In certain cancers, the human epidermal growth factor receptor 2 (HER2) gene is amplified and overexpressed. Trastuzumab (Herceptin®) is a humanized monoclonal antibody, HER2 receptor antagonist, used for the treatment of various cancers including breast and metastatic gastric or gastroesophageal junction adenocarcinoma works by halting the out-of-control growth prompted by an overabundance of the HER2/neugene.

Trastuzumab-pkrb (Herzuma®), trastuzumab-anns (Kanjinti™), trastuzumab-dttb (Ontruzant®), trastuzumab-dkst (Ogivri®), or trastuzumab-qyyp (Trazimera™) are biosimilars of trastuzumab (Herceptin).

Preferred Products

Trastuzumab-anns (Kanjinti) and trastuzumab-qyyp (Trazimera) are the preferred trastuzumab biosimilars for individuals initiating new therapy for oncologic indications when the clinical criteria within this policy are met. A non-preferred product will be considered when the individual has a documented therapy failure after an adequate therapeutic trial of a preferred product, or the preferred product has not been tolerated or is contraindicated.

Adequate therapeutic trial is defined as 180 days from first dose of therapy at Food and Drug Administration (FDA) or compendia based therapeutic doses of preferred product.

New therapy is defined as no previous utilization within the 180 last calendar days.

The use of trastuzumab (Herceptin) may be considered medically necessary when the presence of the HER2-over expression is confirmed by the following:

HER2-overexpression must be verified by ANY ONE of the following FDA approved diagnostic tests:

• An immunohistochemical (IHC) assay with a result of 3+ (positive); or
• A positive fluorescence in situ hybridization (FISH) test (ratio greater than 2.0); or
• Single-probe in situ hybridization (ISH) test with average HER2  copy number 6.0 signals/cell or greater; or
• 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); or
• 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; or
• 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); or
• 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).

Trastuzumab (Herceptin) may be considered medically necessary for ANY of the following indications:

 Food and Drug Administration (FDA) Indications

Breast Cancer

·         For adjuvant treatment of HER2-overexpressing node positive or node negative (estrogen receptor/progesterone [ER/PR] receptor negative or with one high risk feature) breast cancer in ANY of the following:

o    As part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; or

o    As part of a treatment regimen with docetaxel and carboplatin; or

o    As a single agent following multi-modality anthracycline based therapy; or

·         For metastatic breast cancer in ANY of the following:

o    In combination with paclitaxel for first-line treatment of HER2-ovrexpressing metastatic breast cancer; or

o    As a single agent for treatment of HER2-overexpressing breast  cancer in individuals who have received one or more chemotherapy regimens for metastatic disease; or

Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma

·         For treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma in combination with cisplatin and capecitabine or 5-fluorouracil in individuals who have not received prior treatment for metastatic disease.

The use of trastuzumab (Herceptin) for any other indication listed above is considered experimental/investigational, and therefore, not covered. The safety and/or efficacy cannot be established by review of the available published peer-reviewed literature.

Trastuzumab (Herceptin) may be considered medically necessary for ANY of the following:

National Comprehensive Cancer Network (NCCN) Recommendations

Central Nervous System Cancers- Extensive Brain Metastases

• When used in combination with capecitabine and tucatinib as treatment for extensive brain metastases in individuals with HER2-positive breast cancer if previously treated with one or more anti-HER2-based regimens:
  • As primary treatment in select individuals with small asymptomatic brain metastases; or
  • As treatment for recurrent disease with stable systemic disease or reasonable systemic treatment options; or

Central Nervous System Cancers- Limited Brain Metastases

• When used in combination with capecitabine and tucatinib as treatment for limited brain metastases in individuals with HER2-positive breast cancer if previously treated with one or more anti-HER2-based regimens:
  • As initial treatment in selected individuals with small asymptomatic brain metastases; or
  • As treatment for recurrent brain metastases; or
  • As treatment of relapsed disease with either stable systemic disease or reasonable systemic treatment options; or

Colon Cancer

• As therapy in combination with pertuzumab or lapatinib in individuals with HER2-amplified and RAS and BRAF wild-type who are not appropriate for intensive therapy in ANY of the following:
  • As adjuvant treatment following resection and/or local therapy for resectable metachronous metastases in individuals who have received previous chemotherapy; or
  • As adjuvant treatment for unresectable metachronous metastases that converted to resectable disease after primary treatment; or
• As subsequent therapy in combination with pertuzumab or lapatinib for progression of advanced or metastatic disease, HER2-amplified and RAS and BRAF wild-type, not previously treated with HER2 inhibitor, in individuals previously treated with ANY of the following:
  • Oxaliplatin-based therapy without irinotecan; or
  • Irinotecan-based therapy without oxaliplatin; or
  • Oxaliplatin and irinotecan; or
  • Without irinotecan or oxaliplatin; or
  • Without irinotecan or oxaliplatin followed by FOLFOX or CapeOX with or without bevacizumab; or
• As therapy in combination with pertuzumab or lapatinib in individuals with HER2-amplified and RAS and BRAF wild-type who are not appropriate for intensive therapy, if no previous treatment with a HER2 inhibitor, in ANY of the following:
  • As primary treatment for locally unresectable or medically inoperable disease; or
  • For unresectable synchronous liver and/or lung metastases that remain unresectable after primary systemic therapy; or
  • As primary treatment for synchronous abdominal/peritoneal metastases that are non-obstructing, or following local therapy for individuals with existing or imminent obstruction; or
  • For synchronous unresectable metastases of other sites; or
  • As primary 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 5-FU/LV or capecitabine therapy, or who have not received any previous chemotherapy; or
  • For unresectable metachronous metastases that remain unresectable after primary treatment; or

Endometrial Carcinoma

• When used in combination with carboplatin and paclitaxel for advanced stage III/IV or recurrent HER2-positive uterine serous carcinoma; or

Esophageal and Esophagogastric Junction Cancers

• For use as palliative therapy for individuals who are not surgical candicates or have unresectable locally advanced, recurrent, or metastatic disease with HER2 overexpressing adenocarcinoma and Karnofsky performance score equal to or greater than 60% or Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to 2 as first-line therapy in combination with systemic chemotherapy; or

Gastric Cancer

• Preferred primary treatment in combination with systemic chemotherapy for medically fit individuals with surgically unresectable locoregional HER2 overexpression positive adenocarcinoma; or
• For use as palliative therapy for individuals who are not surgical candicates or have unresectable locally advanced, recurrent, or metastatic disease with HER2 overexpressing adenocarcinoma and Karnofsky performance score equal to or greater than 60% or ECOG performance score of less than or equal to 2 as first-line therapy in combination with systemic chemotherapy; or
  
  
  

Invasive Breast Cancer

• As preoperative systemic therapy for individuals with HER2-positive tumors and locally advanced clinical stage T2 and greater, N+ and M0 disease in ANY of the following:
  • In combination with paclitaxel and pertuzumab following AC (doxorubicin and cyclophosphamide) regimen; or
  • In combination with paclitaxel following AC regimen; or
  • As a component of TCH (docetaxel, carboplatin, and trastuzumab) regimen; or
  • As a component of TCHP (docetaxel, carboplatin, trastuzumab, pertuzumab) regimen; or
  • In combination with docetaxel with or without pertuzumab following AC regimen; or
  • In combination with docetaxel and cyclophosphamide; or
• As adjuvant systemic therapy* for individuals with HER2-positive tumors and T1-3, N0 or N+, M0 (pTa-3 and pN0 or pN+ tumors) disease in ANY of the following:
  • In combination with paclitaxel following AC regimen; or
  • As a component of TCH regimen; or
  • In combination with docetaxel following AC regimen; or
  • In combination with docetaxel and cyclophosphamide; or
  • As a component of TCHP regimen with pertuzumab for node positive tumors; or
  • In combination with pertuzumab and paclitaxel, or pertuzumab and docetaxel following AC regimen for node positive tumors; or
  • 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; or
• As adjuvant systemic therapy for individuals with HER2-positive tumors and locally advanced clinical stage T2 or greater, N+ and M0 disease following completion of planned chemotherapy and following mastectomy or lumpectomy with surgical axillary staging, with or without pertuzumab if ANY of the following:
  • ypT0N0 or pCR; or
  • ypT1-4N0 (if ado-trastuzumab discontinued for toxicity); or
  • ypN1 or greater (if ado-trastuzumab discontinued for toxicity); or
• When used in combination with tamoxifen, fulvestrant, or aromatase inhibition with or without lapatinib, for the treatment of recurrent or stage IV (M1) hormone receptor-positive non-visceral or asymptomatic visceral HER2-positive disease in postmenopausal women** or premenopausal women treated with ovarian ablation/suppression; or
• When used for recurrent or stage IV (M1) HER2-positive disease that is either hormone receptor-negative, hormone receptor-positive with or without endocrine therapy in ANY of the following:
  • As first-line therapy in combination with pertuzumab with docetaxel or paclitaxel; or
  • In combination with docetaxel, vinorelbine, or capecitabine or with paclitaxel with or without carboplatin as third-line therapy and beyond; or
  • In combination with carboplatin, cisplatin, cyclophosphamide, eribulin, gemcitabine, ixabepilone, lapatinib (without cytotoxic therapy) or albumin-bound paclitaxel as third-line therapy and beyond; or
  • 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; or
• Third- or fourth-line therapy in combination with capecitabine and tucatinib (in individuals with both systemic and CNS progression on ado-trastuzumab emtansine) for recurrent unresectable (local or regional) or stage IV (M1) human epidermal growth factor receptor 2 (HER2)-positive disease that is:
  • Hormone receptor-negative; or
  • Hormone receptor-positive with or without endocrine therapy; or

Leptomeningeal Metastases

• For use as intra-cerebrospinal fluid (CSF) treatment for leptomeningeal metastases from breast cancer for ANY of the following:
  • Primary treatment in individuals with good risk status; or
  • Maintenance treatment in individuals with negative CSF cytology or in clinically stable individuals with persistently positive CSF cytology; or
  • Treatment in individuals with positive CSF cytology that have progressed after receiving prior treatment; or
    
    
    

Rectal Cancer

·       Therapy in combination with pertuzumab or lapatinib in individuals (HER2-amplified and RAS and BRAF wild-type) who are not appropriate for intensive therapy, if no previous treatment with a HER2 inhibitor:

•  
  • As primary treatment for T3, N Any; T1-2, N1-2; T4, N Any; or locally unresectable or medically inoperable disease if resection is contraindicated following neoadjuvant or total neoadjuvant therapy; or
  • For synchronous liver only and/or lung only metastases that are unresectable or medically inoperable and remain unresectable (with no progression of primary tumor) after primary systemic therapy; or
  • Following palliative radiation therapy (RT) or chemo/RT for synchronous liver only and/or lung only metastases that are unresectable or medically inoperable and remain unresectable (with progression of primary tumor) after primary systemic therapy; or
  • As primary treatment for synchronous abdominal/peritoneal metastases that are nonobstructing, or following local therapy for patients with existing or imminent obstruction; or
  • As primary treatment for synchronous unresectable metastases of other sites; or
  • As primary treatment for unresectable isolated pelvic/anastomotic recurrence; or
  • As primary treatment for unresectable metachronous metastases in patients 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; or
  • For unresectable metachronous metastases that remain unresectable after primary treatment; or

·       Subsequent therapy in combination with pertuzumab or lapatinib for progression of advanced or metastatic disease (HER2-amplified and RAS and BRAF wild-type) not previously treated with HER2 inhibitor, in individuals previously treated:

o   With oxaliplatin-based therapy without irinotecan; or

o   With irinotecan-based therapy without oxaliplatin; or

o   With oxaliplatin and irinotecan; or

o   Without irinotecan or oxaliplatin; or

o   Without irinotecan or oxaliplatin followed by FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CapeOX (capecitabine and oxaliplatin) with or without bevacizumab; or

·         Therapy in combination with pertuzumab or lapatinib in individuals (HER2-amplified and RAS and BRAF wild-type) who are not appropriate for intensive therapy:

o   As adjuvant treatment (following resection and/or local therapy) for resectable metachronous metastases in individuals who have received previous chemotherapy; or

o   As adjuvant treatment for unresectable metachronous metastases that converted to resectable disease after primary treatment. Biologic therapy is only appropriate for continuation of favorable response from conversion therapy; or

Salivary Gland Tumors

• As systemic therapy for HER2-positive recurrent disease with distant metastases in individuals with performance status (PS) of 0-3, unresectable locoregional recurrence or second primary with prior radiation therapy:
  • As a single agent; or
  • In combination with docetaxel; or
  • In combination with pertuzumab

The use of trastuzumab (Herceptin) for any other indication listed above is considered experimental/investigational, and therefore, not covered. The safety and/or efficacy cannot be established by review of the available published peer-reviewed literature.

Trastuzumab-pkrb (Herzuma), trastuzumab-anns (Kanjinti), trastuzumab-dttb (Ontruzant), trastuzumab-dkst (Ogivri), or trastuzumab-qyyp (Trazimera) may be considered medically necessary for ANY of the following:

FDA Indications

Breast Cancer

• For adjuvant treatment of HER2-overexpressing node positive or node negative (ER/PR negative or with one high risk feature) breast cancer in ANY of the following:
  • As part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; or
  • As part of a treatment regimen with docetaxel and carboplatin; or
  • As a single agent following multi-modality anthracycline based therapy; or
• For metastatic breast cancer in ANY of the following:
  • In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer; or
  • As a single agent for treatment of HER2-overexpressing breast cancer in individuals who have received one or more chemotherapy regimens for metastatic disease; or

Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma

• For the treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma in individuals who have not received prior treatment for metastatic disease; or 

NCCN Recommendations

As a substitute for trastuzumab (Herceptin) for the treatment of ANY of the following where trastuzumab (Herceptin) was recommended:

• Invasive Breast Cancer; or
• Colorectal Cancer; or
• Esophageal and Esophagogastric Junction Cancers; or
• Gastric Cancer; or
• Endometrial Carcinoma.

The use of a trastuzumab biosimilar for any other indication listed above is considered experimental/investigational and therefore, not covered. The safety and/or efficacy cannot be established by review of the available published peer-reviewed literature.

Trastuzumab and hyaluronidase-oysk (Herceptin Hylecta™) may be considered medically necessary for ANY of the following:

FDA Indications 

Breast Cancer

• For adjuvant treatment of HER2-overexpressing node positive or node negative (ER/PR negative or with one high risk feature) breast cancer in ANY of the following:
  • As part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; or
  • As part of a treatment regimen with docetaxel and carboplatin; or
  • As a single agent following multi-modality anthracycline based therapy; or
• For metastatic breast cancer in ANY of the following:
  • In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer; or
  • As a single-agent for treatment of HER2-overexpressing breast cancer in individuals who have received one or more chemotherapy regimens for metastatic disease; or

NCCN Recommendations

Invasive Breast Cancer

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

The use of trastuzumab and hyaluronidase-oysk (Herceptin Hylecta) for any other indication listed above is considered experimental/investigational and therefore, not covered. The safety and/or efficacy cannot be established by review of the available published peer-reviewed literature.

NOTE: In addition to the above criteria, product specific dosage and/or frequency limits may apply in accordance with the U.S. Food and Drug Administration (FDA)-approved product prescribing information, national compendia, Centers for Medicare and Medicaid Services (CMS) and other peer reviewed resources or evidence-based guidelines. Highmark may deny, in full or in part, reimbursement for utilization that does not fall within the applicable dosage and/or frequency limits. 

*Note: If no residual disease after preoperative therapy or no preoperative therapy, complete up to one year of HER2-targetted 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 (Kadcyla™) is discontinued for toxicity, then trastuzumab with or without pertuzumab to complete one year of therapy can be used. 

**Note: 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. 

Do not substitute trastuzumab (Herceptin, Herzuma, Kanjinti, Ogivri, Ontruzant, or Trazimera) or trastuzumab and hyaluronidase-oysk (Herceptin Hylecta) for or with ado-trastuzumab emtansine (Kadcyla) or fam-trastuzumab deruxtecan-nxki (Enhertu).