Sunflower Health Plan AFINITOR, Everolimus ZORTRESS, Everolimus (Immunosuppressant) AFINITOR DISPERZ, Everolimus Form

Everolimus (Afinitor®, Afinitor Disperz®, Zortress®) is an mTOR kinase inhibitor. ____________ *For Health Insurance Marketplace (HIM), Afinitor Disperz is non-formulary and should not be approved using these criteria; refer to the formulary exception policy, HIM.PA.103. Afinitor Zortress --- --- --- Afinitor Disperz X - adults X - adults X - adults X - adults per NCCN X - adults per NCCN X - adults per NCCN X - adults per NCCN X - adults X - adults X - adults per NCCN X - 1 year and older X - 1 year and older X - 2 years and older --- --- --- FDA Approved Indication(s) Indication Labeled uses (and recommended NCCN uses by product as indicated) Breast cancer PNET (pancreas) NET (GI, lung, [thymic-off- label]) RCC TSC-AML (renal) TSC-SEGA TSC-seizures Prophylaxis of organ rejection Recommended NCCN uses (adults) Meningioma HL STS-GIST STS-PEComa, angiomyolipoma, lymphangioleiomyomatosis Thymoma/thymic carcinoma DTC WM/LPL Endometrial carcinoma Histiocytic neoplasms Abbreviations: DTC (differentiated thyroid carcinoma), GI (gastrointestinal), HL (Hodgkin lymphoma), PNET (pancreatic neuroendocrine tumor), NET (neuroendocrine tumors), RCC (renal cell carcinoma), STS-GIST (soft tissue sarcoma-gastrointestinal stromal tumor), STS-PEComa (soft tissue sarcoma-perivascular epithelioid cell tumor), TSC-AML (tuberous sclerosis complex- angiomyolipoma), TSC-SEGA (tuberous sclerosis complex- subepndymal giant cell astrocytoma), TSC-seizures (tuberous sclerosis complex-seizures). WM/LPL (Waldenstrom macroglobulinemia/lymphoplasmacytic lymphoma) --- --- --- --- X - adults --- --- --- --- --- --- --- --- --- X X X X X X X X X X X X X X X X X X Page 1 of 13 CLINICAL POLICY Everolimus Afinitor is indicated for the treatment of: • Postmenopausal women with advanced hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole. • Adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) and adults with progressive, well-differentiated, non-functional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin that are unresectable, locally advanced or metastatic.* • Adult patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. • Adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery. Afinitor and Afinitor Disperz are indicated for the treatment of adult and pediatric patients aged 1 year and older with tuberous sclerosis complex (TSC) who have subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected. Afinitor Disperz is indicated for the adjunctive treatment of adult and pediatric patients aged 2 years and older with TSC-associated partial-onset seizures. Zortress is indicated for the prophylaxis of organ rejection in adult patients:† • Kidney transplant: at low-moderate immunologic risk. Use in combination with basiliximab, cyclosporine (reduced doses) and corticosteroids. • Liver transplant: administer no earlier than 30 days post-transplant. Use in combination with tacrolimus (reduced doses) and corticosteroids. ____________ * Limitation(s) of use: Afinitor is not indicated for the treatment of patients with functional carcinoid tumors. † Limitation(s) of use: Safety and efficacy of Zortress have not been established in the following: • Kidney transplant patients at high immunologic risk • Recipients of transplanted organs other than kidney or liver • Pediatric patients (less than 18 years) 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 everolimus are medically necessary when the following criteria are met: I. Initial Approval Criteria A. Breast Cancer (must meet all): 1. Request is for Afinitor or Afinitor Disperz; 2. Diagnosis of recurrent or metastatic breast cancer; 3. Prescribed by or in consultation with an oncologist; 4. Age ≥ 18 years; Page 2 of 12 CLINICAL POLICY Everolimus 5. Disease is HR-positive and HER2-negative; 6. History of endocrine therapy (see Appendix B) unless contraindicated or clinically significant adverse effects are experienced; 7. For Afinitor or Afinitor Disperz requests, member must use generic everolimus, if available, unless contraindicated or clinically significant adverse effects are experienced; 8. Prescribed in combination with exemestane, fulvestrant or tamoxifen; 9. Request meets one of the following (a or b):* a. Dose does not exceed all of the following (i, ii, and iii): i. 20 mg per day; ii. Afinitor: 2 tablets per day; iii. Afinitor Disperz: 4 tablets per day; 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: Medicaid – 6 months HIM – 6 months (refer to HIM.PA.103 for Afinitor Disperz) Commercial – 12 months or duration of request, whichever is less B. Neuroendocrine Tumor (must meet all): 1. Request is for Afinitor or Afinitor Disperz; 2. Diagnosis of NET of one of the following origins (a, b, c, d, or e): a. Pancreatic; b. GI tract; c. Lung; d. Bronchopulmonary (off-label); e. Thymus (off-label); 3. Disease is unresectable, locally advanced or metastatic; 4. Prescribed by or in consultation with an oncologist; 5. Age ≥ 18 years; 6. For Afinitor or Afinitor Disperz requests, member must use generic everolimus, if available, unless contraindicated or clinically significant adverse effects are experienced; 7. Request meets one of the following (a or b):* a. Dose does not exceed all of the following (i, ii, and iii): i. 20 mg per day; ii. Afinitor: 2 tablets per day; iii. Afinitor Disperz: 4 tablets per day; 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: Medicaid – 6 months HIM – 6 months (refer to HIM.PA.103 for Afinitor Disperz) Commercial – 12 months or duration of request, whichever is less Page 3 of 12 CLINICAL POLICY Everolimus C. Renal Cell Carcinoma (must meet all): 1. Request is for Afinitor or Afinitor Disperz; 2. Diagnosis of relapsed or stage IV (unresectable or metastatic) RCC; 3. Prescribed by or in consultation with an oncologist; 4. Age ≥ 18 years; 5. For Afinitor or Afinitor Disperz requests, member must use generic everolimus, if available, unless contraindicated or clinically significant adverse effects are experienced; 6. If clear cell histology, failure of a prior therapy (see Appendix B) unless contraindicated or clinically significant adverse effects are experienced; *Prior authorization may be required for prior therapies 7. Request meets one of the following (a or b):* a. Dose does not exceed all of the following (i, ii, and iii): i. 20 mg per day; ii. Afinitor: 2 tablets per day; iii. Afinitor Disperz: 4 tablets per day; 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: Medicaid – 6 months HIM – 6 months (refer to HIM.PA.103 for Afinitor Disperz) Commercial – 12 months or duration of request, whichever is less D. Renal Angiomyolipoma with Tuberous Sclerosis Complex (must meet all): 1. Request is for Afinitor or Afinitor Disperz; 2. Diagnosis of renal angiomyolipoma associated with TSC, not requiring immediate surgery; 3. Prescribed by or in consultation with an oncologist; 4. Age ≥ 18 years; 5. For Afinitor or Afinitor Disperz requests, member must use generic everolimus, if available, unless contraindicated or clinically significant adverse effects are experienced; 6. Request meets one of the following (a or b):* a. Dose does not exceed all of the following (i, ii, and iii): i. 20 mg per day; ii. Afinitor: 2 tablets per day; iii. Afinitor Disperz: 4 tablets per day; 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: Medicaid – 6 months HIM – 6 months (refer to HIM.PA.103 for Afinitor Disperz) Commercial – 12 months or duration of request, whichever is less Page 4 of 12 CLINICAL POLICY Everolimus E. Tuberous Sclerosis Complex with Subependymal Giant Cell Astrocytoma (must meet all): 1. Request is for Afinitor or Afinitor Disperz; 2. Diagnosis of SEGA associated with TSC; 3. Prescribed by or in consultation with an oncologist; 4. Age ≥ 1 year; 5. Member is not a candidate for curative surgical resection. 6. For Afinitor or Afinitor Disperz requests, member must use generic everolimus, if available, unless contraindicated or clinically significant adverse effects are experienced; Approval duration: Medicaid – 6 months HIM – 6 months (refer to HIM.PA.103 for Afinitor Disperz) Commercial – 12 months or duration of request, whichever is less F. Tuberous Sclerosis Complex-Associated Partial-Onset Seizures (must meet all): 1. Request is for Afinitor Disperz; 2. Diagnosis of partial-onset seizures associated with TSC; 3. Prescribed by or in consultation with an oncologist or neurologist; 4. Age ≥ 2 years; 5. Afinitor Disperz will be used as adjunctive therapy; 6. For Afinitor Disperz requests, member must use generic everolimus, if available, unless contraindicated or clinically significant adverse effects are experienced. Approval duration: Medicaid – 6 months HIM – refer to HIM.PA.103 Commercial – 12 months or duration of request, whichever is less G. Prophylaxis of Organ Rejection (must meet all): 1. Request is for Zortress; 2. Member has received or is scheduled for a kidney or liver transplant; 3. Prescribed by or in consultation with a nephrologist, hepatologist, or transplant specialist; 4. Age ≥ 18 years; 5. For kidney transplant, failure of tacrolimus unless contraindicated or clinically significant adverse effects are experienced; 6. For Zortress requests, member must use generic everolimus, if available, unless contraindicated or clinically significant adverse effects are experienced; 7. Prescribed in combination with one of the following (a or b): a. For kidney transplant: Simulect®, cyclosporine, and corticosteroids; b. For liver transplant: tacrolimus and corticosteroids. Approval duration: Medicaid/HIM – 6 months Commercial – 12 months or duration of request, whichever is less Page 5 of 12 CLINICAL POLICY Everolimus H. NCCN Compendium Indications (off-label) (must meet all): 1. Request is for Afinitor or Afinitor Disperz; 2. Diagnosis of one of the following (a, b, c, or d): a. Afinitor or Afinitor Disperz is prescribed as single-agent therapy: i. HL, WM/LPL, thymoma, or thymic carcinoma (refractory, recurrent, progressive, unresectable, or metastatic disease, or disease not responding to previous therapy); ii. PEComa, recurrent angiomyolipoma, or lymphangioleiomyomatosis; iii. Histiocytic neoplasms (i.e., Erdheim-Chester disease, Langerhans cell histiocytosis, Rosai-Dorfman disease) b. Endometrial carcinoma, prescribed in combination with letrozole; c. GIST, prescribed in combination with imatinib, Sutent®, or Stivarga® for disease progression after therapy with imatinib, Sutent, and Stivarga;* *Prior authorization may be required for imatinib, Sutent, and Stivarga d. DTC (i.e., follicular, oncolytic carcinoma/Hurthle cell or papillary carcinoma); 3. Prescribed by or in consultation with an oncologist; 4. Age ≥ 18 years; 5. For Afinitor or Afinitor Disperz requests, member must use generic everolimus, if available, unless contraindicated or clinically significant adverse effects are experienced; 6. 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 – 6 months HIM – 6 months (refer to HIM.PA.103 for Afinitor Disperz) Commercial – 12 months or duration of request, whichever is less I. Other diagnoses/indications (must meet 1 or 2): 1. 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 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. Page 6 of 12 CLINICAL POLICY Everolimus II. Continued Therapy A. All Indications in Section I (must meet all): 1. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Afinitor, Afinitor Disperz, or Zortress for a covered indication and has received this medication for at least 30 days; 2. Member is responding positively to therapy; 3. For Afinitor, Afinitor Disperz, Zortress requests, member must use generic everolimus, if available, unless contraindicated or clinically significant adverse effects are experienced; 4. For all indications, except partial-onset seizures associated with TSC, SEGA associated with TSC, and organ rejection prophylaxis, if request is for a dose increase, request meets one of the following (a or b):* a. New dose does not exceed all of the following (i, ii, and iii): i. 20 mg per day; ii. Afinitor: 2 tablets per day; iii. Afinitor Disperz: 4 tablets per day; 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: Medicaid – 12 months HIM – 12 months (refer to HIM.PA.103 for Afinitor Disperz) Commercial – 12 months or duration of request, whichever is less B. Other diagnoses/indications (must meet 1 or 2): 1. 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 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. Page 7 of 12 CLINICAL POLICY Everolimus IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key AML: angiomyolipoma ER: estrogen receptor DTC: differentiated thyroid cancer FDA: Food and Drug Administration GI: gastrointestinal GIST: gastrointestinal stromal tumor HER-2: human epidermal growth factor receptor-2 HL: Hodgkin lymphoma HR: hormone receptor NET: neuroendocrine tumor PEComa: perivascular epithelioid cell tumor PNET: pancreatic neuroendocrine tumor RCC: renal cell carcinoma SEGA: subepndymal giant cell astrocytoma STS: soft tissue sarcoma TSC: tuberous sclerosis complex WM/LPL: Waldenstrom macroglobulinemia/lymphoplasmacytic 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 Breast cancer: Examples of endocrine therapies per NCCN • Nonsteroidal aromatase inhibitors (anastrozole and letrozole); • Steroidal aromatase inhibitors Varies (exemestane) • Serum estrogen receptor (ER) modulators (tamoxifen, toremifene) Varies • ER down-regulators (fulvestrant) • Progestin (megestrol acetate) • Androgens (fluoxymesterone) • High-dose estrogen (ethinyl estradiol) RCC: Examples of first and second-line therapies for relapsed or stage IV disease with clear cell histology per NCCN • Votrient® (pazopanib) • Sutent® (sunitinib) • Opdivo® (nivolumab) ± Yervoy® Varies Varies (iplimumab) • Proleukin® (aldesleukin) • Cabometyx® (cabozantinib) • Torisel® (temsirolimus) • • Afinitor/Afinitor Disperz (everolimus) Inlyta® (axitinib) ± Lenvima (lenvatinib) • Nexavar (sorafenib) Page 8 of 12 CLINICAL POLICY Everolimus Drug Name Dosing Regimen Dose Limit/ Maximum Dose • Tarceva® (erlotinib) GIST imatinib (Gleevec®) Sutent (sunitinib) Stivarga (regorafenib) DTC Lenvima (lenvatinib) Nexavar (sorafenib) 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. 400 mg PO QD or BID 50 mg PO QD 160 mg PO QD 800 mg/day 50 mg/day 160 mg/day 24 mg PO QD 400 mg PO QD 24 mg/day 400 mg/day Appendix C: Contraindications/Boxed Warnings • Contraindication(s): o Afinitor and Afinitor Disperz: clinically significant hypersensitivity to everolimus or to other rapamycin derivatives o Zortress: known hypersensitivity to everolimus, sirolimus, or to components of the drug product • Boxed warning(s) for Zortress: malignancies and serious infections, kidney graft thrombosis, nephrotoxicity, and mortality in heart transplantation when used in de novo patients within the first three months post-transplantation Appendix D: General Information • Heart transplant: Although the off-label use of Zortress in heart transplant is not supported by the Micromedex DrugDex compendium, it does have both literature and guideline support. Individual risk-benefit ratios must be considered prior to such use because of safety concerns (see Appendix C – boxed warnings). Examples of patient- specific scenarios where use may be appropriate include, but are not limited to: patient already established on therapy, refractory or recurrent rejection, renal insufficiency, cardiac allograft vasculopathy (CAV), history of malignancies, calcineurin inhibitor (CNI) toxicity. V. Dosage and Administration Indication Breast cancer, PNET (pancreas), NET (GI, lung), RCC, TSC-AML (renal) TSA-SEGA TSC-associated partial- onset seizures Kidney transplant rejection prophylaxis Dosing Regimen Afinitor 10 mg PO QD Afinitor/Afinitor Disperz 4.5 mg/m2 PO QD; adjust dose to attain trough concentrations of 5-15 ng/mL Afinitor Disperz 5 mg/m2 PO QD; adjust dose to attain trough concentrations of 5-15 ng/mL Zortress Maximum Dose 20 mg/day Based on trough concentrations Page 9 of 12 CLINICAL POLICY Everolimus Indication Liver transplant rejection prophylaxis Maximum Dose Dosing Regimen 0.75 mg PO BID; adjust dose to attain trough concentrations of 3 to 8 ng/mL Zortress 1 mg PO BID; adjust dose to attain trough concentrations of 3 to 8 ng/mL VI. Product Availability Drug Name Everolimus (Afinitor) Everolimus (Afinitor Disperz) Everolimus (Zortress) Availability Tablets: 2.5 mg, 5 mg, 7.5 mg, 10 mg Tablets for oral suspension: 2 mg, 3 mg, 5 mg Tablets: 0.25 mg, 0.5 mg, 0.75 mg, 1 mg VII.