LENVIMA, Lenvatinib Mesylate Form

Lenvatinib (Lenvima®) is a kinase inhibitor. FDA Approved Indication(s) Lenvima is indicated: • For the treatment of patients with locally recurrent or metastatic, progressive, radioactive • • iodine-refractory differentiated thyroid cancer (DTC). In combination with pembrolizumab, for the first line treatment of adult patients with advanced renal cell carcinoma (RCC). In combination with everolimus, for the treatment of patients with advanced RCC following one prior anti-angiogenic therapy. • For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). • In combination with pembrolizumab, for the treatment of patients with advanced endometrial carcinoma (EC) that is mismatch repair proficient (pMMR), as determined by an FDA- approved test, or not microsatellite instability-high (MSI-H), who have disease progression following prior systemic therapy in any setting and are not candidates for curative surgery or radiation.
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 Lenvima is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Differentiated Thyroid Cancer (must meet all):

1. Diagnosis of DTC (i.e., papillary, follicular, or Hürthle cell carcinoma);
   2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. Disease is radioactive iodine-refractory and recurrent, metastatic, or progressive;
   5. For brand Lenvima requests, member must use generic lenvatinib, 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 both of the following (i and ii):
   i. 24 mg per day;
   ii. 3 capsules per day; Page 1 of 10

   CLINICAL POLICY Lenvatinib 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 B. Medullary Thyroid Carcinoma (off-label) (must meet all):

3. Diagnosis of medullary thyroid carcinoma (MTC), and both a and b: a. Disease is recurrent, progressive, or metastatic; b. Failure of Cometriq® or Caprelsa®, unless clinically significant adverse effects are experienced or both are contraindicated;Prior authorization may be required for Cometriq and Caprelsa.
4. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. For brand Lenvima requests, member must use generic lenvatinib, 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 both of the following (i and ii):
   i. 24 mg per day;
   ii. 3 capsules per day;
   b. 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 C. Renal Cell Carcinoma (must meet all):
6. Diagnosis of advanced RCC (i.e., relapsed, metastatic, or stage IV disease);
   2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. Lenvima is prescribed in one of the following ways (a or b): a. In combination with Keytruda®; b. In combination with Afinitor®, and: i. If RCC histology is clear cell or unknown, failure of a prior RCC therapy (see Appendix B), unless clinically adverse effects are experienced or all are contraindicated; Prior authorization may be required for prior RCC therapies Prior authorization may be required for Keytruda and Afinitor
7. For brand Lenvima requests, member must use generic lenvatinib, if available, unless contraindicated or clinically significant adverse effects are experienced;

8. Request meets one of the following (a, b, or c):* a. If prescribed in combination with Keytruda dose does not exceed both of the following (i and ii): i. 20 mg per day; Page 2 of 10

   CLINICAL POLICY Lenvatinib ii. 2 capsules per day; b. If prescribed in combination with Afinitor dose does not exceed both of the following (i and ii):
   i. 18 mg per day;
   ii. 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. Hepatocellular Carcinoma (must meet all):

9. Diagnosis of HCC;
   2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. Prescribed as single agent;
   5. For brand Lenvima requests, member must use generic lenvatinib, if available, unless contraindicated or clinically significant adverse effects are experienced;
10. Request meets one of the following (a, b, or c): a. For actual body weight ≥ 60 kg, dose does not exceed both of the following (i and ii):
    i. 12 mg per day;
    ii. 3 capsules per day;
    b. For actual body weight < 60 kg, dose does not exceed both of the following (i and ii):
    i. 8 mg per day;
    ii. 2 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 E. Endometrial Carcinoma (must meet all):
11. Diagnosis of EC;
    2. Prescribed by or in consultation with an oncologist;
    3. Age ≥ 18 years;
    4. Prescribed in combination with Keytruda; *Prior authorization may be required for Keytruda

12. Disease is pMMR or not MSI-H;

    6. Disease has progressed following prior systemic therapy (e.g., carboplatin/paclitaxel);
    7. Member is not a candidate for curative surgery or radiation;
    8. For brand Lenvima requests, member must use generic lenvatinib, if available, unless contraindicated or clinically significant adverse effects are experienced; Page 3 of 10

    CLINICAL POLICY Lenvatinib

13. Request meets one of the following (a or b): a. Dose does not exceed both of the following (i and ii):
    i. 20 mg per day; ii. 2 capsules per day; 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. Thymic Carcinomas (must meet all):
14. Diagnosis of thymic carcinoma (TC);
    
    2. Prescribed by or in consultation with an oncologist;
    3. Age ≥ 18 years;
    4. Disease is unresectable, locally advanced, or metastatic;
    5. Prescribed as single agent therapy for members who have not tolerated or responded to NCCN recommended agents (see Appendix B);
15. For brand Lenvima requests, member must use generic lenvatinib, if available, unless contraindicated or clinically significant adverse effects are experienced;
16. Request meets one of the following (a or b): a. Dose does not exceed both of the following (i and ii):
    i. 24 mg per day;
    ii. 3 capsules per day;
    b. 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 G. Cutaneous Melanoma (off-label) (must meet all):
17. Diagnosis of cutaneous melanoma;
    
    2. Prescribed by or in consultation with an oncologist;
    3. Age ≥ 18 years;
    4. Disease is metastatic or unresectable;
    5. Prescribed in combination with Keytruda; *Prior authorization may be required for Keytruda
18. Disease has progressed following treatment with an anti-PD-1/PD-L1-based therapy (e.g., Keytruda, Opdivo®);
19. For brand Lenvima requests, member must use generic lenvatinib, if available, unless contraindicated or clinically significant adverse effects are experienced;

20. Request meets one of the following (a or b):* a. Dose does not exceed both of the following (i and ii):
    i. 20 mg per day;
    ii. 2 capsules per day;
    Page 4 of 10

    CLINICAL POLICY Lenvatinib b. 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 H. 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): 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.
    II. Continued Therapy A. All Indications in Section I (must meet all):
23. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Lenvima for a covered indication and has received this medication for at least 30 days;
24. Member is responding positively to therapy;
    3. For brand Lenvima requests, member must use generic lenvatinib, if available, unless contraindicated or clinically significant adverse effects are experienced;

25. If request is for a dose increase, request meets one of the following (a, b, c, d, or e):* a. DTC, MTC, TC: New dose does not exceed both of the following (i and ii):
    i. 24 mg per day; ii. 3 capsules per day;
    b. RCC in combination with Afinitor: New dose does not exceed both of the following (i and ii): i. 18 mg per day;
    ii. 3 capsules per day;
    c. HCC: New dose does not exceed one of the following (i or ii):
    i. For actual body weight ≥ 60 kg (1 and 2):
    1) 12 mg per day;
    2) 3 capsules per day;
    Page 5 of 10

    CLINICAL POLICY Lenvatinib ii. For actual body weight < 60 kg (1 and 2): 1) 8 mg per day;
    2) 2 capsules per day; d. RCC in combination with Keytruda, EC, cutaneous melanoma: New dose does not exceed both of the following (i and ii): i. 20 mg per day; ii. 2 capsules per day; e. 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 After completing 2 years of combination therapy with Keytruda, Lenvima may be administered as a single agent until disease progression or until unacceptable toxicity 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):

26. 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

27. 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 cancer EC: endometrial carcinoma FDA: Food and Drug Administration HCC: hepatocellular carcinoma MSI-H: microsatellite instability-high
    MTC: medullary thyroid cancer NCCN: National Comprehensive Cancer Network
    pMMR: mismatch repair proficient RCC: renal cell carcinoma Page 6 of 10

    CLINICAL POLICY Lenvatinib TC: thymic 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 RCC: 10 mg PO QD RCC: varies Dose Limit/ Maximum Dose 10 mg/day Varies Afinitor (everolimus) RCC therapeutic agents: Avastin® (bevacizumab) Cabometyx® (cabozantinib) Keytruda® (pembrolizumab) Inlyta® (axitinib)
    Nexavar® (sorafenib) Opdivo® (nivolumab) Proleukin® (aldesleukin, rIL-2) Sutent® (sunitinib) Tarceva® (erlotinib) Torisel® (temsirolimus) Votrient® (pazopanib) Yervoy® (ipilimumab) Caprelsa® (vandetanib) Cometriq® (cabozantinib) EC systemic therapies: carboplatin/paclitaxel, cisplatin/docetaxel, cisplatin/doxorubicin, carboplatin/paclitaxel/bevacizumab, carboplatin/paclitaxel/trastuzumab, ifosfamide/paclitaxel, cisplatin/ifosfamide, everolimus/letrozole, temsirolimus, Keytruda (pembrolizumab) ____ Monotherapy treatment of combination regimens may also be used (refer to NCCN Uterine Neoplasms Guidelines) TC systemic therapies: carboplatin/paclitaxel
    Cutaneous Melanoma anti-PD- 1/PD-L1-based therapy:
    Keytruda (pembrolizumab), Opdivo (nivolumab) MTC: 300 mg PO QD MTC: 140 to 180 mg PO QD EC: varies 300 mg/day 180 mg/day Varies carboplatin AUC 6 mg/mL/min +
    paclitaxel 200 mg/m2 IV every 3 weeks Varies See dosing regimen Varies Page 7 of 10

    CLINICAL POLICY Lenvatinib 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 Dosing Regimen DTC EC RCC 24 mg PO QD In combination with Keytruda: 20 mg PO QD In combination with Keytruda: 20 mg PO QD. After completing 2 years of combination therapy, Lenvima may be administered as a single agent until disease progression or until unacceptable toxicity Maximum Dose 24 mg/day 20 mg/day With Keytruda: 20 mg/day With Afinitor: 18 mg/day
    HCC In combination with Afinitor: 18 mg PO QD 12 mg PO QD (if actual body weight ≥ 60 kg) or 8 mg PO QD (if actual body weight < 60 kg) 12 mg/day
    VI. Product Availability
    Capsules: 4 mg, 10 mg VII.