Trifluridine/Tipiracil (Lonsurf) Form

Trifluridine/tipiracil (Lonsurf®) is a combination of trifluridine, a nucleoside metabolic inhibitor, and tipiracil, a thymidine phosphorylase inhibitor. FDA Approved Indication(s) Lonsurf is indicated for the treatment of adult patients with: • Metastatic colorectal cancer (CRC) as a single agent or in combination with bevacizumab who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-vascular endothelial growth factor (VEGF) biological therapy, and if RAS wild-type, an anti-epidermal growth factor receptor (EGFR) therapy; • Metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma previously treated with at least two prior lines of chemotherapy that included a fluoropyrimidine, a platinum, either a taxane or irinotecan, and if appropriate, HER2/neu-targeted therapy.
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 Lonsurf is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Colorectal Cancer (must meet all):

1. Diagnosis of metastatic or advanced CRC (including appendiceal adenocarcinoma);

   2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. Documentation of RAS (KRAS or NRAS) wild-type gene status;
   5. Member has progressed through all available regimens for CRC that include all the following agents, unless clinically significant adverse effects are experienced or all are contraindicated: a. 5-fluorouracil or capecitabine; b. Oxaliplatin and irinotecan; c. An anti-VEGF agent: bevacizumab, Cyramza®, Stivarga®, or Zaltrap®; d. If tumor expresses the RAS wild-type gene, an anti-EGFR agent: Erbitux® or Vectibix®; Prior authorization may be required. Page 1 of 10

   CLINICAL POLICY Trifluridine/Tipiracil

2. For brand Lonsurf requests, member must use generic trifluridine/tipiracil, if available, unless contraindicated or clinically significant adverse effects are experienced;
3. Prescribed as a single agent or in combination with bevacizumab; Prior authorization may be required
4. Documentation of member’s body surface area (m2);
   9. Request meets one of the following (a or b): a. Dose does not exceed 70 mg/m2 per day up to a maximum of 160 mg per day (based on the trifluridine component; round dose to the nearest 5 mg increment given 15 and 20 mg tablets) on Days 1 through 5 and 8 through 12 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 B. Gastric Cancer or Gastroesophageal Junction Adenocarcinoma (must meet all):
5. Diagnosis of gastric cancer (GC) or GEJ adenocarcinoma;
   2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. One of the following (a or b): a. Disease is metastatic, advanced, unresectable, or recurrent; b. Member is not a candidate for surgery;
   5. Documentation of HER2/neu gene status;
   6. Member has previously been treated with at least two prior lines of chemotherapy that include all of the following agents, unless contraindicated or clinically significant adverse effects are experienced (a, b, and c): a. 5-fluorouracil or capecitabine;
      b. Cisplatin, carboplatin, or oxaliplatin; c. Docetaxel, paclitaxel, or irinotecan; Prior authorization may be required.
6. If tumor is HER2/neu-positive (i.e., HER2-overexpressing): Failure of trastuzumab, unless contraindicated or clinically significant adverse effects are experienced; *Prior authorization may be required for trastuzumab.
7. For brand Lonsurf requests, member must use generic trifluridine/tipiracil, if available, unless contraindicated or clinically significant adverse effects are experienced;

8. Prescribed as a single agent;

   10. Documentation of member’s body surface area (m2);
   11. Request meets one of the following (a or b):* a. Dose does not exceed 70 mg/m2 per day up to a maximum of 160 mg per day (based on the trifluridine component; round dose to the nearest 5 mg increment given 15 and 20 mg tablets) on Days 1 through 5 and 8 through 12 of each 28-day cycle; Page 2 of 10

   CLINICAL POLICY Trifluridine/Tipiracil 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. Other diagnoses/indications (must meet 1 or 2):

9. 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
10. 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):
11. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Lonsurf for a covered indication and has received this medication for at least 30 days;
12. Member is responding positively to therapy;
    
    3. For brand Lonsurf requests, member must use generic trifluridine/tipiracil, if available, unless contraindicated or clinically significant adverse effects are experienced;

13. Documentation of member’s body surface area (m2);

    5. If request is for a dose increase, request meets one of the following (a or b): a. New dose does not exceed 70 mg/m2 per day up to a maximum of 160 mg per day (based on the trifluridine component) on Days 1 through 5 and 8 through 12 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 Page 3 of 10

    CLINICAL POLICY Trifluridine/Tipiracil B. 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 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 5-FU: 5-fluorouracil CRC: colorectal carcinoma
    EGFR: epidermal growth factor receptor FDA: Food and Drug Administration GC: gastric cancer GEJ: gastroesophageal junction 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 for all relevant lines of business and may require prior authorization.
    Drug Name Dosing Regimen Dose Limit/ Maximum Dose Fluoropyrimidine, platinum, and irinotecan therapeutic agents and examples of regimens 5 FU (fluorouracil)* CRC 2,400 mg/m2
    400 mg/m2 IV on day 1, 1,200 mg/m2 for 2 days OR 225 mg/m2 IV over 24 hours 5 to 7 days/week Page 4 of 10

    CLINICAL POLICY Trifluridine/Tipiracil Drug Name Dosing Regimen Dose Limit/ Maximum Dose GC/GEJ adenocarcinoma 750-1,000 mg/m2 IV daily on Days 2-4 of every 28-day cycle in combination with cisplatin OR 2,000 mg/m2 IV on Day 1 of every 14-day cycle in combination with leucovorin and cisplatin OR 800 mg/m2 IV on Days 1-5 of every 28-day cycle CRC 1,250 mg/m2 PO BID on Days 1-14.
    Repeat every 21 days for 8 cycles. GC/GEJ adenocarcinoma 1000-1,250 mg/m2 PO BID on Days 1-14 of every 21-day cycle OR 1,000 mg/m2 PO BID on Days 1-14 in combination with cisplatin 80 mg/m2 IV on Day 1 of every 21-day cycle OR 1,000 mg/m2 PO BID on Days 1-14 in combination with oxaliplatin 130 mg/m2 IV on Day 1 of every 21-day cycle CRC 125 mg/m2 IV in combination with 5-FU based chemotherapy GC/GEJ adenocarcinoma 180 mg/m2 IV on Day 1 of each 14-day cycle in combination with leucovorin and fluorouracil OR 80 mg/m2 IV on Day 1 weekly for 6 weeks followed by 2 weeks off treatment, in combination with leucovorin and fluorouracil 85 mg/m2 IV in combination with 5-FU based chemotherapy CRC Eloxatin (oxaliplatin) 85 mg/m2 IV on Day 1; leucovorin 200 mg/m2 IV on Days 1 & 2, followed by 5-FU 400 mg/m2 IV bolus, Page 5 of 10 2500 mg/m2/day 350 mg/m2 130 mg/m2 Varies capecitabine (Xeloda®)* irinotecan (Camptosar®) oxaliplatin FOLFOX = Infusional 5- FU/leucovorin /Eloxatin™

    CLINICAL POLICY Trifluridine/Tipiracil Drug Name Dosing Regimen (oxaliplatin) followed by 5-FU 600 mg/m2 IV on Days 1 & 2. Repeat cycle every 14 days. Dose Limit/ Maximum Dose FOLFIRI = Infusional 5- FU/leucovorin/ irinotecan (Camptosar®) Gastric cancer/GEJ adenocarcinoma Eloxatin (oxaliplatin) 85 mg/m2 IV on Day 1; leucovorin 400 mg/m2 IV on Day 1; 5-FU 400 mg/m2 IV bolus on Day 1, followed by 5-FU 1,200 mg/m2 IV on Days 1 & 2. Repeat cycle every 14 days. OR Eloxatin (oxaliplatin) 85 mg/m2 IV on Day 1; leucovorin 200 mg/m2 IV on Day 1; 5-FU 2,600 mg/m2 IV continuous infusion on Day

    1. Repeat cycle every 14 days. CRC Irinotecan 180 mg/m2 IV over 90 minutes day 1; leucovorin 400 mg/m2 IV over 2 hours day 1 followed by 5-FU 400 mg/m2 IV bolus over 2-4 minutes, followed by 2.4-3 gm/m2 IV 5-FU continuous infusion over 46 hours. Repeat cycle every 14 days. GC/GEJ adenocarcinoma Irinotecan 180 mg/m2 IV on Day 1; leucovorin 400 mg/m2 IV on Day 1; 5-FU 400 mg/m2 IV bolus on Day 1, followed by 1200 mg/m2 IV continuous infusion on Days 1 and 2. Repeat cycle every 14 days. Varies
       Anti-VEGF therapy for CRC
       Avastin, Mvasi, Zirabev (bevacizumab, bevacizumab-awwb, bevacizumab-bvzr) Cyramza (ramucirumab) Stivarga (regorafenib) Zaltrap (ziv- aflibercept) Anti-EGFR therapy for CRC
       Erbitux (cetuximab)
       5 or 10 mg/kg IV every 14 days in combination with 5-FU based chemotherapy 8 mg/kg IV every 2 weeks plus FOLFIRI regimen 160 mg PO QD on Days 1-21 of each 28-day cycle 4 mg/kg IV every 14 days in combination with FOLFIRI 400 mg/m2 IV for initial dose, then weekly infusions of 250 mg/m2 IV 20 mg/kg 10 mg/kg per dose 160 mg/day 4 mg/kg every 2 weeks 400 mg/m2 Page 6 of 10

    CLINICAL POLICY Trifluridine/Tipiracil Drug Name Dosing Regimen Vectibix (panitumumab) HER2/neu therapy for GC or GEJ adenocarcinoma 6 mg/kg IV every 2 weeks Herceptin, Herzuma, Kanjinti, Ogivri, Ontruzant, Trazimera (trastuzumab, trastuzumab- pkrb,anns,dttb,dkst,q yyp) Taxanes for GC or GEJ adenocarcinoma With chemotherapy:
    8 mg/kg IV loading dose on Day 1 of cycle 1, then 6 mg/kg IV every 21 days
    OR 6 mg/kg IV loading dose on Day 1 of cycle 1, then 4 mg/kg IV every 14 days Dose Limit/ Maximum Dose 9 mg/kg every 3 weeks 8 mg/kg/dose docetaxel paclitaxel
    100 mg/m2 250 mg/m2 75-100 mg/m2 IV on Day 1 of every 21-day cycle 135-250 mg/m2 IV on Day 1 of every 21-day cycle OR 80 mg/m2 IV on Day 1 weekly of every 28- day cycle OR 80 mg/m2 IV on Days 1, 8, and 15 of every 28-day cycle 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. *5-FU and capecitabine are examples of fluoropyrimidine chemotherapeutic agents. Appendix C: Contraindications/Boxed Warnings None reported
    V. Dosage and Administration
    Indication Metastatic CRC, GC, and GEJ adenocarcinoma Dosing Regimen 35 mg/m2/dose PO BID on Days 1 through 5 and Days 8 through 12 of each 28-day cycle Maximum Dose 160 mg/day (based on the trifluridine component) VI. Product Availability
    Tablets: 15 mg trifluridine/6.14 mg tipiracil, 20 mg trifluridine/8.19 mg tipiracil VII.