Trastuzumab (Herceptin and biosimilars), Trastuzumab and Hyaluronidase-oysk (Herceptin Hylecta)

Number: 0313

Commercial CPB  |  Medicare CPB

Brand Selection for Medically Necessary Indications

As defined in Aetna commercial policies, health care services are not medically necessary when they are more costly than alternative services that are at least as likely to produce equivalent therapeutic or diagnostic results. Herzuma (trastuzumab-pkrb) and Ogivri (trastuzumab-dkst) brands of trastuzumab are more costly to Aetna than other HER2/neu receptor antagonists. There is a lack of reliable evidence that Herzuma or Ogivri are superior to the lower cost HER2/neu receptor antagonists Herceptin (trastuzumab), Kanjinti (trastuzumab-anns), and Trazimera (trastuzumab-qyyp) for the same medically necessary indications. Therefore, Aetna considers Herzuma and Ogivri to be medically necessary only if the member has had a documented intolerable adverse event to Herceptin (trastuzumab), Kanjinti (trastuzumab-anns), and Trazimera (trastuzumab-qyyp) for medically necessary indications, and the adverse event was not an expected adverse event attributed to the active ingredient as described in the prescribing information (i.e., known adverse reaction for both the brand and biosimilar medication).

Policy

Note: Requires Precertification.

For precertification of products listed in this policy, call (866) 752-7021 (Commercial), (866) 503-0857 (Medicare), or fax (866) 267-3277.

Trastuzumab (Herceptin), trastuzumab-pkrb (Herzuma), trastuzumab-anns (Kanjinti), trastuzumab-dkst (Ogivri), Trastuzumab-dttb (Ontruzant), and trastuzumab-qyyp (Trazimera)

1. Criteria for Initial Approval

   Aetna considers trastuzumab (Herceptin), trastuzumab-pkrb (Herzuma), trastuzumab-anns (Kanjinti), trastuzumab-dkst (Ogivri), trastuzumab-dttb (Ontruzant) or trastuzumab-qyyp (Trazimera) medically necessary for use in members with one of the following conditions:

   1. Breast cancer - when used in one of the following settings:

      1. Neoadjuvant treatment of HER2-positive breast cancer as part of a complete treatment regimen; or
      2. Adjuvant treatment of HER2-positive breast cancer; or
      3. Treatment of HER2-positive recurrent, advanced unresectable, or metastatic (including brain metastases) breast cancer; or
      4. Intra-CSF treatment for leptomeningeal metastases from HER2-positive breast cancer; or

   2. Colorectal cancer - for treatment of colorectal cancer with HER2-amplified and RAS and BRAF wild-type disease in combination with pertuzumab or lapatinib when either of the following are met:

      1. Member is not appropriate for intensive therapy; or
      2. Trastuzumab will be used as subsequent therapy for progression of advanced or metastatic disease.

   3. Esophageal, Gastric, or Gastroesophageal Junction Cancer - for treatment of HER2-positive esophageal, gastric, or gastroesophageal junction cancer in combination with chemotherapy; or

   4. Salivary gland tumors - for treatment of HER2-positive salivary gland tumors; or

   5. Uterine Serous Carcinoma - for treatment of HER2-positive advanced or recurrent uterine serous carcinoma in combination with carboplatin and paclitaxel.

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).  

2. Continuation of Therapy

   Aetna considers continued treatment with Herceptin, Herzuma, Kanjinti, Ogivri, Ontruzant, or Trazimera medically necessary in members requesting reauthorization for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen. Adjuvant and neoadjuvant treatment of breast cancer will be approved for a total of 12 months of therapy.

Trastuzumab and hyaluronidase-oysk (Herceptin Hylecta) 

1. Criteria for Initial Approval

   Aetna considers trastuzumab and hyaluronidase-oysk (Herceptin Hylecta) medically necessary for breast cancer, when used in one of the following settings:

   1. Adjuvant treatment of HER2-positive breast cancer; or
   2. HER2-positive recurrent, unresectable advanced, or metastatic breast cancer; or 
   3. Neoadjuvant treatment of HER2-positive breast cancer as part of a complete treatment regimen.

   Aetna considers all other indications as experimental and investigational.

2. Continuation of Therapy

   Aetna considers continued treatment with Herceptin Hylecta medically necessary in members requesting reauthorization for an indication outlined in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen. Adjuvant and neoadjuvant treatment of breast cancer will be approved for a total of 12 months of therapy.

Note: For Perjeta and Kadcyla - see CPB 0973 - Pertuzumab (Perjeta) and CPB 0974 - Ado-trastuzumab (Kadcyla). 

Dosage and Administration

Trastuzumab (Herceptin) Dosing

Trastuzumab is available as Herceptin for Injection as a 150 mg single dose vial or as a 420 mg multidose vial.

According to the FDA approved labeling of Herceptin for breast cancer, the usual dose of trastuzumab is a 4 mg/kg loading dose, followed by 2 mg/kg every week (Genentech, 2006).  An alternative every 3 weeks dosing schedule for breast cancer, used in the Herceptin Adjuvant (HERA) trial, is an 8 mg/kg loading dose of trastuzumab, followed by 6 mg/kg every 3 weeks (Piccart-Gebhart et al, 2005; Smith et al, 2007).

For gastric cancer, Herceptin should be administered at an initial dose of 8 mg/kg as a 90-min intravenous infusion followed by subsequent doses of 6 mg/kg as an intravenous infusion over 30 to 90 mins every 3 weeks until disease progression.

Twelve months of adjuvant trastuzumab is the usual medically necessary duration for persons with HER2-positive early breast cancer (Goldhirsch et al, 2013; Pivot et al, 2013).

Trastuzumab (Herzuma) Dosing

Trastuzumab is available as Herzuma for Injection as a 420 mg lyophilized powder in a multidose vial.

For the adjuvant treatment of HER2-overexpressing Breast Cancer, the initial dose of 4 mg/kg over 90 minute IV infusion, then 2 mg/kg over 30 minute IV infusion weekly for 12 weeks (with paclitaxel or docetaxel) or 18 weeks (with docetaxel and carboplatin). One week after the last weekly dose of Herzuma, administer 6 mg/kg as an IV infusion over 30−90 minutes every three weeks to complete a total of 52 weeks of therapy.

For metastatic HER2-overexpressing Breast Cancer, initial dose of 4 mg/kg as a 90 minute IV infusion followed by subsequent weekly doses of 2 mg/kg as 30 minute IV infusions. 

For metastatic HER2-overexpressing Gastric Cancer, initial dose of 8 mg/kg over 90 minute IV infusion, followed by 6 mg/kg over 30 to 90 minute IV infusion every 3 weeks

Source: Celltrion 2019.

Trastuzumab-anns (Kanjinti) Dosing

Kanjinti (trastuzumab-anns) for injection 420 mg/vial is supplied in a multiple-dose vial as a white to pale yellow lyophilized sterile powder, under vacuum. Each carton contains one multiple-dose vial of Kanjinti. 

For intravenous (IV) infusion only. Do not administer as an IV push or bolus.  Do not substitute Kanjinti (trastuzumab-anns) for or with ado-trastuzumab emtansine. Perform HER2 testing using FDA-approved tests by laboratories with demonstrated proficiency.

Adjuvant Treatment of HER2-Overexpressing Breast Cancer: Administer at either:

• Initial dose of 4 mg/kg over 90 minute IV infusion, then 2 mg/kg over 30 minute IV infusion weekly for 12 weeks (with paclitaxel or docetaxel) or 18 weeks (with docetaxel and carboplatin). One week after the last weekly dose of Kanjinti, administer 6 mg/kg as an IV infusion over 30−90 minutes every three weeks to complete a total of 52 weeks of therapy, or
• Initial dose of 8 mg/kg over 90 minutes IV infusion, then 6 mg/kg over 30–90 minutes IV infusion every three weeks for 52 weeks.

Metastatic HER2-Overexpressing Breast Cancer: Initial dose of 4 mg/kg as a 90 minute IV infusion followed by subsequent weekly doses of 2 mg/kg as 30 minute IV infusions.

Metastatic HER2-Overexpressing Gastric Cancer: Initial dose of 8 mg/kg over 90 minutes IV infusion, followed by 6 mg/kg over 30 to 90 minutes IV infusion every 3 weeks.

Sources: FDA, 2019; Genentech, 2018; Genentech, 2017; Genentech, 2019. 

Trastuzumab-dkst (Ogivri) Dosing

Ogivri (trastuzumab-dkst) for injection 420 mg/vial is supplied in a multiple-dose vial as an off-white to pale yellow lyophilized sterile powder, under vacuum. Each carton contains one multiple-dose vial of Ogivri and one vial (20 mL) of Bacteriostatic Water for Injection (BWFI), USP, containing 1.1% benzyl alcohol as a preservative.

For intravenous (IV) infusion only. Do not administer as an IV push or bolus. Do not substitute Ogivri (trastuzumab-dkst) for or with ado-trastuzumab emtansine.

Adjuvant Treatment of HER2-Overexpressing Breast Cancer. Administer at either:

• Initial dose of 4 mg/kg over 90 minute IV infusion, then 2 mg/kg over 30 minute IV infusion weekly for 12 weeks (with paclitaxel or docetaxel) or 18 weeks (with docetaxel and carboplatin). One week after the last weekly dose of Ogivri, administer 6 mg/kg as an IV infusion over 30 to 90 minutes every three weeks to complete a total of 52 weeks of therapy, or
• Initial dose of 8 mg/kg over 90 minutes IV infusion, then 6 mg/kg over 30 to 90 minutes IV infusion every three weeks for 52 weeks.

Metastatic HER2-Overexpressing Breast Cancer: Initial dose of 4 mg/kg as a 90 minute IV infusion followed by subsequent weekly doses of 2 mg/kg as 30 minute IV infusions.

Metastatic HER2-Overexpressing Gastric Cancer: Initial dose of 8 mg/kg over 90 minutes IV infusion, followed by 6 mg/kg over 30 to 90 minutes IV infusion every 3 weeks.

Sources: Mylan 2019.

Trastuzumab-dttp (Ontruzant) Dosing

Ontruzant (trastuzumab-dttb) for injection 420 mg/vial is supplied in a multiple-dose vial as an off-white to pale yellow lyophilized sterile powder, under vacuum. Each carton contains one multiple-dose vial of Ontruzant and one vial (20 mL) of Bacteriostatic Water for Injection (BWFI), USP, containing 1.1% benzyl alcohol as a preservative.

For intravenous (IV) infusion only. Do not administer as an IV push or bolus. Do not substitute Ontruzant (trastuzumab-dttb) for or with ado-trastuzumab emtansine.

Adjuvant Treatment of HER2-Overexpressing Breast Cancer. Administer at either:

• Initial dose of 4 mg/kg over 90 minute IV infusion, then 2 mg/kg over 30 minute IV infusion weekly for 12 weeks (with paclitaxel or docetaxel) or 18 weeks (with docetaxel and carboplatin). One week after the last weekly dose of Ontruzant, administer 6 mg/kg as an IV infusion over 30 to 90 minutes every three weeks to complete a total of 52 weeks of therapy; or
• Initial dose of 8 mg/kg over 90 minutes IV infusion, then 6 mg/kg over 30 to 90 minutes IV infusion every three weeks for 52 weeks.

Metastatic HER2-Overexpressing Breast Cancer: Initial dose of 4 mg/kg as a 90 minute IV infusion followed by subsequent weekly doses of 2 mg/kg as 30 minute IV infusions.

Metastatic HER2-Overexpressing Gastric Cancer: Initial dose of 8 mg/kg over 90 minutes IV infusion, followed by 6 mg/kg over 30 to 90 minutes IV infusion every 3 weeks.

Source: Merck 2020. 

Trastuzumab-qyyp (Trazimera) Dosing

For intravenous (IV) infusion only. Do not administer as an IV push or bolus. Do not substitute Trazimera (trastuzumab-qyyp) for or with ado-trastuzumab emtansine.

Adjuvant Treatment of HER2-Overexpressing Breast Cancer. Administer at either:

• Initial dose of 4 mg/kg over 90 minute IV infusion, then 2 mg/kg over 30 minute IV infusion weekly for 12 weeks (with paclitaxel or docetaxel) or 18 weeks (with docetaxel and carboplatin). One week after the last weekly dose of Trazimera, administer 6 mg/kg as an IV infusion over 30 to 90 minutes every three weeks to complete a total of 52 weeks of therapy, or
• Initial dose of 8 mg/kg over 90 minutes IV infusion, then 6 mg/kg over 30 to 90 minutes IV infusion every three weeks for 52 weeks.

Metastatic HER2-Overexpressing Breast Cancer: Initial dose of 4 mg/kg as a 90 minute IV infusion followed by subsequent weekly doses of 2 mg/kg as 30 minute IV infusions.

Metastatic HER2-Overexpressing Gastric Cancer: Initial dose of 8 mg/kg over 90 minutes IV infusion, followed by 6 mg/kg over 30 to 90 minutes IV infusion every 3 weeks.

Source: Pfizer 2020.

Trastuzumab and Hyaluronidase-oysk (Herceptin Hylecta) Dosing

The recommended dose is 600 mg/10,000 units (600 mg trastuzumab and 10,000 units hyaluronidase) administered subcutaneously over approximately 2 to 5 minutes once every 3 weeks.

Patients with adjuvant breast cancer should be treated for 52 weeks or until disease recurrence, whichever occurs first; extending treatment in adjuvant breast cancer beyond 1 year is not recommended.

Patients with metastatic breast cancer (MBC) should be treated until progression of disease.

Source: Genentech 2019.

Experimental and Investigational

Trastuzumab (Herceptin), trastuzumab-pkrb (Herzuma), trastuzumab-anns (Kanjinti), trastuzumab-dkst (Ogivri), Trastuzumab-dttb (Ontruzant), and trastuzumab-qyyp (Trazimera)

Aetna considers Herceptin, Herzuma, Kanjinti, Ogivri, Ontruzant, or Trazimera alone or in combination with chemotherapy, experimental and investigational for the treatment of the following types of cancer (not an all-inclusive list) and all other indications because trastuzumab has not been proven to be effective for these indications:

• Ampullary adenocarcinoma
• Bladder cancer
• Cancers of unknown primary
• Dermal adnexal cancer
• Hepatobiliary cancers (cholangiocarcinoma and gallbladder cancer)
• Intra-hepatic bile duct cancer
• Melanoma
• Neuroendocrine cervical cancer
• Non-small cell lung cancer
• Osteosarcoma
• Ovarian cancer
• Pancreatic cancer
• Penile cancer
• Prostate cancer
• Vulvar cancer.

Background

Trastuzumab (Herceptin), trastuzumab-pkrb (Herzuma), trastuzumab-anns (Kanjinti), trastuzumab-dkst (Ogivri), Trastuzumab-dttb (Ontruzant), and trastuzumab-qyyp (Trazimera)

U.S. Food and Drug Administration (FDA)-Approved Indications

• Adjuvant breast cancer

  Treatment of human epidermal growth factor receptor 2 (HER2)-overexpressing node positive or node negative (estrogen receptor (ER)/progesterone receptor (PR) negative or with one high risk feature) breast cancer:

  • As part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel
  • As part of a treatment regimen with docetaxel and carboplatin
  • As a single agent following multi-modality anthracycline based therapy
    
    

• Metastatic breast cancer

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

• Metastatic gastric cancer

  In combination with cisplatin and capecitabine or 5-fluorouracil, for the treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, who have not received prior treatment for metastatic disease.

Compendial Uses

• HER2-positive breast cancer
  
  
  • Neoadjuvant therapy
  • Treatment of recurrent, advanced unresectable, or stage IV (M1) disease
    
    
• Intra-cerebrospinal fluid (CSF) treatment for leptomeningeal metastases from HER2-positive breast cancer
• HER2- positive esophageal and esophagogastric junction cancer
• HER2- positive advanced or recurrent uterine serous carcinoma
• HER2-amplified and RAS and BRAF wild-type colorectal cancer in combination with pertuzumab or lapatinib
• HER2- positive salivary gland tumor

Trastuzumab (Herceptin)

Herceptin (trastuzumab) is a recombinant DNA‐derived humanized monoclonal antibody that selectively binds the extracellular domain of the human epidermal growth factor receptor 2 (HER2) protein. Herceptin (trastuzumab) inhibits the proliferation of human tumor cells that over express HER2.

The HER2 protein belongs to a family of four transmembrane receptor tyrosine kinases that mediate the growth, differentiation, and survival of cells. Over expression of the HER2 protein, amplification of the HER2 gene, or both occurs in approximately 15 to 25% of breast cancer cases. Tumors that over express HER2 are more often hormone-receptor negative and poorly differentiated, rapidly‐progressing and associated with poor prognosis (decrease in disease‐free survival and overall survival). Herceptin (trastuzumab) is indicated for:  

• The treatment of HER2-overexpressing breast cancer; and
• The treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma

Patients are given trastuzumab intravenously once a week.  The appropriate duration of therapy is unknown, although studies have reported patients that have been treated with trastuzumab for 9 weeks.

Trastuzumab is supplied as Herceptin Intravenous Powder for Solution: 440 MG per vial and one vial containing 20 mL of Bacteriostatic Water for Injection, USP, 1.1% benzyl alcohol. Reconstitution yields a 21mg/ml product.

Recommended dosing is 4 mg/kg IV loading dose x one dose over 90 min, followed by 2 mg/kg IV weekly over 30 minutes OR 8 mg/kg IV loading dose x one dose over 90 min, followed by 6 mg/kg IV over 30‐ 90 minutes every three weeks.

Therapy with Herceptin (trastuzumab) is necessary for up to one year in the adjuvant (breast cancer) setting or until disease progression in either the metastatic (breast cancer) or advanced gastric cancer setting.

Herceptin (trastuzumab) should not be used concomitantly with anthracycline therapy due to increased risk of cardiomyopathy. Trastuzumab may be used before or after course of anthracycline. A baseline cardiac function test measuring Ejection Fraction is recommended prior to initiating either anthracycline or Herceptin (trastuzumab) therapy. Further cardiac function monitoring is recommended at three, six, and nine months during Herceptin (trastuzumab) therapy.

Herceptin (trastuzumab) administration can result in left ventricular dysfunction and congestive heart failure (CHF). Left ventricular function should be evaluated in all patients prior to and during treatment with Herceptin (trastuzumab). The incidence and severity of left ventricular cardiac dysfunction/CHF was highest in patients who received Herceptin (trastuzumab) concurrently with anthracycline‐containing chemotherapy regimens. Discontinue Herceptin (trastuzumab) treatment in patients receiving adjuvant therapy for breast cancer and strongly consider discontinuation of Herceptin (trastuzumab) in patients with metastatic breast cancer who develop a clinically significant decrease in left ventricular function.

Herceptin (trastuzumab) can cause fetal harm when administered to a pregnant woman. In post‐marketing reports, use of Herceptin during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Prescribers should advise women of the potential hazard to the fetus resulting from Herceptin exposure during pregnancy and provide contraception counseling to women of childbearing potential.

Herceptin (trastuzumab) administration can result in serious infusion reactions and pulmonary toxicity. Rarely, these have been fatal. In most cases, symptoms occurred during or within 24 hours of administration of Herceptin (trastuzumab). Herceptin (trastuzumab) infusion should be interrupted for patients experiencing dyspnea or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve. Discontinuation of Herceptin (trastuzumab) should be strongly considered for infusion reactions manifesting as anaphylaxis, angioedema, pneumonitis, or acute respiratory distress syndrome. Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity.

Herceptin should not be used in persons with hypersensitivity to trastuzumab or any component of the product.

The safety and efficacy of Herceptin in pediatric patients has not been established.

Herceptin Biosimilars: Trastuxumab-pkrb (Herzuma), Trastuzumab-anns (Kanjinti), Trastuzumab-dkst (Ogivri), Trastuzumab-dttb (Ontruzant), and Trastuzumab-qyyp (Trazimera)

The U.S. Food and Drug Administration (FDA) has approved several biosimilar products to Herceptin (trastuzumab): Ogivri (trastuzumab-dkst) on December 17, 2017,  Herzuma (trastuzumab-pkrb) on December 14, 2018, Ontruzant (trastuzumab-dttb) on January 18, 2019, Trazimera (trastuzumab-qyyp) on March 11, 2019,  and Kanjinti (trastuzumab-anns) on June 13, 2019. 

All biosimilars were approved for all approved indications of the reference product, Herceptin (trastuzumab), which includes:

• The treatment of HER2-overexpressing breast cancer; and 
• The treatment of HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma.

Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as a reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product. 

Trastuzumab Patient Selection

Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product. The HER2 gene normally produces a small amount of protein called HER2 growth factor cell-surface receptor, which is responsible for growth and division of cells.  In 25 to 30 % of women with breast cancer, there is a genetic alteration in the HER2 gene that results in increased amounts of this protein, and this protein over-expression is associated with more aggressive disease and shortened survival because it may be resistant to chemotherapy and other forms of treatment.

The HercepTest, manufactured by Dako, is a commercially available test that specifically identifies over-expression of HER2/neu (c-erbB-2) protein in patients with breast cancer, and has been approved by the Food and Drug Administration (FDA) for selecting patients for treatment with trastuzumab.  It is an immunohistochemical antibody assay designed for the detection of HER2 over-expression of HER2/neu protein using specific antibodies, and localizes over-expressed protein in cells or tissues. HER2 expression has been broken down into 4 levels: 0, 1, 2, 3.  HER2/neu over-expression is defined as 2 or 3 circumferential membranous staining with an anti-HER2 antibody by immunohistochemistry (IHC) performed on a paraffin embedded tissue.  Clinical trastuzumab trials showed that patients with level 0 to 1 HER2 expression do not benefit from the drug; a few patients with level 2 expression do benefit from the drug; and many patients with level 3 expression also benefit. The trastuzumab monoclonal antibody seeks out and binds to the specific HER2 or HER2/neu receptors on the surface of HER2 over-expressing breast cancer cells and directly inhibits tumor cell growth.

The HER2/neu is over-expressed/amplified in a range of other tumor types including ovarian, bladder, pancreatic, salivary gland, endometrial and non-small-cell lung cancer (Scholl et al, 2001).  HER2 is implicated in disease initiation and progression, associated with poor prognosis, and may also predict the response to chemotherapy and hormonal therapy.  The prevalence of HER2 over-expression/amplification in various tumor types raises the possibility of using trastuzumab to antagonize the abnormal function of over-expressed HER2 receptors in HER2-positive tumors other than breast.  Clinical trials are either planned or underway to assess the therapeutic role of trastuzumab in non-small cell lung cancer, bladder and ovarian cancer.

HER/2 neu gene amplification is uncommon in bladder cancer.  Evidence from breast cancer suggests that only tumors with HER2/neu gene amplification respond to trastuzumab.  If this were true for bladder cancer, only  approximately 5 % of muscle-invasive transitional cell carcinomas of the bladder would be suitable for treatment (Latif et al, 2004; Kruger et al, 2002).  Latif et al concluded that “[t[]e role of trastuzumab in these tumours remains untested at present.” 

HER2/neu gene amplification has also been rarely found in non-small cell lung cancer (Zinner et al, 2004), and clinical studies to date have failed show a demonstrable advantage of trastuzumab in the majority of non-small cell lung cancer patients (Hirsch and Langer, 2004; Zinner et al, 2004).  Langer et al (2004), reporting on the results of the Eastern Cooperative Oncology Group Phase II study of trastuzumab in non-small cell lung cancer, concluded that overall survival in patients treated with trastuzumab, carboplatin and paclitaxel is similar to historical data using carboplatin and paclitaxel alone.  The investigators reported, however, that patients with 3+ HER2/neu expression did well in contrast to historical data suggesting potential benefit for trastuzumab in this rare subset of non-small cell lung cancer.  This finding needs to be confirmed by prospective clinical studies with internal controls.

Fluorescent in situ hybridization (FISH) assays have also been validated for use in the selection of candidates for trastuzumab therapy.  FISH assays contain a direct label DNA probe designed to bind to the HER2 gene, allowing direct visualization of the gene.  Two FISH kits for HER2 are now available: PathVysion from Visis; and Inform, developed by Oncor and now marketed by Ventana.  Tumors that are candidates for trastuzumab therapy can be detected at the DNA level by FISH assays because there is a high correlation between over-expression of the HER2 protein and amplification of the gene that codes for it.  Both the PathVysion and Inform FISH tests have been approved by the FDA for quantifying HER2/neu amplification.  However, only the PathVysion FISH test has been approved by the FDA for selecting patients with metastatic breast cancer for trastuzumab therapy.  FISH assays of HER2 gene amplification have been found to have a high correlation with immunochemical antibody assays for HER2 over-expression.  The American Society of Clinical Oncology (ASCO) recommends using either immunohistochemical antibody assays or FISH assays for selecting patients for trastuzumab therapy.  ASCO's clinical practice guidelines for the use of tumor markers in breast and colorectal cancer (2001) states that, "[h]igh levels of c-erbB-2 [HER2/neu] expression or c-erbB-2 [HER2/neu] amplification can be used to identify patients for whom trastuzumab expression on a new or stored specimen of tumor tissue.  This assay may be of benefit for the treatment of metastatic, recurrent, or treatment-refractory unresectable locally advanced breast cancer."

Trastuzumab for Breast Cancer

In a large, randomized controlled trial, trastuzumab improved response rates to chemotherapy by 53 % in women with metastatic breast cancer that over-expressed HER2.  In this clinical trial, overall response rates were 43 % with trastuzumab and chemotherapy, compared to only 28 % in women treated with chemotherapy alone.  The greatest improvement in response rates was seen in patients who received trastuzumab plus the chemotherapeutic agent paclitaxel.  Thirty six percent of women treated with trastuzumab plus paclitaxel had a tumor response, compared to only 15 % of women receiving paclitaxel alone.  Median duration of response, which is measured from the time the cancer responds to therapy to the time the cancer begins to spread or grow again, was 7 months longer in women treated with trastuzumab and paclitaxel than it was in women treated with paclitaxel alone.

Trastuzumab can also induce responses in patients with HER2 over-expressing metastatic breast cancers who have failed to respond to chemotherapy.  In a trial of 222 women who had failed 1 or 2 prior chemotherapy regimens, 14 % of women treated with trastuzumab alone had objective tumor responses with tumor shrinkage of 50 % or more.

Two large randomized controlled clinical trials sponsored by the National Cancer Institute involving more than 3,300 patients with early-stage HER2 positive invasive breast cancer found that those patients who received trastuzumab in combination with standard chemotherapy (doxorubicin and cyclophosphamide followed by paclitaxel) had a statistically significant 52 % decrease in risk for breast cancer recurrence compared with patients who received chemotherapy alone (Romond et al, 2005).  These studies included women with HER2-positive and node-positive breast cancer with no distant metastatic disease.  One study also included persons with high-risk node-negative breast cancer: tumor greater than 2 cm, estrogen/progestin receptor negative, nuclear grade 2 to 3 or age less than 35 years.  In one study, Herceptin therapy was administered weekly for 3 months, then every 21 days for 1 year.  In another study, Herceptin therapy was administered weekly for 1 year.  Four years into the study, 85 % of women with early-stage HER2 positive breast cancer who received trastuzumab were free of recurrence, compared with 67 % of women who did not receive the drug.  The data monitoring committees overseeing the combined analysis of these trials recommended that the results of a combined interim analysis be made public because the studies had met their primary endpoints of increasing disease-free survival (DFS) and overall survival (OS) in patients receiving trastuzumab in combination with chemotherapy.  Most patients in these studies had lymph node-positive breast cancer, with only a minority having lymph node-negative disease.  The limited information in the node-negative group did not allow for a separate analysis of this group.  In these studies, the likelihood of congestive heart failure in women receiving standard combination chemotherapy and trastuzumab was increased by 3 % to 4 %.

An international, multi-center, randomized controlled clinical trial (Herceptin Adjuvant Trial (HERA)) found that 1 year treatment with trastuzumab after adjuvant chemotherapy significantly improved DFS among women with early stage HER2-positive breast cancer (Piccart-Gebhart et al, 2005).  The study compared 1 or 2 years of trastuzumab given every 3 weeks with observation in women with HER2-positive and either node-negative or node-positive breast cancer who had completed locoregional therapy (surgery with or without radiotherapy) and at least 4 cycles of neoadjuvant or adjuvant chemotherapy.  Eligible subjects had node-positive disease (regardless of tumor size) or node-negative disease (if tumor size was greater than 1 cm) and no distant metastases.  Subjects in the HERA study were assigned to 3 groups: 

1. 2 years of treatment with trastuzumab, 
2. 1 year of trastuzumab, and
3. observation.

The study by Piccart-Gebhart reported results only of the groups assigned to 1 year of trastuzumab treatment and observation.  At the first planned interim analysis (median follow-up of 1 year), 347 events (recurrence of breast cancer, contralateral breast cancer, second non-breast malignant disease, or death) were observed; 127 events in the trastuzumab group and 220 in the observation group.   The unadjusted hazard ratio (HR) for an event in the trastuzumab group, as compared with the observation group, was 0.54 (95 % confidence interval [CI]: 0.43 to 0.67), representing an absolute benefit in terms of DFS at 2 years of 8.4 %.  Overall survival in the 2 groups was not statistically significantly different (29 deaths with trastuzumab versus 37 with observation).  Severe cardiotoxicity developed in 0.5 % of the women who were treated with trastuzumab.

Viani and colleagues (2007) performed a meta-analysis of completed clinical trials of adjuvant trastuzumab in the adjuvant setting.  Survival, recurrence, brain metastases, cardiotoxicity and directions for future research were discussed.  Relevant reports were reviewed by two reviewers independently and the references from these reports were searched for additional trials, using guidelines set by QUOROM statement criteria.  Pooled results from that 5 randomized trials of adjuvant trastuzumab showed a significant reduction of mortality (p < 0.00001), recurrence (p < 0.00001), metastases rates (p < 0.00001) and second tumors other than breast cancer (p = 0.007) as compared to no adjuvant trastuzumab patients.  There were more grade III or IV cardiac toxicity after trastuzumab (203/4,555 = 4.5 %) versus no trastuzumab (86/4,562 = 1.8 %).  The likelihood of cardiac toxicity was 2.45-fold higher (95 % CI: 1.89 to 3.16) in trastuzumab arms, however that result was associated with heterogeneity.  The likelihood of brain metastases was 1.82-fold higher (95 % CI: 1.16 to 2.85) in patients who received trastuzumab.  The authors concluded that the findings from this meta-analysis are sufficiently compelling to consider 1 year of adjuvant trastuzumab treatment for women with HER2-positive early breast cancer based on the risk: benefit ratio demonstrated in these studies.

Larsen et al (2013) noted that patients with HER2-positive breast cancer are living still longer and increasingly experiencing brain metastases.  Current HER2-targeted therapies have limited potential to cross the blood-brain-barrier.  These researchers performed a systematic review to investigate data on HER2-targeting therapies in the treatment of brain metastases in breast cancer.  They searched PUBMED for all human studies published 1998 to 2012 using the following search terms: breast neoplasm/cancer, human epidermal growth factor receptor 2/HER2, ErbB2, trastuzumab, lapatinib, brain/cerebral neoplasm/metastases and blood-brain barrier.  They identified few and mostly small clinical studies.  Study designs were very heterogeneous making comparisons on end-points difficult.  Overall survival for patients treated with trastuzumab varied from 8 to 25 months and 5.5 to 11 months for patients receiving lapatinib.  The majority of studies were retrospective, thus possibly biasing data.  Only 3 studies were identified comparing trastuzumab to lapatinib.  The authors concluded that no solid data exist on how to treat patients with HER2-positive disease and brain metastases.  Although continuous HER2-blockade is recommended by international consensus guidelines, it is still not evident which HER2-targeting agent should be preferred when brain metastases occur.  The choice of chemotherapy to accompany the blockade is not obvious and these investigators do not know if dual is better than single blockade.  They stated that further clinical trials are urgently needed.

Zagouri et al (2013) stated that leptomeningeal carcinomatosis (MC) represents an uncommon, but devastating manifestation of metastatic breast cancer.  This was the first systematic review/pooled analysis to synthesize all available data evaluating the safety and effectiveness of intra-thecal (IT) administration of trastuzumab for the treatment of MC in HER2-positive breast cancer patients.  This study was performed in accordance with the PRISMA guidelines.  A total of 13 articles (17 patients) were eligible.  The mean age of patients at IT trastuzumab administration was 48.2 years (SD 8.4, range of 38 to 66).  The mean total dose was 399.8 mg (SD 325.4, range of 35 to 1,110 mg).  Intra-thecal trastuzumab alone or as part of combination therapies seemed to be safe; no serious adverse events were reported in 88.2 % of cases.  In 68.8 % of cases, a significant clinical improvement was observed, while stabilization or progression of the disease was noticed in 31.2 % of cases.  Cerebrospinal fluid (CSF) response was noted in 66.7 % of cases. The median OS was 13.5 months, whereas the median central nervous system-progression-free survival (CNS-PFS) was 7.5 months.  In 23.5 % of cases, IT trastuzumab was administered beyond CNS progression with a response noticed in 75 % of cases and a CNS-PFS of 9.4 months.  The cumulative dose of IT trastuzumab given was 1,040 mg (SD 697.9, median of 1,215, range of 55 to 1,675).  The protective effect of prior radiosurgery or neurosurgery upon CNS-PFS was sizeable but did not reach formal statistical significance (HR 0.28, 95 % CI: 0.06 to 1.37).  Clinical improvement (HR 0.14, 95 % CI: 0.02 to 0.91) and CSF response (HR 0.09, 95 % CI: 0.01 to 0.89) were associated with longer CNS-PFS.  The authors concluded that IT administration seems to represent a safe and in some cases effective option for the treatment of HER2-positive breast cancer patients with leptomeningeal involvement.  Moreover, they stated that clinical trials are urgently needed to establish the definite role of IT trastuzumab in HER2-positive metastatic breast cancer patients with MC.

In January 2008, the FDA rendered trastuzumab the additional indication of adjuvant monotherapy for early-stage HER2-positive breast cancer.  The FDA decision was predicated on 1-year data from the HERA (HERceptin Adjuvant) trial.  It found a significant 46 % reduction in recurrence among women who took trastuzumab for 52 weeks following multi-modality anthracycline-based therapy compared with controls.  The HERA trial also reported a significant increase in disease-free survival among women who received adjuvant therapy with trastuzumab.  Trastuzumab was, however, associated with a higher rate of congestive heart failure -- 2 % versus 0.3 % in the control group.  Serious infusion reactions including fatal infusion reactions as well as pulmonary toxicity have been reported with trastuzumab.  In most cases symptoms occurred during infusion or within 24 hours of infusion.  Trastuzumab infusion should be interrupted for patients with dyspnea or clinically significant hypotension.  Patients should be monitored until signs and symptoms completely resolve.  Trastuzumab should be discontinued for infusion reactions manifesting as anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome.

Goldhirsch and colleagues (2013) stated that trastuzumab has established effectiveness against breast cancer with over-expression or amplification of the HER2 oncogene.  The standard of care is 1 year of adjuvant trastuzumab, but the optimum duration of treatment is unknown.  In an open-label, RCT, these investigators compared 2 years of treatment with trastuzumab with 1 year of treatment, and updated the comparison of 1 year of trastuzumab versus observation at a median follow-up of 8 years, for patients enrolled in the HERceptin Adjuvant (HERA) trial.  The HERA trial was an international, multi-center, randomized, open-label, phase III clinical trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant chemotherapy, adjuvant chemotherapy, or both in 5,102 patients with HER2-positive early breast cancer.  The primary end-point was DFS.  The comparison of 2 years versus 1 year of trastuzumab treatment involved a landmark analysis of 3,105 patients who were disease-free 12 months after randomization to one of the trastuzumab groups, and was planned after observing at least 725 DFS events.  The updated intention-to-treat comparison of 1 year trastuzumab treatment versus observation alone in 3,399 patients at a median follow-up of 8 years (range of 0 to 10) was also reported.  These researchers recorded 367 events of DFS in 1,552 patients in the 1 year group and 367 events in 1,553 patients in the 2 year group (HR 0.99, 95 % CI: 0.85 to 1.14, p = 0.86).  Grade 3 to 4 adverse events and decreases in left ventricular ejection fraction (LVEF) during treatment were reported more frequently in the 2 year treatment group than in the 1 year group (342 [20.4 %] versus 275 [16.3 %] grade 3 to 4 adverse events, and 120 [7.2 %] versus 69 [4.1 %] decreases in LVEF, respectively).  Hazard ratios for a comparison of 1 year of trastuzumab treatment versus observation were 0.76 (95 % CI: 0.67 to 0.86, p < 0.0001) for DFS and 0.76 (0.65 to 0.88, p = 0·0005) for OS, despite cross-over of 884 (52 %) patients from the observation group to trastuzumab therapy.  The authors concluded that 2 years of adjuvant trastuzumab is not more effective than is 1 year of treatment for patients with HER2-positive early breast cancer.  Moreover, 1 year of treatment provided a significant DFS and OS benefit compared with observation and remains the standard of care.

Pivot and associates (2013) noted that since 2005, 12 months of adjuvant trastuzumab has been the standard treatment for patients with HER2-positive early-stage breast cancer.  However, the optimum duration of treatment has been debated.  These investigators performed a non-inferiority trial of a shorter exposure of 6 months versus the standard 12 months of trastuzumab for patients with early breast cancer.  They did an open-label, randomized, phase III clinical trial in 156 centers in France.  Patients with HER2-positive early breast cancer who had received at least 4 cycles of chemotherapy, had breast-axillary surgery, and had received up to 6 months of trastuzumab (administered by intravenous infusions over 30 to 90 mins every 3 weeks; initial loading dose 8 mg/kg; 6 mg/kg thereafter) before randomization were eligible.  Patients were randomly assigned via central randomization procedure with web-based software to continue trastuzumab for another 6 months (12 months total duration; control group) or to discontinue trastuzumab at 6 months (6 months total duration; experimental group).  Randomization was stratified by concomitant or sequential administration of trastuzumab with chemotherapy, estrogen-receptor status, and center using a minimization algorithm.  The primary end-point was DFS, with a pre-specified non-inferiority margin of 1.15.  Analyses were carried out in the intention-to-treat population.  A total of 1,691 patients were randomly assigned to receive 12 months of trastuzumab and 1,693 to receive 6 months of trastuzumab; 1,690 patients in each group were included in the intention-to-treat analyses.  After a median follow-up of 42.5 months (IQR 30.1 to 51.6), 175 DFS events were noted in the 12-month group and 219 in the 6-month group; 2-year DFS was 93.8 % (95 % CI: 92.6 to 94.9) in the 12-month group and 91.1 % (89.7 to 92.4) in the 6-month group (HR 1.28, 95 % CI: 1.05 to 1.56; p = 0.29). 119 (93 %) of the 128 cardiac events (clinical or based on assessment of LVEF) occurred while patients were receiving trastuzumab.  Significantly more patients in the 12-month group experienced a cardiac event than did those in the 6-month group (96 [5.7 %] of 1690 patients versus 32 [1.9 %] of 1,690 patients, p < 0.0001).  The authors concluded that after 3.5 years follow-up, they failed to show that 6 months of treatment with trastuzumab was non-inferior to 12 months of trastuzumab.  Moreover, they stated that despite the higher rates of cardiac events, 12 months of adjuvant trastuzumab should remain the standard of care.

Trastuzumab for Gastric Cancer 

Advanced gastric cancer is an incurable disease; several authorities have stated that new and less toxic treatments are needed.  HER2 over-expression has been reported in 6 % to 35 % of stomach and gastroesophageal tumors.  Gravalos and Jimeno (2008) noted that gastric cancer is the second leading cause of cancer mortality in the world and its management, especially in advanced stages, has evolved relatively little.  In particular, no targeted modality has so far been incorporated to its treatment armamentarium.  HER2 over-expression is increasingly recognized as a frequent molecular abnormality, driven as in breast cancer by gene amplification.  There is mounting evidence of the role of HER2 over-expression in patients with gastric cancer, and it has been solidly correlated to poor outcomes and a more aggressive disease.  Additionally, pre-clinical data are showing significant anti-tumor efficacy of anti-HER2 therapies (particularly monoclonal antibodies directed towards the protein) in in-vitro as well as in-vivo models of gastric cancer.  As a result, several clinical trials are exploring in different settings and with diverse designs the potential of anti-HER2 therapies in gastric cancer patients. 

A randomized trial investigating anti-HER2 therapy in advanced gastric cancer showed that trastuzumab plus chemotherapy was superior to chemotherapy alone (van Custem et al, 2009).  The ToGA study is the first randomized, prospective, multi-center, phase III trial to study the efficacy and safety of trastuzumab in HER2- positive gastric cancer.  Patients with HER2-positive gastro-esophageal and gastric adenocarcinoma (locally advanced, recurrent, or metastatic) were randomized to receive trastuzumab plus chemotherapy (5-fluorouracil or capecitabine and cisplatin) every 3 weeks for 6 cycles or chemotherapy alone.  Trastuzumab was given until disease progression.  The primary end point was OS; secondary end points included overall response rate (ORR), progression-free survival, time to progression, duration of response, and safety.  An interim analysis was planned at 75 % of deaths and the Independent Data Monitoring Committee recommended releasing the data as the pre-specified boundary was exceeded and median follow-up of patients was 17.1 months.  Tumors from 3,807 patients were centrally tested for HER2 status: 22.1 % were HER2-positive; 594 patients were randomized 1:1 at sites in Europe, Latin America, and Asia.  The investigators reported that baseline characteristics were well-balanced across arms.  Median OS was significantly improved with trastuzumab plus chemotherapy compared to chemotherapy alone: 13.5 versus 11.1 months, respectively (p = 0.0048; HR 0.74; 95 % CI: 0.60 to 0.91). ORR was 47.3 % in the trastuzumab plus chemotherapy arm and 34.5 % in the chemotherapy arm (p = 0.0017).  Safety profiles were similar with no unexpected adverse events in the trastuzumab plus chemotherapy arm.  There was no difference in symptomatic congestive heart failure between arms.  Asymptomatic left ventricular ejection fraction decreases were reported in 4.6 % of patients in the trastuzumab plus chemotherapy arm and 1.1 % in the chemotherapy arm.  The investigators concluded that this randomized trial investigating anti-HER2 therapy in advanced gastric cancer showed that herceptin plus chemotherapy is superior to chemotherapy alone.

Pazo Cid and Anton (2013) stated that trastuzumab has emerged as the first targeted drug to improve OS when combined with chemotherapy in advanced HER2-positive gastric cancer.  Primary and secondary resistance to trastuzumab has become a major problem and new strategies to overcome this resistance are needed.  A high percentage of advanced HER2-positive gastric cancer patients who progress on trastuzumab therapy are candidates for second-line therapy.  New families of targeted drugs, including tyrosine kinase inhibitors such as lapatinib and PF-00299804, mammalian target of rapamycin pathway inhibitors such as everolimus, heat-shock protein 90 inhibitors such as AUY922, HER dimerization inhibitors such as pertuzumab, and antibody-chemotherapy conjugates such as trastuzumab-emtansine, could offer alternative second-line treatments when trastuzumab-based first-line therapy fails.

Trastuzumab for Non-Small Cell Lung Cancer

In a multi-center, phase II clinical study, Clamon and colleagues (2005) determined whether trastuzumab would effect responses in patients with non-small cell lung carcinoma who had tumors that over-expressed HER2.  Patients were required to have Stage IIIB or Stage IV non-small cell lung carcinoma and tumors with 2+ or 3+ expression of HER2, as determined with immunohistochemistry, and they may have received up to 1 prior chemotherapy regimen.  Trastuzumab at a dose of 4 mg/kg was given intravenously on week 1; then, weekly doses of 2 mg/kg were given.  Response revaluation was performed every 8 weeks.  Among 209 screened patients, 24 patients (11 %) had tumors with 2+ or 3+ expression of HER2.  One patient achieved a partial response, and 1 patient experienced a treatment-related death due to pulmonary toxicity.  These investigators concluded that single-agent trastuzumab did not exhibit significant clinical activity against non-small cell lung carcinoma when HER2 expression levels were measured by immunohistochemistry.

In a randomized controlled phase II clinical trial, Krug et al (2005) examined whether combined trastuzumab with weekly taxanes would improve outcomes over standard chemotherapy in patients with advanced non-small cell lung cancer.  The primary goal was to determine whether docetaxel plus trastuzumab or paclitaxel plus trastuzumab was the superior regimen based on response and toxicity, and to determine whether either regimen was appropriate for further testing in a randomized phase III clinical trial.  After stratification based on the results of HER2 immunohistochemistry, chemotherapy-naive patients were randomized to receive trastuzumab plus docetaxel or trastuzumab plus paclitaxel.  The study was designed so patients with or without HER2 over-expression would be distributed equally between the study arms.  Immunohistochemistry for HER2 protein expression was attempted for 182 pathologic samples from 169 patients.  Twenty-eight of the 179 evaluable samples (16 %) revealed 2+ or 3+ staining.  The objective response rate was 23 % (7 of 30 patients) in the patients treated with docetaxel plus trastuzumab and 32 % (11 of 34 patients) in the patients treated with paclitaxel plus trastuzumab (p = 0.76).  No difference was noted in the median survival (16 months versus 14 months) or 1-year survival (57 % versus 55 %) (p = 0.998).  Toxicities were mild in both treatment arms.  No difference with regard to response rates or survival was noted between HER2-positive (2+ or 3+) and HER2-negative (0-1+) patients.  These authors concluded that the expression of HER-2 protein in patients with advanced non-small cell lung cancer in this study was found to be similar to that reported in previous series.  The response rates and toxicities for patients treated with docetaxel and trastuzumab or paclitaxel and trastuzumab were not significantly different, though survival in both arms was better than expected.  HER2 expression status did not appear to affect outcomes for this uniform group of patients who were treated in a comparable fashion.  Because of the infrequency of HER2 over-expression, and the absence of improved outcomes in patients with non-small cell lung cancer who were treated with trastuzumab plus chemotherapy in other studies, neither regimen tested will be advanced to a Phase III clinical trial.

Trastuzumab for Salivary Gland Cancer

In a review on systemic therapies for recurrent and/or metastatic salivary gland cancers, Vattemi and colleagues (2008) noted that salivary gland carcinomas are rare cancers, comprising 1 to 5 % of head and neck cancers.  They represent a morphologically and clinically diverse group of tumors.  The most commonly histopathological types are muco-epidermoid cancer, adenoid cystic cancer and adenocarcinomas.  Malignant salivary gland tumors generally present as painless, slow-growing tumors that are indistinguishable from benign tumors.  Surgery is the principal treatment and is curative in early stage.  Radiation therapy should be considered in most patients after surgical resection.  Chemotherapy is reserved for palliative treatment of metastatic disease but results are disappointing.  Recent studies have investigated the role of targeted therapies in a palliative setting.  Multi-center co-operative group clinical trials are required to assess novel therapies to maximize patient resources in this uncommon tumor.

Thorpe and colleagues (2017) noted that salivary ductal carcinoma and carcinoma ex pleomorphic adenoma (CEPA) are aggressive salivary gland cancers with poor prognosis.  The standard of care is resection with or without radiotherapy, and there are no established systemic therapy options.  These researchers described 1 patient with metastatic CEPA and 1 patient with metastatic recurrent salivary duct carcinoma whose tumors were evaluated by comprehensive genomic profiling.  Testing identified HER2 amplification in both patients, and an additional activating HER2 mutation in the CEPA case.  Both patients were treated with the HER2-targeting monoclonal antibody trastuzumab (Herceptin) plus chemotherapy and experienced rapid responses.  Subsequently, both patients were given single-agent maintenance trastuzumab and continued to experience durable disease control.  The authors concluded that given the poor prognosis for salivary gland cancers and the limited therapeutic options upon recurrence or metastasis, patients should be tested for all classes of HER2 alterations; and in cases with HER2 over-expression or activation, targeted therapies, such as trastuzumab are promising.

Trastuzumab for Bladder (Urothelial ) Cancer

Moussaid et al (2014) stated that about 10 % of metastatic urothelial carcinoma over-express oncogenic HER2/neu receptor.  Recent preliminary data suggested that patients with this particular molecular subset could benefit from trastuzumab therapy, which specifically targets the receptor and thus inhibits downstream activation pathway.  These investigators reported a case illustrating this clinical benefit, with complete response reported as third line therapy in a heavily pre-treated patient with diffuse metastatic urothelial carcinoma of the bladder.  It also highlighted the usefulness of 18-Fluorodeoxyglucose Positron Emission Tomography (18-FDG PET) as a biomarker for response to trastuzumab.  The authors concluded that there is insufficient evidence for incorporating trastuzumab in routine for treatment of bladder carcinoma.  They stated that further studies are needed to better determine its place in the management of bladder carcinoma, and more particularly after failure of platinum-based therapy.

Zhu et al (2015) stated that the treatment of advanced urothelial cancer of the bladder has evolved substantially during recent years.  Chemotherapy has been the mainstay of treatment and confers survival advantage.  Despite such advances, the chemotherapy of bladder cancer is far from satisfactory due to severe side effects.  Targeted therapy with novel drugs directed at specific molecular pathways opens promising new avenues to improve patient outcome.  A systematic review examined the clinical data for novel targeted agents in 10 phase II trials, with a focus on bevacizumab, aflibercept, sunitinib, sorafenib, gefitinib, lapatinib and trastuzumab.  Besides, these investigators presented studies on other novel, promising targeted agents, including pazopanib, cetuximab and everolimus.  Although bevacizumab and trastuzumab have shown promising results for patients with advanced bladder cancer, other targeted agents have not achieved the same clinical benefit in this disease as seen in other common epithelial cancers.  Ultimately, combination targeted therapy, sequential therapy, adjuvant and neoadjuvant therapy may yield the best outcomes.

In a multi-center, randomized phase II clinical trial, Oudard et al (2015) examined the safety and effectiveness of gemcitabine and platinum salt, with or without trastuzumab, in patients with locally advanced or metastatic urothelial carcinoma over-expressing Her2.  The main eligibility criterion was Her2 over-expression on immunohistochemistry (IHC 2+ or 3+) of primary tumor tissue confirmed by fluorescence in-situ hybridization (FISH).  Patients were randomized to Arm A: gemcitabine 1,000 mg/m(2) (days 1 and 8) plus either cisplatin (70 mg/m(2)) or carboplatin (AUC = 5) (day 1 every 3 weeks) or Arm B: added trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 21 days until progression).  The primary end-point was progression-free survival (PFS).  Among 563 screened patients, 75 (13.3 %) were Her2 positive (IHC 2+/3+ and FISH+) and 61 met all eligibility criteria (median age of 64 years; 54/61 males; 50/61 baseline ECOG-PS 0 to 1; 11 locally advanced and 50 metastatic).  There was no significant difference between Arms A and B in median PFS (10.2 versus 8.2 months, respectively, p = 0.689), objective response rate (65.5 % versus 53.2 %, p = 0.39), and median overall survival (15.7 versus 14.1 months, respectively, p = 0.684).  In an exploratory analysis, trastuzumab-treated patients receiving cisplatin rather than carboplatin-based chemotherapy fared better (PFS: 10.6 versus 8.0; OS: 33.1 versus 9.5 months).  Myelosuppression was the main grade 3/4 toxicity.  A case of grade 3 cardiotoxicity and 1 death from febrile neutropenia occurred in arm B.  The authors concluded that the unexpectedly low incidence of Her2 over-expression precluded the detection of a significant difference in efficacy on addition of trastuzumab to platinum-based chemotherapy with gemcitabine.  However, the satisfactory tolerance of the combination warrants further studies, especially of the cisplatin-based combination, in well-defined patient subsets.

UpToDate reviews on “Treatment of metastatic urothelial cancer of the bladder and urinary tract” (Bellmunt, 2016) and “Overview of the initial approach and management of urothelial bladder cancer” (Lerner and Raghavan, 2016) did not mention trastuzumab as a therapeutic option.

Trastuzumab for Penile Cancer

The NCCN clinical practice guideline on “Penile cancer” (Version 2.2018) does not mention the use of trastuzumab as a therapeutic option.

The NCCN Drugs & Biologics Compendium (2020) does not list penile cancer as a recommended indication of trastuzumab.

Trastuzumab for Rectal Cancer

Sorscher (2011) noted that over-expression or HER-2 gene amplification occurs in approximately 25 % of invasive breast cancers and predicts response to the targeting therapeutic antibody trastuzumab.  In this report, trastuzumab was used in the treatment of a patient with metastatic colorectal cancer harboring HER-2 gene amplification and over-expression.  There was a marked radiographic response to the trastuzumab.  The authors concluded that if a larger series confirmed the efficacy of trastuzumab use in patients with colorectal cancers with HER-2 gene amplification, trastuzumab could help improve the outlook for patients with this unusual colorectal cancer variant.

Ingold et al (2014) stated that anti-HER2/neu therapy is well-established in breast and gastric carcinoma.  The increased understanding of this pathway led to the identification of new promising drugs in addition to trastuzumab, offering further perspectives.  The role of HER2/neu in colorectal carcinoma was controversially discussed, as discrepant data has been reported.  These researchers retrospectively assessed the prevalence of HER2/neu positivity in a large series of colorectal carcinoma, testing HER2/neu status according to current recommendations.  They correlated the results to clinico-pathological data and patient survival.  Overall, in 1,645 primary colorectal carcinoma cases, 1.6 % of the cases were HER2/neu positive.  HER2/neu positivity significantly correlated with higher UICC stages (p = 0.017) and lymph node metastases (p = 0.029).  In the subgroup of sigmoidal and rectal carcinomas, positive HER2/neu status was associated with T-category (p = 0.041) and higher UICC stages (p = 0.022).  Although statistically not significant, HER2/neu-positive colorectal carcinomas displayed a tendency to poorer overall survival.  The authors concluded that these results illustrated the importance of testing HER2/neu by approved diagnostic techniques and scoring systems.  They assumed that although the prevalence of HER2/neu positivity in colorectal carcinoma is low, HER2/neu testing in advanced, nodal-positive colorectal carcinoma is reasonable, offering a potential target in high risk colorectal carcinoma.

Trastuzumab for Cervical Cancer

Bellone and colleagues (2003) compared HER-2/neu expression on biopsies obtained from early stage cervical cancer, primary cell lines established therefrom, established cervical cancer cell lines, and metastatic or recurrent sites of disease; and evaluated the sensitivity of primary cervical cancer cell lines to treatment with a humanized MAb against HER-2/neu (Herceptin).  Surface HER-2/neu expression on 18 cervical cancer cell lines was compared to HER-2/neu detection by immunohistochemistry on biopsies obtained from the original tumors (10 patients) and sites of recurrence (2 patients).  Primary cell lines were tested for sensitivity to Herceptin-mediated antibody-dependent cellular cytotoxicity (ADCC) and sensitivity to Herceptin-mediated inhibition of proliferation; 9 out of 10 primary (90 %) and 8 out of 8 (100 %) established cervical cancer cell lines expressed HER-2/neu by flow cytometry.  Surprisingly, all HER-2/neu-positive primary cell lines were derived from tumor biopsies that scored negative (i.e., 0 to 1+) for HER-2/neu expression by immuno-histochemistry.  Heavy staining for HER-2/neu (i.e., 3+) was found in the recurrent/metastatic lesions of the 2 relapsed patients.  Importantly, all HER-2/neu-positive primary cell lines were highly sensitive to Herceptin-mediated ADCC, and their proliferation was also significantly inhibited by Herceptin.  A significant enhancement of Herceptin-mediated ADCC was demonstrated when effector cells were exposed to low doses of IL-2 in-vitro.  The authors concluded that early stage cervical cancer may develop a population of HER-2/neu-positive cells with a selective growth advantage over HER-2/neu-negative cells.  Therapy which targets HER-2/neu may be more effective in patients with cervical cancer than indicated by the commonly low expression of HER-2/neu in tumors removed at the time of primary treatment.

Chavez-Blanco and associates (2004) stated that trastuzumab, a humanized monoclonal antibody against the HER2 receptor is currently being used in breast and other tumor types.  Early studies have shown that a variable proportion of cervical carcinoma tumors over-express the HER2 receptor as evaluated by diverse techniques and antibodies.  Currently, it is known that a tumor response to trastuzumab strongly correlates with the level of HER2 expression evaluated by the Hercep Test, thus, it appeared desirable to evaluate the status of expression of this receptor using the FDA-approved Hercep Test and grading system to gain insight in the feasibility of using trastuzumab in cervical cancer patients.  These researchers analyzed a series of cervical cancer cell lines, the primary tumors of 35 cases of cervical cancer patients and 4 recurrent cases, with the Hercep Test in order to establish whether this tumor type over-express HER2 at level of 2+/3+ as trastuzumab is currently approved for breast cancer having such level of expression.  The results indicated that only 1 out of 35 primary tumors cases over-expressed the receptor at this level, however, 2 out of 4 recurrent tumors that tested negative at diagnosis shifted to Hercep Test 2+ and 3+, respectively.  The authors concluded that the low frequency of expression in primary cases suggested that trastuzumab could have a limited value for the primary management of cervical cancer patients, however, the finding of "conversion" to Hercep Test 2+ and 3+ of recurrent tumors indicated the need to further evaluate the expression of HER2 in the metastatic and recurrent cases.

Meira and co-workers (2009) noted that cervical cancer (CC) annually kills 288,000 women worldwide.  Unfortunately, responses to chemo-radiation are partial and are of short duration.  As anti-EGFR monoclonal antibodies sensitize tumors, these investigators examined cetuximab's toxicity plus chemo-radiation on CC cells, which express different EGFR levels.  EGFR, HER2, AKT and MAPK expression and phosphorylation status were determined by western blotting.  Cytotoxicity was assessed by MTT or clonogenic assays (CA) in cell lines treated with cetuximab alone or in combinations.  Cetuximab with cisplatin and radiation achieved maximum cytotoxic effects for A431, Caski and C33A cells (high, intermediate and low EGFR expression, respectively) in CA.  Cetuximab efficiently decreased MAPK and AKT phosphorylation in A431 cells but slightly less in Caski and C33A cells.  To check whether further EGFR, HER2 or MAPK inhibition would improve cetuximab's cytotoxicity, these researchers combined it with an EGFR tyrosine kinase inhibitor (TKI), trastuzumab or a MEK1/2 inhibitor (PD98059).  In Caski, but not in C33A cells, cetuximab cooperated with the TKI, reducing cell survival and AKT and MAPK phosphorylation.  However, cetuximab with trastuzumab or PD98059 reduced survival and MAPK phosphorylation of both cell lines.  The authors concluded that these findings suggested that cetuximab combined with chemo-radiation, trastuzumab or MAPK inhibitors has useful applications for CC treatment, independently of EGFR expression.

Hiroshima and associates (2015) previously developed mouse models of HER-2-positive cervical cancer.  Tumors in nude mice had histological structures similar to the original tumor and were stained by anti-HER-2 antibody in the same pattern as the patient's cancer.  These researchers have also previously developed tumor-targeting Salmonella typhimurium A1-R and have demonstrated its efficacy against patient-derived tumor mouse models, both alone and in combination.  In the current study, they determined the efficacy of S. typhimurium A1-R in combination with trastuzumab on a patient-cancer nude-mouse model of HER-2 positive cervical cancer.  Mice were randomized to 5 groups and treated as follows: (i) no treatment; (ii) carboplatinum (30 mg/kg, ip, weekly, 5 weeks); (iii) trastuzumab (20 mg/kg, ip, weekly, 5 weeks); (iv) S. typhimurium A1-R (5 × 107 CFU/body, ip, weekly, 5 weeks); and (v) S. typhimurium A1-R (5 × 107 CFU/body, ip, weekly, 5 weeks) + trastuzumab (20 mg/kg, ip, weekly, 5 weeks).  All regimens had significant efficacy compared to the untreated mice.  The relative tumor volume of S. typhimurium A1-R + trastuzumab-treated mice was smaller compared to trastuzumab alone (p = 0.007) and S. typhimurium A1-R alone (p = 0.039).  No significant body weight loss was found compared to the no treatment group except for carboplatinum-treated mice (p = 0.021).  Upon histological examination, viable tumor cells were not detected, and replaced by stromal cells in the tumors treated with S. typhimurium A1-R + trastuzumab.  The authors concluded that the results of the present study suggested that S. typhimurium A1-R and trastuzumab in combination are highly effective against HER-2-expressing cervical cancer.

Oh and colleagues (2015) noted that surgery and radiation are the current standard treatments for cervical cancer.  However, there is no effective therapy for metastatic or recurrent cases, necessitating the identification of therapeutic targets.  In order to create preclinical models for screening potential therapeutic targets, these researchers established 14 patient-derived xenograft (PDX) models of cervical cancers using sub-renal implantation methods.  Serially passaged PDX tumors retained the histopathologic and genomic features of the original tumors.  Among the 9 molecularly profiled cervical cancer patient samples, a HER2-amplified tumor was detected by array comparative genomic hybridization (CGH) and targeted next-generation sequencing (NGS).  These investigators confirmed HER2 over-expression in the tumor and serially passaged PDX.  Co-administration of trastuzumab and lapatinib in the HER2-over-expressed PDX significantly inhibited tumor growth compared to the control.  Thus, the authors established histopathologically and genomically homologous PDX models of cervical cancer using sub-renal implantation.  Furthermore, they proposed HER2 inhibitor-based therapy for HER2-amplified cervical cancer refractory to conventional therapy.

Trastuzumab for Other Cancers: Esophageal, Endometrial, Dermal Adnexal Carcinoma, Melanoma, Osteosarcoma, Ovarian, Gallbladder, Neuroendocrine, and Ampullary

Homs and colleagues (2009) evaluated current treatment strategies and new developments including targeted therapy for esophageal cancer.  Published clinical trials as well as abstracts were selected regarding chemo-radiation or targeted therapy for esophageal cancer.  Pre-operative chemotherapy may offer a survival advantage compared to surgery alone, but the evidence is inconclusive.  For pre-operative chemo-radiation, only 2 of 10 randomized trials showed advanced survival compared to surgery alone, and, therefore, more phase III trials and, consequently, meta-analyses are needed.  Until now, for palliative chemotherapy, no survival benefit has been shown.  This is largely due to a lack of studies and difficulties in performing randomized trials.  The application of targeted therapy is widespread and reported for several tumor types.  For esophageal cancer, most studies have been performed with epidermal growth factor receptor (EGFR) inhibitors, including cetuximab, gefitinib, erlotinib and trastuzumab.  Limited experience is available with angiogenesis inhibitors, apoptosis inhibitors and COX-2 inhibitors.  As yet, targeted therapies are proven to be safe often in combination with chemo-radiation, but modestly effective for esophageal cancer.  Phase III trials have not been published yet and, therefore, for targeted therapies also, possibly using new concepts, more studies are needed.

Fleming et al (2010) evaluated the effectiveness of single-agent trastuzumab against advanced or recurrent HER2-positive endometrial carcinoma (EC), and explored predictors for HER2 amplification.  Eligible patients had measurable stage III, IV, or recurrent EC.  There was no limit on prior therapy although total prior doxorubicin dose was limited to 320 mg/m(2).  Tumors were required to have HER2 over-expression (2+ or 3+ immunohistochemical staining) or HER2 amplification (FISH HER2/CEP 17 ratio greater than 2.0).  Trastuzumab was administered intravenously at a dose of 4 mg/kg in week 1, then 2 mg/kg weekly until disease progression.  The primary end point was tumor response.  Of the 286 tumors centrally screened by LabCorp, 33 (11.5 %) were HER2-amplified.  Three of 8 clear (38 %) cell carcinomas and 7 of 25 serous carcinomas (28 %) screened exhibited HER2 amplification compared with 7 % (2/29) of endometrioid adenocarcinomas.  Over-expression of HER2 was correlated with amplification of HER2 (r = 0.459; p < 0.0001).  A total of 34 women were enrolled; 1 was excluded (refused treatment); and 18 had tumors with known HER2 amplification.  No major tumor responses were observed.  Twelve women experienced stable disease, 18 had increasing disease, and 3 were indeterminate for tumor response.  Neither HER2 over-expression nor HER2 amplification appeared to be associated with progression-free survival or OS.  The authors concluded that trastuzumab as a single agent did not exhibit activity against endometrial carcinomas with HER2 over-expression or HER2 amplification, although full planned accrual of women with HER2 amplified tumors was not achieved due to slow recruitment.  Serous and clear cell endometrial carcinomas appear to be more likely to demonstrate HER2 amplification.

Nash and colleagues (2007) reported the case of a 44-year old man was referred for a right chest nodule of 3-month duration.  A "benign" nodule had been excised from this location 8 years prior.  On examination, palpable nodes were noted in the right axilla.  Radiographical studies were significant only for right axillary lymphadenopathy.  Histologically, a nodular dermal proliferation composed of poorly differentiated epithelioid cells in nests and focally forming ducts with pseudopapillary architecture comprised the primary tumor.  Features of a clear cell hidradenoma were noted focally.  Immunohistochemical (IHC) analysis revealed reactivity for HMW cytokeratins, CK5 and CK7, p53, p63, CEA (focal), androgen receptor, EGFR, estrogen receptor (ER), MUC5AC, and strong/diffuse membranous staining for Her-2/neu.  Negative stains included villin, TTF-1, CDX2, S-100 protein, vimentin, gross cystic disease fluid protein 15 (GCDFP-15), mammoglobulin, and MUC2.  A wide local excision and axillary node dissection was performed.  Metastatic tumor involved 9 of 28 nodes.  Inter-phase fluorescence in situ hybridization (FISH) demonstrated chromosomal amplification of the Her-2/neu locus within the tumor and a nodal metastasis.  The patient has completed adjuvant and radiotherapy, including trastuzumab, and is asymptomatic.  The authors believed this to be the first demonstration of Her-2/neu amplification in a malignant skin adnexal tumor.  In analogy to breast carcinoma, these findings suggested the applicability of trastuzumab for patients with metastatic adnexal carcinomas demonstrating Her-2/neu amplification.  The role of trastuzumab, if any, for the treatment of dermal adnexal carcinoma needs to be validated by well-designed studies.

Inman et al (2003) noted that currently available systemic therapies for malignant melanoma produce low response rates in patients, and more effective treatment modalities are clearly needed.  Trastuzumab has had a significant impact on therapy for patients with HER2-over-expressing metastatic breast cancer.  This study examined the incidences of HER2 protein over-expression and HER2 gene amplification in metastatic malignant melanoma, which remain unclear in the literature.  The study evaluated patients with stage III and stage IV malignant melanoma who were treated between 1983 and 1999.  Tissue blocks were retrieved and reviewed to confirm the diagnosis.  From the 101 cases identified, 49 (31 stage III and 18 stage IV) had sufficient residual tumor sample to enable an assay to be performed.  The blocks were tested for HER2 over-expression using the DAKO HercepTest immunohistochemical (IHC) assay.  Any sample that tested 1+ or greater for HER2 expression on IHC and a randomly selected subset of HER2-negative samples were tested for the presence of HER2 gene amplification using the Vysis PathVysion fluorescence in situ hybridization (FISH) assay.  The median age of the 49 selected patients was 52.2 years, and the male-to-female ratio was 1.23:1 (27 men to 22 women).  All of the 49 cases of malignant melanoma were negative for HER2 over-expression by IHC. However, 2 samples (3 %) were found to have a weak level of HER2 expression (1+ level of staining).  Subsequent FISH results on the samples that were 1+ on IHC were negative for HER2 gene amplification.  FISH results on 21 other randomly selected IHC-negative samples were also negative for HER2 amplification.  Flow cytometry failed to show HER2 over-expression in 2 melanoma cell lines, and treatment of these cells with trastuzumab did not affect their proliferation rate.  These researchers  found a low incidence of HER2 expression and no evidence of HER2 protein over-expression or HER2 gene amplification in metastatic malignant melanoma tissues.  Therefore, routine testing for HER2 over-expression or HER2 amplification would not be of benefit in this patient population.  These results also imply that anti-HER2 therapy with trastuzumab is highly unlikely to provide benefit for patients with metastatic melanoma.

Kluger et al (2004) noted that melanoma is among the most chemotherapy-resistant malignancies.  Numerous new agents have been developed that target specific molecules on cancer cells, including the monoclonal antibody trastuzumab, which targets Her2/neu and has been very beneficial in the treatment of breast cancer.  There are conflicting reports in the literature about Her2/neu expression in melanoma specimens, but all of the cohorts studied have been small.  These researchers therefore examined Her2/neu expression in a very large cohort of melanoma specimens in order to determine the value of exploring trastuzumab therapy for melanoma patients.  Immunohistochemical staining was performed on 2 tissue microarrays, together containing 600 intact specimens.  Expression was evaluated semi-quantitatively and correlated with tumor stage and other clinicopathological data.  Of the 600 specimens in the cohort, 31 patients (5.2 %) had positive Her2/neu expression.  Among the primary cutaneous specimens (n = 269), 7 % had positive Her2/neu staining, while 3.6 % of the recurrent or metastatic specimens (n = 331) had positive Her2/neu staining (p = 0.06).  Among the primary lesions there was no significant correlation between Her2/neu expression, Clark level and ulceration; however, Her2/neu expression was associated with lesions with a Breslow depth of less than 2 mm (p = 0.05).  Using this very large cohort of melanoma specimens, these researchers found only a few cases with aberrant Her2/neu expression, many of them being primary cutaneous lesions rather than recurrent or metastatic lesions.  The authors concluded that these findings suggested that drugs that specifically target Her2/neu are not likely to be useful for the treatment of metastatic melanoma or as adjuvant therapy for melanoma patients at high risk for recurrence.

In a phase II clinical trial, Ebb and colleagues (2012) examined the safety and feasibility of delivering biologically targeted therapy by combining trastuzumab with standard chemotherapy in patients with metastatic osteosarcoma and HER2 over-expression.  Among 96 evaluable patients with newly diagnosed metastatic osteosarcoma, 41 had tumors that were HER2-positive by immunohistochemistry.  All patients received chemotherapy with cisplatin, doxorubicin, methotrexate, ifosfamide, and etoposide.  Dexrazoxane was administered with doxorubicin to minimize the risk of cardiotoxicity from treatment with trastuzumab and anthracycline.  Only patients with HER2 over-expression received concurrent therapy with trastuzumab given for 34 consecutive weeks.  The 30-month event-free and OS rates for patients with HER2 over-expression treated with chemotherapy and trastuzumab were 32 % and 59 %, respectively.  For patients without HER2 over-expression, treated with chemotherapy alone, the 30-month event-free and OS rates were 32 % and 50 %, respectively.  There was no clinically significant short-term cardiotoxicity in patients treated with trastuzumab and doxorubicin.  The authors concluded that despite intensive chemotherapy plus trastuzumab for patients with HER2-positive disease, the outcome for all patients was poor, with no significant difference between the HER2-positive and HER2-negative groups.  The authors concluded that although these findings suggested that trastuzumab can be safely delivered in combination with anthracycline-based chemotherapy and dexrazoxane, its therapeutic benefit remains uncertain.  They stated that definitive assessment of trastuzumab's potential role in treating osteosarcoma would require a randomized study of patients with HER2-positive disease.

Sorscher (2013) stated that trastuzumab is a monoclonal antibody targeting HER-2; and HER-2 over-expression has been described in gallbladder cancer and in cholangiocarcinoma.  The author described the first case of a patient with HER-2 over-expressing metastatic gallbladder adenocarcinoma and responding radiographically and biochemically to trastuzumab alone.  The finding of this case study needs to be validated by well-designed studies.  Moreover, the NCCN’s clinical practice guideline on “Hepatobiliary cancers” do not mention the use of trastuzumab, pertuzumab, or ado-trastuzumab emtansine as a therapeutic option.

Although cervical neuroendocrine tumors are rare, they are addressed in the NCCN guidelines on “Neuroendocrine tumors” (Version 1.2015), which state that the classic small cell neuroendocrine tumor is poorly differentiated and occurs in the lung.  They note that, although rare, extra-pulmonary large or small cell neuroendocrine tumors occur in a wide variety of organs.  The NCCN guidelines state that the cervix is the most common extra-pulmonary location of these tumors, followed by the esophagus, larynx and pharynx, colon and rectum, and prostate.   For chemotherapy of these large and small cell neuroendocrine tumors, the NCCN guidelines recommend chemotherapy with a small cell lung cancer regimen.  They note that, in general, cisplatin or carboplatin and etoposide are recommended as primary treatment.  The NCCN Compendium has no recommendation for use of trastuzumab (Herceptin) for small cell lung cancer or neuroendocrine tumors.

The authors of an UpToDate chapter on “Small cell neuroendocrine carcinoma of the cervix” state that they administer a similar chemotherapy regimen as the one used for small cell lung cancer such as etoposide plus cisplatin (Leitao and Zivanovic, 2015).

An UpToDate review on “Ampullary carcinoma: Treatment and prognosis” (Ryan et al, 2015) does not mention the use of trastuzumab as a therapeutic option.

The value of trastuzumab in ovarian carcinoma is limited by the low frequency of HER2/neu over-expression and the low response rate of response to trastuzumab among patients with HER2/neu over-expression.  Bookman et al (2003) reported on the results of a Gynecology Oncology Group Phase II study of trastuzumab in patients with persistent or recurrent epithelial ovarian or primary peritoneal carcinoma with 2+/3+ HER2 expression.  Only 11.4 percent of subjects screened for HER2 expression exhibited the requisite 2+ or 3+ HER2 expression level to be eligible for this study.  The investigators reported an overall response rate of 7.3 % after a median treatment duration of 8 weeks, and the median progression-free interval was 2 months.  The investigators concluded that “the clinical value of single-agent trastuzumab in recurrent ovarian cancer is limited by the low frequency of HER2 over-expression and low rate of objective response among patients with HER2 over-expression.”  Iwamoto et al (2003) found HER2/neu over-expression in only 1 of 15 clear cell ovarian carcinoma cases that were immunostained for HER-2 /neu using HercepTest.  The investigators concluded that HER-2 /neu over-expression appeared to be uncommon in ovarian clear cell carcinomas.  “Herceptin may thus target only a small proportion of ovarian clear cell carcinomas and be of limited clinical value for treatment of this carcinoma” (Iwamoto et al, 2003).

Pertuzumab in combination with Trastuzumab

In a randomized, multi-center, open-label, phase II study, Gianni et al (2012) examined the combination of pertuzumab or trastuzumab, or both, with docetaxel and the combination of pertuzumab and trastuzumab without chemotherapy in the neoadjuvant setting.  Treatment-naive women with HER2-positive breast cancer were randomly assigned (1:1:1:1) centrally and stratified by operable, locally advanced, and inflammatory breast cancer, and by hormone receptor expression to receive 4 neoadjuvant cycles of: trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m(2), escalating, if tolerated, to 100 mg/m(2) every 3 weeks; group A) or pertuzumab (loading dose 840 mg, followed by 420 mg every 3 weeks) and trastuzumab plus docetaxel (group B) or pertuzumab and trastuzumab (group C) or pertuzumab plus docetaxel (group D).  The primary end-point, examined in the intention-to-treat population, was pathological complete response (pCR) in the breast.  Neither patients nor investigators were masked to treatment.  Of 417 eligible patients, 107 were randomly assigned to group A, 107 to group B, 107 to group C, and 96 to group D.  Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pCR rate (49 of 107 patients; 45.8 % [95 % CI: 36.1 to 55.7]) compared with those given trastuzumab plus docetaxel (group A; 31 of 107; 29.0 % [20.6 to 38.5]; p = 0.0141); 23 of 96 (24.0 % [15.8 to 33.7]) women given pertuzumab plus docetaxel (group D) had a pCR, as did 18 of 107 (16.8 % [10.3 to 25.3]) given pertuzumab and trastuzumab (group C).  The most common adverse events of grade 3 or higher were neutropenia (61 of 107 women in group A, 48 of 107 in group B, 1 of 108 in group C, and 52 of 94 in group D), febrile neutropenia (8, 9, 0, and 7, respectively), and leucopenia (13, 5, 0, and 7, respectively).  The number of serious adverse events was similar in groups A, B, and D (15 to 20 serious adverse events per group in 10 to 17 % of patients) but lower in group C (4 serious adverse events in 4 % of patients).  The authors concluded that patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pCR rate compared with those given trastuzumab plus docetaxel, without substantial differences in tolerability.  Pertuzumab and trastuzumab without chemotherapy eradicated tumors in a proportion of women and showed a favorable safety profile.  The authors stated that these findings justified further exploration in adjuvant trials and support the neoadjuvant approach for accelerating drug assessment in early breast cancer.

In a randomized phase II clinical trial, Schneeweiss et al (2013) evaluated the tolerability, with particular focus on cardiac safety, of trastuzumab and pertuzumab (P) with chemotherapy in the neoadjuvant treatment of HER2-positive early breast cancer.  In this multi-center, open-label phase II study, patients with operable, locally advanced, or inflammatory breast cancer were randomized 1 : 1 : 1 to receive 6 neoadjuvant cycles q3w (Arm A: 5-fluorouracil, epirubicin, cyclophosphamide [FEC] + H + P ×3 → docetaxel [T] + H + P ×3; Arm B: FEC ×3 → T + H + P ×3; Arm C: T + carboplatin + H [TCH]+P ×6).  Pathologic complete response was assessed at surgery and adjuvant therapy given to complete 1 year of H.  A total of 225 patients were randomized.  During neoadjuvant treatment, 2 patients (2.7 %; Arm B) experienced symptomatic left ventricular systolic dysfunction (LVSD) and 11 patients (Arm A: 4 [5.6 %]; Arm B: 4 [5.3 %]; Arm C: 3 [3.9 %]) had declines in left ventricular ejection fraction of greater than or equal to 10 % points from baseline to less than 50 %.  Diarrhea was the most common adverse event.  Pathologic complete response (ypT0/is) was reported for 61.6 % (Arm A), 57.3 % (Arm B), and 66.2 % (Arm C) of patients.  The authors concluded that the combination of P with H and standard chemotherapy resulted in low rates of symptomatic LVSD.

On September 30, 2013, the FDA granted accelerated approval to Perjeta (pertuzumab) as part of a complete treatment regimen for patients with early stage breast cancer before surgery (neoadjuvant setting).  Perjeta is the 1st FDA-approved drug for the neoadjuvant treatment of breast cancer.  Perjeta’s new indication is intended for patients with HER2-positive, locally advanced, inflammatory or early stage breast cancer (tumor greater than 2 cm in diameter or with positive lymph nodes) who are at high risk of having their cancer return or metastasize or of dying from the disease.  It is to be used in combination with trastuzumab and other chemotherapy prior to surgery and, depending upon the treatment regimen used, may be followed by chemotherapy after surgery.  Following surgery, patients should continue to receive trastuzumab to complete 1 year of treatment.  Perjeta’s accelerated approval for neoadjuvant treatment is based on a study designed to measure pCR.  In the study, 417 subjects were randomly assigned to receive 1 of 4 neoadjuvant treatment regimens:

• trastuzumab plus docetaxel,
• Perjeta plus trastuzumab and docetaxel,
• Perjeta plus trastuzumab, or
• Perjeta plus docetaxel.

About 39 % of subjects who received Perjeta plus trastuzumab and docetaxel achieved pCR, compared to about 21 % who received trastuzumab plus docetaxel.  The confirmatory trial for this accelerated approval is being conducted in patients with HER2-positive breast cancer who had prior breast cancer surgery and are at high risk of having their cancer return.  More than 4,800 participants are enrolled in this trial, which will provide further data on safety, effectiveness, and long-term outcomes.  Results are expected in 2016.Swain et al (2013) noted that CLEOPATRA is a phase III study to compare the safety and effectiveness of pertuzumab, trastuzumab, and docetaxel with placebo, trastuzumab, and docetaxel in patients with HER2-positive first-line metastatic breast cancer.  The results of the primary analysis showed significantly longer median PFS in the pertuzumab group than in the placebo group.  Interim analysis of OS favored the pertuzumab group but was not significant.  These researchers reported results for OS after an additional year of follow-up.  The study was a double-blind randomized trial undertaken at 204 centers in 25 countries.  Patients with HER2-positive metastatic breast cancer who had not received previous chemotherapy or biological treatment for their metastatic disease were randomly assigned to receive either pertuzumab, trastuzumab plus docetaxel (n = 402); or the same regimen with a matching placebo replacing pertuzumab (n = 406).

Randomization was in a 1:1 ratio, stratified by geographical region and previous treatment status.  The primary end-point was PFS (assessed independently), which has been reported previously; no follow-up data were gathered for the primary end-point.  Secondary end-points included OS, PFS (assessed by investigator), objective response rate, and safety.  Median follow-up was 30 months in both groups.  Effectiveness end-points were analyzed in the intention-to-treat population and safety was analyzed by treatment received.  The study was completed but safety and survival data continue to be followed-up.  In the intention-to-treat population, 267 patients died by data cut-off (May 14, 2012), 154 (38 %) of 406 in the placebo group and 113 (28 %) of 402 in the pertuzumab group.  Median OS was 37.6 months (95 % CI: 34. To -NE [not estimable]) in the placebo group but had not been reached (95 % CI: 42.4 to NE) in the pertuzumab group (HR 0.66, 95 % CI: 0.52 to 0.84; p = 0.0008).  Investigator-assessed median PFS was 12.4 months (95 % CI: 10.4 to 13.5) in the placebo group and 18.7 months (16.6 to 21.6) in the pertuzumab group (HR 0.69, 95 % CI: 0.58 to 0.81).  Serious adverse events were reported in 115 (29 %) of 396 patients who received placebo, trastuzumab, and docetaxel and 148 (36 %) of 408 who received pertuzumab, trastuzumab, and docetaxel, and included febrile neutropenia, neutropenia, diarrhea, pneumonia, and cellulitis.  Overall, adverse events were similar to those reported at the primary analysis with respect to frequency, severity, and specificity.  The authors concluded that their analysis showed a significant improvement in OS with pertuzumab, trastuzumab, and docetaxel in patients with HER2-positive metastatic breast cancer, compared with placebo, trastuzumab, and docetaxel.  Moreover, they stated that since this effect was not achieved at the expense of adverse events, this regimen represents a substantial improvement on the standard of care for this population of patients.

Kumler et al (2014) stated that HER2 is over-expressed in 15 to 20 % of all breast cancers.  Treatment with trastuzumab has led to an improved outcome and prolonged survival of HER2-positive breast cancer patients and today the drug is established as standard of care in both the adjuvant and metastatic settings.  However, trastuzumab resistance is common and a major focus in the treatment of HER2-positive breast cancer has been developing therapeutic agents to either potentiate the effect of trastuzumab or to target cells which have become resistant to trastuzumab.  These investigators examined the effectiveness and toxicity of dual targeting in HER2-positive breast cancer.  A computer-based literature search was carried out using PubMed; data reported at international meetings and clinicaltrials.gov was included.  This paper described safety and effectiveness of lapatinib, pertuzumab or trastuzumab-DM1 in combination with trastuzumab in the (neo)adjuvant and metastatic settings.  Furthermore, combinations of trastuzumab and drugs targeting the downstream pathway were described.  The authors concluded that dual blockade is likely to represent a substantial advance for patients with HER2-positive breast cancer.  However, the relevant subpopulation remains to be defined and side effects including cardiotoxicity might be a limiting factor to the use.  They stated that there is an urgent need for prospective biomarker-driven trials to identify patients for whom dual targeting is cost-effective.

In a phase-III clinical trial, Tabernero and colleagues (2018) examined the safety and efficacy of pertuzumab versus placebo in combination with trastuzumab and chemotherapy in 1st-line HER2-positive metastatic gastric or gastro-esophageal junction cancer.  JACOB was a double-blind, placebo-controlled, randomized, multi-center, phase-III trial in patients aged 18 years or older with HER2-positive metastatic gastric or gastro-esophageal junction cancer.  Eligible patients had measurable or evaluable non-measurable disease at baseline, ECOG performance status of 0 or 1, and baseline LVEF of 55 % or more.  Patients at 197 oncology clinics (in 30 countries) were randomly assigned (1:1) to receive either pertuzumab (840 mg intravenously) or placebo every 3 weeks, with trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks intravenously), plus chemotherapy (cisplatin 80 mg/m2 every 3 weeks intravenously, oral capecitabine 1,000 mg/m2 twice-daily [2,000 mg/m2 every 24 hours] for 28 doses every 3 weeks, or 5-fluorouracil 800 mg/m2 every 24 hours intravenously [120 hours continuous infusion] every 3 weeks).  Randomization was by a central permuted block randomization scheme (block size of 4) with an interactive voice or web response system, stratified by geographical region, previous gastrectomy, and HER2 positivity.  The primary end-point was OS in the intention-to-treat population.  Between June 10, 2013, and January 12, 2016, of 3,287 patients assessed, 780 eligible patients were randomly assigned to receive either pertuzumab plus trastuzumab and chemotherapy (pertuzumab group, n = 388) or placebo plus trastuzumab and chemotherapy (control group, n = 392).  Median duration of follow-up was 24.4 months (95 % CI: 22.3 to 26.1) in the pertuzumab group and 25.0 months (22.3 to 28.9) in the control group.  After 242 deaths in the pertuzumab group and 262 deaths in the control group (the study was not stopped at this point), OS was not significantly different between treatment groups (median OS 17.5 months [95 % CI: 16.2 to 19.3] in the pertuzumab group and 14.2 months [12.9 to 15.5] in the control group; HR 0.84 [95 % CI: 0.71 to 1.00]; p = 0.057).  Serious AEs occurred in 175 (45 %) of 385 patients in the pertuzumab group and 152 (39 %) of 388 patients in the control group.  Diarrhea was the most common serious AE in both groups (17 [4 %] patients in the pertuzumab group versus 20 [5 %] patients in the control group).  The most common grade 3 to 5 AEs were neutropenia (116 [30 %] patients in the pertuzumab group versus 108 [28 %] patients in the control group), anemia (56 [15 %] versus 65 [17 %]), and diarrhea (51 [13 %] versus 25 [6 %]).  Treatment-related deaths occurred in 7 (2 %) patients in the control group; no treatment-related deaths occurred in the pertuzumab group.  The authors concluded that adding pertuzumab to trastuzumab and chemotherapy did not significantly improve OS in patients with HER2-positive metastatic gastric or gastro-esophageal junction cancer compared with placebo.  These researchers stated that further studies are needed to identify improved 1st-line therapeutic options in these types of cancer and to identify patients with HER2-driven tumors who might benefit from dual HER2-targeted therapy.

Park and colleagues (2018) noted that alterations in the HER2 pathway have been identified in a subset of salivary duct carcinomas.  Dual HER2 inhibition with trastuzumab and pertuzumab has superior anti-tumor efficacy to trastuzumab monotherapy in HER2-positive breast cancer, yet its efficacy in HER2-positive salivary duct carcinoma is unknown.  These investigators reported 2 cases of exceptional responses of HER2-positive salivary duct carcinomas to dual HER2 blockade and docetaxel combination and their molecular characteristics.  A 54-year old man with recurrent metastatic HER2 expressing salivary duct carcinoma of the parotid gland after definitive concurrent chemo-radiation achieved a CR after 6 cycles of trastuzumab, pertuzumab, and docetaxel (TPH).  A 42-year old woman with HER2-positive salivary duct carcinoma of the parotid gland with bone and liver metastases had CR with TPH and remained in remission on maintenance trastuzumab and pertuzumab.  The authors concluded that dual HER2 blockage resulted in CR in patients with HER expressing salivary duct carcinoma and warrants further evaluation in this patient population.

Trastuzumab and Hyaluronidase-oysk (Herceptin Hylecta)

U.S. Food and Drug Administration (FDA)-Approved Indications

• Herceptin Hylecta is indicated for adjuvant treatment of adults with HER2 overexpressing node positive or node negative (ER/PR negative or with one high risk feature) breast cancer:

  • As part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel
  • As part of a treatment regimen with docetaxel and carboplatin
  • As a single agent following multi-modality anthracycline based therapy
    
    

• Herceptin Hylecta is indicated in adults:

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

Compendial Uses

• HER2-positive breast cancer: may be substituted for intravenous trastuzumab and used as a single agent or in combination with other systemic therapies.

On February 28, 2019, the FDA approved trastuzumab and hyaluronidase-oysk (Herceptin Hylecta, Genentech Inc.) injection for subcutaneous use.  Herceptin Hylecta is a combination of trastuzumab, a HER2/neu receptor antagonist, and hyaluronidase, an endoglycosidase, for the treatment of HER2-overexpressing BC.  The FDA approval was based on 2 randomized trials, HannaH (NCT00950300) and SafeHER (NCT01566721).  In the HannaH Trial, a total of 596 patients with HER2-positive operable or locally advanced BC, including inflammatory BC, were randomized to receive 8 cycles of either Herceptin Hylecta or intravenous trastuzumab concurrently with chemotherapy, followed by surgery and continued therapy with either Herceptin Hylecta or intravenous trastuzumab, for an additional 10 cycles.  The HannaH Trial demonstrated comparability between Herceptin Hylecta and intravenous trastuzumab based on co-primary end-points of pCR and pharmacokinetics; pCR was observed in 118 patients (45.4 %) on the Herceptin Hylecta arm and in 107 patients (40.7 %) receiving intravenous trastuzumab (95 % CI for difference in pCR: -4.0 to 13.4).  The SafeHER Trial was a prospective, 2-cohort, non-randomized, multi-national, open-label trial examining the overall safety and tolerability of Herceptin Hylecta with chemotherapy in 1,864 patients with HER2-positive BC.  Patients received a fixed dose of 600 mg Herceptin Hylecta every 3 weeks for 18 cycles.  Herceptin Hylecta was initiated either sequentially with chemotherapy, concurrently with chemotherapy, or without adjuvant chemotherapy, or in combination with neoadjuvant chemotherapy followed by trastuzumab.  The most common AEs of Herceptin Hylecta observed in at least 10 % of patients were fatigue, arthralgia, diarrhea, injection site reaction, upper respiratory tract infection, rash, myalgia, nausea, headache, edema, flushing, pyrexia, cough, and pain in extremity.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
Other CPT codes related to the CPB:
83890 - 83914	Molecular diagnostics
88271 - 88275	Molecular cytogenetics
88341 - 88344	Immunohistochemistry or immunocytochemistry, per specimen
88360 - 88361	Morphometric analysis, tumor immunohistochemistry (e.g., Her-2/neu, estrogen receptor/progesterone receptor), quantitative or semiquantitative, each antibody
88367 - 88377	Morphometric analysis, in situ hybridization
96365	Intravenous infusion, for therapy, prophylaxis, or diagnosis (specify substance or drug); initial, up to 1 hour
96366	each additional hour (List separately in addition to code for primary procedure)
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
96401-96450	Chemotherapy administration
Other HCPCS codes related to the CPB:
G0461	Immunohistochemistry or immunocytochemistry, per specimen; first single or multiplex antibody stain
G0462	each additional single or multiplex antibody stain (list separately in addition to code for primary procedure)
Trastuzumab (Herceptin), trastuzumab-pkrb (Herzuma), trastuzumab-anns (Kanjinti), trastuzumab-dkst (Ogivri), and trastuzumab-qyyp (Trazimera), trastuzumab-dttb (Ontruzant):
HCPCS codes covered if selection criteria are met:
J9355	Trastuzumab, 10 mg
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, 10 mg (Kanjinti)
Other HCPCS codes related to the CPB:
J9045	Carboplatin, [Paraplatin], 50 mg
J9264	Injection, paclitaxel protein-bound particles, 1 mg
J9265	Paclitaxel, 30 mg
ICD-10 codes covered if selection criteria are met:
C08.0 - C08.9	Malignant neoplasm of other and unspecified major salivary glands [not covered for salivary duct cancer]
C15.3 - C15.9	Malignant neoplasm of esophagus [HER2 positive]
C16.0 - C16.9	Malignant neoplasm of stomach [HER2 positive]
C18.0 - C18.9	Malignant neoplasm of colon
C20	Malignant neoplasm of rectum
C34.00 - C34.92	Malignant neoplasm of bronchus and lung [non-small cell lung cancer]
C50.011 - C50.929	Malignant neoplasm of breast [HER2 positive]
C53.0 - C55	Malignant neoplasm of uterus
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C07	Malignant neoplasm of parotid gland
C22.1	Intrahepatic bile duct carcinoma
C23	Malignant neoplasm of gallbladder
C24.0 - C24.9	Malignant neoplasm of other and unspecified parts of biliary tract
C25.0 - C25.9	Malignant neoplasm of pancreas
C40.00 - C41.9	Malignant neoplasm of bone and articular cartilage [osteosarcoma]
C43.0 - C43.9	Malignant melanoma of skin
C51.0 - C51.9	Malignant neoplasm of vulva
C53.0 - C53.9	Malignant neoplasm of cervix uteri
C54.1 - C54.9	Malignant neoplasm of corpus uteri, except isthmus
C56.1 - C56.9	Malignant neoplasm of ovary
C60.0 - C60.9	Malignant neoplasm of penis
C61	Malignant neoplasm of prostate
C67.0 - C67.9	Malignant neoplasm of bladder
C80.1	Malignant (primary) neoplasm, unspecified
Trastuzumab and hyaluronidase-oysk (Herceptin Hylecta):
HCPCS codes covered if selection criteria are met:
J9356	Injection, trastuzumab, 10 mg and Hyaluronidase-oysk (Herceptin Hylecta)
ICD-10 codes covered if selection criteria are met:
C50.011 - C50.929	Malignant neoplasm of breast [HER2 positive]

The above policy is based on the following references: