YERVOY, Ipilimumab Form

Ipilimumab (Yervoy®) is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody.
FDA Approved Indication(s) Yervoy is indicated for: • Unresectable or metastatic melanoma o Treatment of unresectable or metastatic melanoma in adults and pediatric patients 12 years and older as a single agent or in combination with nivolumab • Adjuvant treatment of melanoma o Adult patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm who have undergone complete resection, including total lymphadenectomy • Renal cell carcinoma (RCC) o Treatment of patients with intermediate or poor risk advanced renal cell carcinoma, as first-line treatment in combination with nivolumab • Colorectal cancer (CRC) o Treatment of adult and pediatric patients 12 years of age and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic CRC that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, in combination with nivolumab • Hepatocellular carcinoma (HCC) o In combination with nivolumab, the treatment of patients with HCC who have been previously treated with sorafenib • Non-small cell lung cancer (NSCLC) o In combination with nivolumab, for the first-line treatment of adult patients with metastatic NSCLC whose tumors express programmed death-ligand 1 (PD-L1) ≥ 1% as determined by an FDA-approved test, with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations o In combination with nivolumab and 2 cycles of platinum-doublet chemotherapy, for the first-line treatment of adult patients with metastatic or recurrent NSCLC, with no EGFR or ALK genomic tumor aberrations • Malignant pleural mesothelioma o Treatment of adult patients with unresectable malignant pleural mesothelioma, as first- line treatment in combination with nivolumab Page 1 of 14

CLINICAL POLICY Ipilimumab • Esophageal cancer o Treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC), as first line treatment in combination with nivolumab ____ *This indication is approved under accelerated approval based on tumor response rate and duration of response. 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 Yervoy is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Melanoma (must meet all):

1. Diagnosis of unresectable, metastatic, or lymph node positive melanoma;
   2. Prescribed by or in consultation with an oncologist;
   3. Age is one of the following (a or b):
      a. For unresectable or metastatic disease: ≥ 12 years;
      b. For adjuvant treatment: ≥ 18 years;
2. Prescribed in one of the following ways (a, b, or c): a. As a single agent; b. In combination with Opdivo® for unresectable or metastatic melanoma; c. In combination with Keytruda® for unresectable or metastatic melanoma; *Prior authorization may be required for Opdivo and Keytruda
3. Request meets one of the following (a, b, or c): a. Unresectable or metastatic disease: Dose does not exceed 3 mg per kg every 3 weeks for a maximum of 4 doses; b. Adjuvant treatment: Dose does not exceed 10 mg/kg every 3 weeks for 4 doses, followed by 10 mg/kg every 12 weeks for up to 3 years; 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: 6 months
   B. Renal Cell Carcinoma (must meet all):

4. Diagnosis of advanced or metastatic RCC;

   2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 12 years;
   4. Prescribed in combination with Opdivo;Prior authorization may be required for Opdivo
   5. Request meets one of the following (a or b):* a. Dose does not exceed 1 mg/kg IV every 3 weeks for a maximum of 4 doses; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Page 2 of 14

   CLINICAL POLICY Ipilimumab *Prescribed regimen must be FDA-approved or recommended by NCCN Approval duration: 16 weeks (maximum of 4 doses) C. Colorectal Cancer (must meet all):

5. Diagnosis of MSI-H or dMMR CRC;
   2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 12 years;
   4. Disease is unresectable or metastatic;
   5. Prescribed in combination with Opdivo;
   6. Request meets one of the following (a or b): a. Dose does not exceed 1 mg/kg IV every 3 weeks for a maximum of 4 doses; 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: 16 weeks (maximum of 4 doses) D. Hepatocellular Carcinoma (must meet all):
6. Diagnosis of HCC;
   2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. Member has previously received Nexavar®, Lenvima®, or Tecentriq® + bevacizumab (Mvasi® and Zirabev™ are preferred), or Imfinzi®; *Prior authorization may be required for Nexavar, Lenvima, Tecentriq, bevacizumab, and Imfinzi
7. Prescribed in combination with Opdivo; Prior authorization may be required for Opdivo
   6. Documentation of Child-Pugh Class A status;
   7. Request meets one of the following (a or b):
   a. Dose does not exceed 3 mg/kg IV every 3 weeks for a maximum of 4 doses; 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: 16 weeks (maximum of 4 doses) E. Non-Small Cell Lung Cancer (must meet all):
8. Diagnosis of recurrent, advanced, or metastatic NSCLC;
   2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. Prescribed in combination with Opdivo;Prior authorization may be required for Opdivo
9. Member does not have contraindications to PD-1/PD-L1 inhibitor therapy (e.g., Opdivo, Keytruda, Tecentriq, Imfinzi) (see Appendix D);

10. Request meets one of the following (a, b, c, d, e, or f): a. Disease mutation status is negative for actionable biomarkers (EGFR, KRAS, ALK, ROS1, BRAF, NTRK1/2/3, MET, RET and ERBB2 [HER2]), and member has not received prior systemic therapy for advanced disease; Page 3 of 14

    CLINICAL POLICY Ipilimumab b. Disease mutation status is positive for EGFR S768I, L861Q, and/or G719X, and member has received prior afatinib, osimertinib, erlotinib, gefitinib, or dacomitinib; c. Disease mutation status is positive for EGFR exon 19 deletion or L858R, and member has received prior erlotinib ± (ramucirumab or bevacizumab), afatinib, gefitinib, osimertinib, or dacomitinib; d. Disease mutation status is positive for ROS1 rearrangement, and member has received prior crizotinib, entrectinib, or ceritinib; e. Disease mutation status is positive for ALK rearrangement, and member has received prior crizotinib, ceritinib, alectinib, brigatinib, or lorlatinib; f. Disease mutation status is positive for EGFR exon 20, KRAS G12C, NRTK1/2/3,
    BRAF V600E, MET exon 14 skipping, RET rearrangement, or ERBB2 (HER2); *Prior authorization may be required

    7. Request meets one of the following (a or b): a. Dose does not exceed 1 mg/kg IV every 6 weeks in combination with Opdivo; 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 F. Malignant Pleural Mesothelioma (must meet all):
11. Diagnosis of unresectable malignant pleural mesothelioma;
    2. Prescribed by or in consultation with an oncologist;
    3. Age ≥ 18 years;
    4. Prescribed in combination with Opdivo;Prior authorization may be required for Opdivo.
    5. Request meets one of the following (a or b): a. Dose does not exceed 1 mg/kg IV every 6 weeks in combination with Opdivo; 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 G. Esophageal Cancer (must meet all):

12. Diagnosis of unresectable advanced or metastatic ESCC;

    2. Prescribed by or in consultation with an oncologist;
    3. Age ≥ 18 years;
    4. Prescribed in combination with Opdivo;Prior authorization may be required for Opdivo.
    5. Request meets one of the following (a or b): a. Dose does not exceed 1 mg/kg IV every 6 weeks in combination with Opdivo; 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 Page 4 of 14

    CLINICAL POLICY Ipilimumab H. NCCN Compendium Indications (off-label) (must meet all):

13. Diagnosis of one of the following (a-f): a. MSI-H or dMMR small bowel adenocarcinoma; b. Metastatic uveal melanoma; c. MSI-H or dMMR ampullary adenocarcinoma;
    d. Bone cancer (e.g., chondrosarcoma, osteosarcoma, chordoma, Ewing sarcoma), and both of the following (i and ii): i. Disease is unresectable or metastatic with tissue tumor mutation burden-high tumors with 10 or more mutations per megabase; ii. Disease has progressed following prior treatment and no satisfactory alternative treatment options exist; e. BRAF non-specific melanoma brain metastases; f. Classic Kaposi sarcoma as subsequent systemic therapy;
14. Prescribed by or in consultation with an oncologist;
    
    3. Age ≥ 12 years;
    4. Prescribed in combination with Opdivo for all of the following (a-d):* a. MSI-H/dMMR small bowel adenocarcinoma;
       b. MSI-H/dMMR ampullary adenocarcinoma;
       c. Bone cancer;
       d. Classic Kaposi sarcoma;
15. For uveal melanoma or brain metastases: Prescribed as a single agent or in combination with Opdivo;Prior authorization may be required for Opdivo
16. 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 I. Other diagnoses/indications (must meet 1 or 2):
17. 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

18. 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 5 of 14

    CLINICAL POLICY Ipilimumab II. Continued Therapy A. Melanoma - Unresectable or Metastatic

19. Reauthorization beyond 16 weeks is not permitted. Members must meet the initial approval criteria, at a minimum of 3 months since initial treatment discontinuation. Approval duration: Not applicable B. Renal Cell Carcinoma, Colorectal Cancer, Hepatocellular Carcinoma
20. Reauthorization beyond 16 weeks is not permitted. Members must meet the initial approval criteria. Approval duration: Not applicable C. Melanoma (Adjuvant Treatment), Non-Small Cell Lung Cancer, Malignant Pleural Mesothelioma, Esophageal Cancer (must meet all):
    1. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Yervoy and has received this medication for at least 30 days;
21. Member is responding positively to therapy;
    3. If request is for a dose increase, request meets one of the following (a, b, or c): a. For melanoma: New dose does not exceed 10 mg/kg every 12 weeks for up to 3 years; b. For NSCLC, malignant pleural mesothelioma, and ESCC: New dose does not exceed 1 mg/kg IV every 6 weeks in combination with Opdivo; 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: 12 months or up to a total duration of 3 years (cutaneous melanoma) or 2 years (NSCLC, malignant pleural mesothelioma, ESCC), whichever is less D. NCCN Compendium Indications (off-label) (must meet all):
22. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Yervoy for a covered indication and has received this medication for at least 30 days;
23. Member is responding positively to therapy;
    3. 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: 12 months E. Other diagnoses/indications (must meet 1 or 2):

24. 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: Page 6 of 14

    CLINICAL POLICY Ipilimumab 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

25. 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.
    IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key ALK: anaplastic lymphoma kinase BRAF: B-Raf proto-oncogene, serine/ threonine kinase CRC: colorectal cancer
    CTLA-4: cytotoxic T-lymphocyte antigen 4 dMMR: mismatch repair deficient
    EGFR: epidermal growth factor receptor FDA: Food and Drug Administration HCC: hepatocellular carcinoma MET: mesenchymal-epithelial transition MSI-H: microsatellite instability-high PD-1: programmed death-1 PD-L1: programmed death-ligand 1 RCC: renal cell carcinoma ROS1: ROS proto-oncogene 1 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 and may require prior authorization.
    Drug Name Dosing Regimen Opdivo (nivolumab) MSI-H/dMMR small bowel adenocarcinoma 3 mg/kg IV once every 3 weeks for four doses, then 3 mg/kg IV or 240 mg IV every 2 weeks with or without ipilimumab Unresectable or metastatic melanoma Adult and pediatric weighing ≥ 40 kg: nivolumab 1 mg/kg every 3 weeks for four doses in combination with ipilimumab 3 mg/kg every 3 weeks, then nivolumab 240 mg every 2 Page 7 of 14 Dose Limit/ Maximum Dose RCC, HCC, melanoma: 480 mg/dose CRC, small bowel adenocarcinoma, pediatric (weighing < 40 kg) melanoma: 240 mg/dose

    CLINICAL POLICY Ipilimumab Drug Name Dosing Regimen Dose Limit/ Maximum Dose weeks or 480 mg every 4 weeks as a single agent until disease progression or unacceptable toxicity Pediatric weighing < 40 kg: nivolumab 1 mg/kg every 3 weeks for four doses in combination with ipilimumab 3 mg/kg every 3 weeks, then nivolumab 3 mg/kg every 3 weeks or 6 mg/kg mg every 6 weeks as a single agent until disease progression or unacceptable toxicity Melanoma Adult: 200 mg every 3 weeks or 400 mg every 6 weeks Pediatric: 2 mg/kg (up to 200 mg) every 3 weeks HCC 400 mg PO BID HCC 12 mg PO QD (patients ≥ 60 kg) or 8 mg PO QD (patients < 60 kg)
    HCC Tecentriq: 840 mg IV every 2 weeks, 1,200 mg IV every 3 weeks, or 1,680 mg IV every 4 weeks
    Bevacizumab: 15 mg/kg IV every 3 weeks HCC Varies NSCLC – squamous cell carcinoma paclitaxel + carboplatin
    dose varies NSCLC – nonsquamous cell carcinoma pemetrexed + [carboplatin or cisplatin]
    dose varies NSCLC Varies See regimen 800 mg/day 12 mg/day See regimen Varies Varies Varies Page 8 of 14 Keytruda (pembrolizumab) Nexavar (sorafenib) Lenvima (lenvatinib) Tecentriq (atezolizumab) + bevacizumab (Avastin®, Mvasi, Zirabev) Imfinzi (durvalumab)* platinum- containing regimens EGFR S768I, L861Q, and/or G719X targeted therapies: afatinib, osimertinib, erlotinib, gefitinib, dacomitinib

    CLINICAL POLICY Ipilimumab Drug Name Dosing Regimen NSCLC Varies ROS1 targeted therapies: crizotinib, entrectinib, ceritinib 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. *Off-label Appendix C: Contraindications and Boxed Warnings • Bristol-Myers Squibb was released from the REMS program for Yervoy in March 2015. • Boxed warning(s): none reported • Contraindication(s): none reported Appendix D: General Information
    • NCCN no longer recommends the use of Yervoy for the following indications:
    o Small cell lung cancer
    o Tumor mutation burden NSCLC o Cutaneous melanoma, as adjuvant systemic therapy in combination with Opdivo if no evidence of disease following metastasis-directed therapy or systemic therapy for oligometastatic disease
    o Colon cancer for patients who are not appropriate for intensive therapy
    • Per NCCN, contraindications for treatment with PD-1/PD-L1 inhibitors may include active or previously documented autoimmune disease and/or current use of immunosuppressive agents, or presence of an oncogene (i.e., EGFR exon 19 deletion or L858R, ALK rearrangements), which would predict lack of benefit. V. Dosage and Administration
    Indication Melanoma (adjuvant treatment) Melanoma (unresectable or metastatic) RCC Dosing Regimen 10 mg/kg IV every 3 weeks for 4 doses, followed by 10 mg/kg every 12 weeks for up to 3 years or until documented disease recurrence or unacceptable toxicity. Monotherapy: 3 mg/kg IV every 3 weeks for a total of 4 doses Maximum Dose 10 mg/kg/dose 3 mg/kg/dose In combination with nivolumab: 3 mg/kg every 3 weeks with nivolumab 1 mg/kg for a maximum of 4 doses or until unacceptable toxicity, whichever occurs earlier. Nivolumab 3 mg/kg IV, followed by ipilimumab 1 mg/kg IV on the same day, every 3 weeks for a 1 mg/kg/dose Page 9 of 14

    CLINICAL POLICY Ipilimumab Indication CRC HCC NSCLC Malignant pleural mesothelioma ESCC Dosing Regimen maximum of 4 doses, then nivolumab 240 mg IV every 2 weeks or 480 mg IV every 4 weeks Nivolumab 3 mg/kg IV, followed by ipilimumab 1 mg/kg IV on the same day, every 3 weeks for a maximum of 4 doses or until intolerable toxicity or disease progression, then nivolumab 240 mg IV every 2 weeks or 480 mg IV every 4 weeks Nivolumab 1 mg/kg IV, followed by ipilimumab 3 mg/kg IV on the same day, every 3 weeks for a maximum of 4 doses, then nivolumab 240 mg IV every 2 weeks or 480 mg IV every 4 weeks In combination with nivolumab: nivolumab 3 mg/kg IV every 2 weeks and ipilimumab 1 mg/kg IV every 6 weeks until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression In combination with nivolumab and platinum- doublet chemotherapy: nivolumab 360 mg IV every 3 weeks and ipilimumab 1 mg/kg IV every 6 weeks and histology-based platinum-doublet chemotherapy every 3 weeks for 2 cycles until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression 1 mg/kg every 6 weeks with nivolumab 360 mg every 3 weeks until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression. 1 mg/kg every 6 weeks with nivolumab 3 mg/kg every 2 weeks or 360 mg every 3 weeks until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression. Maximum Dose 1 mg/kg/dose 3 mg/kg/dose 1 mg/kg/dose 1 mg/kg/dose 1 mg/kg/dose VI. Product Availability
    Single-use vials: 50 mg/10 mL, 200 mg/40 mL VII.