STIVARGA, Regorafenib Form

Regorafenib (Stivarga®) is a kinase/vascular endothelial growth factor receptor (VEGFR) inhibitor. FDA Approved Indication(s) Stivarga is indicated for treatment of patients with: • Metastatic colorectal cancer (CRC) who have been previously treated with fluoropyrimidine, oxaliplatin and irinotecan-based chemotherapy, an anti-vascular endothelial growth factor (VEGF) therapy, and, if RAS wild-type, an anti-epidermal growth factor receptor (EGFR) therapy.
• Locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate and sunitinib malate.
• Hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. 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 Stivarga is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Colorectal Cancer (must meet all):

1. Diagnosis of advanced or metastatic CRC;
   2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. Previously treated with systemic chemotherapy (see Appendix B);
   5. Prescribed as a single agent therapy;
   6. For brand Stivarga requests, member must use generic regorafenib, if available, unless contraindicated or clinically significant adverse effects are experienced;

2. Request meets one of the following (a or b): a. Dose does not exceed 160 mg per day on days 1 to 21 of each 28-day cycle; 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 Page 1 of 9

   CLINICAL POLICY Regorafenib Commercial – 12 months or duration of request, whichever is less B. Gastrointestinal Stromal Tumor (must meet all):

3. Diagnosis of GIST;
   
   2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. Request is for one of the following (a, b, or c): a. As single-agent therapy for locally advanced, unresectable, recurrent, progressive, or metastatic disease previously treated with imatinib (Gleevec®) and Sutent®, unless clinically significant adverse effects are experienced or both are contraindicated; b. In combination with everolimus for unresectable, recurrent, progressive, or metastatic disease after progression on approved therapies (i.e., imatinib, Sutent or Sprycel®, and Qinlock®) (off-label); c. SDH mutation positive disease as a single agent therapy (off-label); Prior authorization may be required
4. For brand Stivarga requests, member must use generic regorafenib, if available, unless contraindicated or clinically significant adverse effects are experienced;
5. Request meets one of the following (a or b): a. Dose does not exceed 160 mg per day on days 1 to 21 of each 28-day cycle; 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 – 12 months or duration of request, whichever is less C. Hepatocellular Carcinoma (must meet all):
6. Diagnosis of HCC;
   2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. Prescribed as a single agent therapy;
   5. Prescribed as a second or subsequent-line therapy (see Appendix B);
   6. Member has Child-Pugh class A disease (see Appendix D);
   7. For brand Stivarga requests, member must use generic regorafenib, 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 160 mg per day on days 1 to 21 of each 28-day cycle; 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 – 12 months or duration of request, whichever is less D. Soft Tissue Sarcoma (off-label) (must meet all):

8. Diagnosis of one of the following soft tissue sarcomas (a, b, or c): Page 2 of 9

   CLINICAL POLICY Regorafenib a. Non-adipocytic sarcoma as subsequent therapy for advanced, metastatic, recurrent unresectable or recurrent stage IV disease;
   b. Pleomorphic rhabdomyosarcoma that is advanced or metastatic; c. Angiosarcoma;

9. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. Prescribed as a single agent therapy;
   5. For brand Stivarga requests, member must use generic regorafenib, if available, unless contraindicated or clinically significant adverse effects are experienced;
10. Request meets one of the following (a or b): a. Dose does not exceed 160 mg per day on days 1 to 21 of each 28-day cycle; 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 – 12 months or duration of request, whichever is less E. Bone Cancer (off-label) (must meet all):
11. Diagnosis of osteosarcoma;
    2. Prescribed by or in consultation with an oncologist;
    3. Age ≥ 18 years;
    4. Request is for second-line therapy for relapsed/refractory or metastatic disease (see Appendix D);
12. Prescribed as a single agent therapy;
    6. For brand Stivarga requests, member must use generic regorafenib, if available, unless contraindicated or clinically significant adverse effects are experienced;
13. Request meets one of the following (a or b): a. Dose does not exceed 160 mg per day on days 1 to 21 of each 28-day cycle; 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 – 12 months or duration of request, whichever is less F. Glioblastoma (off-label) (must meet all):
14. Diagnosis of glioblastoma;
    2. Prescribed by or in consultation with an oncologist;
    3. Age ≥ 18 years;
    4. Request is for recurrent disease;
    5. Prescribed as a single agent therapy;
    6. For brand Stivarga requests, member must use generic regorafenib, if available, unless contraindicated or clinically significant adverse effects are experienced;

15. Request meets one of the following (a or b):* a. Dose does not exceed 160 mg per day on days 1 to 21 of each 28-day cycle; Page 3 of 9

    CLINICAL POLICY Regorafenib 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 – 12 months or duration of request, whichever is less G. Other diagnoses/indications (must meet 1 or 2):

16. 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
17. 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 (must meet all):
18. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Stivarga for a covered indication and has received this medication for at least 30 days;
19. Member is responding positively to therapy;
    3. For brand Stivarga requests, member must use generic regorafenib, if available, unless contraindicated or clinically significant adverse effects are experienced;
20. If request is for a dose increase, request meets one of the following (a or b): a. New dose does not exceed 160 mg per day on days 1 to 21 of each 28-day cycle; 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 – 12 months or duration of request, whichever is less B. Other diagnoses/indications (must meet 1 or 2):

21. 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): Page 4 of 9

    CLINICAL POLICY Regorafenib 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

22. 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 CRC: colorectal cancer EGFR: epidermal growth factor receptor FDA: Food and Drug Administration GIST: gastrointestinal stromal tumor HCC: hepatocellular carcinoma VEGF: vascular endothelial growth factor VEGFR: vascular endothelial growth factor receptor
    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 Dosing Regimen Dose Limit/ Maximum Dose Colorectal Cancer (CRC): Examples of Systemic Chemotherapy 5-FU (fluorouracil)† Varies upon protocol and patient tolerance Avastin® (bevacizumab) Varies upon protocol and patient tolerance Camptosar® (irinotecan) Varies upon protocol and patient tolerance Cyramza® Varies upon protocol and patient tolerance (ramucirumab) Eloxatin® (oxaliplatin) Erbitux® (cetuximab)
    Lonsurf® (trifluridine and tipiracil) Varies upon protocol and patient tolerance Varies upon protocol and patient tolerance 35 mg/m2/dose by mouth (PO) twice daily (BID) on Days 1 through 5 and Days 8 through 12 of each 28-day cycle. Varies upon protocol and patient tolerance Vectibix® (panitumumab) Varies 70 mg/m2/day Varies Page 5 of 9

    CLINICAL POLICY Regorafenib Drug Dosing Regimen Xeloda® (capecitabine)† 1250 mg/m2 PO BID for 2 weeks followed by a 1-week rest period given as 3-week cycles. Varies upon protocol and patient tolerance Zaltrap® (ziv- aflibercept) FOLFOX CAPEOX FOLFIRI FOLFOXIRI IROX imatinib (Gleevec®) Sutent® (sunitinib) Varies upon protocol and patient tolerance Varies upon protocol and patient tolerance Varies upon protocol and patient tolerance Varies upon protocol and patient tolerance Varies upon protocol and patient tolerance Gastrointestinal Stromal Tumor (GIST) 400 mg PO daily up to 400 mg PO BID 50 mg PO daily for 4 weeks followed by 2 weeks off Dose Limit/ Maximum Dose 2500/m2/day Varies 800 mg/day 87.5 mg/day 400 mg PO BID 8-12 mg PO QD Varies Hepatocellular Carcinoma (HCC): Examples of Preferred First-line Systemic Therapy 800 mg/day 12 mg/day Varies Nexavar® (sorafenib) Lenvima® (lenvatinib) Tecentriq® (atezolizumab) + bevacizumab 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. FOLFOX: oxaliplatin, leucovorin, fluorouracil (5-FU); CAPEOX: oxaliplatin, capecitabine (Xeloda); FOLFIRI: irinotecan, leucovorin, 5-FU; FOLFOXIRI: irinotecan, oxaliplatin, leucovorin, 5-FU; IROX: oxaliplatin, irinotecan †Examples of fluoropyrimidines include fluorouracil (5-FU) and capecitabine (Xeloda). Appendix C: Contraindications/Boxed Warnings • Contraindication(s): none reported • Boxed warning(s): hepatotoxicity
    Appendix D: General Information • First-line Therapies for Osteosarcoma per NCCN o Preferred regimens: cisplatin and doxorubicin, MAP (high-dose methotrexate, cisplatin, and doxorubicin) o Other recommended regimen: doxorubicin, cisplatin, ifosfamide, and high-dose methotrexate • Child-Pugh Score Bilirubin Albumin INR 1 Point Less than 2 mg/dL Less than 34 umol/L Over 3.5 g/dL Over 35 g/L Less than 1.7 2 Points 2-3 mg/dL 34-50 umol/L 2.8-3.5 g/dL 28-35 g/L 1.7 - 2.2 3 Points Over 3 mg/dL Over 50 umol/L Less than 2.8 g/dL Less than 28 g/L Over 2.2 Page 6 of 9

    CLINICAL POLICY Regorafenib 1 Point Ascites None Encephalopathy None 2 Points Mild / medically controlled Mild / medically controlled Grade I-II 3 Points Moderate-severe / poorly controlled Moderate-severe / poorly controlled. Grade III-IV Child-Pugh class is determined by the total number of points: A = 5-6 points; B = 7-9 points; C = 10-15 points V. Dosage and Administration
    Indication CRC, GIST, HCC 160 mg PO QD for the first 21 days of each 28- Dosing Regimen Maximum Dose 160 mg/day day cycle VI. Product Availability
    Tablet: 40 mg VII.