CYRAMZA, Ramucirumab Form

Ramucirumab (Cyramza®) is a human vascular endothelial growth factor receptor 2 (VEGFR2) antagonist. • FDA Approved Indication(s) Cyramza is indicated: • As a single agent or in combination with paclitaxel, for treatment of advanced or metastatic gastric or gastro-esophageal junction (i.e., esophagogastric junction; EGJ) adenocarcinoma, with disease progression on or after prior fluoropyrimidine- or platinum-containing chemotherapy. In combination with erlotinib, for first-line treatment of metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) mutations. In combination with docetaxel, for treatment of metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving Cyramza. In combination with FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil), for the treatment of metastatic colorectal cancer (CRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. • • • As a single agent, for the treatment of hepatocellular carcinoma (HCC) in patients who have an alpha fetoprotein (AFP) of ≥ 400 ng/mL and have been treated with sorafenib.
Policy/Criteria Provider must submit documentation (including 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 Cyramza is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Esophageal, Esophagogastric Junction, and Gastric Cancer (must meet all):

1. Diagnosis of esophageal, EGJ or gastric cancer;

   2. Disease is unresectable, locally advanced, recurrent, or metastatic;
   3. Prescribed by or in consultation with an oncologist;
   4. Age ≥ 18 years; Page 1 of 9

   CLINICAL POLICY Ramucirumab

2. Prescribed as subsequent therapy in one of the following ways (a, b, or c):
   a. As a single agent; b. In combination with paclitaxel; c. In combination with irinotecan with or without fluorouracil; Prior authorization may be required for paclitaxel, fluorouracil or irinotecan.
3. Request meets one of the following (a or b): a. Dose does not exceed 8 mg per 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: 6 months B. Non-Small Cell Lung Cancer (must meet all):
4. Diagnosis of metastatic, recurrent, or advanced NSCLC;
   2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. Request meets one of the following (a or b): a. Prescribed as subsequent therapy in combination with docetaxel; b. Prescribed in combination with erlotinib (Tarceva®); Prior authorization may be required for docetaxel or erlotinib
5. If prescribed in combination with erlotinib, disease is positive for a sensitizing EGFR mutation (e.g., EGFR exon 19 deletions or exon 21 [L858R] substitution mutation);
6. Request meets one of the following (a, b, or c): a. In combination with docetaxel: dose does not exceed 10 mg/kg on day 1 of a 21- day cycle; b. In combination with erlotinib: dose does not exceed 10 mg/kg on day 1 every 2 weeks; 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 C. Colorectal Cancer (must meet all):
7. Diagnosis of advanced or metastatic CRC;
   2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. Prescribed in combination with irinotecan or FOLFIRI (irinotecan, folinic acid, and 5-fluorouracil);Prior authorization may be required for irinotecan or FOLFIRI.

8. Request meets one of the following (a or b): a. Dose does not exceed 8 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: 6 months Page 2 of 9

   CLINICAL POLICY Ramucirumab D. Hepatocellular Carcinoma (must meet all):

9. Diagnosis of HCC;
   2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. AFP ≥ 400 ng/mL;
   5. Disease has progressed on or after therapy with sorafenib;Prior authorization may be required for sorafenib
10. Prescribed as single-agent therapy;
    7. Confirmation of Child-Pugh class A status;
    8. Request meets one of the following (a or b): a. Dose does not exceed 8 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: 6 months E. Mesothelioma (off-label) (must meet all):
11. Diagnosis of mesothelioma classified as one of the following: a. Pleural; b. Pericardial; c. Tunica vaginalis testis;
12. Prescribed by or in consultation with an oncologist;
    3. Age ≥ 18 years;
    4. Prescribed in combination with gemcitabine;Gemcitabine may require prior authorization
13. Prescribed as subsequent therapy;
    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: 6 months F. Other diagnoses/indications (must meet 1 or 2):
14. 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

15. 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 Page 3 of 9

    CLINICAL POLICY Ramucirumab 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 (must meet all):

16. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Cyramza for a covered indication and has received this medication for at least 30 days;
17. Member is responding positively to therapy;
    3. If request is for a dose increase, request meets one of the following (a, b, c, or d): a. Esophageal/EGJ/gastric cancer, CRC, HCC: new dose does not exceed 8 mg/kg every 2 weeks; b. NSCLC in combination with docetaxel: new dose does not exceed 10 mg/kg on day 1 of a 21-day cycle; c. NSCLC in combination with erlotnib: new dose does not exceed 10 mg/kg every 2 weeks; d. 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):
18. 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

19. 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 policy – CP.CPA.09 for commercial, HIM.PA.154 for health insurance marketplace, and CP.PMN.53 for Medicaid, or evidence of coverage documents. Page 4 of 9

    CLINICAL POLICY Ramucirumab IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key AFP: alpha fetoprotein CRC: colorectal carcinoma EGJ: esophagogastric junction
    EGFR: epidermal growth factor receptor FDA: Food and Drug Administration HCC: hepatocellular carcinoma FOLFIRI: fluorouracil, leucovorin, irinotecan
    NCCN: National Comprehensive Cancer Network NSCLC: non-small cell lung cancer VEGFR2: vascular endothelial growth factor receptor 2
    Dose Limit/ Maximum Dose Varies 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 Dosing Regimen Varies 150 mg/day Varies Esophageal, EGF, or gastric cancer: Varies NSCLC: Varies NSCLC: 150 mg PO QD CRC: Varies docetaxel, paclitaxel, irinotecan, 5-FU docetaxel (Taxotere®) erlotinib (Tarceva®) irinotecan (Camptosar®), FOLFIRI (5-FU, leucovorin, irinotecan), FOLFOX (5-FU, leucovorin, oxaliplatin), CAPEOX (capecitabine, oxaliplatin) sorafenib (Nexavar®) cisplatin + pemetrexed ± bevacizumab, Opdivo® (nivolumab)/Yervoy® (ipilimumab), cisplatin + gemcitabine 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. HCC: 400 mg PO BID Mesothelioma: Varies 800 mg/day Varies Appendix C: Contraindications/Boxed Warnings None reported V. Dosage and Administration
    Indication Gastric or EGJ adenocarcinoma
    NSCLC Dosing Regimen 8 mg/kg IV every 2 weeks as a single agent or in combination with weekly paclitaxel 10 mg/kg IV on day 1 of a 21-day cycle prior to docetaxel Maximum Dose 8 mg/kg 10 mg/kg Page 5 of 9

    CLINICAL POLICY Ramucirumab Indication CRC HCC Dosing Regimen 10 mg/kg IV every 2 weeks with daily erlotinib 8 mg/kg IV every 2 weeks prior to FOLFIRI 8 mg/kg IV every 2 weeks Maximum Dose 8 mg/kg 8 mg/kg VI. Product Availability
    Single-dose vial: 100 mg/10 mL (10 mg/mL) solution, 500mg/50mL (10mg/mL) solution VII.