Last Review Date: 06/04/2024

Date of Origin: 02/04/2020

Dates Reviewed: 02/2020, 06/2020, 09/2020, 02/2021, 03/2022, 06/2022, 09/2022, 06/2023, 05/2024, 06/2024

1. Length of Authorization

Coverage will be provided for 6 months and may be renewed.

2. Dosing Limits

1. Quantity Limit (max daily dose) [NDC Unit]:

• Enhertu 100 mg vial: 7 vials every 21 days 

2. Max Units (per dose and over time) [HCPCS Unit]:

• Breast Cancer, CNS Cancer, NSCLC, HER2-Positive Solid Tumors, Colorectal Cancer, & Appendiceal Adenocarcinoma: 600 billable units every 21 days
• Gastric, Esophageal, and Esophagogastric Junction Cancers & Head and Neck Cancers: 700 billable units every 21 days

3. Initial Approval Criteria ¹

Coverage is provided in the following conditions:

• Patient is at least 18 years of age; AND

Universal Criteria ¹

• Left ventricular ejection fraction (LVEF) is within normal limits prior to initiating therapy and will be assessed at regular intervals (e.g., every 3 months) during treatment; AND
• Used as a single agent; AND
• Therapy will not be substituted with or for any trastuzumab-based formulation (i.e., trastuzumab [or trastuzumab biosimilar product], ado-trastuzumab emtansine, trastuzumab-hyaluronidase, pertuzumab/trastuzumab and hyaluronidase-zzxf, etc.); AND

Breast Cancer † ‡ ^{1,2,4,8,15,16,20}

• Patient has recurrent unresectable (local or regional) or metastatic disease OR inflammatory breast cancer with no response to preoperative systemic therapy; AND
  • Patient has human epidermal growth factor receptor 2 (HER2)-positive* disease as determined by an FDA-approved or CLIA-compliant testv; AND
    • • Used as subsequent therapy; OR
      • Used as first-line therapy in patients who have experienced disease progression within 6 months of neoadjuvant or adjuvant therapy (12 months for pertuzumab-containing regimens); OR
  • Patient has HER2-low§ disease as determined by an FDA-approved or CLIA-compliant testv; AND
    • Patient has hormone receptor-negative disease OR hormone receptor-positive disease with visceral crisis or endocrine therapy refractory; AND
      • • Used as subsequent therapy; OR
        • Patient has developed disease recurrence during or within 6 months after completing adjuvant chemotherapy

Central Nervous System (CNS) Cancers ‡ ²

• Patient has brain metastases from HER2-positive* breast cancer as confirmed by an FDA-approved or CLIA-compliant testv; AND
  • Used as initial treatment in patients with small asymptomatic brain metastases; OR
  • Patient has relapsed limited brain metastases with either stable systemic disease or reasonable systemic treatment options; OR
  • Patient has recurrent limited brain metastases; OR
  • Patient has recurrent extensive brain metastases with stable systemic disease or reasonable systemic treatment options

Gastric, Esophageal, and Esophagogastric Junction Cancers † ‡ Ф ^1,2,9,17,18

• Patient has human epidermal growth factor receptor 2 (HER2)-positive* disease as determined by an FDA-approved or CLIA-compliant testv; AND
• Patient has adenocarcinoma histology; AND
• Patient is not a surgical candidate OR has unresectable locally advanced, recurrent, or metastatic disease; AND
• Used as subsequent therapy

Colorectal Cancer (CRC) ‡ ^2,10-12

• Patient has human epidermal growth factor receptor 2 (HER2)-positive* disease as determined by an FDA-approved or CLIA-compliant testv; AND
• Used in one of the following treatment settings:
  • Used as initial treatment for unresectable metastatic disease and previous FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) within the past 12 months; AND

• Patient has mismatch repair proficient/microsatellite-stable (pMMR/MSS) disease; OR
  • Used as subsequent therapy for progression of advanced or metastatic disease; AND

• Patient has mismatch repair proficient/microsatellite-stable (pMMR/MSS) disease; OR

• Patient has mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) disease or polymerase epsilon/delta (POLE/POLD1) mutation; AND
  • Patient is not eligible for or has progressed on checkpoint inhibitor immunotherapy; OR

• • Used as adjuvant treatment for unresectable metastatic disease that converted to resectable disease after initial treatment (ONLY applies to Colon Cancer); AND
• Patient has mismatch repair proficient/microsatellite-stable (pMMR/MSS) disease; OR
• Patient has mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) disease or polymerase epsilon/delta (POLE/POLD1) mutation; AND
  • Patient is not eligible for or has progressed on checkpoint inhibitor immunotherapy

Appendiceal Adenocarcinoma – Colon Cancer ‡ ^2,11

• Patient has human epidermal growth factor receptor 2 (HER2)-positive* disease as determined by an FDA-approved or CLIA-compliant testv; AND

• Used as subsequent therapy for progression of advanced or metastatic disease; AND
  • Patient has mismatch repair proficient/microsatellite-stable (pMMR/MSS) disease; OR

• • • • • Patient has mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) disease or polymerase epsilon/delta (POLE/POLD1) mutation; AND
    • Patient is not eligible for or has progressed on checkpoint inhibitor immunotherapy

Non-Small Cell Lung Cancer (NSCLC) † ‡ ^{1,2,14,21,22,27}

• Used as subsequent therapy; AND
  • Patient has ERBB2 (HER2) mutation positive disease as determined by an FDA-approved or CLIA-complaint testv; AND

• • Patient has recurrent, advanced, unresectable, or metastatic disease (excluding locoregional recurrence or symptomatic local disease without evidence of disseminated disease) or mediastinal lymph node recurrence with prior radiation therapy; OR

• • Patient has human epidermal growth factor receptor 2 (HER2)-positive* disease as determined by an FDA-approved or CLIA-compliant testv; AND

• • Patient has recurrent, advanced, or metastatic disease (excluding locoregional recurrence or symptomatic local disease without evidence of disseminated disease) or mediastinal lymph node recurrence with prior radiation therapy

Head and Neck Cancers ‡ ^2,26

• Patient has human epidermal growth factor receptor 2 (HER2)-positive* disease as determined by an FDA-approved or CLIA-compliant testv; AND
• Patient has salivary gland tumors; AND
• Patient has recurrent disease with one of the following:
  • Distant metastases; OR
  • Unresectable locoregional recurrence with prior radiation therapy (RT); OR
  • Unresectable second primary with prior RT

HER2-Positive Solid Tumors † ‡ ^1,2,21,24,25

• Patient has human epidermal growth factor receptor 2 (HER2)-positive* solid tumors as determined by an FDA-approved or CLIA-compliant testv; AND
• Patient has, but is not limited to, one of the following tumor types ¥:
  • Biliary Tract Cancers (Gallbladder Cancer or Intra-/Extra-Hepatic Cholangiocarcinoma) ^1,2
    • Used as subsequent treatment for progression on or after systemic treatment for unresectable, resected gross residual (R2), or metastatic disease
  • Bladder Cancer ^1,2
    • Patient has one of the following diagnoses:
      • Locally advanced or metastatic urothelial carcinoma; OR
      • Muscle invasive bladder cancer with local recurrence or persistent disease in a preserved bladder treated with curative intent; OR
      • Metastatic or local bladder cancer recurrence post-cystectomy treated with curative intent; OR
      • Recurrent or metastatic primary carcinoma of the urethra (excluding recurrence of stage T3-4 disease or palpable inguinal lymph nodes); OR
      • Metastatic upper genitourinary (GU) tract tumors; OR
      • Metastatic urothelial carcinoma of the prostate; AND
    • Patient has received prior systemic treatment and has no satisfactory alternative treatment options
  • Cervical Cancer** ^1,2
    • Used as subsequent therapy for unresectable, recurrent, or metastatic disease
  • Occult Primary/Cancer of Unknown Primary (CUP) ²
    • Disease has progressed on or following prior systemic treatment and patient has no satisfactory alternative treatment options; AND
      • Patient has adenocarcinoma or carcinoma not otherwise specified AND one of the following:
        • Axillary involvement in those with a prostate or post-prostatectomy if clinically indicated; OR

• • • • • Lung nodules or breast marker-negative pleural effusion; OR
        • Resectable liver disease; OR
        • Peritoneal mass or ascites with non-ovarian histology; OR
        • Retroperitoneal mass of non-germ cell histology in selected patients; OR
        • Unresectable liver disease or disseminated metastases; OR
          • • • • Patient has squamous cell carcinoma; AND
• Patient has multiple lung nodules, pleural effusion, or disseminated metastases
  • Ovarian, Fallopian Tube, and Primary Peritoneal Cancer** ^1,2
    • Patient has platinum-resistant recurrent or persistent Grade 1 Endometrioid Carcinoma, Carcinosarcoma (Malignant Mixed Müllerian Tumors), Mucinous Carcinoma of the Ovary, Epithelial Ovarian/Fallopian Tube/Primary Peritoneal Cancer, or Clear Cell Carcinoma of the Ovary; AND
      • • Patient is not experiencing an immediate biochemical relapse (i.e., rising CA-125 without radiographic evidence of disease); OR
    • Patient has platinum-resistant recurrent Low-Grade Serous Carcinoma
  • Pancreatic Adenocarcinoma ²
    • Used as subsequent therapy for locally advanced or metastatic disease that has progressed; AND
      • • Patient has good performance status (defined as ECOG PS 0-1, with good biliary drainage and adequate nutritional intake); OR
    • Used as alternative systemic therapy, if not previously used, for patients with good performance status (ECOG PS 0-1); AND
      • • Patient has local recurrence in the pancreatic operative bed after resection; OR
        • Patient has recurrent metastatic disease
          • • • Small Bowel Adenocarcinoma ²

• • • Used as subsequent therapy for advanced or metastatic disease
      • • Uterine Neoplasms – Endometrial Carcinoma** ²
          • Patient has carcinosarcoma, clear cell carcinoma, endometrioid adenocarcinoma, serous carcinoma, undifferentiated/dedifferentiated carcinoma; AND
          • Used as subsequent therapy for recurrent, unresectable, or metastatic disease
        • Vaginal Cancer** ²
          • Used as subsequent therapy for recurrent or metastatic disease
        • Vulvar Cancer** ²
          • Used as subsequent therapy for advanced or recurrent/metastatic disease

¥ Note: Solid tumors not listed, that are HER2-positive*, will be reviewed on a case-by-case basis and considered medically necessary when all other relevant medication and indication specific criteria are met.

     vIf confirmed using an FDA approved assay - http://www.fda.gov/companiondiagnostics

† FDA Approved Indication(s); ‡ Compendia Recommended Indication(s); Ф Orphan Drug (only applies to Gastric and Esophagogastric Junction Cancers)

4. Renewal Criteria ¹

Coverage may be renewed based upon the following criteria:

• Patient continues to meet the universal and other indication-specific relevant criteria such as concomitant therapy requirements (not including prerequisite therapy), performance status, etc. identified in section III; AND
• Disease response with treatment as defined by stabilization of disease or decrease in size of tumor or tumor spread; AND
• Absence of unacceptable toxicity from the drug. Examples of unacceptable toxicity include: pulmonary toxicity (e.g., interstitial lung disease, pneumonitis), neutropenia (including febrile neutropenia), left ventricular dysfunction (including symptomatic congestive heart failure), etc.; AND
• Left ventricular ejection fraction (LVEF) within the previous 3 months as follows:
  • LVEF is > 45% and absolute decrease is ≤ 20% from baseline; OR
  • LVEF is 40% to 45% and absolute decrease is < 10% from baseline

5. Dosage/Administration ^{1,11-13,16,21,23,25,26-28}

6. Billing Code/Availability Information

HCPCS Code:

• J9358 – Injection, fam-trastuzumab deruxtecan-nxki, 1 mg: 1 billable unit = 1 mg

NDC:

• Enhertu 100 mg single-dose vial: 65597-0406-xx 

7. References

1. Enhertu [package insert]. Basking Ridge, NJ; Daiichi Sankyo, Inc; April 2024. Accessed May 2024.
2. Referenced with permission from the NCCN Drugs & Biologics Compendium (NCCN Compendium^®) fam-trastuzumab deruxtecan-nxki. National Comprehensive Cancer Network, 2024. The NCCN Compendium^® is a derivative work of the NCCN Guidelines^®. NATIONAL COMPREHENSIVE CANCER NETWORK^®, NCCN^®, and NCCN GUIDELINES^® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Compendium, go online to NCCN.org. Accessed May 2024.
3. Fahrenbruch R, Kintzel P, Bott AM, et al. Dose Rounding of Biologic and Cytotoxic Anticancer Agents: A Position Statement of the Hematology/Oncology Pharmacy Association. J Oncol Pract. 2018 Mar;14(3):e130-e136.

4. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Breast Cancer, Version 2.2024. National Comprehensive Cancer Network, 2024. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, and NCCN GUIDELINES® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Guidelines, go online to NCCN.org. Accessed May 2024.
5. Wolff AC, Hammond EH, Allison KH, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. J Clin Oncol 2018;36:2105-2122.
6. Hematology/Oncology Pharmacy Association (2019). Intravenous Cancer Drug Waste Issue Brief. Retrieved from http://www.hoparx.org/images/hopa/advocacy/Issue-Briefs/Drug_Waste_2019.pdf
7. Bach PB, Conti RM, Muller RJ, et al. Overspending driven by oversized single dose vials of cancer drugs. BMJ. 2016 Feb 29;352:i788.
8. Modi S, Saura C, Yamashita T, et al; DESTINY-Breast01 Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med. 2019 Dec 11. Doi: 10.1056/NEJMoa1914510.
9. Shitara K, Bang YJ, Iwasa S, et al; DESTINY-Gastric01 Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N Engl J Med. 2020 Jun 18;382(25):2419-2430.
10. Siena S, Di Bartolomeo M, Raghav KPS, et al. A phase II, multicenter, open-label study of trastuzumab deruxtecan in patients with HER2-expressing metastatic colorectal cancer (mCRC): DESTINY-CRC01. J Clin Oncol 2020;38(suppl; abstr 4000).
11. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Colon Cancer, Version 2.2024. National Comprehensive Cancer Network, 2024. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, and NCCN GUIDELINES® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Guidelines, go online to NCCN.org. Accessed May 2024.
12. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Rectal Cancer 2.2024. National Comprehensive Cancer Network, 2023. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, and NCCN GUIDELINES® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Guidelines, go online to NCCN.org. Accessed May 2024.
13. Smit EF, Nakagawa K, Nagasaka M, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-mutated metastatic non-small cell lung cancer (NSCLC): interim results of DESTINY-Lung01[abstract]. J Clin Oncol 2020;38:Abstract 9504.
14. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Non-Small Cell Lung Cancer, Version 5.2024. National Comprehensive Cancer Network, 2024. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, and NCCN GUIDELINES® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Guidelines, go online to NCCN.org. Accessed May 2024.
15. Gennari A, André F, Barrios CH, et al.; ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol. 2021 Dec;32(12):1475-1495. doi: 10.1016/j.annonc.2021.09.019. Epub 2021 Oct 19. PMID: 34678411.
16. Cortés J, Kim SB, Chung WP, et al; DESTINY-Breast03 Trial Investigators. Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer. N Engl J Med. 2022 Mar 24;386(12):1143-1154. doi: 10.1056/NEJMoa2115022.
17. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Esophageal and Esophagogastric Junction Cancers, Version 3.2024. National Comprehensive Cancer Network, 2024. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, and NCCN GUIDELINES® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Guidelines, go online to NCCN.org. Accessed May 2024.
18. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Gastric Cancer, Version 1.2024. National Comprehensive Cancer Network, 2024. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, and NCCN GUIDELINES® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Guidelines, go online to NCCN.org. Accessed May 2024.
19. Bartley AN, Washington MK, Colasacco C, et al. HER2 Testing and Clinical Decision Making in Gastroesophageal Adenocarcinoma: Guideline From the College of American Pathologists, American Society for Clinical Pathology, and the American Society of Clinical Oncology. J Clin Oncol. 2017 Feb;35(4):446-464. doi: 10.1200/JCO.2016.69.4836.
20. Modi S, Jacot W, Yamashita T, et al; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. doi: 10.1056/NEJMoa2203690.
21. Li BT, Smit EF, Goto Y, et al; DESTINY-Lung01 Trial Investigators. Trastuzumab Deruxtecan in HER2-Mutant Non-Small-Cell Lung Cancer. N Engl J Med. 2022 Jan 20;386(3):241-251. doi: 10.1056/NEJMoa2112431.
22. Smit EFF, Li BT, Mazieres J, et al. 1361TiP Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-mutated (HER2m) metastatic non-small cell lung cancer (NSCLC): A phase (ph) II study (DESTINY-Lung02). Annals of Oncology, Volume 32, S1032 – S1033. DOI:https://doi.org/10.1016/j.annonc.2021.08.1962.
23. Jerusalem G, Park YH, Yamashita T, et al. Trastuzumab Deruxtecan in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases: A DESTINY-Breast01 Subgroup Analysis. Cancer Discov. 2022 Dec 2;12(12):2754-2762. doi: 10.1158/2159-8290.CD-22-0837.
24. Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial. J Clin Oncol. 2024 Jan 1;42(1):47-58. doi: 10.1200/JCO.23.02005. Epub 2023 Oct 23. PMID: 37870536; PMCID: PMC10730032.
25. Raghav KPS, Yoshino T, Guimbaud R, et al. Trastuzumab deruxtecan in patients with HER2-overexpressing locally advanced, unresectable, or metastatic colorectal cancer (mCRC): A randomized, multicenter, phase 2 study (DESTINY-CRC02).. JCO 39, TPS3620-TPS3620(2021). DOI:10.1200/JCO.2021.39.15_suppl.TPS3620
26. Bando H, Kinoshita I, Modi S, et al. Trastuzumab deruxtecan (T-DXd) in patients with human epidermal growth factor receptor 2 (HER2)-expressing salivary duct carcinoma: Subgroup analysis of two phase 1 studies. Journal of Clinical Oncology Volume 39, Number 15_suppl. https://doi.org/10.1200/JCO.2021.39.15_suppl.607
27. Smit E, Felip E, Uprety D, et al. Trastuzumab deruxtecan in patients with metastatic non-small-cell lung cancer (DESTINY-Lung01): primary results of the HER2-overexpressing cohorts from a single-arm, phase 2 trial. Lancet Oncol. 2024 Apr;25(4):439-454. doi: 10.1016/S1470-2045(24)00064-0.
28. Bernstam F, Makker V, Oakin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: primary results from the DESTINY-PanTumor02 phase II trial. J Clin Oncol 2024;42:47-58. doi: 10.1200/JCO.23.02005. Epub 2023 Oct 23.
29. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Head and Neck Cancers, Version 4.2024. National Comprehensive Cancer Network, 2024. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, and NCCN GUIDELINES® are trademarks owned by the National Comprehensive Cancer Network, Inc. To view the most recent and complete version of the Guidelines, go online to NCCN.org. Accessed May 2024.
30. First Coast Service Options, Inc. Local Coverage Article: Billing and Coding: Trastuzumab -Trastuzumab Biologics (A56660). Centers for Medicare & Medicaid Services, Inc. Updated on 10/14/2021 with effective date of 10/01/2021. Accessed May 2024.

Appendix 1 – Covered Diagnosis Codes

Appendix 2 – Centers for Medicare and Medicaid Services (CMS)

The preceding information is intended for non-Medicare coverage determinations. Medicare coverage for outpatient (Part B) drugs is outlined in the Medicare Benefit Policy Manual (Pub. 100-2), Chapter 15, §50 Drugs and Biologicals. In addition, National Coverage Determinations (NCDs) and/or Local Coverage Determinations (LCDs) may exist and compliance with these policies is required where applicable. Local Coverage Articles (LCAs) may also exist for claims payment purposes or to clarify benefit eligibility under Part B for drugs which may be self-administered. The following link may be used to search for NCD, LCD, or LCA documents: https://www.cms.gov/medicare-coverage-database/search.aspx. Additional indications, including any preceding information, may be applied at the discretion of the health plan.