COMETRIQ, Cabozantinib S-Malate CABOMETYX, Cabozantinib S-Malate Form

Cabozantinib (Cabometyx®, Cometriq®) is a kinase inhibitor. FDA Approved Indication(s) Cabometyx is indicated for the treatment of:
• Patients with advanced renal cell carcinoma (RCC) • Patients with advanced renal cell carcinoma, as a first-line treatment in combination with nivolumab • Patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib • Adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible. Cometriq is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). 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 Cabometyx and Cometriq are medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Renal Cell Carcinoma (must meet all):

1. Request is for Cabometyx;
   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 Cabometyx request, member must use cabozantinib, if available, unless contraindicated or clinically significant adverse effects are experienced;

2. Request meets one of the following (a, b, c, or d):* a. For monotherapy, dose does not exceed both of the following (i and ii): i. 60 mg per day; ii. 1 tablet per day; Page 1 of 10

   CLINICAL POLICY Cabozantinib b. For use in combination with Opdivo, dose does not exceed both of the following (i and ii): i. 40 mg per day; ii. 1 tablet per day; c. Documentation that member is concurrently taking a strong CYP3A4 inducer (see Appendix D) and dose does not exceed both of the following (i and ii): i. 80 mg per day; ii. 2 tablets per day; d. 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 B. Hepatocellular Carcinoma (must meet all):

3. Request is for Cabometyx;
   2. Diagnosis of unresectable, inoperable, or metastatic HCC;
   3. Prescribed by or in consultation with an oncologist;
   4. Age ≥ 18 years;
   5. Prescribed as subsequent-line therapy;
   6. Prescribed as a single-agent therapy;
   7. For Cabometyx request, member must use cabozantinib, if available, unless contraindicated or clinically significant adverse effects are experienced;
4. Confirmation of Child-Pugh class A status;
   9. Request meets one of the following (a, b, or c): a. Dose does not exceed both of the following (i and ii): i. 60 mg per day; ii. 1 tablet per day;
      b. Documentation that member is concurrently taking a strong CYP3A4 inducer (see Appendix D) and dose does not exceed both of the following (i and ii): i. 80 mg per day; ii. 2 tablets per day; 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:
      Medicaid/HIM – 6 months Commercial – 12 months or duration of request, whichever is less C. Thyroid Carcinoma (must meet all):
5. Diagnosis of one of the following (a or b): a. Recurrent, unresectable, progressive, or metastatic medullary thyroid carcinoma (MTC); b. Locally advanced, unresectable, or metastatic DTC (i.e., follicular, oncocytic [formerly known as Hurthle cell], or papillary thyroid carcinoma);

6. Prescribed by or in consultation with an oncologist; Page 2 of 10

   CLINICAL POLICY Cabozantinib

7. Request is for one of the following (a or b): a. If MTC, request is for Cometriq; b. If DTC, request is for either Cabometyx or Cometriq;
8. Member meets one of the following (a or b): a. For Cabometyx request, age ≥ 12 years; b. For Cometriq request, age ≥ 18 years
9. Prescribed as single-agent therapy;
   6. For Cabometyx or Cometriq requests, member must use cabozantinib, if available, unless contraindicated or clinically significant adverse effects are experienced;
10. If DTC, both of the following are met (a and b): a. Failure of Lenvima® and/or sorafenib unless contraindicated or clinically significant adverse effects are experienced; Prior authorization may be required. b. Disease is not amenable (e.g., iodine-refractory or ineligible) to radioactive iodine therapy;
11. Request meets one of the following (a, b, or c):* a. For Cabometyx, one of the following (i, ii, or iii): i. BSA is ≥ 1.2 m2 and dose does not exceed both (1 and 2):
12. 60 mg per day;
    2. 1 tablet per day; ii. BSA is < 1.2 m2 and dose does not exceed both (1 and 2)
13. 40 mg per day;
    2. 1 tablet per day; iii. Documentation that member is concurrently taking a strong CYP3A4 inducer (see Appendix D) and dose does not exceed both of the following (1 and 2):
    3. 80 mg per day;
    4. 2 tablets per day; b. For Cometriq, one of the following: i. Dose does not exceed both (1 and 2):
14. 140 mg per day;
    2. 4 capsules per day ii. Documentation that member is concurrently taking a strong CYP3A4 inducer (see Appendix D) and dose does not exceed both (1 and 2):
    3. 180 mg per day;
    4. 3 capsules per day 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:
       Medicaid/HIM – 6 months Commercial – 12 months or duration of request, whichever is less D. Non-Small Cell Lung Cancer (off-label) (must meet all):

15. Diagnosis of non-small cell lung cancer (NSCLC) that is both of the following (a and b): a. Recurrent, advanced or metastatic; b. Positive for RET gene rearrangement; Page 3 of 10

    CLINICAL POLICY Cabozantinib

16. Prescribed by or in consultation with an oncologist;
    3. Age ≥ 18 years;
    4. Prescribed as single-agent therapy;
    5. For Cabometyx or Cometriq requests, member must use cabozantinib, if available, unless contraindicated or clinically significant adverse effects are experienced;
17. 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/HIM – 6 months Commercial – 12 months or duration of request, whichever is less E. Additional NCCN Recommended Uses (off-label) (must meet all):
18. Request is for Cabometyx;
    2. Diagnosis of one of the following (a, b, or c): a. Gastrointestinal stromal tumor (GIST); b. Recurrent or metastatic endometrial carcinoma; c. Bone cancer identified as one of the following (i or ii): i. Ewing sarcoma; ii. Osteosarcoma;
19. Prescribed by or in consultation with an oncologist;
    4. Age ≥ 18 years;
    5. For GIST: Prescribed for unresectable, recurrent, or metastatic disease as both (a and b): a. Single-agent therapy; b. Subsequent therapy;
20. For endometrial carcinoma and bone cancer: Prescribed as single-agent second-line therapy;
21. For Cabometyx requests, member must use cabozantinib, if available, unless contraindicated or clinically significant adverse effects are experienced;
22. 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/HIM – 6 months Commercial – 12 months or duration of request, whichever is less F. Other diagnoses/indications (must meet 1 or 2):

23. 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 Page 4 of 10

    CLINICAL POLICY Cabozantinib 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

24. 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):
25. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Cabometyx or Cometriq for a covered indication and has received this medication for at least 30 days;
26. Member is responding positively to therapy;
    3. For Cabometyx or Cometriq requests, member must use cabozantinib, if available, unless contraindicated or clinically significant adverse effects are experienced;
    4. If request is for a dose increase, request meets one of the following (a, b, or c):* a. For Cabometyx, one of the following: i. For monotherapy, dose does not exceed both of the following(1 and 2):
27. 60 mg per day;
    2. 1 tablet per day; ii. For use in combination with Opdivo, dose does not exceed both of the following (1 and 2):
    3. 40 mg per day;
    4. 1 tablet per day; iii. Documentation that member is concurrently taking a strong CYP3A4 inducer (see Appendix D) and dose does not exceed both (1 and 2):
    5. 80 mg per day;
    6. 2 tablets per day b. For Cometriq, one of the following:
       i. Dose does not exceed both (1 and 2):

28. 140 mg per day;

    2. 4 capsules per day; ii. Documentation that member is concurrently taking a strong CYP3A4 inducer (see Appendix D) and dose does not exceed both (1 and 2):
    3. 180 mg per day;
    4. 3 capsules per day; 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:
       Medicaid/HIM – 12 months
       Commercial – 12 months or duration of request, whichever is less Page 5 of 10

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

29. 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

30. 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 DTC: differentiated thyroid carcinoma FDA: Food and Drug Administration
    GIST: gastrointestinal stromal tumor
    HCC: hepatocellular carcinoma MTC: medullary thyroid cancer NCCN: National Comprehensive Cancer Network NSCLC: non-small cell lung cancer RCC: renal cell carcinoma 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 sorafenib (Nexavar®) Lenvima® (lenvatinib) DTC, HCC: 400 mg PO BID DTC: 24 mg PO QD, HCC: 8-12 mg PO QD HCC: Varies 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. Varies Dose Limit/ Maximum Dose 800 mg/day 24 mg/day Page 6 of 10

    CLINICAL POLICY Cabozantinib Appendix C: Contraindications/Boxed Warnings None reported Appendix D: General Information • Cometriq capsules are not interchangeable with Cabometyx tablets. • Examples of strong CYP3A4 inducers: o Apalutamide o Carbamazepine o Enzalutamide o Fosphenytoin o Lumacaftor o Lumacaftor-ivacaftor o Mitotane o Phenobarbital o Phenytoin o Primidone o Rifampin (rifampicin) V. Dosage and Administration
    Drug Name Cabozantinib (Cabometyx)
    Indication Dosing Regimen HCC, RCC, DTC HCC, RCC monotherapy Monotherapy: 60 mg PO QD Strong CYP3A4 inhibitors: Reduce the daily cabozantinib dose by 20 mg Strong CYP3A4 inducers: Increase the daily cabozantinib dose by 20 mg RCC combination therapy
    40 mg PO QD with Opdivo (nivolumab) 240 mg IV every 2 weeks or 480 mg IV every 4 weeks DTC Adults and pediatric patients with BSA ≥ 1.2 m2: 60 mg PO QD Pediatric patients with BSA ≤ 1.2 m2: 40 mg PO QD 140 mg PO QD Strong CYP3A4 inhibitors: Reduce the daily cabozantinib dose by 40 mg Strong CYP3A4 inducers: Increase the daily cabozantinib dose by 40 mg Maximum Dose 80 mg/day 180 mg/day Cabozantinib (Cometriq) MTC VI. Product Availability
    Drug Name Cabometyx Cometriq Availability Tablets: 20 mg, 40 mg, 60 mg Capsules: 20 mg, 80 mg VII.