Fam-Trastuzumab Deruxtecan-nxki (Enhertu) Form

Fam-trastuzumab deruxtecan-nxki (Enhertu®) is a human epidermal growth factor receptor 2 (HER2)-directed antibody and topoisomerase inhibitor conjugate. FDA Approved Indication(s) Enhertu is indicated for the treatment of adult patients with: • Unresectable or metastatic HER2-positive breast cancer who have received a prior anti- HER2 based regimen either:
o In the metastatic setting, or
o In the neoadjuvant setting and have developed disease recurrence during or within six months of completing therapy. • Unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-approved test, who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. • Unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. • Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen. This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
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 Enhertu is medically necessary when the following criteria are met:
I. Initial Approval Criteria
A. Breast Cancer (must meet all):

1. Diagnosis of recurrent, unresectable, or metastatic breast cancer that is one of the following (a or b): a. HER2-positive; b. HER2-low (IHC 1+ or IHC 2+/ISH-); Page 1 of 11

   CLINICAL POLICY Fam-Trastuzumab Deruxtecan-nxki

2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. Member meets one of the following (a or b):
      a. For HER2-positive breast cancer, one of the following (i or ii): i. Failure of one prior anti-HER2-based regimen (see Appendix B), unless contraindicated or clinically significant adverse effects are experienced; ii. Rapid disease progression within 6 months of neoadjuvant or adjuvant therapy (12 months for pertuzumab-containing regimens);
      *Prior authorization may be required for anti-HER2-based regimens b. For HER2-low (IHC 1+ or IHC2+/ISH-) breast cancer, one of the following (i or ii):
      i. Failure of at least one prior line of chemotherapy (if hormone-receptor [HR]- positive, previous therapy should include an endocrine therapy, unless ineligible) (see Appendix B for examples); ii. Disease recurrence during or within 6 months of completing adjuvant chemotherapy;
3. Request meets one of the following (a or b): a. Dose does not exceed 5.4 mg/kg every 3 weeks; 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 – 6 months or to the member’s renewal date, whichever is longer B. Gastric and Gastroesophageal Junction Cancer (must meet all):
   1. Diagnosis of HER2-positive gastric or GEJ adenocarcinoma;
   2. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. Disease is locally advanced, recurrent, or metastatic;
   5. Failure of a trastuzumab-based regimen (see Appendix B);
   6. Request meets one of the following (a or b): a. Dose does not exceed 6.4 mg/kg every 3 weeks; 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 – 6 months or to the member’s renewal date, whichever is longer C. Non-Small Cell Lung Cancer (must meet all):

4. Diagnosis of unresectable or metastatic NSCLC;

   2. Disease has activating HER2 (ERBB2) mutations;
   3. Prescribed by or in consultation with an oncologist;
   4. Age ≥ 18 years;
   5. Failure of one prior line of chemotherapy (see Appendix B for examples); Page 2 of 11

   CLINICAL POLICY Fam-Trastuzumab Deruxtecan-nxki

5. Request meets one of the following (a or b): a. Dose does not exceed 5.4 mg/kg every 3 weeks; 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 – 6 months or to the member’s renewal date, whichever is longer D. Colon or Rectal Cancer (off label) (must meet all):
6. Diagnosis of advanced or metastatic colon or rectal cancer, including appendiceal adenocarcinoma;
7. Prescribed by or in consultation with an oncologist;
   3. Age ≥ 18 years;
   4. Member meets one of the following (a or b): a. Documentation supports failure of or presence of clinically significant adverse effects or contraindication to at least two FDA approved medications for the relevant diagnosis (e.g., oxaliplatin, irinotecan, FOLFOX [fluorouracil, leucovorin, and oxaliplatin] or CapeOX [capecitabine and oxaliplatin], bevacizumab); b. Enhertu is prescribed as adjuvant therapy for rectal cancer as a single agent for unresectable metachronous metastases (HER2-amplified and RAS and BRAF wild-type) (proficient mismatch repair/microsatellite-stable [pMMR/MSS] only) that converted to resectable disease after initial treatment;
8. 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 – 6 months or to the member’s renewal date, whichever is longer E. Other NCCN Recommended Uses (off-label) (must meet all):
9. Diagnosis of one of the following (a, b, or c): a. Recurrent or metastatic HER2-positive cervical cancer; b. Recurrent HER2-positive salivary gland tumors; c. Recurrent or metastatic HER2-positive endometrial carcinoma;
10. Prescribed or in consultation with an oncologist;
    3. Age ≥ 18 years;
    4. For cervical cancer: Prescribed as a single agent following failure of ≥ 1 prior therapy (see Appendix B);

11. For salivary gland tumors: Prescribed as a single agent and member has one of the following (a or b): a. Distant metastases in patients with a performance status (PS) of 0-3; b. Unresectable locoregional recurrence or second primary with prior radiation therapy; Page 3 of 11

    CLINICAL POLICY Fam-Trastuzumab Deruxtecan-nxki

12. For endometrial carcinoma: Prescribed as a single agent following failure of ≥ 1 prior therapy (see Appendix B);
13. 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 – 6 months or to the member’s renewal date, whichever is longer F. 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.
    II. Continued Therapy A. All Indications in Section I (must meet all):
16. Currently receiving medication via Centene benefit, or documentation supports that member is currently receiving Enhertu for a covered indication and has received this medication for at least 30 days;

17. Member is responding positively to therapy;

    3. If request is for a dose increase, request meets one of the following (a, b, or c): a. For breast cancer or NSCLC: New dose does not exceed 5.4 mg/kg every 3 weeks; b. For gastric or GEJ adenocarcinoma: New dose does not exceed 6.4 mg/kg every 3 weeks;
       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 – 6 months or to the member’s renewal date, whichever is longer Page 4 of 11

    CLINICAL POLICY Fam-Trastuzumab Deruxtecan-nxki B. Other diagnoses/indications (must meet 1 or 2):

18. 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

19. 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 FDA: Food and Drug Administration GEJ: gastroesophageal junction HER2: human epidermal growth factor receptor 2 HR: hormone-receptor NCCN: National Comprehensive Center Network NSCLC: non-small cell lung cancer 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 Varies HER2+ Breast Cancer NCCN examples of systemic therapies for recurrent or metastatic disease: • Aromatase inhibitor ± trastuzumab • Aromatase inhibitor ± lapatinib • Pertuzumab + trastuzumab + docetaxel Varies Page 5 of 11

    CLINICAL POLICY Fam-Trastuzumab Deruxtecan-nxki Drug Name Breast Cancer • Examples of systemic therapies include but are not limited to: eribulin, capecitabine, gemcitabine, nab- paclitaxel, paclitaxel • Examples of endocrine therapies for HR+ disease include but are not limited to: sacituzumab, palbocicib, ribociclib, abemacicilib, tamoxifen, letrozole, anastrozole, exemestane Gastric and Gastroesophageal Junction Cancer trastuzumab-based regimen NSCLC Examples of systemic therapies include but are not limited to: • Carboplatin or cisplatin + pemetrexed + pembrolizumab
    • Carboplatin + paclitaxel + bevacizumab + atezolizumab
    • Carboplatin + albumin-bound paclitaxel + atezolizumab
    • Carboplatin + paclitaxel or albumin-bound paclitaxel

    • pembrolizumab
      • Nivolumab + ipilimumab + paclitaxel + carboplatin or cisplatin
      Examples of targeted therapies include but are not limited to: • EGFR mutation positive: afatinib, erlotinib, dacomitinib, gefitinib, osimertinib, erlotinib + ramucirumab, erlotinib + bevacizumab (non- squamous) • BRAF: dabrafenib/trametinib, dabrafenib, vemurafenib • ALK: alectinib, brigatinib, ceritinib, crizotinib, lorlatinib ROS1: ceritinib, crizotinib, entrectinib
      Cervical Cancer Examples of first-line therapies include but are not limited to: • Cisplatin or carboplatin + paclitaxel ± bevacizumab Page 6 of 11 Dosing Regimen Varies Dose Limit/ Maximum Dose Varies 8 mg/kg IV followed by 6 mg/kg IV q 3 weeks Varies 8 mg/kg Varies Varies Varies

    CLINICAL POLICY Fam-Trastuzumab Deruxtecan-nxki Drug Name Dosing Regimen Dose Limit/ Maximum Dose • Topotecan + paclitaxel ± bevacizumab
    • Cisplatin + topotecan • Cisplatin • Carboplatin Examples of NCCN-preferred second-line or subsequent therapies include but are not limited to: • Tisotumab vedotin-tftv • Cemiplimab • Bevacizumab • Paclitaxel • Albumin-bound paclitaxel • Docetaxel • Fluorouracil • Gemcitabine • Pemetrexed • Topotecan • Vinorelbine • Irinotecan Endometrial Carcinoma Examples of first-line therapies include but are not limited to: • Carboplatin + paclitaxel + trastuzumab • Carboplatin + docetaxel • Carboplatin + paclitaxel + bevacizumab
    Examples of NCCN-preferred second-line or subsequent therapies include but are not limited to: • Cisplatin + doxorubicin • Cisplatin + doxorubicin + paclitaxel • Cisplatin • Carboplatin • Doxorubicin • Liposomal doxorubicin • Paclitaxel • Albumin-bound paclitaxel • Topotecan • Bevacizumab • Temsirolimus • Cabozantinib Page 7 of 11 Varies Varies

    CLINICAL POLICY Fam-Trastuzumab Deruxtecan-nxki Drug Name Dosing Regimen Dose Limit/ Maximum Dose Ifosfamide (for carcinosarcoma) Ifosfamide + paclitaxel (for carcinosarcoma) • Docetaxel • • • Cisplatin + ifosfamide 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 • Contraindication(s): none reported • Boxed warning(s): interstitial lung disease and pneumonitis; embryo-fetal toxicity V. Dosage and Administration
    Indication Breast cancer, NSCLC Gastric, GEJ cancer Dosing Regimen 5.4 mg/kg IV every 3 weeks 5.4 mg/kg 6.4 mg/kg IV every 3 weeks 6.4 mg/kg Maximum Dose VI. Product Availability
    Single-dose vial: 100 mg lyophilized powder VII.