ROZLYTREK, Entrectinib Form

Entrectinib (Rozlytrek®) is a kinase inhibitor. FDA Approved Indication(s) Rozlytrek is indicated for the treatment of:
• Adult patients with ROS1-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test.
• Adult and pediatric patients older than 1 month of age with solid tumors that:
o have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion as detected by an FDA- approved test without a known acquired resistance mutation,
o are metastatic or where surgical resection is likely to result in severe morbidity, and o have either progressed following treatment or have no satisfactory alternative therapy.
This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the 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 Rozlytrek is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Non-Small Cell Lung Cancer (must meet all):

1. Diagnosis of recurrent, advanced, or metastatic NSCLC;
   2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. Disease is ROS1 positive;
   5. For brand Rozlytrek requests, member must use generic entrectinib, 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, ii, and iii): i. 600 mg per day; ii. 3 capsules per day; iii. 12 packets per day; b. Dose is supported by practice guidelines or peer-reviewed literature for the relevant off-label use (prescriber must submit supporting evidence). Page 1 of 8

   CLINICAL POLICY Entrectinib *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. NTRK Fusion-Positive Solid Tumor (must meet all):

3. Diagnosis of a solid tumor (see Appendix D for examples);
   2. Prescribed by or in consultation with an oncologist;
   3. Age > 1 month;
   4. Meets one of the following (a or b): a. Disease is metastatic; b. Member has failed or is not a candidate for primary therapy (e.g., surgery, chemotherapy, radiation);
4. Tumor is positive for an NTRK gene fusion (e.g., ETV6-NTRK3, TPM3-NTRK1) without a known resistance mutation;
5. For brand Rozlytrek requests, member must use generic entrectinib, if available, unless contraindicated or clinically significant adverse effects are experienced;

6. Member has not received prior NTRK targeted therapy (e.g., Vitrakvi®);

   8. Documentation of member’s current body surface area (BSA) (m2);
   9. Request meets one of the following (a, b, c, or d):* a. Adults: Dose does not exceed any of the following (i, ii, and iii):
      i. 600 mg per day; ii. 3 capsules per day; iii. 12 packets per day; b. Pediatrics age > 6 months: Dose does not exceed any of the following (i – v): i. BSA ≥ 1.51 m2 (1, 2, and 3): 1) 600 mg PO QD; 2) 3 capsules per day; 3) 12 packets per day; ii. BSA 1.11 to 1.50 m2 (1, 2, and 3):
      1) 400 mg PO QD; 2) 3 capsules per day; 3) 8 packets per day; iii. BSA 0.81 to 1.10 m2: (1, 2, and 3):
      1) 300 mg PO QD; 2) 2 capsules per day;
      3) 6 packets per day; iv. BSA 0.51 to 0.80 m2: (1, 2, and 3):
      1) 200 mg PO QD; 2) 2 capsules per day;
      3) 4 packets per day; v. BSA ≤ 0.50 m2: (1, 2, and 3):
      1) 300 mg/m2 PO QD; 2) 2 capsules per day;
      3) 3 packets per day; Page 2 of 8

   CLINICAL POLICY Entrectinib c. Pediatrics age > 1 month to ≤ 6 months: Dose does not exceed 250 mg/m2 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 C. Other diagnoses/indications (must meet 1 or 2):

7. 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
8. 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):
9. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Rozlytrek for a covered indication and has received this medication for at least 30 days;
10. Member is responding positively to therapy;
    3. If member has a diagnosis of NTRK fusion-positive solid tumor, documentation of member’s current BSA (m2);

11. If request is for a dose increase, request meets one of the following (a, b, c, or d):* a. Adults: New dose does not exceed any of the following (i, ii, and iii):
    i. 600 mg per day; ii. 3 capsules per day; iii. 12 packets per day; b. Pediatrics age > 6 months:: New dose does not exceed any of the following (i – v): i. BSA ≥ 1.51 m2 (1, 2, and 3):
    1) 600 mg PO QD; 2) 3 capsules per day; 3) 12 packets per day; ii. BSA 1.11 to 1.50 m2 (1, 2, and 3):
    1) 400 mg PO QD; Page 3 of 8

    CLINICAL POLICY Entrectinib 2) 3 capsules per day;
    3) 8 packets per day; iii. BSA 0.81 to 1.10 m2 (1, 2, and 3):
    1) 300 mg PO QD; 2) 2 capsules per day; 3) 6 packets per day; iv. BSA 0.51 to 0.80 m2: (1, 2, and 3):
    1) 200 mg PO QD; 2) 2 capsules per day;
    3) 4 packets per day; v. BSA ≤ 0.50 m2: (1, 2, and 3):
    1) 300 mg/m2 PO QD; 2) 2 capsules per day;
    3) 3 packets per day; c. Pediatrics age > 1 month to ≤ 6 months: New dose does not exceed 250 mg/m2 per day; d. 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):

12. 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

13. 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. Page 4 of 8

    CLINICAL POLICY Entrectinib IV. Appendices/General Information Appendix A: Abbreviation/Acronym Key BSA: body surface area FDA: Food and Drug Administration NCCN: National Comprehensive Cancer Network Appendix B: Therapeutic Alternatives
    Not applicable NSCLC: non-small cell lung cancer
    NTRK: neurotrophic tyrosine receptor kinase
    Appendix C: Contraindications/Boxed Warnings None reported Appendix D: Examples of Solid Tumors (Examples are drawn from the Rozyltrek pivotal trials, as described in the FDA prescribing information, as well as the National Comprehensive Center Network (NCCN) Rozyltrek compendium.) • Ampullary adenocarcinoma • Breast cancer • Central nervous system cancers • Cholangiocarcinoma • Colorectal cancer • Cutaneous melanoma • Esophageal and esophagogastric junction cancers • Gastric cancers • Gynecological cancers (e.g., epithelial ovarian cancer/fallopian tube cancer/primary peritoneal cancer, uterine cancers, vulvar cancers (squamous cell), cervical cancers) • Hepatobilliary cancers • Histiocytic neoplasms (Langerhans cell, Erdheim-Chester disease, Rosai-Dorfman disease) • Lung cancer • Neuroendocrine cancers • Pancreatic cancer • Salivary gland tumor • Small bowel adenocarcinoma • Soft tissue sarcoma (e.g., retroperitoneal/intraabdominal, angiosarcoma, rhabdosarcoma/rhabdomyosarcoma, sarcoma of the extremity, solitary fibrous tumor, superficial trunk, undifferentiated pleomorphic sarcoma, extremity/body wall, or head/neck) • Thyroid cancer (papillary, Hurthle cell, anaplastic, or follicular carcinoma) Page 5 of 8

    CLINICAL POLICY Entrectinib V. Dosage and Administration
    Indication ROS1-positive NSCLC NTRK fusion- positive solid tumor Dosing Regimen Adults: 600 mg PO QD 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 Product Availability
    • Capsules: 100 mg, 200 mg • Pellets: 50 mg Maximum Dose 600 mg/day Adults: 600 mg/day Pediatrics: see regimen VI.