Coverage Policy Manual
Policy #: 2020015
Category: Pharmacy
Initiated: July 2020
Last Review: September 2023
  Fam-trastuzumab deruxtecan-nxki (e.g., Enhertu®)
Description:
Fam-trastuzumab deruxtecan-nxki (e.g., Enhertu®), is an antibody –drug conjugate that is composed of a humanized monoclonal antibody specifically targeting HER2-overexpressing tumor cells, with the same amino acid sequence as trastuzumab. Internalization and intracellular linker cleavage of the drug by lyzozomal enzymes within the tumor cell leads to DNA damage and apoptotic cell death. Trastuzumab deruxtecan has a higher drug-to antibody ration than trastuzumab emtasine (approximately 8 vs 3 to 4).  
 
Enhertu has a black box warning for interstitial lung disease and embryo-fetal toxicity. Interstitial lung disease (ILD) and pneumonitis, including fatal cases, have been reported with Enhertu. Individuals should be monitored for signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Enhertu should be discontinued in all individuals with Grade 2 or higher ILD/pneumonitis.
 
Regulatory Status
 
On December 20, 2019 the U.S. Food and Drug Administration approved fam-trastuzumab deruxtecan-nxki (e.g., Enhertu®) use in unresectable or metastatic HER2-postive breast cancer. Accelerated approval was granted based on tumor 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.
 
On January 15, 2021, the Food and Drug Administration approved Fam-trastuzumab deruxtecan-nxki for the treatment of adult individuals with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen.
 
On August 5, 2022, the FDA approved an expanded indication fam-trastuzumab-deruxtecan-nxki to treat unresectable or metastatic HER2-low breast cancer. It is the first targeted therapy approved by the FDA for HER 2-low breast cancer and received Priority Review and Breakthrough Therapy designations for this indication.  
 
On August 11, 2022, fam-trastuzumab deruxtecan-nxki was granted accelerated approval by the FDA for treatment of adult individuals with unresectable or metastatic non-small cell lung cancer (NSCLC) who’s tumors have activating HER2 (ERBB2) mutations as detected by an FDA approved test* and have received a prior systemic therapy.  Continued approval for this indication will be contingent fam-trastuzumab deruxtecan-nxki upon confirmation of a clinical benefit.  
 
*The FDA also approved two companion diagnostics for Enhertu: Oncomine DX Target Test (for tissue) and Guardant 360 CDX (for plasma).  If a mutation is not detected in a plasma specimen, the tumor tissue should be tested.
 
Coding
 
See CPT/HCPCS Code section below.
 
Policy/
Coverage:
Effective August 1, 2021, for members of plans that utilize an oncology benefits management program, Prior Approval is required for this service and is managed through the oncology benefits management program.
 
Effective September 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use fam-trastuzumab deruxtecan-nxki (e.g., Enhertu®) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness improving health outcomes for treatment of adults with the following indications when ALL the following are met:
 
1. Unresectable or metastatic HER2-positive breast cancer who have received prior anti-HER2 based regimens either in the metastatic setting or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy:
a. Must be greater than or equal to 18 years old (FDA, 2019)
b. Must have documentation of unresectable and/or metastatic HER2 breast cancer:
i. Circumferential membrane staining that is complete, intense and in greater than 10% of tumor cells (IHC 3+) – diagnosis is HER2 positive (Wolff, 2018)
ii. If the HER2/CEP17 ratio remains less than 2.0 with greater than or equal to 6.0 HER2 signals per cell, diagnosis is HER2 positive (Wolff, 2018)
c. Used as a single-agent as second-line therapy (preferred) (NCCN 1).
d. Must have an ECOG score of 0-1.
e. It is contraindicated in those individuals with pneumonitis or interstitial lung disease. (NCCN, 2021)
f. Must not have active brain metastases.
g. Must not have myocardial disease. For individuals with a history of heart failure, there must be documentation of left ventricular ejection fraction (LVEF) greater than 50%.
h. Must be dosed in accordance with the FDA label.
 
2. Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.
a. Must be greater than or equal to 18 years of age (FDA, 2019)
b. Must have documentation of locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma.
i. Centrally confirmed human epidermal growth factor receptor 2 overexpression (immunohistochemistry [IHC] 3+ or IHC2+/in situ hybridization positive) on archival tissue (or fresh sample if archived tissue is inadequate) (Yamaguchi, 2021)
c. Have had a prior trastuzumab-based regimen. (NCCN 2A)
d. Must have ECOG score of 0-1. (NCCN 2A)
e. It is contraindicated in those individuals with history of (noninfectious) interstitial lung disease (ILD)/pneumonitis that required steroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening. (NCCN, 2021)
f. Must not have myocardial disease. .For individuals with a history of heart failure, there must be documentation of left ventricular ejection fraction (LVEF) greater than 50%.
g. Must be dosed in accordance with the FDA label.
 
3. Unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of competing adjuvant chemotherapy.
 
a. Must be greater than or equal to 18 years of age (FDA, 2022)
b. Must have documentation of unresectable and/or metastatic HER2-low breast cancer:
i. IHC 2+ based on circumferential membrane staining that is incomplete and/or weak/moderate and within greater 10% of the invasive tumor cells or complete and circumferential membrane staining that is intense and within less than or equal to 10% of the invasive tumor cells.
ii. ISH negative based on:
1. Single-probe average HER2 copy number less than 4.0 signals/cell o Dual-probe HER2/CEP17 ratio less than 2.0 with an average HER2 copy number less than 4.0 signals/cell OR
iii. IHC 1+ as defined by incomplete membrane staining that is faint/barely perceptible and within greater than 10% of the invasive tumor cells.
c. Have had at least one prior chemotherapy in the metastatic setting that is:
i. Hormone receptor negative; OR  
ii. Hormone receptor positive and endocrine therapy refractory.  (NCCN 1)
d. It is contraindicated in those individuals with history of (noninfectious) interstitial lung disease (ILD)/pneumonitis that required steroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening. (NCCN, 2021)
e. Must not have myocardial disease. .For individuals with a history of heart failure, there must be documentation of left ventricular ejection fraction (LVEF) greater than 50%.
f. Must be dosed in accordance with the FDA label.
 
4. 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.
 
a. Must be greater than or equal to18 years of age (FDA, 2022)
b. Must have documentation of unresectable or metastatic nonsquamous NSCLC with activating HER2 mutations as detected in a tumor tissue sample (by Oncomine Dx Target Test) that has:
i. Relapsed during standard treatment OR
ii. Refractory to standard treatment
c. Have at least one measurable lesion (as defined by RECIST)
d. ECOG score of 0 or 1
e. Have had at least one prior line of chemotherapy.  
f. Must be dosed in accordance with the FDA label.
 
The ECOG or Eastern Cooperative Oncology Group Performance Status is based on the following scale:
    • 0 = Fully active, able to carry on all pre-disease performance without restriction
    • 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light housework, office work
    • 2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
    • 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
    • 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
    • 5 = Dead
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
Dosage and Administration
Dosing per FDA Guidelines
 
Breast Cancer – HER2 and HER2 low
The recommended dose is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21 day-cycle) until disease progression or unacceptable toxicity.
 
Gastric Cancer
The recommended dose 6.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cle) until disease progression or unacceptable toxicity.  
 
NSCLC
The recommended dosage for lung cancer is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.
 
Please see FDA prescription guidance for recommended dose modifications, temporary interruption or treatment discontinuation in management of adverse reactions.
 
Fam-trastuzumab debruxtecan-nxki is available as 100 mg lyophilized powder in a single-dose vial.
 
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Fam-trastuzumab deruxtecan-nxki (e.g., Enhertu®), for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
 
For members with contracts without primary coverage criteria, fam-trastuzumab deruxtecan-nxki (e.g., Enhertu®), for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificate of coverage.
 
Effective January 12, 2023 to August 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use fam-trastuzumab deruxtecan-nxki (e.g., Enhertu®) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness improving health outcomes for treatment of adults with the following indications when ALL of the following are met:
 
A. Unresectable or metastatic HER2-positive breast cancer who have received prior anti-HER2 based regimens either in the metastatic setting or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy:
1. Must be > 18 years old (FDA, 2019)
2. Must have documentation of unresectable and/or metastatic HER2 breast cancer:
· Circumferential membrane staining that is complete, intense and in >10% of tumor cells (IHC 3+) – diagnosis is HER2 positive (Wolff, 2018)
· If the HER2/CEP17 ratio remains <2.0 with > 6.0 HER2 signals per cell, diagnosis is HER2 positive (Wolff, 2018)
3. Used as a single-agent as second-line therapy (preferred) (NCCN 1).
4. Must have an ECOG score of 0-1.
5. It is contraindicated in those patients with pneumonitis or interstitial lung disease. (NCCN, 2021)
6. Must not have active brain metastases.
7. Must not have myocardial disease. For individuals with a history of heart failure, there must be documentation of left ventricular ejection fraction (LVEF) greater than 50%.
 
B. Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.
1. Must be >18 years of age (FDA, 2019)
2. Must have documentation of locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma
· Centrally confirmed human epidermal growth factor receptor 2 overexpression (immunohistochemistry [IHC] 3+ or IHC2+/in situ hybridization positive) on archival tissue (or fresh sample if archived tissue is inadequate) (Yamaguchi, 2021)
3. Have had a prior trastuzumab-based regimen. (NCCN 2A)
4. Must have ECOG score of 0-1. (NCCN 2A)
5. It is contraindicated in those patients with history of (noninfectious) interstitial lung disease (ILD)/pneumonitis that required steroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening. (NCCN, 2021)
6. Must not have myocardial disease. .For individuals with a history of heart failure, there must be documentation of left ventricular ejection fraction (LVEF) greater than 50%.
 
C. Unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of competing adjuvant chemotherapy.
 
1. Must be >18 years of age (FDA, 2022)
2. Must have documentation of unresectable and/or metastatic HER2-low breast cancer:
· IHC 2+ based on circumferential membrane staining that is incomplete and/or weak/moderate and within >10% of the invasive tumor cells or complete and circumferential membrane staining that is intense and within ≤10% of the invasive tumor cells.
· ISH negative based on:
· Single-probe average HER2 copy number < 4.0 signals/cell o Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number < 4.0 signals/cell OR
· IHC 1+ as defined by incomplete membrane staining that is faint/barely perceptible and within > 10% of the invasive tumor cells.
3. Have had at least one prior chemotherapy in the metastatic setting that is
· hormone receptor negative.  OR  
· hormone receptor positive and endocrine therapy refractory.  (NCCN 1)
4. It is contraindicated in those patients with history of (noninfectious) interstitial lung disease (ILD)/pneumonitis that required steroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening. (NCCN, 2021)
5. Must not have myocardial disease. .For individuals with a history of heart failure, there must be documentation of left ventricular ejection fraction (LVEF) greater than 50%.
 
D. 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.
 
1. Must be >18 years of age (FDA, 2022)
2. Must have documentation of unresectable or metastatic nonsquamous NSCLC with activating HER2 mutations as detected in a tumor tissue sample (by Oncomine Dx Target Test) that has:
· Relapsed during standard treatment OR
· Refractory to standard treatment
3. Have at least one measurable lesion (as defined by RECIST)
4. ECOG score of 0 or 1
5. Have had at least one prior line of chemotherapy.  
 
The ECOG or Eastern Cooperative Oncology Group Performance Status is based on the following scale:
0 = Fully active, able to carry on all pre-disease performance without restriction
1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light housework, office work
2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5 = Dead
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
Dosage and Administration
 
Breast Cancer – HER2 and HER2 low
The recommended dose is 5.4 mg/kg IV once every 3 weeks (21 day-cycle) until disease progression or unacceptable toxicity.
 
Gastric Cancer
The recommended dose 6.4 mg/kg IV once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.  
 
NSCLC
The recommended dosage for lung cancer is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.
 
Please see FDA prescription guidance for recommended dose modifications, temporary interruption or treatment discontinuation in management of adverse reactions.
 
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Fam-trastuzumab deruxtecan-nxki (e.g., Enhertu®) does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any circumstance or any indication other than those outlined above.
 
For members with contracts without primary coverage criteria, the use of fam-trastuzumab deruxtecan-nxki (e.g., Enhertu®) in any other condition than listed above is considered investigational
 
Investigational services are specific contract exclusions in most member benefit certificate of coverage.
 
Effective September 2022 to January 11, 2023
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use fam-trastuzumab deruxtecan-nxki (Enhertu®) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness improving health outcomes for treatment of adults with the following indications when ALL of the following are met:
 
A. Unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 based regimens either in the metastatic setting or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy:
1. Must be > 18 years old (FDA, 2019)
2. Must have documentation of unresectable and/or metastatic HER2 breast cancer:
· Circumferential membrane staining that is complete, intense and in >10% of tumor cells (IHC 3+) – diagnosis is HER2 positive (Wolff, 2018)
· If the HER2/CEP17 ratio remains <2.0 with > 6.0 HER2 signals per cell, diagnosis is HER2 positive (Wolff, 2018)
3. Have had at least 2 prior anti-HER2 based therapies (i.e. trastuzumab combinations; pertuzumab combinations etc) (NCCN 2A)
4. Must have an ECOG score of 0-1
5. It is contraindicated in those patients with pneumonitis or interstitial lung disease (NCCN, 2021)
6. Must not have active brain metastases.
7. Must not have myocardial disease. .For individuals with a history of heart failure, there must be documentation of left ventricular ejection fraction (LVEF) greater than 50%.
 
B. Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.
1. Must be >18 years of age (FDA, 2019)
2. Must have documentation of locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma
· Centrally confirmed human epidermal growth factor receptor 2 overexpression (immunohistochemistry [IHC] 3+ or IHC2+/in situ hybridization positive) on archival tissue (or fresh sample if archived tissue is inadequate) (Yamaguchi, 2021)
3. Have had a prior trastuzumab-based regimen. (NCCN 2A)
4. Must have ECOG score of 0-1. (NCCN 2A)
5. It is contraindicated in those patients with history of (noninfectious) interstitial lung disease (ILD)/pneumonitis that required steroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening. (NCCN, 2021)
6. Must not have myocardial disease. .For individuals with a history of heart failure, there must be documentation of left ventricular ejection fraction (LVEF) greater than 50%.
 
C. Unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of competing adjuvant chemotherapy.
 
1. Must be >18 years of age (FDA, 2022)
2. Must have documentation of unresectable and/or metastatic HER2-low breast cancer:
· IHC 2+ based on circumferential membrane staining that is incomplete and/or weak/moderate and within >10% of the invasive tumor cells or complete and circumferential membrane staining that is intense and within ≤10% of the invasive tumor cells.
· ISH negative based on:
· Single-probe average HER2 copy number < 4.0 signals/cell o Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number < 4.0 signals/cell OR
· IHC 1+ as defined by incomplete membrane staining that is faint/barely perceptible and within > 10% of the invasive tumor cells.
3. Have had at least one prior chemotherapy in the metastatic setting that is
· hormone receptor negative.  OR  
· hormone receptor positive and endocrine therapy refractory.  (NCCN 1)
4. It is contraindicated in those patients with history of (noninfectious) interstitial lung disease (ILD)/pneumonitis that required steroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening. (NCCN, 2021)
5. Must not have myocardial disease. .For individuals with a history of heart failure, there must be documentation of left ventricular ejection fraction (LVEF) greater than 50%.
 
D. 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.
 
1. Must be >18 years of age (FDA, 2022)
2. Must have documentation of unresectable or metastatic nonsquamous NSCLC with activating HER2 mutations as detected in a tumor tissue sample (by Oncomine Dx Target Test) that has:
· Relapsed during standard treatment OR
· Refractory to standard treatment
3. Have at least one measurable lesion (as defined by RECIST)
4. ECOG score of 0 or 1
5. Have had at least one prior line of chemotherapy.  
 
The ECOG or Eastern Cooperative Oncology Group Performance Status is based on the following scale:
o 0 = Fully active, able to carry on all pre-disease performance without restriction
o 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light housework, office work
o 2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
o 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
o 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
o 5 = Dead
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
Dosage and Administration
 
Breast Cancer – HER2 and HER2 low
The recommended dose is 5.4 mg/kg IV once every 3 weeks (21 day-cycle) until disease progression or unacceptable toxicity.
 
Gastric Cancer
The recommended dose 6.4 mg/kg IV once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.  
 
NSCLC
The recommended dosage for lung cancer is 5.4 mg/kg given as an intravenous infusion once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.
 
Please see FDA prescription guidance for recommended dose modifications, temporary interruption or treatment discontinuation in management of adverse reactions.
 
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Fam-trastuzumab deruxtecan-nxki (e.g., Enhertu®) does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any circumstance or any indication other than those outlined above.
 
For members with contracts without primary coverage criteria, the use of fam-trastuzumab deruxtecan-nxki (e.g., Enhertu®) in any other condition than listed above is considered investigational
 
Investigational services are specific contract exclusions in most member benefit certificate of coverage.
 
Effective August 2021 to August 2022
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use fam-trastuzumab deruxtecan-nxki (Enhertu®) for treatment of adults with the following indications:
 
    1. Unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 based regimens in the metastatic setting meets primary coverage criteria when ALL of the following are met:
 
        1. Must be > 18 years old (FDA, 2019)
        2. Must have documentation of unresectable and/or metastatic HER2 breast cancer:
            • Circumferential membrane staining that is complete, intense and in >10% of tumor cells (IHC 3+) – diagnosis is HER2 positive (Wolff, 2018)
            • If the HER2/CEP17 ratio remains <2.0 with > 6.0 HER2 signals per cell, diagnosis is HER2 positive (Wolff, 2018)
3. Have had at least 2 prior anti-HER2 based therapies (i.e. trastuzumab combinations; pertuzumab combinations etc)  (NCCN 2A)
4. Must have an ECOG score of 0-1
5. It is contraindicated in those patients with pneumonitis or interstitial lung disease (NCCN, 2021)
6. Must not have active brain metastases.
7. Must not have myocardial disease.
 
2. Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.
 
        1. Must be >18 years of age (FDA, 2019)
        2. Must have documentation of locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma
            • Centrally confirmed human epidermal growth factor receptor 2 overexpression (immunohistochemistry [IHC] 3+ or IHC2+/in situ hybridization positive) on archival tissue (or fresh sample if archived tissue is inadequate) (Yamaguchi, 2021)
3. Have had a prior trastuzumab-based regimen. (NCCN 2A)
4. Must have ECOG score of 0-1. (NCCN 2A)
5. It is contraindicated in those patients with history of (noninfectious) interstitial lung disease (ILD)/pneumonitis that required steroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening. (NCCN, 2021)
6. Must not have myocardial disease.
 
The ECOG or Eastern Cooperative Oncology Group Performance Status is based on the following scale:
    • 0 = Fully active, able to carry on all pre-disease performance without restriction
    • 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light housework, office work
    • 2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
    • 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
    • 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
    • 5 = Dead
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
Dosage and Administration
 
Breast Cancer
The recommended dose is 5.4 mg/kg IV once every 3 weeks (21 day-cycle) until disease progression or unacceptable toxicity.
 
Gastric Cancer
The recommended dose 6.4 mg/kg IV once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.  
 
Please see FDA prescription guidance for recommended dose modifications, temporary interruption or treatment discontinuation in management of adverse reactions.
 
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
 
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Fam-trastuzumab deruxtecan-nxki (Enhertu®) does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any circumstance or any indication other than those outlined above.
 
For members with contracts without primary coverage criteria, the use of fam-trastuzumab deruxtecan-nxki (Enhertu®) in any other condition than listed above is considered investigational
 
Investigational services are specific contract exclusions in most member benefit certificate of coverage.
 
Effective July 2021
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use fam-trastuzumab deruxtecan-nxki (Enhertu®) for treatment of adults with the following indications:
 
    1. Unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 based regimens in the metastatic setting meets primary coverage criteria when ALL of the following are met:
 
        1. Must be > 18 years old.  
        2. Must have documentation of unresectable and/or metastatic HER2 breast cancer:
            • Circumferential membrane staining that is complete, intense and in >10% of tumor cells (IHC 3+) – diagnosis is HER2 positive.
            • If the HER2/CEP17 ratio remains <2.0 with > 6.0 HER2 signals per cell, diagnosis is HER2 positive
3. Have had at least 2 prior anti-HER2 based therapies (i.e. trastuzumab combinations; pertuzumab combinations etc)  
4. Must have an ECOG score of 0-1
5. It is contraindicated in those patients with pneumonitis or interstitial lung disease.
6. Must not have active brain metastases.
7. Must not have myocardial disease.
 
2. Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen.
        1. Must be >18 years of age
        2. Must have documentation of locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma
            • Centrally confirmed human epidermal growth factor receptor 2 overexpression (immunohistochemistry [IHC] 3+ or IHC2+/in situ hybridization positive) on archival tissue (or fresh sample if archived tissue is inadequate)
3. Have had progression on and after >2 prior regimens that included fluoropyrimidine, a platinum agent, and trastuzumab or approved trastuzumab biosimilar.
4. Must have ECOG score of 0-1.
5. It is contraindicated in those patients with history of (noninfectious) interstitial lung disease (ILD)/pneumonitis that required steroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
6. Must not have myocardial disease.
 
The ECOG or Eastern Cooperative Oncology Group Performance Status is based on the following scale:
    • 0 = Fully active, able to carry on all pre-disease performance without restriction
    • 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light housework, office work
    • 2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
    • 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
    • 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
    • 5 = Dead
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
 
Dosage and Administration
 
Breast Cancer
The recommended dose is 5.4 mg/kg IV once every 3 weeks (21 day-cycle) until disease progression or unacceptable toxicity.
 
Gastric Cancer
The recommended dose 6.4 mg/kg IV once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.  
 
Please see FDA prescription guidance for recommended dose modifications, temporary interruption or treatment discontinuation in management of adverse reactions.
 
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
 
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Fam-trastuzumab deruxtecan-nxki (Enhertu®) does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for any circumstance or any indication other than those outlined above.
 
For members with contracts without primary coverage criteria, the use of fam-trastuzumab deruxtecan-nxki (Enhertu®) in any other condition than listed above is considered investigational
 
Investigational services are specific contract exclusions in most member benefit certificate of coverage.
 
 
Effective July 2020 to June 2021
 
Policy/guidelines:
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
The use fam-trastuzumab deruxtecan-nxki (Enhertu®) for treatment of adults with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 based regimens in the metastatic setting meets primary coverage criteria when ALL of the following are met
 
    1. Must be > 18 years old.  
    2. Must have documentation of unresectable and/or metastatic HER2 breast cancer:
      • Circumferential membrane staining that is complete, intense and in >10% of tumor cells (IHC 3+) – diagnosis is HER2 positive.
      • If the HER2/CEP17 ratio remains <2.0 with > 6.0 HER2 signals per cell, diagnosis is HER2 positive
3. Have had at least 2 prior anti-HER2 based therapies (i.e. trastuzumab combinations; pertuzumab combinations etc)  
4. Must have an ECOG score of 0-1
5. It is contraindicated in those patients with pneumonitis or interstitial lung disease.
 
The ECOG or Eastern Cooperative Oncology Group Performance Status is based on the following scale:
    • 0 = Fully active, able to carry on all pre-disease performance without restriction
    • 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light house work, office work
    • 2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
    • 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
    • 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
    • 5 = Dead
 
NCCN 1 and 2A recommendations are covered in accordance with Coverage Policy #2000030
 
Dosage and Administration
The recommended dose is 5.4 mg/kg IV once every 3 weeks (21 day-cycle) until disease progression or unacceptable toxicity.
    • Please see FDA prescription guidance for recommended dose modifications, temporary interruption or treatment discontinuation in management of adverse reactions.  
 
Please refer to a separate policy on Site of Care or Site of Service Review policy #2018030 for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
For members with contracts without primary coverage criteria, the use of fam-trastuzumab deruxtecan-nxki (Enhertu®) in any other condition (such a gastric cancer) than listed above is considered investigational
 
Investigational services are specific contract exclusions in most member benefit certificate of coverage.
Rationale:
A phase 2 study (Modi S, et al 2019) was performed with trastuzumab deruxtecan in 184 patients with HER2 positive pathologically documented unresectable or metastatic breast cancer who had previously treated with trastuzumab emtansine. Eligible patients were age 18 or greater and had an ECOG score of 0 or 1.  Excluded reasons were untreated or symptomatic brain metastases, history of noninfectious interstitial lung disease, (ILD), or pneumonitis or current or suspected ILD or pneumonitis. This study was evaluating the safety and efficacy of the recommended dose, 5.4 mg/kg, in those who in the first phase received this dose.  
 
The primary endpoint was overall response (complete plus partial response) to the trastuzumab deruxtecan therapy in those who had tumor progression during or after trastuzumab emtansine and had received the 5.4 mg/kg of trastuzumab deruxtecan in phase 1 and 2 of the study. Secondary endpoints included response duration, progression free survival and overall survival rate.
 
Of the 184 participants, 52.7% had hormone receptor-positive tumors.  Median number or previous lines of therapy for metastatic disease was 6 and 100% included trastuzumab emtansine, and trastuzumab and 65.8% had pertuzumab. Results showed an overall response rate of 60.3%, complete response rate of 4.3% and a partial response rate of 56%.  There was also a median duration of response of 14.8 months and a disease control rate of 97.3%.  Median progression free survival (PFS) was 13.4 months, after a median follow-up of 11.1 months.  9% of the patients experienced ILD including severe, life threatening and fatal cases.  Fatal outcomes from either ILD or pneumonitis occurred in 2.6%of patients.
 
2021 Update
In an open-label, randomized, phase 2 trial, trastuzumab deruxtecan as compared with chemotherapy in patients with HER2-positive advanced gastric cancer was evaluated. Patients with centrally confirmed HER2-positive gastric or gastroesophageal junction adenocarcinoma that had progressed while they were receiving at least two previous therapies, including trastuzumab, were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan (6.4 mg per kilogram of body weight every 3 weeks) or physician’s choice of chemotherapy. The primary end point was the objective response, according to independent central review. Secondary end points included overall survival, response duration, progression-free survival, confirmed response (response persisting ≥4 weeks), and safety.
 
Of 187 treated patients, 125 received trastuzumab deruxtecan and 62 chemotherapy (55 received irinotecan and 7 paclitaxel). An objective response was reported in 51% of the patients in the trastuzumab deruxtecan group, as compared with 14% of those in the physician’s choice group (P<0.001). Overall survival was longer with trastuzumab deruxtecan than with chemotherapy (median, 12.5 vs. 8.4 months; hazard ratio for death, 0.59; 95% confidence interval, 0.39 to 0.88; P = 0.01, which crossed the prespecified O’Brien–Fleming boundary [0.0202 on the basis of number of deaths]). The most common adverse events of grade 3 or higher were a decreased neutrophil count (in 51% of the trastuzumab deruxtecan group and 24% of the physician’s choice group), anemia (38% and 23%, respectively), and decreased white-cell count (21% and 11%). A total of 12 patients had trastuzumab deruxtecan–related interstitial lung disease or pneumonitis (grade 1 or 2 in 9 patients and grade 3 or 4 in 3), as adjudicated by an independent committee. One drug-related death (due to pneumonia) was noted in the trastuzumab deruxtecan group; no drug related deaths occurred in the physician’s choice group.
 
Therapy with trastuzumab deruxtecan led to significant improvements in response and overall survival, as compared with standard therapies, among patients with HER2-positive gastric cancer. Myelosuppression and interstitial lung disease were the notable toxic effects. (Shitara K, Bang YJ, Iwasa S, et. al., 2020).
 
2022 Update
HER 2-low breast cancer
HER2-low breast cancer is a newly defined breast cancer subtype. According to the FDA, “about 60% of patients previously classified as having HER2-negative subtype can now be considered as HER2-low.” It describes cancers that have “some HER2 proteins on the cell surface, but not enough to be classified as HER2-positive.” HER2-low breast cancers may be hormone receptor-positive (HR+) or triple negative.
 
Fam-trastuzumab deruxtecan’ s expanded approval for HER 2-low breast cancer was based on data from the multicenter, open-label DESTINY-Breast04 trial, which enrolled 557 adult patients with unresectable or metastatic HER2-low breast cancer, including both HR- and HR+ patients. Low HER2 expression was defined as an immunohistochemistry (IHC) score of 1+ or 2+ with a negative in situ hybridization (ISH) test. Patients were randomized 2:1 to receive either Enhertu every 3 weeks or physician’s choice of chemotherapy.
 
Treatment with fam-trastuzumab deruxtecan resulted in a median progression-free survival (PFS) of 9.9 months (95% CI, 9.0–11.3) versus 5.1 months (95% CI, 4.2–6.8) with chemotherapy (hazard ratio, 0.50; 95% CI, 0.40–0.63). The median overall survival was 23.4 months (95% CI, 20.0–24.8) with fam-trastuzumab deruxtecan compared with 16.8 months (95% CI, 14.5–20.0) with chemotherapy, translating to a 6.6-month improvement in survival (hazard ratio, 0.64; 95% CI, 0.49–0.84; P = 0.001).
An estimated 287,850 new cases of female breast cancer will be diagnosed in the United States in 2022, of which 80%– 85% were previously considered to be HER2-negative. About 60% of these cancers previously defined as HER2-negative can now be considered HER2-low (approximately 48%–51% of all new U.S. breast cancer cases). Patients with HER2-low breast cancer will be eligible for fam-trastuzumab deruxtecan if they have received a prior chemotherapy in the metastatic setting, or their cancer returned during, or within 6 months of completing, adjuvant chemotherapy.
HER2-Mutant NSCLC
The accelerated approval by the FDA was based on the results from the DESTINY-Lung02 Phase II trial. A total of 91 patients were enrolled. The median duration of follow-up was 13.1 months (range, 0.7 to 29.1). Centrally confirmed objective response occurred in 55% of the patients (95% confidence interval [CI], 44 to 65). The median duration of response was 9.3 months (95% CI, 5.7 to 14.7). Median progression-free survival was 8.2 months (95% CI, 6.0 to 11.9), and median overall survival was 17.8 months (95% CI, 13.8 to 22.1). The safety profile was generally consistent with those from previous studies; grade 3 or higher drug-related adverse events occurred in 46% of patients, the most common event being neutropenia (in 19%). Adjudicated drug-related interstitial lung disease occurred in 26% of patients and resulted in death in 2 patients. Responses were observed across different HER2 mutation subtypes, as well as in patients with no detectable HER2 expression or HER2 amplification.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through September 2023. No new literature was identified that would prompt a change in the coverage statement.
CPT/HCPCS:
J9358Injection, fam trastuzumab deruxtecan nxki, 1 mg
References: Enhertu®,(fam-trastzumab deruxtecan-nxki). [package insert]. Basking Ridge, NJ: Daiichi Sankyo, Inc; 2019.

Modi S, et al.(2019) Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med 2020;382:610-21. DOI: 10:1056/NEJMoa1914510

National Comprehensive Cancer Network (NCCNA)(2021) National Comprehensive Cancer Network, Inc. 2021 Practice Guidelines in Oncology—Breast Cancer v.5.2021. Available at https://www.nccn.org/professionals/drug_compendium/content/. Accessed August 16, 2021.

National Comprehensive Cancer Network (NCCNA)(2021) National Comprehensive Cancer Network, Inc. 2021 Practice Guidelines in Oncology—Gastric Cancer. V.4.2021. Available at https://www.nccn.org/professionals/drug_compendium/content/. Accessed August 16, 2021.

NCCN Guidelines®.(2020) Breast Cancer version 4.2020 – May 18,2020 Last accessed 6/20/2020.

Shitara K, Bang YJ, Iwasa S, et.al.(2020) Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer. N Engl J Med. 2020 Jun 18;382(25):2419-2430. doi: 10.1056/NEJMoa2004413. Epub 2020 May 29. PMID: 32469182.

U.S. Food and Drug Administration (FDA).(2019) fam-trastuzumab deruxtecan-nxki. Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209939orig1s000,209940orig1s000lbl.pdf. Last accessed August 16, 2021.

Wolff AC, Hammond EH, Allison KH, et.al.(2018) 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 2018:36:20:2105-24 DOI: https://doi.org/10.1200/JCO.2018.778738.

Yamaguchi K, Bang YJ, Iwasa S, et. al.,(2021) Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-positive advanced gastric or gastroesophageal junction (FEJ) adenocarcinoma: Final overall survival (OS) results from a randomized, multicenter, ope-label, phase 2 study (DESTINY-Gastric01). ASCO Annual Meeting 2021. J Clin Oncol 39, 2021. DOI:10.1200/JCO.2021.39.15_suppl.4048
Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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