Commercial

Medical Policy

Notification

Trastuzumab (Herceptin®) and Related Biosimilars, Trastuzumab and Hyaluronidase-oysk (Herceptin Hylecta)

Notification Issue Date:

This version of the policy will become effective 05/15/2020.

This policy has been updated to communicate the Company's designation of two biosimilars as its preferred products: trastuzumab-qyyp (Trazimera^TM) and trastuzumab-anns (Kanjinti^TM)

On February 20, 2020, the following language was added to the Company-Designated Preferred Products section of the Policy section: Coverage of a biosimilar product as an alternate to a reference product is not considered a form of step therapy by the Company.

Title:

Trastuzumab (Herceptin®) and Related Biosimilars, Trastuzumab and Hyaluronidase-oysk (Herceptin Hylecta)

Policy #:

08.00.33w

Policy

The Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition.

MEDICALLY NECESSARY

COMPANY-DESIGNATED PREFERRED PRODUCTS
Although there are many trastuzumab products on the market (e.g., trastuzumab [Herceptin], trastuzumab-qyyp [Trazimera], trastuzumab-anns [Kanjinti], trastuzumab-dttb [Ontruzant], trastuzumab-pkrb [Herzuma], trastuzumab-dkst [Ogivri], trastuzumab-strf [Hercessi]), there is no reliable evidence of the superiority of any one product of trastuzumab compared with other products. The Company has designated the following trastuzumab biosimilar products as its preferred products: trastuzumab-dttb (Ontruzant), trastuzumab-dkst (Ogivri), and trastuzumab-anns (Kanjinti).

These products are less costly and at least as likely to produce equivalent therapeutic results as the nonpreferred products, which include, but are not limited to, trastuzumab (Herceptin) and any other nonpreferred trastuzumab biosimilars.

According to the US Food and Drug Administration (FDA), “a biosimilar is a biological product that has no clinically meaningful differences from the existing FDA-approved reference product. All biosimilar products meet the FDA’s rigorous standards for approval for the indications described in the product labeling. Once a biosimilar has been approved by the FDA, the safety and effectiveness of these products have been established, just as they have been for the reference product.” Coverage of a biosimilar product as an alternate to a reference product is not considered a form of step therapy by the Company.

NON-PREFERRED PRODUCTS

Use of a non-preferred product trastuzumab (Herceptin) or any non-preferred biosimilar to treat the specified indication is eligible for coverage when the individual has documentation of a contraindication(s) or intolerance(s) (e.g., as documented per the FDA labeling), or inadequate response to the preferred product.

TRASTUZUMAB AND RELATED BIOSIMILARS
Trastuzumab and related biosimilars are considered medically necessary and, therefore, covered for individuals whose human epidermal growth factor receptor 2 (HER2) status has been verified by one of the FDA-approved diagnostic tests listed in the guideline section and the individual has a left ventricular ejection fraction of 50% or greater for the following indications and regimens when the requirements for COMPANY-DESIGNATED PREFERRED PRODUCTS and NON-PREFERRED PRODUCTS are met:

Adjuvant Breast Cancer

As adjuvant therapy for HER2-overexpressing node-positive or node-negative (estrogen receptor/progesterone receptor [ER/PR] negative or with one high-risk feature) breast cancer as part of a treatment regimen containing:

Doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel
Docetaxel and carboplatin
As a single agent following multimodality anthracycline-based therapy

Invasive Breast Cancer

As adjuvant systemic therapy** for individuals with HER2-positive tumors and (pT1-3 and pN0 or pN+ tumors) disease for any of the following regimens:

In combination with paclitaxel following AC (doxorubicin and cyclophosphamide) regimen (dose-dense or every 3 weeks) (both useful in certain circumstances)*
As a component of TCH (docetaxel, carboplatin, and trastuzumab) regimen (National Comprehensive Cancer Network [NCCN]-preferred regimen)
In combination with docetaxel following AC regimen*
In combination with paclitaxel, carboplatin, and pertuzumab for pT2-3 and pN0 or pN+ tumors only
In combination with docetaxel and cyclophosphamide
As a component of TCHP (docetaxel, carboplatin, trastuzumab, and pertuzumab) regimen (NCCN-preferred regimen) for pT2-3 and pN0 or pN+ tumors only
In combination with pertuzumab and paclitaxel following AC regimen (dose-dense or every 3 weeks) for pT2-3 and pN0 or pN+ tumors only*
In combination with pertuzumab and docetaxel following AC regimen for pT2-3 and pN0 or pN+ tumors only*
In combination with paclitaxel and pertuzumab for pT2-3 and pN0 or pN+ tumors only
in combination with docetaxel and pertuzumab
In combination with paclitaxel for low-risk T1, N0, M0, HER2-positive tumors particularly for individuals not eligible for other standard adjuvant regimens due to comorbidities (NCCN-preferred regimen)

NCCN notes:

*It is acceptable to change administration sequence to taxane (with or without HER2-targeted therapy) followed by AC.
**If no residual disease after preoperative therapy or no preoperative therapy, complete up to 1 year of HER2-targeted therapy with trastuzumab with or without pertuzumab after completing planned chemotherapy regimen course. If residual disease is present after preoperative therapy and adotrastuzumab emtansine is discontinued for toxicity, then trastuzumab with or without pertuzumab to complete 1 year of therapy can be used (NCCN preferred).

As preoperative systemic therapy for individuals with HER2-positive tumors and locally advanced c≥T2 or cN+ and M0 disease or cT1c, cN0 disease for any of the following regimens:

As a component of TCHP (docetaxel, carboplatin, trastuzumab, and pertuzumab) regimen (NCCN-preferred regimen)
In combination with docetaxel with or without pertuzumab following AC regimen*
In combination with paclitaxel, carboplatin, and pertuzumab
In combination with paclitaxel following AC (doxorubicin and cyclophosphamide) regimen (dose-dense or every 3 weeks) (both useful in certain circumstances)*
In combination with paclitaxel and pertuzumab following AC regimen (dose-dense or every 3 weeks) (both useful in certain circumstances)*
In combination with docetaxel and cyclophosphamide
In combination with paclitaxel and pertuzumab
In combination with docetaxel and pertuzumab

NCCN note: *It is acceptable to change the administration sequence to taxane (with or without HER2-targeted therapy) followed by AC.

Treatment of recurrent unresectable (local or regional) or stage IV (M1) hormone receptor-positive HER2-positive disease in postmenopausal women* or premenopausal women treated with (or without if used with tamoxifen) ovarian ablation/suppression

In combination with tamoxifen
In combination with fulvestrant
In combination with aromatase inhibition with or without lapatinib
As first-line therapy in combination with an aromatase inhibitor, palbociclib and pertuzumab

NCCN notes: *Men with breast cancer should be treated similarly to postmenopausal women, except that use of an aromatase inhibitor is ineffective without concomitant suppression of testicular steroidogenesis

For recurrent unresectable (local or regional) or stage IV (M1) HER2-positive disease that is either hormone receptor-negative, or hormone receptor-positive with or without endocrine therapy for any of the following:

As NCCN-preferred first-line therapy in combination with pertuzumab with either docetaxel or paclitaxel
As fourth-line therapy and beyond in combination with docetaxel, vinorelbine, or capecitabine, or with paclitaxel with or without carboplatin
As fourth-line therapy and beyond in combination with cyclophosphamide, eribulin, gemcitabine, ixabepilone, lapatinib (without cytotoxic therapy), or albumin-bound paclitaxel
In combination with pertuzumab with or without cytotoxic therapy (e.g., vinorelbine or taxane) for one line of therapy in individuals previously treated with chemotherapy and trastuzumab in the absence of pertuzumab

As second or third-line therapy and beyond in combination with capecitabine and tucatinib (NCCN preferred in individuals with both systemic and central nervous system [CNS] progression in the third-line setting and beyond) for recurrent unresectable (local or regional) or stage IV (M1) HER2-positive disease that is:

Hormone receptor-negative
Hormone receptor-positive with or without endocrine therapy

As NCCN-preferred adjuvant systemic therapy for individuals with HER2-positive tumors and locally advanced disease, following completion of planned chemotherapy and following mastectomy or breast-conserving surgery (BCS) with surgical axillary staging, for any of the following:

With or without pertuzumab if ypT0N0 or pCR
With or without pertuzumab ypT1-4N0 or ypN≥1 (if ado-trastuzumab discontinued for toxicity)
With pertuzumab if ypT1-4N0 or ypN≥1 and node positive at initial staging (if ado-trastuzumab discontinued for toxicity)
With pertuzumab if ypT0N0 or pCR and node positive at initial staging

As third-line and beyond therapy in combination with neratinib and fulvestrant for individuals with stage IV (M1) disease with HER2 (ERBB2) activating mutations* and one of the following:

Hormone receptor (estrogen and/or progesterone) positive, HER2-negative disease in individuals who have already received a CDK4/6 inhibitor therapy, or
Triple negative disease

As third-line and beyond therapy in combination with tucatinib with or without fulvestrant for individuals with stage IV (M1) disease with HER2 (ERBB2) activating mutations* and one of the following:

Hormone receptor (estrogen and/or progesterone) positive, HER2-negative disease in individuals who have already received a CDK4/6 inhibitor therapy, or

Triple negative disease

*See GUIDELINES section for this mutation list.

Inflammatory Breast Cancer

Preoperative systemic therapy for HER2-positive disease for any of the following:

As a component of TCHP (docetaxel, carboplatin, trastuzumab, and pertuzumab) regimen (NCCN-preferred regimen)
In combination with docetaxel with or without pertuzumab following AC regimen*
In combination with paclitaxel, carboplatin, and pertuzumab
In combination with paclitaxel following AC (doxorubicin and cyclophosphamide) regimen (dose-dense or every 3 weeks)*
In combination with paclitaxel and pertuzumab following AC regimen (dose-dense or every 3 weeks)*
In combination with paclitaxel and pertuzumab
In combination with docetaxel and pertuzumab

NCCN notes: *It is acceptable to change administration sequence to taxane followed by AC.

For the treatment of individuals with recurrent unresectable (local or regional) or stage IV (M1) hormone receptor–positive HER2-positive disease in postmenopausal women* or premenopausal women treated with ovarian ablation/suppression in combination with tamoxifen, fulvestrant, or aromatase inhibition with or without lapatinib.
Used in combination with tamoxifen, fulvestrant, or aromatase inhibition with or without lapatinib, for the treatment of individuals with recurrent unresectable (local or regional) or stage IV (M1) hormone receptor–positive HER2-positive disease in postmenopausal women* or premenopausal women treated with ovarian ablation/suppression
Treatment of individuals with no response to preoperative systemic therapy or recurrent unresectable (local or regional) or stage IV (M1) hormone receptor-positive HER2-positive disease in postmenopausal women* or premenopausal women treated with (or without if used with tamoxifen) ovarian ablation/suppression
- In combination with tamoxifen
- In combination with fulvestrant
- In combination with aromatase inhibition with or without lapatinib
- As first-line therapy in combination with an aromatase inhibitor, palbociclib and pertuzumab

As a third-line therapy and beyond (may also be given in the second-line setting) in combination with capecitabine and tucatinib (NCCN preferred in individuals with both systemic and CNS progression in the third-line setting and beyond) for individuals with no response to preoperative systemic therapy, or recurrent unresectable (local or regional) or stage IV (M1) HER2-positive disease that is:

Hormone receptor-negative
Hormone receptor-positive with or without endocrine therapy

NCCN notes: *It is acceptable to change administration sequence to taxane (with or without HER2-targeted therapy) followed by AC.

For individuals with no response to preoperative systemic therapy, or recurrent unresectable (local or regional) or stage IV (M1) HER2-positive disease that is either hormone receptor-negative, or hormone receptor-positive with or without endocrine therapy for any of the following lines of therapy:

As NCCN-preferred first-line therapy in combination with pertuzumab with either docetaxel or paclitaxel
As fourth-line therapy and beyond in combination with docetaxel, vinorelbine, or capecitabine, or with paclitaxel with or without carboplatin
As fourth-line therapy and beyond in combination with cyclophosphamide, eribulin, gemcitabine, ixabepilone, lapatinib (without cytotoxic therapy), or albumin-bound paclitaxel
In combination with pertuzumab with or without cytotoxic therapy (e.g., vinorelbine or taxane) for one line of therapy in individuals previously treated with chemotherapy and trastuzumab in the absence of pertuzumab

Adjuvant systemic therapy** for individuals who had a response to preoperative systemic therapy, followed by surgery, and need to complete planned chemotherapy, for individuals with HER2-positive tumors for any of the following regimens:

In combination with paclitaxel following AC (doxorubicin and cyclophosphamide) regimen (dose-dense or every 3 weeks)*
As a component of TCH (docetaxel, carboplatin, and trastuzumab) regimen (NCCN-preferred regimen)
In combination with docetaxel following AC regimen*
In combination with paclitaxel, carboplatin, and pertuzumab for node-positive pT2-3 and pN0 or pN+ tumors only
In combination with docetaxel and cyclophosphamide
As a component of TCHP (docetaxel, carboplatin, trastuzumab, and pertuzumab) regimen (NCCN-preferred regimen) for pT2-3 and pN0 or pN+ tumors only
In combination with pertuzumab and paclitaxel following AC regimen (dose-dense or every 3 weeks) for node-positive pT2-3 and pN0 or pN+ tumors only*
In combination with pertuzumab and docetaxel following AC regimen for pT2-3 and pN0 or pN+ tumors only*
In combination with paclitaxel and pertuzumab for pT2-3 and pN0 or pN+ tumors
In combination with docetaxel and pertuzumab
In combination with paclitaxel for low-risk T1, N0, M0, HER2-positive tumors particularly for individuals not eligible for other standard adjuvant regimens due to comorbidities (NCCN-preferred regimen)

NCCN notes: *It is acceptable to change administration sequence to taxane (with or without HER2-targeted therapy) followed by AC.
**If no residual disease after preoperative therapy or no preoperative therapy, complete up to 1 year of HER2-targeted therapy with trastuzumab with or without pertuzumab after completing planned chemotherapy regimen course. If residual disease is present after preoperative therapy and ado-trastuzumab emtansine is discontinued for toxicity, then trastuzumab with or without pertuzumab to complete 1 year of therapy can be used (NCCN preferred).

As third-line and beyond therapy in combination with tucatinib with or without fulvestrant for individuals with stage IV (M1) disease with HER2 (ERBB2) activating mutations* and one of the following:

Hormone receptor positive HER2-negative disease in individuals who have already received a CDK4/6 inhibitor therapy
Triple negative disease

Metastatic Breast Cancer

As first-line therapy for HER2-overexpressing metastatic breast cancer in combination with paclitaxel
As a single agent for the treatment of HER2-overexpressing breast cancer in individuals who have received one or more chemotherapy regimens for metastatic disease

Central Nervous System Metastases

Intra-cerebrospinal fluid (CSF) treatment for leptomeningeal metastases from HER2-positive breast cancer, as part of the following treatment options:

Primary treatment of individuals with good risk status (Karnofsky performance score [KPS] ≥60, no major neurologic deficits, minimal systemic disease, and reasonable systemic treatment options if needed)
As a maintenance therapy for individuals with negative CSF cytology or for clinically stable individuals with persistently positive CSF cytology

As NCCN-preferred regimen for limited brain metastases treatment, in combination with capecitabine and tucatinib as a treatment in individuals with HER2-positive breast cancer, if previously treated with one or more regimens:

As initial treatment in select individuals (e.g., individuals with small asymptomatic brain metastases) for newly diagnosed or stable systemic disease or if reasonable systemic treatment options exist
Treatment for recurrent brain metastases

As NCCN-preferred regimen for treatment of extensive brain metastases in combination with capecitabine and tucatinib in individuals with HER2-positive breast cancer if previously treated with one or more anti-HER2–based regimens:

As primary treatment in select individuals (e.g., individuals with small asymptomatic brain metastases)
Treatment for recurrent disease with either stable systemic disease or reasonable systemic treatment options

For extensive brain metastases in high doses in combination with pertuzumab as treatment in individuals with HER2-positive breast cancer for any of the following indications:
- As primary treatment in select individuals (e.g., individuals with small asymptomatic brain metastases)
- As a treatment for a recurrent disease with stable systemic disease or reasonable systemic treatment options
For limited brain metastases in high doses in combination with pertuzumab as treatment in individuals with HER2-positive breast cancer for any of the following indications:
- As initial treatment in select individuals (e.g., individuals with small asymptomatic brain metastases) for newly diagnosed or stable systemic disease or if reasonable systemic treatment options exist
- As a treatment for recurrent brain metastases

Appendiceal Neoplasms and Cancers

Second-line and subsequent therapy (if not previously given) in combination with pertuzumab or tucatinib for individuals with HER2-positive and RAS and BRAF wild type (WT) disease for any of the following
- Recurrence with serial tumor marker elevation or radiographic progression and progressive or positive findings
- Biopsy-proven recurrence of high-risk disease if cytoreductive surgery was previously received or not possible
- Progressive disease or inadequate response after neoadjuvant systemic therapy for metastatic peritoneal-only disease
- Extraperitoneal disease

Colon Cancer

Second-line and subsequent therapy (biomarker-directed) in combination with pertuzumab, lapatinib, or tucatinib for progression of advanced or metastatic disease (HER2-amplified and RAS and BRAF wild type) pMMR/MSS or ineligible for or progressed on checkpoint inhibitor immunotherapy for dMMR/MSI-H or POLE/POLD1 mutation with ultrahypermutated phenotype (e.g., TMB >50 mut/Mb) not previously treated with HER2 inhibitor

Initial treatment in combination with pertuzumab, lapatinib, or tucatinib in individuals (HER2-amplified and RAS and BRAF wild-type) deficient mismatch repair/microsatellite instability-high [dMMR/MSI-H] or polymerase epsilon/delta (POLE/POLD1) mutation with ultrahypermutated phenotype (e.g., TMB >50 mut/Mb and individual is not a candidate for immunotherapy) for individuals with unresectable metachronous metastases and previous FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPEOX (capecitabine and oxaliplatin) within the past 12 months

Therapy in combination with pertuzumab or lapatinib in individuals (HER2-amplified and RAS and BRAF wild-type) (pMMR/MSS) or ineligible for or progressed on checkpoint inhibitor immunotherapy for dMMR/MSI-H or POLE/POLD1 mutation with ultrahypermutated phenotype (e.g., TMB >50 mut/Mb) if intensive therapy not recommended and no previous treatment with a HER2 inhibitor for any of the following conditions:

As primary treatment for locally unresectable or medically inoperable disease
As primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for individuals with existing or imminent obstruction
For synchronous unresectable metastases of other sites
As initial treatment for unresectable metachronous metastases in individuals who have not received previous adjuvant FOLFOX or CapeOX within the past 12 months, who have received previous fluorouracil/leucovorin (5-FU/LV) or capecitabine therapy, or who have not received any previous chemotherapy

Esophageal, Esophagogastric Junction

As palliative therapy for individuals who are not surgical candidates or have an unresectable locally advanced, recurrent, or metastatic disease with HER2 (ERBB2)-positive (IHC 3+ or IHC 2+ and ISH/FISH+) adenocarcinoma and KPS of 60% or greater, or Eastern Cooperative Oncology Group (ECOG) performance score of two or less, as first-line therapy in combination with any of the following systemic chemotherapy:
- Fluorouracil or capecitabine and oxaliplatin or cisplatin (NCCN preferred)
- Fluorouracil and irinotecan
- Paclitaxel with or without carboplatin or cisplatin
- Docetaxel with or without cisplatin
- Fluorouracil
- Capecitabine
- Docetaxel, cisplatin or oxaliplatin, and fluorouracil
As NCCN-preferred palliative therapy for HER2-overexpression–positive adenocarcinoma in individuals who are not surgical candidates or have unresectable locally advanced, recurrent, or metastatic disease and KPS 60% or greater or ECOG performance score 2 or less as first-line therapy in combination with one of the following:

Fluorouracil, cisplatin or oxaliplatin, and pembrolizumab (if no prior checkpoint inhibitor or if no prior tumor progression while on therapy with a checkpoint inhibitor)
Capecitabine, cisplatin or oxaliplatin, and pembrolizumab (if no prior checkpoint inhibitor or if no prior tumor progression while on therapy with a checkpoint inhibitor)

Gastric Cancers

Primary treatment in combination with systemic chemotherapy for individuals who are medically fit for surgery but with surgically unresectable locoregional HER2 (ERBB2)-positive (IHC 3+ or IHC 2+ and ISH/FISH+) adenocarcinoma in combination with any of the following regimens:

Fluorouracil or capecitabine and oxaliplatin or cisplatin (NCCN preferred)
Fluorouracil and irinotecan
Paclitaxel with or without carboplatin or cisplatin
Docetaxel with or without cisplatin
Fluorouracil
Capecitabine
Docetaxel, cisplatin or oxaliplatin, and fluorouracil

As palliative therapy for individuals who are not surgical candidates or have unresectable locally advanced, recurrent, or metastatic disease (including peritoneal only metastatic disease, including positive cytology) with HER2 (ERBB2)-positive (IHC 3+ or IHC 2+ and ISH/FISH+) adenocarcinoma with PD-L1 CPS ≥1 and KPS ≥60% or ECOG performance score ≤2 as first-line therapy in combination with any of the following:

Cisplatin, pembrolizumab, and fluorouracil or capecitabine (if no prior tumor progression while on therapy with a checkpoint inhibitor) (NCCN preferred)
Oxaliplatin, pembrolizumab, and fluorouracil or capecitabine (if no prior tumor progression while on therapy with a checkpoint inhibitor) (NCCN preferred)

As primary treatment (NCCN preferred) for medically fit individuals with surgically unresectable locoregional HER2 (ERBB2)-positive (IHC 3+ or IHC 2+ and ISH/FISH+) adenocarcinoma and PD-L1 CPS ≥1 is given in combination with one of the following:

Cisplatin, pembrolizumab, and fluorouracil or capecitabine
Oxaliplatin, pembrolizumab, and fluorouracil or capecitabine

Palliative therapy for individuals who are not surgical candidates or have unresectable locally advanced, recurrent, or metastatic disease (including peritoneal only metastatic disease, including positive cytology) with HER2 (ERBB2)-positive (IHC 3+ or IHC 2+ and ISH/FISH+) adenocarcinoma and KPS ≥60% or ECOG performance score ≤2 as first-line therapy in combination with any systemic chemotherapy listed below:

Fluorouracil or capecitabine and oxaliplatin or cisplatin (NCCN preferred)
Fluorouracil and irinotecan
Paclitaxel with or without carboplatin or cisplatin
Docetaxel with or without cisplatin
Fluorouracil
Capecitabine
Docetaxel, cisplatin or oxaliplatin, and fluorouracil

Head and neck cancers

Salivary Gland Tumors

As a single agent, in combination with docetaxel, or in combination with pertuzumab for HER2-positive recurrent disease with one of the following:

Distant metastases in individuals with a performance status (PS) of 0–3
Unresectable locoregional recurrence or second primary with prior radiation therapy

Biliary Tract Cancers

Gallbladder Cancer/Intrahepatic Cholangiocarcinoma/Extrahepatic Cholangiocarcinoma

As subsequent therapy in combination with pertuzumab or tucatinib for progression on or after systemic treatment for unresectable or resected gross residual (R2) disease or metastatic disease that is HER2-positive (IHC3+/ISH+/NGS amplification)

Rectal Cancer

Therapy in combination with pertuzumab, or lapatinib or tucatinib in individuals (HER2-amplified and RAS and BRAF wild-type) (pMMR/MSS) or ineligible for or progressed on checkpoint inhibitor immunotherapy for dMMR/MSI-H or POLE/POLD1 mutation with ultrahypermutated phenotype (e.g., TMB >50 mut/Mb]) if intensive therapy not recommended and no previous treatment with a HER2 inhibitor for the following indications:

As primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for individuals with existing or imminent obstruction
As primary treatment for synchronous unresectable metastases of other sites
As primary treatment for unresectable isolated pelvic/anastomotic recurrence
As initial treatment for unresectable metachronous metastases in individuals who have not received previous FOLFOX or CapeOX within the past 12 months, who have received previous 5-FU/LV or capecitabine therapy, or who have not received any previous chemotherapy

Initial treatment in combination with pertuzumab, lapatinib, or tucatinib for individuals (HER2-amplified and RAS and BRAF wild-type) with unresectable metachronous metastases (pMMR/MSS or dMMR/MSI-H) or polymerase epsilon/delta (POLE/POLD1) mutation with ultrahypermutated phenotype (e.g., TMB >50 mut/Mb and are not candidates for immunotherapy) and previous FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPEOX (capecitabine and oxaliplatin) within the past 12 months
As primary treatment for T3, N Any; T1-2, N1-2; T4, N Any; or locally unresectable or medically inoperable disease (HER2-amplified and RAS and BRAF wild type) if resection is contraindicated following total neoadjuvant therapy (pMMR/MSS) or ineligible for or progressed on checkpoint inhibitor immunotherapy for dMMR/MSI-H or POLE/POLD1 mutation with ultrahypermutated phenotype (e.g., TMB >50 mut/Mb) or neoadjuvant/definitive immunotherapy (dMMR/MSI-H) if intensive therapy not recommended
Second-line and subsequent therapy (biomarker-directed therapy) in combination with pertuzumab or lapatinib or tucatinib, if not previously given, for progression of advanced or metastatic disease (HER2-amplified and RAS and BRAF wild-type) (pMMR/MSS or ineligible for or progressed on checkpoint inhibitor immunotherapy for dMMR/MSI-H or POLE/POLD1 mutation with ultrahypermutated phenotype [e.g., TMB >50 mut/Mb]) not previously treated with HER2 inhibitor, in individuals previously treated:

With oxaliplatin-based therapy without irinotecan
With irinotecan-based therapy without oxaliplatin
With oxaliplatin and irinotecan
Without irinotecan or oxaliplatin

Uterine Neoplasms: Endometrial Carcinoma

First-line therapy if no prior trastuzumab therapy (or second-line or subsequent therapy as clinically appropriate if no prior trastuzumab therapy) in combination with carboplatin and paclitaxel and continued as a single agent for maintenance therapy* (NCCN-preferred regimen) for recurrent HER2-positive uterine serous carcinoma or HER2-positive carcinosarcoma for any of the following:

For isolated metastases
For disseminated metastases with or without sequential palliative external-beam radiation therapy (EBRT)
After surgical exploration, with sequential EBRT for locoregional recurrence (not confined to the vagina or paravaginal soft tissue) in individuals with disease or in pelvic or para-aortic lymph nodes
After surgical exploration, with or without sequential EBRT for locoregional recurrence (not confined to vagina or paravaginal soft tissue) in individuals with microscopic residual upper abdominal or peritoneal disease
With or without sequential palliative EBRT or brachytherapy for locoregional recurrence in individuals who have received prior EBRT to site of recurrence

In combination with carboplatin and paclitaxel and continued as a single agent for maintenance therapy* (NCCN-preferred regimen) for stage III/IV HER2-positive uterine serous carcinoma and for stage III-IV HER2-positive carcinosarcoma for any of the following indications:
- For a disease that is suitable for primary surgery as additional treatment with or without sequential EBRT and with or without vaginal brachytherapy after total hysterectomy/bilateral salpingo-oophorectomy (TH/BSO)
- For a disease that is not suitable for primary surgery as primary treatment with or without sequential EBRT and with or without brachytherapy

NCCN note: *Trastuzumab may be continued as a maintenance therapy.

Small Bowel Adenocarcinoma

Second-line and subsequent therapy in combination with pertuzumab or tucatinib for advanced or metastatic disease that is HER2 (ERBB2) overexpression/amplification and RAS and BRAF WT (if not previously given)

TRASTUZUMAB AND HYALURONIDASE-OYSK (HERCEPTIN HYLECTA)
Trastuzumab and hyaluronidase-oysk subcutaneous injection (Herceptin Hylecta) is considered medically necessary and, therefore, covered for the treatment of adult individuals whose HER2 status has been verified by one of the FDA-approved diagnostic tests and the individual has a left ventricular ejection fraction of 50% or greater for the following indications and regimens:

Invasive or Inflammatory Breast Cancer

As a substitute for intravenous trastuzumab and used as a single agent or in combination with other systemic therapies.

Adjuvant Breast Cancer

Adjuvant treatment of individuals with HER2-overexpressing node-positive or node-negative (ER/PR-negative or with one high-risk feature) breast cancer, as part of any of the following treatment regimens:

In combination with doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel
With docetaxel and carboplatin
As a single agent following multimodality anthracycline-based therapy (e.g., AC=anthracycline (doxorubicin) plus cyclophosphamide)

Metastatic Breast Cancer

Treatment of metastatic breast cancer as part of any of the following treatment regimens:

In combination with paclitaxel for the first-line treatment of HER2-overexpressing metastatic breast cancer
As a single agent for the treatment of HER2-overexpressing breast cancer in individuals who have received one or more chemotherapy regimens for metastatic disease

NOT MEDICALLY NECESSARY

When FDA-approved diagnostic tests do not reveal HER2 protein overexpression, trastuzumab (Herceptin) and related biosimilars and trastuzumab and hyaluronidase-oysk (Herceptin Hylecta) are considered not medically necessary, and, therefore, not covered because the available published peer-reviewed literature does not support their use in the treatment of those diseases.

For individuals receiving their first course of trastuzumab, use of the nonpreferred reference product trastuzumab (Herceptin), or any nonpreferred biosimilars, is considered not medically necessary and, therefore, not covered because they are more costly than the preferred products that are at least as likely to produce equivalent therapeutic results for that individual's illness.

EXPERIMENTAL/INVESTIGATIONAL

All other uses of trastuzumab and related biosimilars and trastuzumab and hyaluronidase-oysk (Herceptin Hylecta) are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company's medical policy on off-label coverage for prescription drugs and biologics.

MANDATES

PENNSYLVANIA MEMBERS

In accordance with the Commonwealth of Pennsylvania's Act 6 of 2020 or Fair Access to Cancer Treatment Act, for members who are enrolled in Pennsylvania commercial products who have Stage 4, advanced metastatic cancer, refer to the medical policy titled Coverage of Anticancer Prescription Oral and Injectable Drugs and Biologics and Supportive Agents (08.01.08) for additional information regarding the applicable coverage of drugs and biologics.

DOSING AND FREQUENCY REQUIREMENTS

Refer to Attachment A for dosing and frequency requirements for trastuzumab and related biosimilars, trastuzumab, and hyaluronidase-oysk (Herceptin Hylecta).

The Company reserves the right to modify the Dosing and Frequency Requirements listed in this policy to ensure consistency with the most recently published recommendations for the use of trastuzumab and related biosimilars, trastuzumab and hyaluronidase-oysk (Herceptin Hylecta). Changes to these guidelines are based on a consensus of information obtained from resources such as, but not limited to, the FDA, Company-recognized authoritative pharmacology compendia, or published peer-reviewed clinical research. The professional provider must supply supporting documentation (i.e., published peer-reviewed literature) in order to request coverage for an amount of trastuzumab and related biosimilars and trastuzumab and hyaluronidase-oysk outside of the Dosing and Frequency Requirements listed in this policy. For a list of Company-recognized pharmacology compendia, view the policy on off-label coverage for prescription drugs and biologics.

Accurate member information is necessary for the Company to approve the requested dose and frequency of this drug. If the member’s dose, frequency, or regimen changes (based on factors such as changes in member weight or incomplete therapeutic response), the provider must submit those changes to the Company for a new approval based on those changes as part of the precertification process. The Company reserves the right to conduct postpayment review and audit procedures for any claims submitted for trastuzumab and related biosimilars.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.

When coverage of trastuzumab and related biosimilars, trastuzumab and hyaluronidase-oysk (Herceptin Hylecta) is requested outside of the Dosing and Frequency Requirements listed in this policy, the prescribing professional provider must supply documentation (i.e., published peer-reviewed literature) to the Company that supports this request.

Guidelines

BLACK BOX WARNINGS

Refer to the specific manufacturer's prescribing information for any applicable Black Box Warnings.

HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2 (HER2) PROTEIN OVEREXPRESSION TESTING

Coverage of trastuzumab and related biosimilars, trastuzumab, and hyaluronidase-oysk (Herceptin Hylecta), requires that HER2 protein overexpression is verified as a positive result by one of the following US Food and Drug Administration (FDA)-approved diagnostic tests:

Immunohistochemical (IHC) assay with a result of 3+
Fluorescence in situ hybridization (FISH) test (ratio >2.0)
Single-probe in situ hybridization (ISH) test with average HER2 copy number 6.0 signals/cell or greater
Dual-probe ISH test HER2/CEP17 (chromosome enumeration probe 17) ratio 2.0 or greater or HER2/CEP17 ratio less than 2.0 AND average HER2 copy number 6.0 signals/cell or greater

Confirmatory tests should be performed for borderline results as follows:

If IHC assay has a result of 2+, confirm with ISH test of the same sample or a new test with IHC or ISH (if new sample available).
If FISH test has a HER2 gene/chromosome 17 ratio of 1.8–2.0, confirm with FISH re-test; additional cell counting and recalculation of the ratio; or IHC assay.
If single-probe ISH assay has an average HER2 copy number result of 4.0 to less than 6.0 signals/cell, confirm with dual-probe ISH or with IHC (if same sample), or with a new ISH or IHC (if new sample available).
If dual-probe ISH assay has a HER2/CEP17 ratio less than 2.0 and an average HER2 copy number result of 4.0 to less than 6.0 signals/cell, confirm with one of the following: IHC (if same sample), alternative ISH chromosome 17 probe, or order a new test with ISH or IHC (if new sample available).

THE EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE STATUS

The ECOG, established in 1955, was one of the first groups to coordinate multicenter cancer clinical trials. The National Cancer Institute (NCI) is the primary funding source, and ECOG has evolved from a small consortium of institutions in the eastern United States to one of the largest clinical cancer research organizations in the country. As part of their work in the treatment of cancer, ECOG has developed the ECOG Performance Status (EPS), originally published in 1982 in the American Journal of Clinical Oncology. The use of the scales and the criteria in the EPS allows clinicians and researchers to determine an individual’s disease progression in terms of how the activities of daily living (ADL) are affected.

ECOG Performance Status
Grade	ECOG
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 (e.g., 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 percent of waking hours
3	Capable of only limited self care, confined to bed or chair more than 50 percent of waking hours
4	Completely disabled. Cannot carry on any self care: Totally confined to bed or chair
5	Dead

Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-655.

THE KARNOFSKY PERFORMANCE STATUS

The Karnofsky Performance Status (KPS) is a standard way of measuring the ability of individuals with cancer to perform ordinary tasks. Performance scores range from 0 to 100; a higher score indicates that the individual is better able to perform activities. KPS may be used to determine an individual's prognosis, to measure changes in an individual's ability to function, or to decide if an individual can participate in a clinical trial.

The Karnofsky Performance Status Scale
100 percent	Normal, no complaints; no signs of disease
90 percent	Capable of normal activity; few symptoms or signs of disease
80 percent	Normal activity with some difficulty; some symptoms or signs of disease
70 percent	Caring for self; not capable of normal activity or work
60 percent	Requiring some help; can take care of most personal requirements
50 percent	Requires help often; requires frequent medical care
40 percent	Disabled; requires special care and help
30 percent	Severely disabled, but no risk of death
20 percent	Very ill; requires supportive measures or treatment
10 percent	Moribund; rapidly progressive fatal disease processes
0 percent	Death

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, trastuzumab and related biosimilars, trastuzumab and hyaluronidase-oysk (Herceptin Hylecta™), are covered under the medical benefits of the Company’s products when the medical necessity criteria and Dosing and Frequency Requirements listed in this medical policy are met.

LIST OF HER2 ACTIVATING MUTATIONS (FOR WHEN HERCEPTIN IS ADMINISTERED IN COMBINATION WITH NERATINIB AND FULVESTRANT DUE TO THESE BIOMARKERS' ACTIVITIES):

L755S

G778_P780dup

V777L

Y772_A775dup

D769Y

S310F

G776V

T862A

V697L

D769H

DLRE

L755_E757S

L755P

L869R

R678Q

G776V; E1154A

L755S; D769Y

S310F; G776V

L755S; V777L

V777L; V726F

G776S; H878Y

D769Y; V777L

US FOOD AND DRUG ADMINISTRATION (FDA)

The FDA granted initial approval for the use of trastuzumab to Genentech, Inc. (South San Francisco, CA) on September 25, 1998; supplemental approvals have since been issued.

The FDA has issued subsequent approvals for biosimilar products.

Description

Trastuzumab and related biosimilars are monoclonal antibodies that bind to the human epidermal growth factor receptor 2 (HER2, previously called HER2/neu) protein. They are used to treat individuals with breast, gastric, uterine, and head and neck cancers, whose tumors overexpress the HER2 protein.

Biosimilar labels do not include the clinical data used to establish biosimilarity. Instead, biosimilar labels contain clinical data from their reference product; thus it is applicable to related biosimilars (e.g., trastuzumab-pkrb [Herzuma®], trastuzumab-dkst [Ogivri™], trastuzumab-dttb [Ontruzant®]).

The HER2 gene is found on chromosome 17 and is involved in the process for making the HER2 protein. The HER2 protein is a receptor on the surface of the cell and sends messages to the cell to grow and divide more frequently. When cells have more than the normal number of copies of the HER2 gene, the gene is called amplified. Amplification of the HER2 gene results in HER2 protein overexpression, which occurs in approximately 25% of breast and gastric cancer cases.

HER2 gene amplification and HER2 protein overexpression are highly correlated with faster tumor growth, shortened disease-free survival time, and shortened overall survival for individuals with breast or gastric cancer. Trastuzumab and related biosimilars are designed to target and block HER2 activity. Trastuzumab and related biosimilars are supplied as sterile lyophilized powders and are administered by intravenous (IV) infusion.

Trastuzumab and hyaluronidase-oysk (Herceptin Hylecta) is a combination of trastuzumab, a HER2/neu receptor antagonist, and hyaluronidase, an endoglycosidase, which is indicated for the treatment of HER2-overexpressing breast cancer in adult individuals who have been diagnosed based on a US Food and Drug Administration (FDA)–approved companion diagnostic for trastuzumab.

BREAST CANCER TREATMENT

METASTATIC BREAST CANCER TREATMENT
The FDA approved the uses of trastuzumab and related biosimilars for the treatment of individuals with metastatic breast cancer whose tumors overexpress the HER2 protein in any of the following regimens:

In combination with paclitaxel as first-line treatment of HER2-overexpressing metastatic disease
As a single agent for individuals who have previously received chemotherapy for metastatic disease
Pertuzumab (Perjeta®) is approved in combination with trastuzumab and docetaxel (Taxotere®) for those who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease

Trastuzumab and related biosimilars were studied for use in the initial treatment of HER2-overexpressing metastatic breast cancer in combination with an anthracycline and cyclophosphamide. However, in a large, randomized, clinical trial, the clinical benefits did not outweigh the increased risk of serious cardiac toxicity. Therefore, the FDA did not grant approval for the use of trastuzumab in combination with anthracycline and cyclophosphamide.

ADJUVANT BREAST CANCER TREATMENT
Trastuzumab and related biosimilars have been studied for use as adjuvant treatment, which is therapy given after the primary treatment to increase the chances of a cure. Since 2006, the FDA has approved the use of trastuzumab in the adjuvant setting for the treatment of individuals with HER2-overexpressing breast cancer in specific chemotherapy regimens.

The use of trastuzumab in the adjuvant setting was supported by three large phase 3 randomized controlled trials (RCTs). The National Cancer Institute (NCI) sponsored two large phase 3 RCTs that studied the use of trastuzumab in combination with standard chemotherapy as an adjuvant to complete surgical resection in early-stage HER2-overexpressing breast cancer. The results of the interim analysis showed that individuals who received trastuzumab in addition to chemotherapy experienced a significant increase in disease-free survival time, as well as a significant reduction in the relative risk of recurrence compared with those who received chemotherapy alone. Based on the significance of these findings, the two trials were stopped, as the studies had met their primary endpoints, and the committees overseeing the trial data recommended that the interim analysis be made public. These data were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) in May 2005 and published in The New England Journal of Medicine in October 2005. A third large phase 3 RCT that studied trastuzumab as adjuvant chemotherapy was the international HERceptin Adjuvant (HERA) trial. Interim data from the HERA trial that demonstrated a statistically significant increase in disease-free survival time at 2 years were also presented at the ASCO meeting in 2005.

NEOADJUVANT BREAST CANCER TREATMENT
Neoadjuvant therapy is treatment given before the primary treatment (e.g., preoperatively). Trastuzumab and related biosimilars are recognized as an appropriate medical treatment in the neoadjuvant setting when used preoperatively in combination with paclitaxel or docetaxel, followed in combination with FEC/CEF (fluorouracil, epirubicin, and cyclophosphamide); with paclitaxel or docetaxel following AC (doxorubicin and cyclophosphamide); or with docetaxel and carboplatin for individuals with breast cancer whose tumors overexpress the HER2 protein and meet additional criteria.

Trastuzumab was approved by the FDA for use in combination with pertuzumab (Perjeta) and docetaxel (Taxotere) for the neoadjuvant treatment of individuals with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either >2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer.

ESOPHAGEAL, ESOPHAGOGASTRIC JUNCTION, AND GASTRIC CANCERS

Trastuzumab and related biosimilars have been shown to improve survival in individuals with advanced gastric and gastroesophageal junction cancers in the international Phase 3 Trastuzumab for Gastric Cancer (ToGA) trial, which compared two treatments in 594 individuals whose tumors showed elevated levels of the HER2 protein. ToGA is the first randomized Phase 3 trial to study the use of trastuzumab in individuals who have inoperable, locally advanced, recurrent, and/or metastatic HER2-positive gastric and gastroesophageal junction cancers. The results for this trial were presented at the American Society of Clinical Oncology (ASCO) 2009 annual meeting. The trial demonstrated that individuals who received chemotherapy alone lived 11.1 months, whereas those who received trastuzumab with chemotherapy lived 13.8 months. The response rate was increased with trastuzumab from 34.5% to 47.3%. In addition, individuals whose gastric and gastroesophageal junction cancers exhibited high levels of HER2 experienced even greater benefit from the addition of trastuzumab (16 months median survival). The chemotherapy arm of the trial consisted of a fluoropyrimidine (capecitabine or IV 5-fluorouracil [5-FU]) and cisplatin every 3 weeks for six cycles; the trastuzumab arm received trastuzumab every 3 weeks until disease progression in combination with a fluoropyrimidine and cisplatin for six cycles.

In October 2010, trastuzumab was approved by the FDA for use in metastatic gastric and gastroesophageal junction adenocarcinomas.

OTHER CANCERS

Trastuzumab has been studied for use in other cancers (e.g., osteosarcoma, non-small cell lung, ovarian, prostate, pancreatic, colorectal, urothelial cancers); however, to date, many phase 2 trials have failed to demonstrate the effectiveness of trastuzumab. Also, some cancers show a low incidence of HER2 protein overexpression. Research is ongoing, and whether trastuzumab use will have an effect on health outcomes in other cancers is not yet determined.

DIAGNOSTIC TESTS FOR HER2 PROTEIN OVEREXPRESSION

HER2 protein overexpression is detected either by immunohistochemical (IHC) assay that measures the amount of HER2 receptor protein on the surface of cells in a breast cancer tissue sample or with a type of in situ hybridization (ISH) test for gene amplification (e.g., fluorescence in situ hybridization [FISH], chromogenic in situ hybridization [CISH], dual in situ hybridization [DISH]). The FDA has approved several commercially available tests to aid in the selection of individuals with breast cancer and metastatic gastric cancer for trastuzumab therapy. Assessment of HER2 protein overexpression and HER2 gene amplification in metastatic gastric cancer should be performed using FDA-approved tests specifically for gastric cancers due to differences in gastric versus breast histopathology. The NCCN and ASCO guidelines further recommend that IHC assay and ISH testing should only be done at laboratories that are accredited to perform HER2 testing.

An IHC test result is reported as 0 or 1+ (negative), 2+ (borderline), or 3+ (positive).
A FISH test result is reported as a HER2 gene/chromosome 17 ratio less than 1.8 (negative), a ratio of 1.8 to less than 2.0 (borderline), or a ratio of 2.0 or greater (positive).
A single-probe ISH test result is reported as: average HER2 copy number less than 4.0 signals/cell (negative); 4.0 to less than 6.0 signals/cell (borderline); 6.0 or greater signals/cell (positive).
A dual-probe ISH test result is reported as HER2/CEP17 (chromosome enumeration probe 17) ratio 2.0 or greater (positive); HER2/CEP17 ratio less than 2.0 AND average HER2 copy number less than 4.0 signals/cell (negative); HER2/CEP17 ratio less than 2.0 AND average HER2 copy number 4.0 to less than 6.0 signals/cell (borderline); HER2/CEP17 ratio less than 2.0 AND average HER2 copy number 6.0 signals/cell or greater (positive).

The NCCN and ASCO both have issued guidelines for HER2 testing in invasive breast cancer that call for confirming a borderline or equivocal result:

IHC assay result of 2+: confirm with ISH test (if same sample), or with a new IHC or ISH test (if new sample available).
FISH assay: confirm with either a repeat FISH test or an additional cell counting and recalculation of the ratio. If a repeat FISH test remains equivocal, then an IHC assay is recommended for confirmation.
Single-probe ISH assay: confirm with dual-probe ISH or with IHC (if same sample), or with a new ISH or IHC (if new sample available).
Dual-probe ISH assay: confirm with one of the following: IHC (if same sample), alternative ISH chromosome 17 probe, or order a new test with ISH or IHC (if new sample available).

Trastuzumab and related biosimilars are not indicated in any type of cancer that does not overexpress the HER2 protein.

OFF-LABEL INDICATIONS

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.

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National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Breast Cancer. V1.2026. [NCCN Web site]. 01/16/2026. Available at: http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf [via free subscription]. Accessed February 16, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines/in Oncology - Central Nervous System Cancers. V3.2025. [NCCN Web site].12/05/2025. Available at: http://www.nccn.org/professionals/physician_gls/pdf/cns.pdf. Accessed February 16, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Colon Cancer. V5.2025. [NCCN Web site]. 10/30/2025. Available at: http://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf. Accessed February 16, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Esophageal and Esophagogastric Junction Cancer. V2.2026. [NCCN Web site]. 01/21/2026. Available at: http://www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf. Accessed February 16, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Gastric Cancer. V2.2026. [NCCN Web site].01/21/2026. Available at: http://www.nccn.org/professionals/physician_gls/PDF/gastric.pdf. Accessed February 16, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Head and Neck Cancers. V1.2026. [NCCN Web site].12/08/2025. Available at: http://www.nccn.org/professionals/physician_gls/PDF/gastric.pdf. Accessed February 16, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Biliary Cancers.
V2.2025. [NCCN Web site].07/02/2025. Available at: http://www.nccn.org/professionals/physician_gls/PDF/gastric.pdf. Accessed February 16, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Rectal Cancer.
V4.2025. [NCCN Web site].10/31/2025. Available at: http://www.nccn.org/professionals/physician_gls/PDF/gastric.pdf. Accessed February 16, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Uterine Neoplasms. V2.2026. [NCCN Web site].11/14/2025. Available at: http://www.nccn.org/professionals/physician_gls/PDF/gastric.pdf. Accessed February 16, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Small Bowel Adenocarcinoma. V1.2026. [NCCN Web site].01/22/2026. Available at: http://www.nccn.org/professionals/physician_gls/PDF/gastric.pdf. Accessed February 16, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology - Appendiceal Neoplasms and Cancers. V1.2026. [NCCN Web site].01/16/2026. Available at: http://www.nccn.org/professionals/physician_gls/PDF/gastric.pdf. Accessed February 16, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium. Pertuzumab (Perjeta®). [NCCN Web site]. Available at: http://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=383. via subscription only]. Accessed February 16, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium. Trastuzumab and hyaluronidase-oysk (Herceptin Hylecta™). [NCCN Web site]. Available at: http://www.nccn.org/professionals/drug_compendium/content/contents.asp [via subscription only]. Accessed February 16, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Drugs & Biologics Compendium. Trastuzumab (Herceptin®) and biosimilars. [NCCN Web site]. Available at: http://www.nccn.org/professionals/drug_compendium/content/contents.asp [via subscription only]. Accessed February 16, 2026.

O’Shaughnessy J, Vukelja SJ, Marsland T, et al. Phase II trial of gemcitabine plus trastuzumab in metastatic breast cancer patients previously treated with chemotherapy: preliminary results. Clin Breast Cancer. 2002;(3 Suppl 1):17-20.

Osoba D, Burchmore M. Health-related quality of life in women with metastatic breast cancer treated with trastuzumab (Herceptin). Semin Oncol. 1999;26(4 Suppl 12):84-88.

Pegram MD, Lipton A, Hayes DF, et al. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment. J Clin Oncol. 1998;16(8):2659-2671.

Pegram MD, Pienkowski T, Northfelt DW, et al. Results of two open-label, multicenter phase II studies of docetaxel, platinum salts, and trastuzumab in HER2-positive advanced breast cancer. J Natl Cancer Inst. 2004;96(10):759-769.

Pegram MD, Slamon DJ. Combination therapy with trastuzumab (Herceptin) and cisplatin for chemoresistant metastatic breast cancer: evidence for receptor-enhanced chemosensitivity. Semin Oncol. 1999;26(4 Suppl 12):89-95.

Persons DL, Bui MM, Lowery MC, et al. Fluorescence in situ hybridization (FISH) for detection of HER-2/neu amplification in breast cancer: a multicenter portability study. Ann Clin Lab Sci. 2000;30(1):41-48.

Peyromaure M, Scotté F, Amsellem-Ouazana D, et al. Trastuzumab (Herceptin) in metastatic transitional cell carcinoma of the urinary tract: report on six patients. Eur Urol. 2005;48(5):771-778.

Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353(16):1659-1672.

Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353(16):1673-1684.

Ross JS, Fletcher JA. HER-2/neu (c-erb-B2) gene and protein in breast cancer. Am J Clin Pathol. 1999;112(1 Suppl 1):S53-S67.

Safran H, Dipetrillo T, Akerman P, et al. Phase I/II study of trastuzumab, paclitaxel, cisplatin and radiation for locally advanced, HER2 overexpressing, esophageal adenocarcinoma. Int J Radiat Oncol Biol Phys. 2007;67(2):405-409.

Salzberg M, Borner M , Bauer JA, et al. Trastuzumab (Herceptin) in patients with HER-2-overexpressing metastatic or locally advanced transitional cell carcinoma of the bladder: report on 7 patients. Eur J Cancer. 2006;42(15):2660-2661.

Seidman A, Hudis C, Pierri MK, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol. 2002;20(5):1215-1221.

Seidman AD, Fornier MN, Esteva FJ, et al. Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol. 2001;19(10):2587-2595.

Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177-182.

Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783-792.

Small EJ, Bok R, Reese DM, et al. Docetaxel, estramustine, plus trastuzumab in patients with metastatic androgen-independent prostate cancer. Semin Oncol. 2001;28(4 Suppl 15):71-76.

Smith I, Procter M, Gelber RD, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet. 2007;369(9555):29-36.

Tan-Chiu E, Yothers G, Romond E, et al. Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol. 2005;23(31):7811-7819.

Tokuda Y, Watanabe T, Omuro Y, et al. Dose escalation and pharmacokinetic study of a humanized anti-HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. Br J Cancer. 1999;81(8):1419-1425.

Truven Health Analytics. Micromedex® DrugDex® Compendium. Trastuzumab, (Herceptin®). Greenwood Village, CO. [Micromedex® Solutions Web site]. 12/18/2025. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed February 16, 2026.

Truven Health Analytics. Micromedex® DrugDex® Compendium. Trastuzumab-dttb, (Ontruzant®). Greenwood Village, CO. [Micromedex® Solutions Web site]. 12/18/2025. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed February 16, 2026.

Truven Health Analytics. Micromedex® DrugDex® Compendium. Trastuzumab-qyyp (Trazimera™). [Micromedex 2.0 Web site]. 12/18/2025. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed February 16, 2026.

Truven Health Analytics. Micromedex® DrugDex® Compendium. Trastuzumab and hyaluronidase-oysk (Herceptin Hylecta™). Greenwood Village, CO. [Micromedex® Solutions Web site]. 01/29/2026. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed February 16, 2026.

Truven Health Analytics. Micromedex® DrugDex® Compendium. Trastuzumab-anns, (Kanjinti^TM). Greenwood Village, CO. [Micromedex® Solutions Web site]. 12/18/2025. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed February 16, 2026.

Truven Health Analytics. Micromedex® DrugDex® Compendium. Trastuzumab-pkrb (Herzuma®). Greenwood Village, CO. [Micromedex® Solutions Web site]. 12/18/2025. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed February 16, 2026.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs@FDA. Trastuzumab (Herceptin®). [FDA Web site]. Original: 09/25/98. Revised: 06/18/2024. Available at: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. Accessed February 16, 2026.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Supplemental Biologics License Application (sBLA) approval letter. Trastuzumab (Herceptin®). [FDA Web site]. 06/18/2024. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2010/103792s5250ltr.pdf. Accessed February 16, 2026.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs @ FDA. trastuzumab-anns (Kanjinti^TM). [FDA Web site]. Original: 06/13/2019. Revised:12/19/2019 Available at: https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed February 16, 2026.

US Food and Drug Administration (FDA). Devices @FDA (HER2). Available at: http://www.accessdata.fda.gov/scripts/cdrh/devicesatfda/index.cfm. Accessed February 16, 2026.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Drugs@FDA. Trastuzumab-dkst (Ogivri™). [FDA Web site]. Original:12/01/2017. Revised: 11/13/2024. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761074s000lbl.pdf. Accessed February 16, 2026.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Biologics License Application (BLA) approval letter. Trastuzumab-dkst (Ogivri™). [FDA Web site]. 11/13/2024. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2017/761074Orig1s000ltr.pdf. Accessed February 16, 2026.

US Food and Drug Administration (FDA). Trastuzumab and hyaluronidase-oysk (Herceptin Hylecta™) prescribing information & approval letter. [FDA Web site]. 06/18/2024. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761106Orig1s000lbl.pdf. Accessed February 16, 2026.

US Food and Drug Administration (FDA). Trastuzumab-pkrb (Herzuma®), prescribing information & approval letter. [FDA Web site]. 02/22/2025. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761091s000lbl.pdf06Orig1s000lbl.pdf. Accessed February 16, 2026.

US Food and Drug Administration (FDA). Trastuzumab-dttb, (Ontruzant®), prescribing information & approval letter. [FDA Web site]. 12/05/2025. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761100s000lbl.pdf. Accessed February 16, 2026.

US Food and Drug Administration (FDA). Trastuzumab-qyyp (Trazimera™), prescribing information & approval letter. [FDA Web site]. 08/21/2020. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761081s000lbl.pdf. Accessed February 16, 2026.

Van Cutsem E, Kang Y, Chung H, et al. Efficacy results from the ToGA trial: A phase III study of trastuzumab added to standard chemotherapy in first-line human epidermal growth factor receptor 2 (HER2) positive advanced gastric cancer. J Clin Oncol (Meeting abstracts). 2009; 27:LBA4509.

Viani GA, Afonso SL, Stefano EJ, et al. Adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of published randomized trials. BMC Cancer. 2007;7:153-163.

Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol. 2002;20(3):719-726.

Wolff AC, Hammond MEH, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31(31):3997-4013.

Wolmark N, Wang J, Mamounas E, et al. Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst Monogr. 2001;30:96-102.

Ziada A, Barqawi A, Glode LM, et al. The use of trastuzumab in the treatment of hormone refractory prostate cancer; phase II trial. Prostate. 2004;60(4):332-337.

Zinner RG, Glisson BS, Fossella FV, et al. Trastuzumab in combination with cisplatin and gemcitabine in patients with Her2-overexpressing, untreated, advanced non-small cell lung cancer: report of a phase II trial and findings regarding optimal identification of patients with Her2-overexpressing disease. Lung Cancer. 2004;44(1):99-110.

Coding

CPT Procedure Code Number(s)

N/A

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

See Attachment B.

HCPCS Level II Code Number(s)

J9355 Injection, trastuzumab, excludes biosimilar, 10 mg

J9356 Injection, trastuzumab, 10 mg and hyaluronidase-oysk

Q5112 Injection, trastuzumab-dttb, biosimilar (Ontruzant), 10 mg

Q5113 Injection, trastuzumab-pkrb, biosimilar (Herzuma), 10 mg

Q5114 Injection, Trastuzumab-dkst, biosimilar (Ogivri), 10 mg

Q5116 Injection, trastuzumab-qyyp, biosimilar (Trazimera), 10 mg

Q5117 Injection, trastuzumab-anns, biosimilar (Kanjinti), 10 mg

Q5146 Injection, trastuzumab-strf (Hercessi), biosimilar, 10 mg

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

Cross Reference

Policy History

Revisions From 08.00.33w:

04/20/2026

This version of the policy will become effective 4/20/2026.

This policy has been updated to be consistent with the US Food and Drug Administration (FDA) labeling and National Comprehensive Cancer Network (NCCN) compendia.

CRITERIA FOR TRASTUZUMAB AND RELATED BIOSIMILARS HAVE BEEN ADDED/UPDATED

MEDICALLY NECESSARY

Breast Cancer
Central Nervous System Metastases
Appendiceal Adenocarcinoma
Esophageal, Esophagogastric Junction Cancers
Gastric Cancers
Gallbladder Cancer/Intrahepatic Cholangiocarcinoma/Extrahepatic Cholangiocarcinoma
Uterine Neoplasms
Small Bowel Adenocarcinoma

The following code was removed from the policy:

C78.89 Secondary malignant neoplasm of other digestive organs

Report the most appropriate diagnosis code in support of medically necessary criteria as listed in the policy.

Revisions From 08.00.33v:

01/01/2026

This version of the policy will become effective 01/01/2026.
This is an interim update.
This policy has been updated to communicate the Company's designation of two biosimilars as its preferred products: trastuzumab-dttb [Ontruzant], trastuzumab-dkst [Ogivri] and one as non-preferred: trastuzumab-qyyp [Trazimera].

Language regarding coverage of nonpreferred trastuzumab biosimilars has been revised. The previous criteria allowing coverage based on prior use have been removed. The updated policy states that use of nonpreferred trastuzumab products is eligible for coverage only when there is documentation of a contraindication(s), intolerance(s) (e.g., as documented per FDA labeling), or inadequate response to the preferred products trastuzumab-dttb [Ontruzant], trastuzumab-dkst [Ogivri] and trastuzumab-anns [Kanjinti].

C50.A0 Malignant inflammatory neoplasm of unspecified breast has been removed from the policy coding table.

Revisions From 08.00.33u:

10/01/2025

This policy has been identified for the ICD-10 CM code update, effective 10/01/2025.

The following ICD-10 CM codes have been added to this policy:

C50.A0 Malignant inflammatory neoplasm of unspecified breast
C50.A01 Malignant inflammatory neoplasm of right breast
C50.A02 Malignant inflammatory neoplasm of left breast

Revisions From 08.00.33t:

06/16/2025

Report the most appropriate diagnosis code in support of medically necessary criteria as listed in the policy.

This version of the policy will become effective 06/16/2025.

This policy has been updated to be consistent with the US Food and Drug Administration (FDA) labeling and National Comprehensive Cancer Network (NCCN) compendia.

The following criteria have been added to this policy:

NCCN guidelines for new recommended indications for trastuzumab (Herceptin®) and related biosimilars were added to the policy.

CRITERIA FOR TRASTUZUMAB AND RELATED BIOSIMILARS HAVE BEEN ADDED/UPDATED

MEDICALLY NECESSARY

Breast Cancer
Central Nervous System Metastases
Appendiceal Adenocarcinoma
Colon Cancer
Esophageal, Esophagogastric Junction Cancers
Gastric Cancers
Gallbladder Cancer/Intrahepatic Cholangiocarcinoma/Extrahepatic Cholangiocarcinoma
Rectal Cancer
Uterine Neoplasms

The following ICD-10 CM code has been removed:

C79.9 Secondary malignant neoplasm of unspecified site

D37.1 Neoplasm of uncertain behavior of stomach

D37.8 Neoplasm of uncertain behavior of other specified digestive organs

Revisions From 08.00.33s:

01/01/2025

This version of the policy will become effective 01/01/2025.

Inclusion of a policy in a Code Update memo does not imply that a full review of
the policy was completed at this time.

The following HCPCS code has been added to this policy:
Q5146 Injection, trastuzumab-strf (hercessi), biosimilar, 10 mg

The following HCPCS codes have been removed from this policy:

C9399 Unclassified drugs or biologicals

J3590 Unclassified biologics

Revisions From 08.00.33r:

08/26/2024

This version of the policy will become effective 08/26/2024.

This policy has been updated to be consistent with the US Food and Drug Administration (FDA) labeling and NCCN compendia.

The following criteria have been added to this policy:

NCCN guidelines for new recommended indications for trastuzumab (Herceptin®) and related biosimilars were added to the policy.

CRITERIA FOR TRASTUZUMAB AND RELATED BIOSIMILARS HAVE BEEN ADDED/UPDATED:

MEDICALLY NECESSARY

Breast Cancer
Central Nervous System Metastases
Colon Cancer
Esophageal, Esophagogastric Junction Cancers
Gastric Cancers
Gallbladder Cancer/Intrahepatic Cholangiocarcinoma/ Extrahepatic Cholangiocarcinoma
Rectal Cancer
Salivary Gland Tumors
Uterine Neoplasms

THE FOLLOWING HCPCS CODES HAVE BEEN ADDED TO REPRESENT TRASTUZUMAB-STRF (HERCESSI):

C9399 Unclassified drugs or biologicals
J3590 Unclassified biologics

The following ICD-10 CM code has been added:

C18.8 Malignant neoplasm of overlapping sites of colon

Revisions From 08.00.33q:

03/13/2023

This version of the policy will become effective 3/13/2023.

This policy has been updated to be consistent with the US Food and Drug Administration (FDA) labeling and NCCN compendia.

The following criteria have been added to this policy:

NCCN guidelines for new recommended indications for trastuzumab (Herceptin®) and related biosimilars were added to the policy.
The coding table was updated to include new indications for trastuzumab (Herceptin®) and related biosimilars.

ADDED/UPDATED CRITERIA FOR TRASTUZUMAB AND RELATED BIOSIMILARS:

MEDICALLY NECESSARY

Breast Cancer
Central Nervous System Metastases
Colon Cancer
Esophageal, Esophagogastric Junction and Gastric Cancers
Gastric Cancers
Salivary Gland Tumors
Uterine Neoplasms

CODING TABLE WAS UPDATED FOR THE FOLLOWING INDICATIONS

Hepatobiliary cancers

DOSING AND FREQUENCY WERE ADDED FOR THE FOLLOWING INDICATIONS

Hepatobiliary cancers

Revisions From 08.00.33p:

04/12/2021

This version of the policy will become effective 04/12/2021.

This policy has been updated to be consistent with the US Food and Drug Administration (FDA) labeling and NCCN compendia.

The following criteria have been added to this policy:

NCCN guidelines for new recommended indications for trastuzumab (Herceptin®) and related biosimilars were added to the policy.
The coding table was updated to include new indications for trastuzumab (Herceptin®) and related biosimilars.
Dosing and frequency were updated to include new indications for trastuzumab (Herceptin®) and related biosimilars.

ADDED/UPDATED CRITERIA FOR TRASTUZUMAB AND RELATED BIOSIMILARS:

MEDICALLY NECESSARY

Breast Cancer
Central Nervous System Metastases
Colon Cancer
Esophageal, Esophagogastric Junction and Gastric Cancers
Rectal Cancer
Salivary Gland Tumors
Uterine Neoplasms

CODING TABLE WAS UPDATED FOR NEW INDICATIONS

Colon Cancer
Rectal Cancer
Salivary Gland Tumors

DOSING AND FREQUENCY WERE ADDED FOR NEW INDICATIONS

Colon Cancer
Rectal Cancer
Salivary Gland Tumors

Revisions From 08.00.33o:

05/15/2020

This policy has been updated to communicate the Company's designation of two biosimilars as its preferred products: trastuzumab-qyyp (Trazimera^TM) and trastuzumab-anns (Kanjinti^TM)

On February 20, 2020, the following language was added to the Company-Designated Preferred Products section of the Policy section: Coverage of a biosimilar product as an alternate to a reference product is not considered a form of step therapy by the Company.

Revisions From 08.00.33n:

10/01/2019

This policy has been identified for the HCPCS code update, effective 10/01/2019.

The following HCPCS codes have been added to this policy:
Q5116 Injection, trastuzumab-qyyp, biosimilar, (Trazimera), 10 mg
Q5117 Injection, trastuzumab-anns, biosimilar, (Kanjinti), 10 mg
The following HCPCS codes have been removed from this policy:
C9399 Unclassified drugs or biologicals
J3590 Unclassified biologics

On February 20, 2020, the following language was added to the Company-Designated Preferred Products section of the Policy section: Coverage of a biosimilar product as an alternate to a reference product is not considered a form of step therapy by the Company.

Revisions From 08.00.33m:

07/01/2019

This version of the policy will become effective 07/01/2019.

This policy has been updated to be consistent with the US Food and Drug Administration (FDA) labeling and NCCN compendia.

The following criteria have been added to this policy:

NCCN guidelines for new recommended indications and dosing and frequency information for trastuzumab (Herceptin®) and related biosimilars were added to the policy.
New FDA approval and dosing and frequency information for hyaluronidase-oysk (Herceptin Hylecta) were added to the policy.
Coding table was updated to include new indications for trastuzumab (Herceptin®) and related biosimilars. HCPCS codes were added for (Herceptin®) related biosimilars and hyaluronidase-oysk (Herceptin Hylecta) what were the codes, use style guide for language and format.
Not medically necessary statement was added for testing results that do not show HER2 protein overexpression
Description for trastuzumab (Herceptin®) code was revised from J9355 Injection, trastuzumab, 10 mg J9355 Injection, trastuzumab, excludes biosimilar, 10 mg .

Revisions From 08.00.33l:

03/09/2018

This policy has undergone a routine review and the medical necessity criteria have been revised to reflect the United States Food and Drug Administration (FDA) labeling and National Comprehensive Cancer Network (NCCN) compendia.

Effective 10/05/2017 this policy has been updated to the new policy template format.

Version Effective Date:

4/20/2026

Version Issued Date:

4/20/2026

Version Reissued Date: