Description
In certain cancers, the human epidermal growth factor receptor 2 (HER2) gene is amplified and overexpressed. Trastuzumab (Herceptin) is a humanized monoclonal antibody that doubles as an HER2-receptor antagonist used to treat various cancers including breast and metastatic gastric or gastroesophageal junction adenocarcinoma. 

For individuals who have HER2-overexpressing breast cancer who receive trastuzumab as treatment for metastatic disease, or as adjuvant or neoadjuvant therapy, the evidence includes multiple randomized controlled trials (RCTs) and meta-analyses. Relevant outcomes are overall survival, disease-specific survival, morbid events, functional outcomes, health status measures, quality of life, and treatment-related mortality and morbidity. When used in treatment regimens, trastuzumab has shown a survival benefit for primary and metastatic breast cancer patients and have become the accepted standard therapy for patients with HER2-positive breast cancer. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome. 

For individuals who have HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who receive trastuzumab plus cisplatin and capecitabine or 5-fluorouracil, the evidence includes a RCT and a single-arm trial. Relevant outcomes are overall survival, disease-specific survival, morbid events, functional outcomes, health status measures, quality of life, and treatment-related mortality and morbidity. The addition of trastuzumab to the chemotherapy regimen has reported a 2-month survival benefit in the trastuzumab arm — and no difference in severe adverse events compared with chemotherapy alone. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome. 

For individuals who have HER2-overexpressing malignancies (besides breast or gastric cancer) who are treated with trastuzumab plus standard of care, the evidence includes multiple single-arm and RCTs. Relevant outcomes are overall survival, disease-specific survival, morbid events, functional outcomes, health status measures, quality of life, treatment-related mortality and morbidity. The majority of these trials were conducted 10 to 15 years ago as pilots with small sample sizes in the early clinical development of trastuzumab. It should be noted that these trials ultimately reported negative or less than optimal efficacy results and they were terminated early due to limited accrual. The evidence is insufficient to determine the effects of technology on health outcomes.

Background
BREAST CANCER
Breast cancer accounts for nearly 1 in 3 cancer diagnoses in U.S. women. Breast cancer is the most common cancer in women followed by nonmelanoma skin cancer, and breast cancer ranks second for cancer mortality after lung cancer. In 2016, an estimated 246,660 new cases of breast cancer were diagnosed in women, and approximately 40,000 women died from the disease.¹ Metastatic breast cancer has a poor prognosis. In a cohort of 3,524 women diagnosed with breast cancer between 1992 and 2007, median overall survival was 39.2 months among patients with de novo Stage IV breast cancer and 27.2 months among patients with relapsed disease (estimates independent of human epidermal growth factor receptor 2 [HER2] status).² Factors associated with reduced survival for patients with metastatic breast cancer include age 50 years or older, visceral disease, shorter disease-free interval, negative hormone receptor status, and HER2-positive status.³ 

Treatment
Systemic treatment for metastatic breast cancer is mainly palliative. Goals of treatment are to prolong survival, alleviate symptoms, and maintain or improve the quality of life. Treatment is primarily with chemotherapeutic and other antitumor drugs. National Comprehensive Cancer Network guidelines for treatment of metastatic breast cancer include specific recommendations for first-line treatment of HER2-positive metastatic breast cancer.⁴ All recommended treatment regimens include trastuzumab. Recommended agents used singly, or in combination with trastuzumab, are paclitaxel, docetaxel, vinorelbine, capecitabine, and carboplatin. 

GASTRIC CANCER
It is estimated that 26,370 people were diagnosed and 10,730 died from gastric cancer in the United States in 2016.⁵ Most patients with gastric cancer are symptomatic and already have advanced incurable disease at the time of presentation. Weight loss and persistent abdominal pain are the most common symptoms at initial diagnosis and prognosis is often poor due to advanced disease at the time of presentation. The 5-year survival rate for patients with completely resected stage I gastric cancer is approximately 70% to 75%, while it drops to 35% or less for stage II, III, and IV disease. 

Treatment
Surgery, including adjuvant chemoradiotherapy, perioperative (preoperative plus postoperative) chemotherapy, and adjuvant chemotherapy, are the main stay of treatment.

HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2
Approximately 20% to 25% of breast cancers overexpress HER2, a transmembrane glycoprotein receptor with tyrosine kinase activity. HER2, previously called HER2/neu, or ErbB-2,⁶ is part of the HER tyrosine kinase receptor family that includes 4 transmembrane receptors (HER1 [also known as epidermal growth factor receptor, HER2, HER3, HER4). These receptors mediate tumor cell growth, survival, and differentiation. Human epidermal growth factor receptors, when activated by extracellular ligand binding, dimerize and activate cell-signaling through the phosphatidyl inositol-3 (PI3)-kinase/AKT pathway, which regulates tumor cell survival, and the mitogen-activated protein kinase pathway, which regulates cellular proliferation. HER2 has no known ligand; it forms active heterodimers (particularly HER2:HER3 ) and, when overexpressed, homodimers (HER2:HER2) that constitutively activate tyrosine kinase signaling.⁷ 

HER2 overexpression is associated with reduced time to disease recurrence and poorer prognosis. Before the advent of HER2-targeted therapy, HER2 overexpression was associated with shorter disease free and overall survival than either lymph node-negative or lymph node‒positive breast cancers; with lack of responsiveness to tamoxifen therapy; and with altered responsiveness to cytotoxic chemotherapy.⁸ 

Treatment of HER2-Positive Breast Cancer 
The Food and Drug Administration (FDA) has approved 4 anti-HER2 therapies. These agents arrest tumor cell growth and promote apoptosis by blocking HER2-mediated intracellular-signaling pathways that mediate cell growth, differentiation, and survival: 

• Trastuzumab (Herceptin) is an intravenous monoclonal antibody to an extracellular domain of the HER2 receptor (subdomain IV) that prevents activation of intracellular tyrosine kinase signaling cascades and also promotes antibody-dependent cell-mediated cytotoxicity.⁶ 
• Lapatinib (Tykerb®) is an oral tyrosine kinase inhibitor that blocks the intracellular tyrosine kinase domain of HER2 and downstream cell-signaling cascades.⁹
• Pertuzumab (Perjeta™) is an intravenous monoclonal antibody to the extracellular dimerization domain of the HER2 receptor (subdomain II) that, like trastuzumab, prevents activation of intracellular tyrosine kinase signaling cascades and also promotes antibody-dependent cellmediated cytotoxicity.¹⁰
• Ado-trastuzumab emtansine (Kadcyla™) is an intravenous antibody-drug conjugate of trastuzumab and emtansine. 

Trastuzumab is recommended as first-line treatment for patients with HER2-positive metastatic breast cancer, either in combination with pertuzumab and a taxane (preferred); in combination with a taxane (paclitaxel with or without carboplatin, or docetaxel), vinorelbine, or capecitabine; or as monotherapy. Treatment with trastuzumab plus an anthracycline (doxorubicin or daunorubicin) is not recommended because of unacceptably high rates of cardiac toxicity. Most patients who initially respond to trastuzumab will eventually progress.^11,12 

For second-line treatment of HER2-positive metastatic breast cancer that progresses after trastuzumab therapy (either in the adjuvant setting or as first-line treatment for metastatic disease), a continuation of the HER2 blockade is recommended. For patients not previously exposed to pertuzumab, combination therapy with trastuzumab plus pertuzumab with or without cytotoxic chemotherapy (e.g., a taxane or vinorelbine) is recommended. Other treatment options are trastuzumab plus lapatinib or capecitabine and lapatinib plus capecitabine. In patients who obtain sustained disease control, the optimal duration of HER2-targeted therapy is unknown.⁴ 

Regulatory Status 
Trastuzumab (Herceptin^®) is a humanized monoclonal antibody against the extracellular domain of HER2. Trastuzumab received FDA marketing approval for treatment of HER2-positive breast cancer, in both the adjuvant and metastatic settings, and metastatic gastric or gastroesophageal junction adenocarcinoma. It first received FDA approval in September 1998 for use in metastatic breast cancer, as a first-line therapy in combination with paclitaxel and as a single agent in second- and third-line therapy.

Current FDA-approved labeling, as of June 2014, states that trastuzumab is indicated as follows:

1. For adjuvant treatment of HER2 overexpressing node positive or node negative (ER/PR negative or with 1 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 multimodality anthracycline-based therapy
     Trastuzumab is administered by intravenous (IV) infusion weekly or every 3 weeks for a total of 52 weeks, depending on the dosing schedule and chemotherapy used for adjuvant treatment
2. For treatment of HER2 overexpressing metastatic breast cancer in combination with paclitaxel for first-line treatment; or as a single agent in patients who have received 1 or more chemotherapy regimens for metastatic disease. Trastuzumab is administered by IV infusion weekly until disease progression.
3. For treatment of HER2 overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, in combination with cisplatin and capecitabine or 5-fluorouracil, in patients who have not received prior treatment for metastatic disease. Trastuzumab is administered by IV infusion every three weeks until disease progression.

 Policy

Herceptin (trastuzumab)
Kanjinti (trastuzumab-anns) 
Trazimera (trastuzumab-qyyp)
Herceptin Hylecta (trastuzumab and hyaluronidase-oysk) 
Ogivri (trastuzumab-dkst) 
Ontruzant  (trastuzumab-dttb)
 Herzuma (trastuzumab-pkrb)

Coverage of these drugs is provided when the criteria below is met and there has been a trial and failure of preferred therapy.

HER2-Positive Breast Cancer
Trastuzumab may be considered MEDICALLY NECESSARY for the treatment of patients with breast cancer whose tumors overexpress the HER2 protein (HER2-positive breast cancer.) This includes use as adjuvant therapy, neoadjuvant therapy and treatment of metastatic disease.

Conditions other than HER2-Positive Breast Cancer
Trastuzumab may be considered MEDICALLY NECESSARY, when used in combination with systemic chemotherapy, for treatment of patients with advanced (locally advanced or metastatic) gastric, endometrial, colorectal cancer or gastroesophageal junction adenocarcinoma whose tumors overexpress the HER2 protein (HER2-positive cancer).

Trastuzumab is considered INVESTIGATIONAL for the treatment of all other conditions including, but not limited to, HER2-negative breast cancer and the following cancers which may be HER2 positive: osteosarcoma, non-small-cell lung, ovarian, prostate, head and neck, esophageal (except as noted above), gastric (except as noted above), pancreatic, and urothelial.

BlueCross BlueShield of South Carolina recognizes uses and indications of injectable oncology medications (including chemotherapy/systemic therapy, therapeutic radiopharmaceuticals, and selected supportive therapies) to be medically necessary if they are listed in the NCCN Drugs and Biologics Compendium with Categories of Evidence + Consensus of 1, 2A and 2B. Treatments listed with a Category of Evidence and Consensus of 3 are considered unproven and not medically necessary.

Policy Guidelines
HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2 TESTING
Appropriate patient selection for trastuzumab therapy is predicated on detection of human epidermal growth factor receptor 2 (HER2) overexpression. HER2 overexpression should be assessed only by facilities with demonstrated proficiency in the specific assay being used. Improper assay performance may yield unreliable results. Several assays are commercially available to aid selection of patients for trastuzumab therapy. They include the HercepTest™ and Pathway^® HER2/neu, which are immunohistochemical assays, and PathVysion^® and HER2 FISH pharmDx™, which are fluorescence in situ hybridization assays. 

CARDIAC MONITORING
The U.S. Food and Drug Administration-approved label recommends that left ventricular ejection fraction should be measured before starting trastuzumab therapy, and shown to be within the treating institution’s normal range. Continued therapy should depend on periodic monitoring (e.g., at 3, 6 and 12 months) without an unacceptable decrease (e.g., > 15%) from baseline left ventricular ejection fraction.

PREOPERATIVE CHEMOTHERAPY
Breast cancer patients considered for preoperative (neoadjuvant or primary systemic) chemotherapy may have early-stage disease, but larger tumors (stages IIA, IIB, or operable T3N1M0), or they may have locally advanced but nonmetastatic (M0) disease.

Benefit Application
BlueCard/National Account Issues
State and federal mandates (e.g., FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational, and thus, these devices may be assessed only on the basis of their medical necessity.

Rationale
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function — including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical uses of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

TRastuzumab for her2-overexpressing Breast Cancer
Clinical Context and Test Purpose
The purpose of trastuzumab in patients who have human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does trastuzumab improve the net health outcome in patients with HER2-overexpressing breast cancer?

The following PICOTS were used to select literature to inform this review.

Patients
The relevant population of interest is individuals with HER2-overexpressing breast cancer.

Interventions
The therapy being considered is trastuzumab as a treatment for HER2-overexpressing breast cancer.

Comparators
The following practice is currently being used to make decisions in this patient group: standard of care without trastuzumab.

Outcomes
The general outcomes of interest include overall survival (OS), progression-free survival (PFS), and treatment- related adverse events.

Timing
The time frame for outcome measures varies from several months for the improvement of symptoms to years to assess long-term survival and quality of life.

Setting
Patients are actively managed by oncologists in an outpatient setting.

Metastatic Breast Cancer
Systematic Reviews
In a Cochrane systematic review and meta-analysis, Balduzzi et al. (2014) evaluated 7 RCTs of trastuzumab-containing regimens for the treatment of metastatic breast cancer.¹⁴ The median follow-up was 2 years. Meta-analyses favored trastuzumab-containing regimens for OS (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.71 to 0.94; p = 0.004; I² = 0%) and for PFS (HR=0.61; 95% CI, 0.54 to 0.70; p < 0.001; I² = 12%). Congestive heart failure occurred more commonly with trastuzumab-containing regimens (relative risk, 3.49; 90% CI, 1.88 to 6.47; p < 0.001; I² = 0%); the incidence of severe cardiac events was increased if trastuzumab was used in conjunction with an anthracycline alone. The meta-analysis was limited by variability in the study protocol and treatment regimens.

Randomized Controlled Trials
Kaufman et al. (2009) reported on results of the first randomized phase 3 trial combining a hormonal agent (aromatase inhibitor, anastrozole) and trastuzumab without chemotherapy.⁹ Patients enrolled were postmenopausal with human epidermal growth factor receptor 2 (HER2)- and hormone receptor-positive metastatic disease. Women with central nervous system metastases were excluded. Patients were randomized to trastuzumab plus anastrozole (n = 103) or anastrozole alone (n = 104). Baseline characteristics were balanced between groups. The primary end point was PFS, defined as the time from randomization to the date of disease progression or death. A total of 187 patients withdrew from treatment, most frequently due to progressive disease. In the anastrozole-only arm, 70% of patients who experienced progressive disease subsequently crossed over to a trastuzumab-containing regimen. PFS was significantly improved in the trastuzumab plus anastrozole arm, with a median PFS of 4.8 months (95% CI, 3.7 to 7.0 months) and 2.4 months (95% CI, 2.0 to 4.6 months) in the anastrozole-only arm (HR = 0.63; 95% CI, 0.47 to 0.84; p = 0.002). Grade 3 and 4 adverse events were 23% and 5%, respectively, in the trastuzumab plus anastrozole arm and 15% and 1% in the anastrozole-only arm, respectively.

Von Minckwitz et al. (2009) investigated whether trastuzumab should be given beyond disease progression in women with HER2-positive locally advanced or metastatic breast cancer.¹⁵ Patients were randomized to chemotherapy (capecitabine) alone (n = 78) or capecitabine plus trastuzumab (n = 78). Follow-up was 15.6 months, during which time there were 38 deaths in the capecitabine arm and 33 in the capecitabine plus trastuzumab arm. The primary end point was time to progression, which was defined as the time between randomization and documented disease progression or disease-related death. The median times to progression were 5.6 months in the capecitabine group and 8.2 months in the combined therapy group (HR = 0.69; 95% CI, 0.48 to 0.97; p = 0.034). The difference in OS was not significant between groups (median, 20.4 months [95% CI, 17.8 to 24.7 months] in the capecitabine group vs 25.5 months [95% CI, 19.0 to 30.7 months] in the combined therapy group; p = 0.257). Von Minckwitz et al. (2011) reported on the final OS analysis from this study.¹⁶ After a median follow-up of 20.7 months, only 32 (21%) of 151 patients were living; 119 (79%) had died. No significant difference between treatment groups was found in median OS (20.6 months in the capecitabine group vs 24.9 months in the combination group; HR = 0.94; 95% CI, 0.65 to 1.35; p = 0.734). In the subgroup of patients who had a clinical response or clinical benefit, the between-group difference in OS was not statistically significant. However, a post hoc analysis demonstrated a survival benefit with postprogression third-line chemotherapy with trastuzumab; in 52 patients who received third-line chemotherapy with trastuzumab, postprogression survival was 18.8 months (95% CI, 12.9 to 24.8 months) vs 13.3 months (95% CI, 10.2 to 14.7 months) in the 88 patients who did not (HR = 0.63; p = 0.02).

The U.S. Food and Drug Administration initially approved trastuzumab in 1998 for treating metastatic breast cancer based on results from 2 pivotal clinical trials. Cobleigh et al. (1999) published an RCT in which a single agent (trastuzumab) was given to women (N = 222) who had received 1 or 2 courses of cytotoxic chemotherapy, yielding an objective response rate of 15% and a median duration of response of 9.1 months.¹⁷ In a second randomized trial, Slamon et al. (2001) evaluated, trastuzumab as part of a first-line combination regimen consisting of doxorubicin plus cyclophosphamide or paclitaxel in 469 patients.¹⁸ The addition of trastuzumab to chemotherapy improved the response rate (50% vs 32%, respectively; p < 0.001), lengthened the median response duration (9.1 months vs 6.1 months, respectively; p < 0.001), and prolonged OS (25.1 months vs 20.3 months, respectively; p = 0.046) compared with chemotherapy alone. Because a significantly higher incidence of New York Heart Association class III or IV cardiotoxicity was reported among patients who received doxorubicin, cyclophosphamide, plus trastuzumab, compared with doxorubicin plus cyclophosphamide, paclitaxel plus trastuzumab, or paclitaxel alone, the Food and Drug Administration and others (Seiman et al. [2002], Keefe et al. [2002]) cautioned against using a regimen that combined trastuzumab with doxorubicin.^12,19

Similar efficacy results were reported by Marty et al. (2005) for the combination of trastuzumab plus docetaxel in 188 patients with metastatic breast cancer.²⁰ Other studies of other trastuzumab combination regimens have included its use with capecitabine, vinorelbine, gemcitabine, and platinum salts, achieving response rates ranging from 27% to 86% (reviewed in Jackisch [2006]²¹ and Demonty et al. [2007]⁸). These early studies also showed that trastuzumab could be combined with nonapproved chemotherapy regimens while adding little to the overall toxicity profile in the metastatic setting.

Subsection Summary: Metastatic Breast Cancer
Multiple RCTs and meta-analyses have shown incremental improvement in overall response rate, PFS, and OS with trastuzumab-containing regimens for treatment of HER2-overexpressing metastatic breast cancer.

Adjuvant Setting
Systematic Reviews
A meta-analysis by Chen et al. (2016) included studies published between 2005 and 2014; reviewers selected 13 RCTs (9 in the adjuvant setting, 4 in the neoadjuvant setting; total N = 14,546 patients).²² in the adjuvant setting favored trastuzumab-containing regimens for OS (HR = 0.79; 95% CI, 0.68 to 0.92; p = 0.002; I² = 62%) and for recurrence (HR = 0.66; 95% CI, 0.58 to 0.75; p < 0.001; I² = 70%). Limitations included variability in treatment protocols, including the use of trastuzumab in some control group protocols.

A meta-analysis by O’Sullivan et al. (2015) included 5 of the 6 adjuvant trastuzumab trials.²³ Median follow-up was 8 years. For 2,263 patients with hormone receptor-positive disease, 8-year cumulative incidence of death was 7.8% for the trastuzumab group and 11.6% for the no-trastuzumab group (p < 0.005); for 1,092 hormone receptor-positive patients with 0 or 1 positive lymph nodes, rates were 5.3% and 7.4% (p < 0.12), respectively. For 1957 patients with hormone receptor-negative disease, OS results were 12.4% and 21.2% (p < 0.001), respectively; for 1040 hormone receptor-negative patients with 0 or 1 positive lymph nodes, rates were 8.2% and 12.2% (p = 0.084), respectively.

Randomized Controlled Trials
Results from randomized trials conducted in 2005 and 2006 have provided data on clinical outcomes of adjuvant trastuzumab therapy: the Breast Cancer International Research Group 006 (BCIRG 006) trial (N = 3222)²⁴; the HERceptin Adjuvant (HERA) Trial (N = 5090)²⁵; the North Central Cancer Treatment Group N9831 (NCCTG N9831) trial (N = 3505)²⁶; the North American National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial (N = 2030)²⁷; the Finnish Herceptin Study (FinHer) Study (N = 232)²⁸; and the Protocol forHerceptin as Adjuvant therapy with Reduced Exposure (PHARE) trial.²⁹ All women enrolled in these studies tested positive for HER2 using either immunohistochemical or fluorescence in situ hybridization assays. There were important differences in patient characteristics, trial designs, and implementation, as reviewed in depth elsewhere.^{8,30,31,32,33} See Tables 1 and 2 for the trial characteristics and results.

Duration of Therapy
Updated results from the HERA trial indicated that 2 years of adjuvant trastuzumab was not more effective than 1 year of treatment but was associated with more adverse events. The PHARE trial supported 1 year of trastuzumab rather than 6 months of treatment. A 2012 Cochrane meta-analysis also supported the use of 1 year of trastuzumab treatment given with adjuvant chemotherapy rather than for shorter periods.

Table 1. Summary of Trastuzumab Trial Characteristics for Adjuvant Therapy of Breast Cancer  

AC: doxorubicin plus cyclophosphamide; C: carboplatin; chemo: chemotherapy; D: docetaxel; ER/PR: estrogen receptor/progesterone receptor; FEC: 5-fluorouracil plus epirubicin plus cyclophosphamide; FU: follow-up; T: Trastuzumab; P: paclitaxel; Q: every; V: vinorelbine.

^a Observation group results included 885 (52%) patients who crossed over to trastuzumab.

Table 2. Summary of Trastuzumab Trial Outcomes for Adjuvant Therapy of Breast Cancer 

AC: doxorubicin plus cyclophosphamide; C: carboplatin; CI: confidence interval; D: docetaxel; DFS: disease- free survival; H: Herceptin; NR, not reported; OS: overall survival.

^a Ratios are for the hazard of disease recurrence or disease-related death (for DFS) andhazard of death (for OS).
^b Statistical testing indicated that the model used to estimate OS (Cox proportional hazards model) was not applicable.

Despite substantial differences in trial designs and patient characteristics, current data from adjuvant trials of trastuzumab have demonstrated consistent, clinically significant improvements in disease-free survival (DFS). 

• Pooled analysis by Dahabreh et al. (2008) of the NSABP B-31, NCCTG N9831, BCIRG, FinHer, and HERA trials has shown significant improvements in OS in patients given adjuvant trastuzumab vs controls.⁴⁰
• Only the HERA trial reported that trastuzumab improved DFS in a subgroup with high-risk, node-negative disease, although 3 other trials included similar patients and found better outcomes in the trastuzumab arm. Few patients were node-negative in the NCCTG N9831 and FinHer trials; in the BCIRG 006 trial, 29% of each arm was node-negative. All trials excluded patients with small ( < 1 cm) node-negative tumors. Thus, there is no evidence that adjuvant trastuzumab benefits this subgroup of HER2-positive patients. 
• Benefits of trastuzumab were independent of estrogen receptor status or type of previous chemotherapy. 
• Results from the 2-year trastuzumab arm of the HERA trial showed no significant differences in DFS or OS for patients who received trastuzumab for 1 or 2 years. Grade 3 and 4 adverse events were more common in patients who received 2 years of trastuzumab (20%) vs 1 year of trastuzumab (16%). 
• Although interim (3-year) results from the FinHer trial suggested that even a short (9-week) course of trastuzumab could reduce risks of recurrence and death in women with HER2-positive, early-stage disease, final (5-year) results did not support this conclusion. More recently, Joensuu et al. (2018) compared a 9-week vs 1-year regimen of trastuzumab in the SOLD RCT; noninferiority between the 2 regimens was not established for 5-year DFS.⁴¹
• Pooled analysis of the NSABP B-31 and NCCTG N9831 trials was planned when the required number of events (710) for the definitive statistical analysis of OS was reached. In this analysis (n = 4046), published by Perez et al. (2014), the median time in the trials was 8.4 years.⁴² Adding trastuzumab to chemotherapy led to a 37% relative improvement in OS (HR = 0.63; 95% CI, 0.54 to 0.73; p < 0.001) and an increase in the 10-year OS rate, from 75.2% to 84%. These results were accompanied by a 40% improvement in DFS (HR = 0.60; 95% CI, 0.53 to 0.68; p < 0.001) and an increase in the 10-year DFS rate from 62.2% to 73.7%. 
• The PHARE trial compared trastuzumab therapy at 6 and 12 months; 6-month treatment was found to be inferior to 12-month treatment.
• A Cochrane review by Moja et al. (2012) pooled data for 12,000 patients across 8 trials comparing chemotherapy plus trastuzumab with chemotherapy alone.⁴³ Reviewers reported a 40% relative reduction in recurrence (HR = 0.60; 95% CI, 0.50 to 0.71) and a 36% improvement in OS (HR = 0.66; 95% CI, 0.57 to 0.77) regardless of the duration of trastuzumab treatment or administration schedule (i.e., concurrent with chemotherapy or sequentially following chemotherapy). 

Preliminary results for the PERSEPHONE trial, a randomized phase 3 noninferiority trial, have suggested that treatment with trastuzumab for 6 months is noninferior at to treatment with trastuzumab for 12 months.⁴⁴ HER2-positive patients with early-stage breast cancer (N = 4089) were followed for a median of 4.9 years after treatment, with both arms showing a 4-year DFS rate of 89% (95% CI, 88% to 91%). Publication of the trial findings is pending.

Adverse Events in the Adjuvant Setting: Cardiotoxicity
Systematic Reviews
A Cochrane systematic review and meta-analysis by Balduzzi et al. (2014), discussed above, evaluated patients with metastatic breast cancer who were treated with trastuzumab-containing regimens.¹⁴ While trastuzumab-containing regimens showed favorable improvements in OS and PFS, these regimens were more frequently associated with congestive heart failure. Of note, severe cardiac events were more frequently seen when trastuzumab was used in conjunction with an anthracycline alone.

Randomized Controlled Trials
The incidence of grade III or IV heart failure or cardiac-related death among patients receiving trastuzumab-containing adjuvant regimens ranged from 0% (FinHer) to 4.1% (NSABP B-31) overall, with age and baseline left ventricular ejection fraction (LVEF) related to the risk for cardiac dysfunction. Concurrent use of trastuzumab and a taxane following 4 cycles of doxorubicin plus cyclophosphamide resulted in the highest incidences of heart failure (1.5%, 2.4%, and 3.4% for the BCIRG, N9831, and B-31 trials, respectively). Sequential administration of anthracyclines, taxanes, and trastuzumab resulted in heart failure incidences of 1.4% and 0.5% for the N9831 and HERA trials, respectively. The nonanthracycline arm of the BCIRG trial had the lowest incidence of heart failure (0.3%). Although the acceptable incidence of cardiac events overall was likely related to rigorous monitoring during the trials, cross-trial comparisons and conclusions are difficult to make due to differences in definitions of cardiac events, evaluations for cardiac safety, analyses of cardiac end points (cumulative vs overall incidence), and durations of follow-up.

De Azambuja et al. (2014) reported on cardiac adverse events in the HERA trial at a median of 8 years of follow-up.⁴⁵ The incidence of severe congestive heart failure, defined as New York Heart Association class III or IV with a significant decrease in LVEF, was 0.8% in both 1-year and 2-year trastuzumab groups. Although a significant LVEF decrease, defined as decline by 10 percentage points or more to below 50%, occurred more commonly in the 2-year trastuzumab group (7.2% vs 4.1%; p < 0.001), slightly more patients in the 2-year group achieved acute recovery, defined as an LVEF of 50% or more at 2 consecutive LVEF assessments (88% of patients in the 2-year group vs 81% of patients in the 1-year group). At approximately 75 months (median) of follow-up, 35% of patients who achieved recovery in each group had a subsequent decline in LVEF to less than 50%. Like the 2014 Sendur study (discussed below), these results suggested that some benefits of trastuzumab on LVEF may be reversible after drug discontinuation.

The long-term evaluation of cardiac toxicity in the N9831 trial was reported by Advani et al. (2016) after a median follow-up of 9.2 years.⁴⁶ The 6-year cumulative incidence of cardiac events ranged from 2.8% to 3.4% in patients who received paclitaxel then trastuzumab or paclitaxel plus trastuzumab followed by trastuzumab alone compared with 0.6% in patients who received paclitaxel alone.

Ganz et al. (2017) assessed long-term cardiac function and quality of life of 441 disease-free, HER2-positive, node-positive breast cancer patients who participated in the NSABP B-31 protocol RCT at a median follow-up of 8.7 years.⁴⁷ A significant reduction in LVEF ( > 10% decline to a value < 50%) was noted in 5 (4.5%) of 110 in the control group and 10 (3.4%) of 297 in the trastuzumab group.

Retrospective Studies
Sendur et al. (2014) reported on a retrospective comparison of outcomes for 2 cohorts based on the duration of treatment — 9 weeks (n = 155) or 52 weeks (n = 116).⁴⁸ There were no statistically significant differences between the 52-week and the 9-week cohorts in estimated 1-, 3-, and 5-year DFS rates (94%, 80%, and 80% vs 97%, 85%, and 75%, respectively) or 1-, 3-, and 5-year OS rates (99%, 95%, and 78% vs 99%, 92%, and 88%, respectively). However, there were notable differences in the baseline characteristics (age, pre- or perimenopausal status, adjuvant therapy) between cohorts; these differences could have limited the interpretation of these findings. The proportion of patients with an asymptomatic decline in LVEF was higher in the 52-week cohort (16%) than in the 9-week cohort (2%). A subsequent report by Sendur et al. (2015) found a greater proportion of patients in the 52-week cohort (30%) than in the 9-week cohort (2%) with asymptomatic decline in LVEF by 15% or more, or by 10% or more to less than 50% (p < 0.001).⁴⁹

Subsection Summary: Adjuvant Setting
Multiple RCTs have established the efficacy of trastuzumab plus chemotherapy as adjuvant treatment for HER2-positive breast cancer. A meta-analysis of 8 RCTs that pooled data for chemotherapy plus trastuzumab with chemotherapy alone yielded the following results: a reduction in recurrence and increased survival occurred when adding trastuzumab to chemotherapy in an adjuvant setting-regardless of the duration or sequence of trastuzumab treatment. While there is a concern about the cardiac toxicities, including congestive heart failure and LVEF declines with use of trastuzumab, most investigators have concluded that the benefits of adjuvant treatment outweigh the risks of side effects.

Neoadjuvant Setting
Systematic Reviews
Valachis et al. (2011) conducted a systematic review and meta-analysis of 515 patients from 5 trials that examined neoadjuvant chemotherapy with trastuzumab for HER2-positive breast cancer.⁵⁰ Adding trastuzumab to chemotherapy improved the probability of achieving pathologic complete response (pCR) (relative risk, 1.85; p < 0.001). A Food and Drug Administration-funded pooled responder analysis of 12 international trials with 11,955 patients concluded that, among those with HER2-positive, hormone receptor-negative tumors who received trastuzumab, pCRwas associated with increased survival. The hazard ratios for event-free survival and OS were 0.15 (95% CI, 0.09 to 0.27) and 0.08 (95% CI, 0.03 to 0.22), respectively. The breast-conserving surgery rates in the Valachis review did not differ significantly with the addition of trastuzumab (odds ratio, 0.98; p = 0.82).

Randomized Controlled Trials
Buzdar et al. (2005) published an RCT that examined the benefits of adding trastuzumab to neoadjuvant chemotherapy.⁵¹ The trial sequentially administered 2 neoadjuvant chemotherapy regimens followed by surgery to breast cancer patients with stage II to IIIA disease. The neoadjuvant chemotherapy regimens compared were paclitaxel (four 3-week cycles) followed by fluorouracil, epirubicin, and cyclophosphamide (FEC; four 3-week cycles) with or without trastuzumab. A data monitoring committee ended the trial after investigators had randomized 42 patients when a requested (but unplanned) analysis showed pCR rates of 25% in the arm without and 67% in the arm with trastuzumab. A similar proportion of patients in each arm (53% without and 57% with trastuzumab) received breast-conserving surgery, but patient choice likely influenced these results. A subsequent report by Buzdar et al. (2007) included longer follow-up for randomized patients and additional nonrandomized patients.⁵² Results showed a pCR rate of 26% (95% CI, 9% to 51%) for 19 patients randomized to neoadjuvant chemotherapy without trastuzumab, of 65% (95% CI, 43% to 84%) of 23 patients randomized to the same neoadjuvant regimen plus trastuzumab, and of 55% (95% CI, 32% to 76%) for 22 consecutive nonrandomized patients also given the same regimen plus trastuzumab. At a median follow-up of 36.1 months for randomized patients, no patients in the trastuzumab arm and 3 patients in the chemotherapy-only arm (one of whom died) experienced a recurrence.

Analyses from other RCTs^53,54,55 and single-arm studies^56,57,58,59 have shown that patients with pCR after neoadjuvant chemotherapy (determined postoperatively) had significantly longer OS, DFS, and/or recurrence-free survival than those who did not achieve pCR. This also was true for those who achieved pCR compared with those who achieved clinically complete responses but were subsequently shown by postoperative pathology to have residual (microscopic) invasive disease. Thus, improving the pCR rate by adding trastuzumab to neoadjuvant chemotherapy for HER2-positive patients with high-risk, larger tumors improves OS and DFS.

Subsection Summary: Neoadjuvant Setting
Multiple RCTs, analyses of follow-up data of cohorts from these RCTs, and meta-analyses of these RCTs have established the efficacy of trastuzumab in the neoadjuvant setting for HER2-positive breast cancer patients and demonstrated improvements in pCR rate, event-free survival and OS.

Unresolved Issues Related to Breast Cancer
RCTs have consistently reported a beneficial effect of adjuvant trastuzumab in combination with adjuvant chemotherapy in patients with completely resected HER2-positive breast cancer. However, these trials have not resolved the issues of initiating trastuzumab before or after adjuvant chemotherapy or taking trastuzumab as a concurrent or sequential therapy. A detailed analysis of these issues is beyond the scope of the present review; the following discussion summarizing the issues.

Starting Trastuzumab After Completing Adjuvant Chemotherapy
Trastuzumab has been rapidly integrated into the adjuvant therapy of patients with HER2-positive early-stage breast cancer. When the interim results were reported in 2005, there was interest in offering trastuzumab to patients who would otherwise meet criteria, but who had already completed adjuvant therapy. This group of patients still has not been studied formally. Patients in the HERA trial started trastuzumab a median of 8 months after diagnosis and 3 months after completing all chemotherapy.

Outcomes
The general outcomes of interest include OS, PFS, treatment response, and adverse events.

Timing
The time frame for outcome measures varies from several months for the improvement of symptoms to years to assess long-term survival and quality of life.

Setting
Patients with HER2-overexpressing and metastatic gastric or gastroesophageal junction adenocarcinoma are actively managed by oncologists in an outpatient setting.

Randomized Controlled Trials
Bang et al. (2010) reported results of the phase 3 Trastuzumab for Gastric Cancer trial, an open-label, randomized, multicenter (122 centers in 24 countries) study that compared chemotherapy with or without trastuzumab in patients who had HER2-positive, locally advanced, recurrent, or metastatic gastroesophageal or gastric adenocarcinoma.⁶⁰ Trastuzumab was administered every 3 weeks for 6 cycles, until disease progression. The primary end point was OS; secondary end points were overall response rate, PFS, time to progression, duration of response, and safety. Median follow-up was 18.6 months in the chemotherapy plus trastuzumab group and 17.1 months in the chemotherapy alone group. Tumors from 3,807 patients were tested for HER2 status; 22% were positive. Five hundred ninety-four patients were randomized to the 2 treatment arms. Median OS for the group that received trastuzumab compared with the group that did not, was 13.8 months (95% CI, 12 to 16 months) and 11.1 months (95% CI, 10 to 13 months) (HR = 0.74; 95% CI, 0.60 to 0.91; p = 0.005), respectively. The overall response rate relative risk was 47% for those who received trastuzumab vs 35% for those who did not (p = 0.002). Rates of overall grade 3 or 4 adverse events (68% in both groups) and cardiac adverse events (6% in both groups) did not differ between groups.

Cohort Studies
Gr valos et al. (2011) reported on a phase 2, single-arm study of 22 chemotherapy-naive patients who had advanced gastric or gastroesophageal junction cancer with overexpression or amplification of HER2.⁶¹ Patients received trastuzumab with chemotherapy (cisplatin) every 21 days until disease progression, unacceptable toxicity, or study withdrawal. Twenty-one (95%) of 22 patients were evaluable. Seven (33%) patients responded (1 complete response, 6 partial responses). The median time to progression was 5.1 months (95% CI, 3.3 to 6.9 months). The median OS was 12.9 months (95% CI, 9.1 to 16.6 months); 6- and 12-month OS rates were 64% and 55%, respectively. The most common grade 3 adverse events were weakness (27%), neutropenia (18%), anorexia (14%), diarrhea (9%), and abdominal pain (9%).

Section Summary: Trastuzumab for HER2-Overexpressing Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma
One an open-labeled RCT and a single-arm study have reported survival benefits with the addition of trastuzumab to chemotherapy in patients with metastatic gastric or gastroesophageal junction adenocarcinoma. The pivotal Trastuzumab for Gastric Cancer trial reported a 16% relative reduction in the risk of death in patients treated with trastuzumab plus chemotherapy compared with those treated with chemotherapy alone.

trastuzumab for HER2-overexpressing malignancies besides breast or gastric cancers
Clinical Context and Test Purpose
The purpose of trastuzumab for patients who have HER2-overexpressing malignancies other than breast or gastric cancers is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does trastuzumab improve the net health outcome in patients with HER2-overexpressing malignancies other than breast or gastric cancers?

Section Summary: Trastuzumab for HER2-Overexpressing Malignancies Besides Breast or Gastric Cancers
Most trials were conducted 10 to 15 years ago as pilots with small sample sizes in the early clinical development of trastuzumab. It should be noted that these trials ultimately reported negative or less than optimal efficacy results and they were terminated early due to limited accrual.

Summary of Evidence
For individuals who have HER2-overexpressing breast cancer who receive trastuzumab as treatment for metastatic disease, or as adjuvant or neoadjuvant therapy, the evidence includes multiple RCTs and meta-analyses. Relevant outcomes are overall survival, disease-specific survival, morbid events, functional outcomes, health status measures, quality of life, and treatment-related mortality and morbidity. When used in treatment regimens, trastuzumab has shown a survival benefit for primary and metastatic breast cancer patients and has become the accepted standard therapy for patients with HER2-positive breast cancer. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who receive trastuzumab plus cisplatin and capecitabine or 5-fluorouracil, the evidence includes an RCT and a single-arm trial. Relevant outcomes are overall survival, disease-specific survival, morbid events, functional outcomes, health status measures, quality of life, and treatment-related mortality and morbidity. The addition of trastuzumab to the chemotherapy regimen has shown a 2-month survival, with no difference in severe adverse events compared with chemotherapy alone. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have HER2-overexpressing malignancies (besides breast or gastric cancer) who are treated with trastuzumab plus standard of care, the evidence includes multiple single-arm and randomized controlled trials. Relevant outcomes are overall survival, disease-specific survival, morbid events, functional outcomes, health status measures, quality of life, treatment-related mortality and morbidity. Most trials were conducted 10 to 15 years ago as pilots with small sample sizes in the early clinical development of trastuzumab. It should be noted that these trials ultimately reported negative or less than optimal efficacy results and they were terminated early due to limited accrual. The evidence is insufficient to determine the effects of technology on health outcomes.

PRACTICE GUIDELINES AND POSITION STATEMENTS
National Comprehensive Cancer Network
Breast Cancer
Current National Comprehensive Cancer Network (NCCN) guidelines (v.1.2018) recommend the use of trastuzumab for breast cancer (see Table 3).⁸¹ 

Table 3. Guidelines on the Use of Trastuzumab for Breast Cancer

COR: category of recommendation; HER2: human epidermal growth factor receptor 2.

Metastatic Breast Cancer
Table 4 summarizes NCCN guideline (v.1.2018) recommendations on metastatic breast cancer for use of trastuzumab.⁸¹

Table 4. Guidelines on the Use of Trastuzumab for Metastatic Breast Cancer

COR: category of recommendation; HER2: human epidermal growth factor receptor 2.

The guidelines note that the optimal duration of trastuzumab in patients with long-term disease control is unknown. Specific recommendations for timing of trastuzumab (i.e., concurrently or sequentially with other treatment) and specific trastuzumab-containing chemotherapy regimens are provided. Concurrent use with an anthracycline (e.g., daunorubicin, doxorubicin) should be avoided due to potential cardiotoxicity.

Gastric Cancer
Current NCCN guidelines on gastric (v.1.2018) and esophageal (v.2.2018) cancers recommend trastuzumab in combination with systemic chemotherapy (category 1 recommendation for first-line therapy in combination with cisplatin and fluoropyrimidine; category 2B recommendation for other chemotherapy combinations) for the treatment of inoperable locally advanced, recurrent, or metastatic gastric or gastroesophageal junction adenocarcinoma that is HER2-positive, as determined by standard methods.^82,83 This recommendation was based on the results of the Trastuzumab for Gastric Cancer trial.⁶⁰ Trastuzumab is not recommended for use with anthracyclines. HER2 positivity by immunohistochemical assays or fluorescence in situ hybridization or other in situ hybridization method is recommended.

Non-Small-Cell Lung Cancer
Current NCCN guidelines (v.5.2018) do not recommend single agent therapy with trastuzumab as "response rates are lower and treatment is less effective when these agents are used for patients with HER2 mutations."⁸⁴ Previously, trastuzumab had been recommended based on a case report by Cappuzzo et al. (2006).⁸⁵

Other Cancers
As of August 2018, use of trastuzumab has not been addressed by the NCCN guidelines for the following malignancies: osteosarcoma,⁸⁶ ovarian,⁸⁷ prostate,⁸⁸ pancreatic,⁸⁹ colon,⁹⁰ rectal,⁹¹ and urothelial⁵⁹ cancers. Use of trastuzumab has is a 2B recommendation for salivary gland tumors⁹² and a 2A recommendation for HER2-positive uterine serous carcinoma.⁹³

American Society of Clinical Oncology
The American Society of Clinical Oncology (2014) published evidence-based guidelines on systemic therapy for patients with advanced HER2-positive breast cancer.⁹⁴ These were updated in 2018.⁹⁵ Trastuzumab is recommended in the first-line setting in combination with pertuzumab and a taxane, unless taxanes are contraindicated (strength of recommendation: strong; evidence quality: high). Trastuzumab may be also used as a third-line treatment in patients in whom the disease has progressed after earlier HER2-targeted treatment (strength of recommendation: weak; evidence quality: insufficient). Further, in selected patients with HER2- and hormone receptor-positive cancer, clinicians may recommend treatment with trastuzumab in conjunction with endocrine therapy (strength of recommendation: moderate; evidence quality: high).

The Society (2016) adapted the Cancer Care Ontario clinical practice guidelines on the selection of optimal adjuvant targeted therapy for HER2-positive breast cancer.⁹⁶ Below is a summary of guidance related to trastuzumab:

U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATIONS
Not applicable

ONGOING AND UNPUBLISHED CLINICAL TRIALS
Some currently unpublished trials that might influence this review are listed in Table 5.

Table 5. Summary of Key Trials 

NCT: national clinical trial.
^a Denotes industry-sponsored or cosponsored trial.

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Coding Section

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

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