ZALTRAP, Ziv-Aflibercept Form

Ziv-aflibercept (Zaltrap®) is a vascular endothelial growth factor (VEGF) inhibitor. FDA Approved Indication(s) Zaltrap, in combination with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI), is indicated for patients with metastatic colorectal cancer (CRC) that is resistant to or has progressed following an oxaliplatin-containing regimen. 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 Zaltrap is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Colorectal Cancer (must meet all):

1. Diagnosis of advanced, unresectable, or metastatic CRC;

   2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. Previous treatment with one of the following (a, b, or c): a. An oxaliplatin-containing regimen (e.g., FOLFOX, CapeOX); b. A 5-fluorouracil and leucovorin-containing regimen (off-label); c. A capecitabine-containing regimen (off-label);
   5. Prescribed in combination with irinotecan or FOLFIRI;
   6. Request meets one of the following (a or b): a. Dose does not exceed 4 mg/kg every 2 weeks; 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/HIM – 6 months
      Commercial – 6 months or to the member’s renewal date, whichever is longer Page 1 of 6

   CLINICAL POLICY
   Ziv-aflibercept B. Other diagnoses/indications (must meet 1 or 2):

2. 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
3. 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. Colorectal Cancer (must meet all):
4. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Zaltrap for a covered indication and has received this medication for at least 30 days;
5. Member is responding positively to therapy;
   3. If request is for a dose increase, request meets one of the following (a or b): a. New dose does not exceed 4 mg/kg every 2 weeks; 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/HIM – 12 months Commercial – 6 months or to the member’s renewal date, whichever is longer B. Other diagnoses/indications (must meet 1 or 2):

6. 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 2 of 6

   CLINICAL POLICY
   Ziv-aflibercept

7. 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 CapeOX: capecitabine and oxaliplatin CRC: colorectal cancer FDA: Food and Drug Administration FOLFIRI: fluorouracil, leucovorin, irinotecan FOLFOX: fluorouracil, leucovorin, oxaliplatin VEGF: vascular endothelial growth factor 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 Dose Limit/ Maximum Dose See dosing regimen See dosing regimen See dosing regimen See dosing regimen Modified FOLFOX 6 CapeOX FOLFIRI 5-fluorouracil and leucovorin Day 1: oxaliplatin 85 mg/m2 IV Day 1: Folinic acid 400 mg/m2 IV Days 1–3: 5-FU 400 mg/m2 IV bolus on day 1, then 1,200 mg/m2/day × 2 days (total 2,400 mg/m2 over 46–48 hours) IV continuous infusion. Repeat cycle every 2 weeks. Day 1: Oxaliplatin 130 mg/m2 IV Days 1–14: Capecitabine 1,000 mg/m2 PO BID. Repeat cycle every 3 weeks. Day 1: Irinotecan 180 mg/m2 IV Day 1: Leucovorin 400 mg/m2 IV Day 1: Fluorouracil 400 mg/m2 IV followed by 2400 mg/m2 continuous IV over 46 hours Repeat cycle every 14 days. Roswell Park regimen: Leucovorin 500 mg/m2 IV followed by 5-FU 500 mg/m2 IV bolus one hour after start of leucovorin on days 1, 8, 15, 22, 29, 36. Repeat every 8 weeks. Page 3 of 6

   CLINICAL POLICY
   Ziv-aflibercept Drug Name Dosing Regimen Biweekly regimen:
   Leucovorin 400 mg/m2 IV on day one followed by 5-FU 400 mg/m2 IV bolus then 1,200 mg/m2 continuous IV. Repeat every 2 weeks. Weekly regimen:
   Leucovorin 20 mg/m2 IV on day one followed 5- FU 500 mg/m2 IV bolus one hour after start of leucovorin. Alternatively 5-FU 2,600 mg/m2 continuous IV with leucovorin 500 mg/m2 IV. Repeat weekly. 850 – 1,250 mg/m2 PO BID on days 1-14. Repeat every 3 weeks. capecitabine Dose Limit/ Maximum Dose 2,500 mg/m2/day 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 V. Dosage and Administration
   Indication CRC Dosing Regimen 4 mg/kg IV over 1 hour every two weeks Maximum Dose 4 mg/kg VI. Product Availability
   Single-use vials for injection: 100 mg/4 mL, 200 mg/8 mL VII.