VITRAKVI, Larotrectinib Sulfate Form

Larotrectinib (Vitrakvi®) is a first-generation selective tropomyosin receptor kinase (TRK) tyrosine kinase inhibitor (TKI). FDA Approved Indication(s) Vitrakvi is indicated for the treatment of adult and pediatric patients with solid tumors that: • Have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, • Are metastatic or where surgical resection is likely to result in severe morbidity, and • Have no satisfactory alternative treatments or that have progressed following treatment. Select patients for therapy based on an FDA-approved test. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. 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 Vitrakvi is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. NTRK Fusion-Positive Cancer (must meet all):

1. Diagnosis of one of the following (a or b): a. Solid tumor (see Appendix D for examples); b. Histiocytic neoplasm (e.g., Erdheim-Chester disease, Langerhans Cell histiocytosis, Rosai-Dorfman disease) (off-label);
   2. Prescribed by or in consultation with one of the following (a or b): a. Oncologist; b. For histiocytic neoplasm, a hematologist;
   3. For Vitrakvi requests, member must use larotrectinib, if available, unless contraindicated or clinically significant adverse effects are experienced;
   4. Tumor is positive for an NTRK-gene fusion (e.g., ETV6-NTRK3, TPM3-NTRK1);

2. Confirmation of no known acquired tropomyosin receptor kinase resistance mutation; Page 1 of 8

   CLINICAL POLICY Larotrectinib

   6. For solid tumor: Disease is persistent, recurrent, advanced, metastatic, unresectable, or resectable with adverse functional outcomes;
   7. Request meets one of the following (a or b): a. Member must use Rozlytrek®, unless contraindicated or clinically significant adverse effects are experienced; Prior authorization may be required for Rozlytrek. b. Request is for Stage IV or metastatic cancer for a State with regulations against step therapy in advanced oncology settings (see Appendix E);
   8. For disease relapse or progression following Rozlytrek therapy, medical justification as to why additional NTRK targeted therapy is warranted;
   9. Request meets one of the following (a, b, or c): a. Adults and pediatric members with body surface area ≥ 1.0 m2: Dose does not b. Pediatric members with body surface area < 1.0 m2: Dose does not exceed 200 exceed 200 mg per day; mg/m2 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 B. Other diagnoses/indications (must meet 1 or 2):
   10. 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
   11. 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. NTRK-Fusion Positive Cancer (must meet all):
   12. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Vitrakvi for a covered indication and has received this medication for at least 30 days;
   13. Member is responding positively to therapy; Page 2 of 8

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   3. For Vitrakvi requests, member must use larotrectinib, if available, unless contraindicated or clinically significant adverse effects are experienced;

3. If request is for a dose increase, request meets one of the following (a, b, c): a. Adults and pediatric members with body surface area ≥ 1.0 m2: New dose does b. Pediatric members with body surface area < 1.0 m2: New dose does not exceed not exceed 200 mg per day; 200 mg/m2 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 B. Other diagnoses/indications (must meet 1 or 2):

   1. 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
   2. 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; B. Known acquired tropomyosin receptor kinase resistance mutation. IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key FDA: Food and Drug Administration NCCN: National Comprehensive Cancer Network NTRK: neurotrophic receptor tyrosine kinase TKI: tyrosine kinase inhibitor TRK: tropomyosin receptor kinase Page 3 of 8

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   Appendix B: Therapeutic Alternatives
   Drug Name Dosing Regimen Rozlytrek® (entrectinib) NTRK fusion-positive solid tumor
   Adults: 600 mg PO QD Pediatrics by body surface area (BSA): Age

   6 months Recommended daily dosage ≤ 0.50 m2: 300 mg/m2 PO QD 0.51 to 0.80 m2: 200 mg PO QD 0.81 to 1.10 m2: 300 mg PO QD 1.11 to 1.50 m2: 400 mg PO QD ≥1.51 m2: 600 mg PO QD 250 mg/m2 PO QD 1 month to ≤ 6 months Dose Limit/ Maximum Dose 600 mg/day 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 Appendix D: Examples of Solid Tumors (Examples are drawn from the Vitrakvi pivotal trials, as described in the FDA prescribing information, as well as the National Comprehensive Center Network (NCCN) Vitrakvi compendium.) • Breast cancer • Central nervous system cancers • Cervical cancer • Cholangiocarcinoma • Colorectal cancer • Epithelial ovarian cancer/fallopian tube cancer/primary peritoneal cancer • Gastric cancer • Hepatocellular carcinoma • Lung cancer • Melanoma • Pancreatic cancer • Salivary gland tumor • Small bowel adenocarcinoma • Soft tissue sarcoma (e.g., extremity/body wall, head/neck, retroperitoneal/intraabdominal, solitary fibrous tumor, infantile fibrosarcoma, gastrointestinal stromal tumor) • Thyroid carcinoma (papillary, Hurthle cell, anaplastic, or follicular histology) Appendix E: States with Regulations against Redirections in Stage IV or Metastatic Cancer State Step Therapy Prohibited? Yes FL Notes For stage 4 metastatic cancer and associated conditions. Page 4 of 8

   CLINICAL POLICY Larotrectinib
   State Step Therapy Prohibited? Yes GA IA LA NV OH OK PA TN TX Yes Yes Yes Yes Yes Yes Yes Yes Notes For stage 4 metastatic cancer. Redirection does not refer to review of medical necessity or clinical appropriateness. For standard of care stage 4 cancer drug use, supported by peer- reviewed, evidence-based literature, and approved by FDA. For stage 4 advanced, metastatic cancer or associated conditions. Exception if “clinically equivalent therapy, contains identical active ingredient(s), and proven to have same efficacy. Stage 3 and stage 4 cancer patients for a prescription drug to treat
   the cancer or any symptom thereof of the covered person Applies to HIM requests only For stage 4 metastatic cancer and associated conditions Applies to HIM requests only For advanced metastatic cancer and associated conditions For stage 4 advanced, metastatic cancer For advanced metastatic cancer and associated conditions For stage 4 advanced, metastatic cancer and associated conditions V. Dosage and Administration
   Indication NTRK fusion- positive solid tumors Dosing Regimen • Adult and pediatric patients with body surface area ≥ 1.0 m2: 100 mg PO BID until disease progression or until unacceptable toxicity • Pediatric patients with body surface area < 1.0 m2: 100 mg/m2 PO BID until disease progression or until unacceptable toxicity
   Maximum Dose 200 mg/day VI. Product Availability
   • Capsules: 25 mg, 100 mg • Oral solution (100 mL bottle): 20 mg/mL
   VII.