consultation with an oncologist or hematologist;
2. Age ≥ 18 years;
3. Recent (within the last 30 days) absolute lymphocyte count (ALC) ≥ 100/µL;
4. Request is for one of the following (a or b): a. Disease is refractory or member has relapsed after ≥ 2 lines of systemic therapy that includes rituximab and one anthracycline-containing regimen (e.g., doxorubicin); b. Disease that is refractory (defined as no complete remission) to or has relapsed (defined as complete remission followed by biopsy-proven disease relapse) no more than 12 months after first-line chemoimmunotherapy that included an anti- CD20 monoclonal antibody (e.g., rituximab) and anthracycline-containing regimen (e.g., doxorubicin);
   *Prior authorization may be required for rituximab
   6. Member does not have a history of or current CNS disease;
5. Member has not previously received treatment with CAR T-cell immunotherapy (e.g., Abecma®, Carvykti™, Breyanzi®, Kymriah™, Tecartus®);
   8. Yescarta is not prescribed concurrently with other CAR T-cell immunotherapy (e.g., Abecma, Carvykti, Breyanzi, Kymriah, Tecartus);
   9. Dose does not exceed 2 x 108 chimeric antigen receptor (CAR)-positive viable T cells. Approval duration: 3 months (1 dose only, with 4 doses of tocilizumab (Actemra) if requested at up to 800 mg per dose) B. Follicular Lymphoma (must meet all): Only for initial treatment dose; subsequent doses will not be covered.
6. Diagnosis of FL grade 1, 2, or 3a;
7. Prescribed by or in consultation with an oncologist or hematologist;
8. Age ≥ 18 years;

9. Disease is relapsed/refractory after ≥ 2 lines of systemic therapy that includes a combination of an anti-CD20 monoclonal antibody (e.g., rituximab or Gazyva®) and an alkylating agent (e.g., bendamustine, cyclophosphamide, chlorambucil); Prior authorization may be required

   5. Member does not have a history of or current CNS disease; Page 2 of 10

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   Axicabtagene Ciloleucel

   6. Member has not previously received treatment with CAR T-cell immunotherapy (e.g., Abecma, Carvykti, Breyanzi, Kymriah, Tecartus);
   7. Yescarta is not prescribed concurrently with other CAR T-cell immunotherapy (e.g., Abecma, Carvykti, Breyanzi, Kymriah, Tecartus);
   8. Dose does not exceed a single administration of 2 x 108 chimeric antigen receptor (CAR)-positive viable T cells. Approval duration: 3 months (1 dose only, with 4 doses of tocilizumab (Actemra) if requested at up to 800 mg per dose) C. Other diagnoses/indications (must meet 1 or 2):
   9. 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
   10. 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
   11. Continued therapy will not be authorized as Yescarta is indicated to be dosed one time only. Approval duration: Not applicable B. Other diagnoses/indications (must meet 1 or 2):
   12. 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 Page 3 of 10

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   Axicabtagene Ciloleucel

   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; B. History of or current CNS disease. IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key ALC: absolute lymphocyte count CAR: chimeric antigen receptor CNS: central nervous system CRS: cytokine release syndrome DLBCL: diffuse large B-cell lymphoma FDA: Food and Drug Administration
      FL: follicular lymphoma LBCL: large B-cell lymphoma MZL: marginal zone lymphoma TFL: transformed follicular 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. Drug Name Dosing Regimen Dose Limit/
      Maximum Dose LBCL First-Line Treatment Regimens RCHOP (Rituxan® (rituximab), cyclophosphamide, doxorubicin, vincristine, prednisone) RCEPP (Rituxan® (rituximab), cyclophosphamide, etoposide, prednisone, procarbazine) RCDOP (Rituxan® (rituximab), cyclophosphamide, liposomal doxorubicin, vincristine, prednisone) DA-EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) + Rituxan® (rituximab) RCEOP (Rituxan® (rituximab), cyclophosphamide, etoposide, vincristine, prednisone) RGCVP (Rituxan®, gemcitabine, cyclophosphamide, vincristine, prednisone) LBCL Second-Line Treatment Regimens Bendeka® (bendamustine) ± Rituxan® (rituximab) CEPP (cyclophosphamide, etoposide, prednisone, procarbazine) ± Rituxan® (rituximab) Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Page 4 of 10

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   Axicabtagene Ciloleucel Drug Name Dosing Regimen Varies Dose Limit/
   Maximum Dose Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies CEOP (cyclophosphamide, etoposide, vincristine, prednisone) ± Rituxan® (rituximab) DA-EPOCH ± Rituxan® (rituximab) GDP (gemcitabine, dexamethasone, cisplatin) ± Rituxan® (rituximab) gemcitabine, dexamethasone, carboplatin ± Rituxan® (rituximab) GemOx (gemcitabine, oxaliplatin) ± Rituxan® (rituximab) gemcitabine, vinorelbine ± Rituxan® (rituximab) lenalidomide ± Rituxan® (rituximab) Rituxan® (rituximab) DHAP (dexamethasone, cisplatin, cytarabine) ± Rituxan® (rituximab) DHAX (dexamethasone, cytarabine, oxaliplatin) ± Rituxan® (rituximab) ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin) ± Rituxan® (rituximab) ICE (ifosfamide, carboplatin, etoposide) ± Rituxan® (rituximab) MINE (mesna, ifosfamide, mitoxantrone, etoposide) ± Rituxan® (rituximab) FL First-Line and Second-Line + Subsequent Treatment Regimens bendamustine + (Gazyva® (obinutuzumab) or rituximab) CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) + (Gazyva® (obinutuzumab) or rituximab) CHOP + Gazyva® (obinutuzumab) or rituximab CVP (cyclophosphamide, vincristine, prednisone) + Gazyva® (obinutuzumab) CVP + Gazyva® (obinutuzumab) or rituximab rituximab ± (lenalidomide, chlorambucil, or cyclophosphamide)
   rituximab
   Gazyva® (obinutuzumab) Zevalin® (ibritumomab tiuxetan) 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. Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Varies Appendix C: Contraindications/Boxed Warnings • Contraindication(s): none reported • Boxed warning(s):
   o Cytokine release syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving Yescarta. Do not administer Yescarta to patients with Page 5 of 10

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   Axicabtagene Ciloleucel active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids o Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving Yescarta, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with Yescarta. Provide supportive care and/or corticosteroids as needed o Yescarta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta and Tecartus REMS Program Appendix D: General Information • The ZUMA-1 trial included only patients that received prior anti-CD20 antibody therapy and an anthracycline-containing regimen. Patients with an ALC < 100/µL were excluded. • ZUMA-1 and ZUMA-7 both excluded patients from these trials with history or presence of non-malignant CNS disorder, such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement. • The ZUMA-1 trial inclusion criteria required a MRI of the brain showing no evidence of CNS lymphoma. Patients with detectable cerebrospinal fluid malignant cells, or brain metastases, or with a history of cerebrospinal fluid malignant cells or brain metastases were excluded. In ZUMA-7, patients were required to have no known history or suspicion of CNS involvement by lymphoma. For primary DLBCL of the CNS (i.e., primary CNS lymphoma), NCCN treatment guidelines for CNS cancers recommend a high-dose methotrexate induction based regimen or whole brain radiation therapy, which consolidation therapy with high-dose chemotherapy with stem cell rescue, high-dose cytarabine with or without etoposide, low dose whole brain radiation therapy, or continuation with monthly high-dose methotrexate-based regimen. • Bennani et al. 2019 reported on the real-world experience of 17 patients treated with Yescarta who had a history of secondary CNS involvement or had active CNS disease at time of CAR-T infusion. Among the 15 patients who received a Yescarta infusion, 10 had resolution of CNS involvement, and 5 had persistent active CNS disease at the time of infusion. The best overall response rates (complete and partial responses) at 30-days between the non-CNS and CNS cohorts were 75% vs 59% respectively (p = 0.15). Best overall response rates at month 6 were 41% vs 31% respectively (p = 0.60). • CRS, including fatal or life-threatening reactions, occurred in patients receiving Yescarta. Do not administer Yescarta to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
   • Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving Yescarta, including concurrently with CRS or after CRS resolution. Monitor for neurologic toxicities after treatment with Yescarta. Provide supportive care and/or corticosteroids, as needed.
   • Yescarta is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Yescarta REMS. Page 6 of 10

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   Axicabtagene Ciloleucel V. Dosage and Administration
   Indication LBCL, FL Dosing Regimen Target dose: 2 × 106 CAR-positive viable T cells per kg body weight Maximum Dose 2 × 108 CAR-positive viable T cells VI. Product Availability
   Single-dose unit infusion bag: frozen suspension of genetically modified autologous T-cells labeled for the specific recipient VII.