Medical Policy Medical Policy
Policy Num: 05.001.012
Policy Name: (Trastuzumab) Herceptin®
Policy ID: [05.001.012] [Ac / B / M+ / P+] [5.01.12]
Last Review: September 11, 2024
Next Review: September 20, 2025
Related Policies: None
| Population Reference No. | Populations | Interventions | Comparators | Outcomes |
| 1 | Individuals: · With HER2-overexpressing breast cancer | Interventions of interest are: · Trastuzumab as treatment for metastatic disease, or as adjuvant or neoadjuvant therapy | Comparators of interest are: · Cytotoxic chemotherapy | Relevant outcomes include: · Overall survival · Disease-specific survival · Morbid events · Functional outcomes · Health status measures · Quality of life · Treatment-related mortality · Treatment-related morbidity |
| 2 | Individuals: · With HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma | Interventions of interest are: · Trastuzumab plus cisplatin and capecitabine or 5-fluorouracil | Comparators of interest are: · Cisplatin · Capecitabine · 5-fluorouracil | Relevant outcomes include: · Overall survival · Disease-specific survival · Morbid events · Functional outcomes · Health status measures · Quality of life · Treatment-related mortality · Treatment-related morbidity |
| 3 | Individuals: · With HER2-overexpressing malignancies (other than breast or gastric cancer) | Interventions of interest are: · Trastuzumab plus standard of care | Comparators of interest are: · Standard of care | Relevant outcomes include: · Overall survival · Disease-specific survival · Morbid events · Functional outcomes · Health status measures · Quality of life · Treatment-related mortality · Treatment-related morbidity |
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 a 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 a treatment for metastatic disease, or as adjuvant or neoadjuvant therapy, the evidence includes multiple randomized controlled trials 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 an 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 randomized controlled trial 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 increase in survival, with no difference in severe adverse events compared with chemotherapy alone. The evidence is sufficient to determine that the technology results in an 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, and 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 that the technology results in an improvement in the net health outcome.
Not applicable.
The objective of this evidence review is to determine whether the use of trastuzumab will improve the net health outcome in patients with human epidermal growth factor receptor 2-positive malignancies.
Trastuzumab may be considered medically necessary for the treatment of patients with breast cancer whose tumors overexpress the human epidermal growth factor receptor 2 (HER2) protein (HER2-positive breast cancer). The use of trastuzumab includes use as adjuvant therapy, neoadjuvant therapy, and treatment of metastatic disease.
Trastuzumab may be considered medically necessary, when used in combination with systemic chemotherapy, for the treatment of patients with advanced (locally advanced or metastatic) gastric 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 types of cancer, 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, colorectal, endometrial, and urothelial.
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 individuals for trastuzumab therapy. These include the HercepTest™ and Pathway HER2/neu, which are immunohistochemical assays, and PathVysion® and HER2 FISH pharmDx, which are fluorescence in situ hybridization assays.
The U.S. Food and Drug Administration-approved label for trastuzumab recommends that left ventricular ejection fraction should be measured before initiating therapy, and shown to be within the treating institution's normal range. Continued therapy should depend on periodic monitoring (eg, at 3, 6, and 12 months) without an unacceptable decrease (eg, >15%) from baseline left ventricular ejection fraction.
Individuals with breast cancer who are 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.
Trastuzumab carries a black box warning for cardiomyopathy, infusion reactions, and embryo-fetal toxicity. The prescribing labels state that individuals should be evaluated for cardiac function before and during treatment as well as use effective contraception prior to and during treatment.
See the Codes table for details.
BlueCard/National Account Issues
State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration-approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.
First treatment of choice will be biosimilars Kanjinti or Trazimera. In order to consider other Trastuzumab agents, patients must have documented previous use and therapeutic failure, intolerance or contraindication to biosimilars Kanjinti, Trazimera.
Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.
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 in cancer mortality after lung cancer. In 2023 , an estimated 297,790 new cases of breast cancer will be diagnosed in women, with approximately 43,170 deaths.1,
Metastatic breast cancer has a poor prognosis. In a cohort of 3524 women diagnosed with breast cancer between 1992 and 2007, median overall survival (OS) 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,
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. Recommended agents used singly, or in combination with trastuzumab, are paclitaxel, docetaxel, vinorelbine, capecitabine, and carboplatin.
It is estimated that 26,500 people will be diagnosed and 11,130 will die from gastric cancer in the U.S. in 2023.1, 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.
Surgery, including adjuvant chemoradiotherapy, perioperative (preoperative plus postoperative) chemotherapy, and adjuvant chemotherapy, are the mainstays of treatment.
Approximately 20% to 25% of breast cancers overexpress HER2, a transmembrane glycoprotein receptor with tyrosine kinase activity. HER2, previously called HER2/neu, or ErbB-2,5, 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 phosphatidylinositol-3-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.6,
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 OS 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.7,
The U.S. Food and Drug Administration (FDA) has approved multiple 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, lapatinib, pertuzumab, ado-trastuzumab emtansine, fam-trastuzumab deruxtecan-nxki, trastuzumab-anns, trastuzumab-dkst, trastuzumab-dttb, trastuzumab-pkrb, trastuzumab-strf, trastuzumab-qyyp, margetuximab-cmkb, neratinib, tucatinib, dacomitinib, pertuzumab and trastuzumab and hyaluronidase-zzxf, and trastuzumab and hyaluronidase-oysk.
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.5, Several biosimilar trastuzumab products have also been approved by the FDA. These include: trastuzumab-anns (Kanjinti™), trastuzumab-dkst (Ogivri®), trastuzumab-dttb (Ontruzant®), trastuzumab-pkrb (Herzuma®), trastuzumab-strf (Hercessi™), and trastuzumab-qyyp (Trazimera™).
Lapatinib (Tykerb®) is an oral tyrosine kinase inhibitor that blocks the intracellular tyrosine kinase domain of HER2 and downstream cell-signaling cascades.8,
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 cell-mediated cytotoxicity.9,
Ado-trastuzumab emtansine (Kadcyla®) is an intravenous antibody-drug conjugate of trastuzumab and emtansine, a microtubule inhibitor.
Neratinib (Nerlynx®), tucatinib (Tukysa®), and dacomitinib (Vizimpro®) are oral kinase inhibitors that reduce HER autophosphorylation by irreversibly binding to HER2. Neratinib is indicated as a single agent for extended adjuvant treatment for early HER2-over expressed breast cancer. The agent is also approved in combination with capecitabine, for the treatment of advanced/metastatic HER2-positive breast cancer in individuals who have received 2 or more prior anti-HER2 based regimens in the metastatic setting. Tucatinib (used in combination with trastuzumab and capecitabine) is indicated for treatment of advanced, unresectable, or metastatic HER2-positive breast cancer in patients, including patients with brain metastases, who have failed ≥1 prior anti-HER2-based regimen. It is also indicated (in combination with trastuzumab) for use in patients with RAS wild-type HER2-positive unresectable/metastatic colorectal cancer that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. Dacomitinib is indicated for first-line treatment of metastatic lung cancer in patients with specific epidermal growth factor receptor mutations.
Trastuzumab and hyaluronidase-oysk (Herceptin Hylecta™) is a subcutaneous combination drug that contains trastuzumab and hyaluronidase. Pertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo™) is a subcutaneous drug that combines trastuzumab, pertuzumab, and hyaluronidase. Hyaluronidase has been shown to increase the absorption rate of trastuzumab into systemic circulation.
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 progress.10,11,
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 (eg, 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.12,
Trastuzumab (Herceptin; Genentech) is a humanized monoclonal antibody active against the extracellular domain of HER2. Trastuzumab was cleared for marketing by the FDA through the biologics license application process (BLA 103792) for the 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 first-line therapy in combination with paclitaxel and as a single agent in second- and third-line therapy.
Current FDA approved labeling states that trastuzumab is indicated as follows13,:
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."
Trastuzumab is administered by intravenous infusion weekly or every 3 weeks for a total of 52 weeks depending on the dosing schedule and chemotherapy used for adjuvant treatment.
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 intravenous infusion weekly until disease progression.
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 intravenous infusion every 3 weeks until disease progression.
While trastuzumab has FDA approval for breast cancer in specific settings and for gastric or gastroesophageal junction adenocarcinoma, its use has been investigated in the preoperative (neoadjuvant) setting for breast cancer, in combination with regimens besides those specified in the FDA approved product label, and in a wide range of other types of cancer that overexpress HER2.
The following biosimilars have been approved by the FDA for trastuzumab for the treatment of HER2-overexpressing breast cancer and/or HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma.
April 2024, Hercessi (trastuzumab-strf; Accord BioPharma Inc.)
June 2019, Kanjinti (trastuzumab-anns; Amgen)
March 2019, Trazimera (trastuzumab-qyyp; Pfizer)
January 2019, Ontruzant (trastuzumab-dttb; Samsung Bioepsis Co)
December 2017, Ogivri (trastuzumab-dkst; Mylan)
This evidence review was created in July 1999 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through July 9, 2024.
Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are the 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 1 or more intended clinical use 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. Randomized controlled trials 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.
Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.
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 following PICO was used to select literature to inform this review.
The relevant population of interest is individuals with HER2-overexpressing breast cancer.
The therapy being considered is trastuzumab as a treatment for metastatic HER2-overexpressing breast cancer, or as adjuvant or neoadjuvant therapy.
The following practice is currently being used to make treatment decisions about HER2-overexpressing breast cancer: standard of care cytotoxic chemotherapy without trastuzumab.
The general outcomes of interest include overall survival (OS), disease-specific survival, morbid events, functional outcomes, health status measures, quality of life, treatment-related mortality, and treatment-related morbidity.
Methodologically credible studies were selected using the following principles:
To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies;
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought;
Studies with duplicative or overlapping populations were excluded.
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=.004; I2=0%) and for progression-free survival (PFS) (HR, 0.61; 95% CI, 0.54 to 0.70; p<.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<.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.
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 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 endpoint 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. Progression-free survival 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) versus 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=.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 endpoint 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=.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=.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=.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 post progression third-line chemotherapy with trastuzumab. In 52 patients who received third-line chemotherapy with trastuzumab, post progression survival was 18.8 months (95% CI, 12.9 to 24.8 months) versus 13.3 months (95% CI, 10.2 to 14.7 months) in the 88 patients who did not (HR, 0.63; p=.02).
The U.S. Food and Drug Administration (FDA) 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<.001), lengthened the median response duration (9.1 months vs. 6.1 months, respectively; p<.001), and prolonged OS (25.1 months vs. 20.3 months, respectively; p=.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 and cyclophosphamide plus trastuzumab, compared to doxorubicin plus cyclophosphamide, paclitaxel plus trastuzumab, or paclitaxel alone, the FDA 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 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.
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.
A meta-analysis by Bradley et al (2021) for the Early Breast Cancer Trialist's Collaborative Group (EBCTCG) included 7 RCTs (N=13,854) in which patients received trastuzumab plus chemotherapy or chemotherapy alone for adjuvant treatment of early-stage, HER2-positive breast cancer.22, Median follow-up was 10.7 years (interquartile range, 9.5 to 11.9). Results favored trastuzumab plus chemotherapy, with lower risk of recurrence (rate ratio, 0.66; 95% CI, 0.62 to 0.71; p<.0001) and death from breast cancer (rate ratio, 0.67; 95% CI, 0.61 to 0.73; p<.0001) compared to chemotherapy alone. Combination therapy also resulted in a 9.0% and 6.4% reduction in risk of 10-year breast cancer recurrence and 10-year breast cancer mortality, respectively (both p<.0001).
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; N=14,546).23, Studies in the adjuvant setting favored trastuzumab-containing regimens for OS (HR, 0.79; 95% CI, 0.68 to 0.92; p=.002; I2=62%) and for recurrence (HR, 0.66; 95% CI, 0.58 to 0.75; p<.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.24, Median follow-up was 8 years. For 2263 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<.005); for 1092 hormone receptor-positive patients with 0 or 1 positive lymph nodes, rates were 5.3% and 7.4% (p<.12), respectively. For 1957 patients with hormone receptor-negative disease, OS results were 12.4% and 21.2% (p<.001), respectively; for 1040 hormone receptor-negative patients with 0 or 1 positive lymph nodes, rates were 8.2% and 12.2% (p=.084), respectively.
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)25,; the HERceptin Adjuvant (HERA) Trial (N=5090)26,; the North Central Cancer Treatment Group N9831 (NCCTG N9831) trial (N=3505)27,; the North American National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial (N=2030)28,; the Finnish Herceptin Study (FinHer) Study (N=232)29,; the Protocol for Herceptin as Adjuvant therapy with Reduced Exposure (PHARE) trial (N=3380)30,; and the 6 versus 12 months of adjuvant trastuzumab for HER2-positive early breast cancer (PERSEPHONE) trial (N=4089)31,. 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.8,32,33,34,35, See Tables 1 and 2 for the trial characteristics and results.
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.36, The PHARE trial supported 1 year of trastuzumab rather than 6 months of treatment.30, A 2012 Cochrane meta-analysis also supported the use of 1 year of trastuzumab treatment given with adjuvant chemotherapy rather than for shorter periods.37,
| Study | Tumor Characteristics | Design | Trastuzumab Schedule | Median Follow-Up, y |
| BCIRG (2005)25,; Slamon et al (2011)38, | Node-positive, or high-risk node-negative | AC→D AC→DT DCT | Every 1 wk with chemotherapy Every 3 wk post-chemotherapy | 3 5 |
| HERA (2005)26,; Gianni et al (2011)39,; Goldhirsch et al (2013)36, | Node-positive, or node-negative with tumor ≥1 cm | Chemotherapy Chemotherapy→T (1 y) Chemotherapy→T (2 y) | Every 3 wk post-chemotherapy | 2 4a 8a |
| NCCTG N9831 (2005),27, (2011)40, | Node-positive, or if node-negative, with primary tumor >1 cm if ER/PR-negative, or >2 cm if ER/PR-positive | AC→P AC→PT | Every 1 wk with chemotherapy Every 1 wk post-chemotherapy | 2 3.9 |
| FinHer (2006)29,; Joensuu et al (2009)41, | Node-positive, or node-negative and ≥2 cm and PR-negative | D or V→FEC DT or VT→FEC | Every 1 wk with chemotherapy | 3 5 |
| PHARE (2013)30, | Node-positive or node-negative with tumor ≥1 cm | Chemotherapy + T | Every 3 wk x 12 or 6 mo with or post-chemotherapy | 3.5 |
| PERSEPHONE (2018)42,42, | Node-positive or node-negative | Chemotherapy + T | Every 3 wks x 12 or 6 mo with or post-chemotherapy | 5.4 |
AC: doxorubicin plus cyclophosphamide; C: carboplatin; D: docetaxel; ER/PR: estrogen receptor/progesterone receptor; FEC: 5-fluorouracil plus epirubicin plus cyclophosphamide; P: paclitaxel; T: trastuzumab; V: vinorelbine.aObservation group results included 885 (52%) patients who crossed over to trastuzumab.
| Study | DFS Hazard Ratio versus Controlsa | OS Hazard Ratio versus Controlsa | ||||
| Hazard Ratio | 95% CI | p | Hazard Ratio | 95% CI | p | |
| BCIRG (2005)25, Slamon et al (2011)38, | AC→DT: 0.61 DCT: 0.67 AC→DT: 0.64 DCT: 0.75 | 0.48 to 0.76 0.54 to 0.83 | <.001 <.001 <.001 .04 | AC→DT: 0.59 DCT: 0.66 AC→DT: 0.63 DCT: 0.77 | 0.42 to 0.85 0.47 to 0.93 | .004 .017 <.001 .04 |
| HERA (2005)26, HERA (2017)43, Gianni et al (2011)39, Goldhirsch et al (2013)36, | 0. 54 0.77 0.76 0.76 2- vs. 1-y: 0.99 | 0.43 to 0. 67 0.68 to 0.86 0.66 to 0.87 0.67 to 0.86 0.85 to 1.14 | <.0001 <.0001 <.0001 <.0001 .86 | 0. 76 0.74 0.85 0.76 2- vs. 1-y: 1.05 | 0.47 to 1.23 0.64 to 0.86 0.70 to 1.04 0.65 to 0.88 0.86 to 1.28 | . 26 <.0001 .11 .0005 .63 |
| NCCTG N9831 (2005),27, (2011)40, | Pooled data: 0.48 0.52 | 0.39 to 0.59 0.45 to 0.60 | <.001 <.001 | Pooled data: 0.67 0.61 | 0.48 to 0.93 0.50 to 0.75 | .015 <.001 |
| FinHer (2006)29, Joensuu et al (2009)41, | 0.42 0.65 | 0.21 to 0.83 0.38 to 1.12 | .01 .12 | 0.41 0.55 | 0.16 to 1.08 0.27 to 1.11 | .07 .094 |
| PHARE (2013)30, | 1.28 | 1.05 to 1.56 | .29 | 1.46 | 1.06 to 2.01 | NRb |
| PERSEPHONE (2018)42,42, | 1.07 | 0.93 to 1.24c | .42d | 1.14 | 0.95 to 1.37c | .22d |
AC: doxorubicin plus cyclophosphamide; C: carboplatin; CI: confidence interval; D: docetaxel; DFS: disease-free survival; H: Herceptin; NR, not reported; OS: overall survival; T: trastuzumab.aRatios are for the hazard of disease recurrence or disease-related death (for DFS) and hazard of death (for OS).bStatistical testing indicated that the model used to estimate OS (Cox proportional hazards model) was not applicable.c90% CI reporteddP-value is for superiority. P-values for noninferiority were 0.011 for DFS and 0.0010 for OS.
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 versus controls.44,
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%) versus 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 versus 1-year regimen of trastuzumab in the Synergism or Long Duration (SOLD) RCT; noninferiority between the 2 regimens was not established for 5-year DFS.45,
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.46, Adding trastuzumab to chemotherapy led to a 37% relative improvement in OS (HR, 0.63; 95% CI, 0.54 to 0.73; p<.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<.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.37, 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 (ie, concurrent with chemotherapy or sequentially following chemotherapy).
Results for the PERSEPHONE trial, a randomized phase 3 noninferiority trial found that treatment with trastuzumab for 6 months is noninferior to treatment with trastuzumab for 12 months.42,HER2-positive patients with early-stage breast cancer (N=4089) were followed for a median of 5.4 years after treatment. The noninferiority margin for the 6-month treatment group was defined as a DFS no worse than an absolute value of 3% below the 4-year DFS of the 12 month group. Results showed a 4-year DFS rate of 89.4% (95% CI, 87.9% to 90.7%) with 6 months of trastuzumab and a DFS rate of 89.8% (95% CI, 88.3% to 91.1%) with 12 months of trastuzumab. The HR for these findings was 1.07 (90% CI, 0.93 to 1.24; p for noninferiority,.011; p for superiority,.42).
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.
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 endpoints (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.47, 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<.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 Sendur et al (2014) study (discussed below), these results suggested that some benefits of trastuzumab on LVEF may be reversible after drug discontinuation. Another analysis of the HERA trial that was performed after a median of 11 years of follow-up reported that LVEF declined by 8.80% to 9.18% in patients who received trastuzumab alone or trastuzumab plus radiation therapy to the left or right heart.48, Cardiovascular events were rare during follow-up (0.62% to 1.08%). The authors concluded that radiation therapy does not increase the risk of trastuzumab-related cardiotoxicity.
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.49, 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.50, 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.
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).51, 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<.001).52,
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 with use of trastuzumab, including congestive heart failure and LVEF declines, most investigators have concluded that the benefits of adjuvant treatment outweigh the risks of side effects.
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.53, Adding trastuzumab to chemotherapy improved the probability of achieving pathologic complete response (pCR) (relative risk, 1.85; p<.001). An FDA-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, pCR was 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 et al (2011) review did not differ significantly with the addition of trastuzumab (odds ratio, 0.98; p=.82).
Buzdar et al (2005) published an RCT that examined the benefits of adding trastuzumab to neoadjuvant chemotherapy.54, 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 (4, 3-week cycles) followed by fluorouracil, epirubicin, and cyclophosphamide (FEC; 4, 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.55, 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%) for 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 (1 of whom died) experienced a recurrence.
Analyses from other RCTs56,57,58, and single-arm studies59,60,61,62, 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.
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.
Randomized controlled trials 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 concurrent or sequential therapy. A detailed analysis of these issues is beyond the scope of the present review; the following discussion summarizes the issues.
Trastuzumab has been rapidly integrated into the adjuvant therapy of patients with HER2-positive early-stage breast cancer. When 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.
At present, a single prospective observational study has assessed the optimal regimen of trastuzumab within the overall regimen of adjuvant therapy, specifically whether concurrent or sequential trastuzumab is the preferred course. Six-year interim results of the NCCTG N9831 trial (see discussion above) have demonstrated longer DFS with concurrent trastuzumab (with paclitaxel) than with sequential trastuzumab.
As noted above in the various subsection summaries, 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.
For individuals who have HER2-overexpressing breast cancer who receive trastuzumab as a treatment for metastatic disease, or as adjuvant or neoadjuvant therapy, the evidence includes multiple RCTs and meta-analyses. Relevant outcomes are OS, 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 an improvement in the net health outcome.
| [X] MedicallyNecessary | [ ] Investigational |
The purpose of trastuzumab for patients who have HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma is to provide a treatment option that is an alternative to or an improvement on existing therapies.
The following PICO was used to select literature to inform this review.
The relevant population of interest is individuals with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma.
The therapy being considered is trastuzumab in combination with cisplatin and capecitabine, or 5-fluorouracil.
The following practice is currently being used to make treatment decisions about metastatic gastric or gastroesophageal junction adenocarcinoma: standard of care (cisplatin, capecitabine, or 5-fluorouracil) without trastuzumab.
The general outcomes of interest include OS, disease-specific survival, morbid events, functional outcomes, health status measures, quality of life, treatment-related mortality, and treatment-related morbidity.
Methodologically credible studies were selected using the following principles:
To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies;
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought;
Studies with duplicative or overlapping populations were excluded.
Bang et al (2010) reported results of the phase 3, Trastuzumab for Gastric Cancer (ToGA) 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.63, Trastuzumab was administered every 3 weeks for 6 cycles, until disease progression. The primary endpoint was OS; secondary endpoints 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 3807 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=.005), respectively. The overall response rate relative risk was 47% for those who received trastuzumab versus 35% for those who did not (p=.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.
Abali et al (2021) reported results of a phase 2, single-arm, open-label, multicenter study in 34 patients with advanced gastric or gastroesophageal cancer with HER2 overexpression who had undergone curative resection.64, Patients received 3 cycles of oxaliplatin plus capecitabine, trastuzumab every 21 days for 1 year, and chemoradiotherapy. The majority of patients had gastric adenocarcinoma (97.1%). At 12 and 24 months, OS was 75% and 58%, respectively. Disease-free survival at the same time points was 65.7% and 55%, respectively. Grade 3 adverse events included nausea, vomiting, diarrhea, and weight loss, which each occurred in <10% of patients.
Hofheinz et al (2021) reported results of a phase 2, single-arm, multicenter study in 56 patients with HER2-positive locally advanced esophagogastric adenocarcinoma.65, Patients received trastuzumab plus 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) every 15 days for 4 cycles preoperatively, followed by 9 postoperative cycles of trastuzumab. The primary endpoint (pCR) was achieved in 12 patients (21.4%). An additional 14 patients (25%) had near complete response. Disease-free survival was 42.5 months (median) and 3-year OS was 82.1%. Grade 3 or 4 adverse events included neutropenia (46.6%), leukopenia (17.9%), and diarrhea (17%).
Gravalos 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 HER2.66, 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 Human Epidermal Growth Factor Receptor 2-Overexpressing Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma
An open-label 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 ToGA 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.
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 OS, 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 increase in survival, with no difference in severe adverse events compared with chemotherapy alone. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
| [X] MedicallyNecessary | [ ] Investigational |
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 following PICO was used to select literature to inform this review.
The relevant population of interest is individuals with HER2-overexpressing malignancies other than breast or gastric cancers.
The therapy being considered for this patient group is trastuzumab in addition to standard of care.
The following practice is currently being used to treat HER2-overexpressing malignancies other than breast or gastric cancers: standard of care without trastuzumab.
The general outcomes of interest include OS, disease-specific survival, morbid events, functional outcomes, health status measures, quality of life, treatment-related mortality, and treatment-related morbidity.
Methodologically credible studies were selected using the following principles:
To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies;
To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought;
Studies with duplicative or overlapping populations were excluded.
Use of trastuzumab has been evaluated in multiple HER2-positive tumors including prostate, ovarian, non-small-cell lung, esophageal, bladder, kidney, pancreatic, bone, and salivary gland cancer. Most trials were conducted 10 to 15 years ago as pilot studies in the early clinical development of trastuzumab. Preliminary pilot studies with small sample sizes have reported poor or suboptimal efficacy results in patients with prostate cancer,67,68,69, recurrent or refractory ovarian or primary peritoneal carcinoma,70, non-small-cell lung cancer,71,72,73,74, esophageal cancer,75,76, bladder and renal pelvis cancer,77,78, urothelial carcinoma,79, pancreatic cancer,80, and osteosarcoma,81, while others were closed early due to limited accrual in patients with prostate,82, salivary gland,83, urothelial carcinoma,84, and pancreatic cancer.85,
Fader et al (2018) published a multicenter phase 2 RCT evaluating the treatment of advanced or recurrent uterine serous carcinoma with overexpressed HER2 with trastuzumab.86, Patients were assigned to treatment with carboplatin-paclitaxel either with (n=32) or without trastuzumab (n=28). Median PFS was 8.0 months in the control arm and 12.6 in the treatment arm (HR, 0.44; 90% CI, 0.26 to 0.76; p=.005). Study results are limited by discrepancies in the trial and control population, as well as a possible over-estimation of PFS and changes in the study protocol.
Strickler et al (2023) published a multicenter phase 2 RCT (MOUNTAINEER) evaluating trastuzumab in patients with chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer.87, Initially, patients were given tucatinib plus trastuzumab (cohort A; n=45) until progression. After trial expansion, patients were randomly assigned (4:3) to either tucatinib plus trastuzumab (cohort B; n=41) or tucatinib monotherapy (cohort C; n=30). The primary outcome was the confirmed objective response rate for cohorts A and B combined as assessed in patients in the full analysis set (ie, patients with HER2-positive disease who received at least 1 dose of study treatment). As of data cutoff in March 2022, the confirmed objective response rate was 38.1% (95% CI, 27.7 to 49.3) in 84 patients (from cohort A and B in the full analysis set). Complete response was reported in 3 patients and partial response in 29 patients.
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.
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 OS, disease-specific survival, morbid events, functional outcomes, health status measures, quality of life, and 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 that the technology results in an improvement in the net health outcome.
| [ ] MedicallyNecessary | [X] Investigational |
The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.
Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.
In 2014, the American Society of Clinical Oncology (ASCO) published evidence-based guidelines on systemic therapy for patients with advanced human epidermal growth factor receptor 2 (HER2)-positive breast cancer.88, These were last updated in 2022.89, 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 deruxtecan is recommended for second-line therapy (strength of recommendation: strong; evidence quality: moderate). Options for third-line therapy include tucatinib plus trastuzumab plus capecitabine, neratinib plus capecitabine, lapatinib plus trastuzumab, chemotherapy plus trastuzumab or margetuximab, hormonal therapy, abemaciclib plus trastuzumab plus fulvestrant, or the following agents if not previously received: trastuzumab emtansine, trastuzumab deruxtecan, or pertuzumab. 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).
In 2016, ASCO adapted the Cancer Care Ontario clinical practice guidelines on the selection of optimal adjuvant targeted therapy for HER2-positive breast cancer.90, The guideline was updated in 202091,. Below is a summary of guidance related to trastuzumab:
Recommended as adjuvant therapy only for patients with HER2-positive breast cancer
Recommended with chemotherapy for patients with any node-positive tumors or node-negative tumors >1 cm
Can be considered with chemotherapy for patients with node-negative tumors ≤1 cm
Recommended concurrent administration with nonanthracycline chemotherapy regimen (potential for cardiotoxicity with anthracycline)
Recommended, "1 year total of adjuvant trastuzumab, with regular assessments of cardiac function".
Any of the available and approved formulations of trastuzumab, including trastuzumab, trastuzumab and hyaluronidase-oysk, and available biosimilars may be offered.
In 2021, ASCO published guidelines on neoadjuvant treatment of breast cancer. The guidelines recommend neoadjuvant treatment with an anthracycline and taxane or non-anthracycline-based regimen in combination with trastuzumab in patients with node-positive or high-risk node-negative HER2-positive breast cancer (high quality evidence, strong recommendation).92,
In 2023, ASCO published guidelines on immunotherapy and targeted therapy for advanced gastroesophageal cancer.93, Below is a summary of guidance related to trastuzumab:
Current National Comprehensive Cancer Network (NCCN) guidelines (v.4.2024) include recommendations for the use of trastuzumab alone or in combination with other medications for neoadjuvant and adjuvant treatment of breast cancer and treatment of metastatic breast cancer.94,
Current NCCN guidelines on gastric (v.2.2024) and esophageal (v.3.2024 cancers recommend trastuzumab in combination with systemic chemotherapy for the treatment of inoperable locally advanced, recurrent, or metastatic gastric or gastroesophageal junction adenocarcinoma that is HER2-positive, as determined by standard methods.95,96, This recommendation was based on the results of the Trastuzumab for Gastric Cancer trial.63, 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.
Current NCCN guidelines (v.7.2024) recommend fam-trastuzumab deruxtecan-nxki as a preferred subsequent therapy option upon disease progression, and lists ado-trastuzumab emtansine as an "other recommended" option in patients with metastatic non-small cell lung cancer and ERBB2 (HER2) mutations.97,
Current NCCN guidelines on colon (v.4.2024) and rectal (v.3.2024) cancers recommend trastuzumab in combination with pertuzumab, lapatinib,or tucatinib as subsequent, systemic therapy for advanced or metastatic HER2-amplified and RAS wild-type colon and rectal cancers (category 2A).98,99, Fam-trastuzumab deruxtecan-nxki is also recommended as a subsequent systemic therapy option for patients with advanced or metastatic disease (HER2-amplified and RAS and BRAF wild-type).
As of July 2024, use of trastuzumab has not been addressed by the NCCN guidelines for the following malignancies: bone cancer,100,and prostate,101, cancers. Use of trastuzumab has a 2A recommendation for salivary gland tumors and a 2B recommendation for fam-trastuzumab deruxtecan-nxki in salivary gland tumors and non-nasopharyngeal cancers. 102,Use of trastuzumab has a 2A recommendation for HER2-positive uterine serous carcinoma (2B for fam-trastuzumab deruxtecan-nxki).103,Use of fam-trastuzumab deruxtecan-nxki has a 2A recommendation for HER2-positive ovarian cancer,94, for HER2-positive pancreatic adenocarcinoma,104, and for HER2-positive bladder cancer.62,
Not applicable.
There is no national coverage determination. In the absence of national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.
Some currently unpublished trials that might influence this review are listed in Table 3.
| NCT No. | Trial Name | Planned Enrollment | Completion Date |
| Ongoing | |||
| NCT01785420 | A Phase III Double Blind Randomized Placebo Controlled Study of Trastuzumab as Short Duration Preoperative Therapy in Patients With HER2-neu Positive Operable Breast Cancer | 1100 | Feb 2027 |
| NCT00470704 | A Phase 2 Study of Lapatinib in Combination With Trastuzumab in Patients With HER2-Positive, Metastatic Breast Cancer | 87 | Dec 2024 |
NCT: national clinical trial.
| Codes | Number | Description |
| CPT | 96374 | Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); intravenous push, single or initial substance/drug |
| HCPCS | J9355 | Injection, trastuzumab, 10 mg |
| J9356 | Injection, trastuzumab, 10 mg and Hyaluronidase-oysk | |
| J9358 | Injection, fam-trastuzumab deruxtecan-nxki, 1 mg (eff 07/01/2020) | |
| Q5112 | Injection, trastuzumab-dttb, biosimilar, (Ontruzant), 10 mg | |
| Q5113 | Injection, trastuzumab-pkrb, biosimilar, (Herzuma), 10 mg | |
| Q5114 | Injection, Trastuzumab-dkst, biosimilar, (Ogivri), 10 mg | |
| Q5116 | Injection, trastuzumab-qyyp, biosimilar, (Trazimera), 10 mg | |
| Q5117 | Injection, trastuzumab-anns, biosimilar, (Kanjinti), 10 mg | |
| ICD-10-CM | C15.3 | Malignant neoplasm of upper third of esophagus |
| C15.4 | Malignant neoplasm of middle third of esophagus | |
| C15.5 | Malignant neoplasm of the lower third of esophagus | |
| C15.8 | Malignant neoplasm of overlapping sites of esophagus | |
| C15.9 | Malignant neoplasm of esophagus, unspecified | |
|
| C16.0-C16.9 | Malignant neoplasm of stomach code range |
| | C50.011-C50.922 | Malignant neoplasm of the breast code range |
| C50.012 | Malignant neoplasm of nipple and areola, left female breast | |
| C50.021 | Malignant neoplasm of nipple and areola, right male breast | |
| C50.022 | Malignant neoplasm of nipple and areola, left male breast | |
| C50.111 | Malignant neoplasm of central portion of right female breast | |
| C50.112 | Malignant neoplasm of central portion of left female breast | |
| C50.121 | Malignant neoplasm of central portion of right male breast | |
| C50.122 | Malignant neoplasm of central portion of left male breast | |
| C50.211 | Malignant neoplasm of upper-inner quadrant of right female breast | |
| C50.212 | Malignant neoplasm of upper-inner quadrant of left female breast | |
| C50.219 | Malignant neoplasm of upper-inner quadrant of unspecified female breast | |
| C50.221 | Malignant neoplasm of upper-inner quadrant of right male breast | |
| C50.222 | Malignant neoplasm of upper-inner quadrant of left male breast | |
| C50.229 | Malignant neoplasm of upper-inner quadrant of unspecified male breast | |
| C50.311 | Malignant neoplasm of lower-inner quadrant of right female breast | |
| C50.312 | Malignant neoplasm of lower-inner quadrant of left female breast | |
| C50.319 | Malignant neoplasm of lower-inner quadrant of unspecified female breast | |
| C50.321 | Malignant neoplasm of lower-inner quadrant of right male breast | |
| C50.322 | Malignant neoplasm of lower-inner quadrant of left male breast | |
| C50.329 | Malignant neoplasm of lower-inner quadrant of unspecified male breast | |
| C50.411 | Malignant neoplasm of upper-outer quadrant of right female breast | |
| C50 412 | Malignant neoplasm of upper-outer quadrant of left female breast | |
| C50.421 | Malignant neoplasm of upper-outer quadrant of right male breast | |
| C50.422 | Malignant neoplasm of upper-outer quadrant of left male breast | |
| C50.511 | Malignant neoplasm of lower-outer quadrant of right female breast | |
| C50.512 | Malignant neoplasm of lower-outer quadrant of left female breast | |
| C50.521 | Malignant neoplasm of lower-outer quadrant of right male breast | |
| C50.522 | Malignant neoplasm of lower-outer quadrant of left male breast | |
| C50.611 | Malignant neoplasm of axillary tail of right female breast | |
| C50.612 | Malignant neoplasm of axillary tail of left female breast | |
| C50.619 | Malignant neoplasm of axillary tail of unspecified female breast | |
| C50.621 | Malignant neoplasm of axillary tail of right male breast | |
| C50.622 | Malignant neoplasm of axillary tail of left male breast | |
| C50.629 | Malignant neoplasm of axillary tail of unspecified male breast | |
| C50.811 | Malignant neoplasm of overlapping sites of right female breast | |
| C50.812 | Malignant neoplasm of overlapping sites of left female breast | |
| C50.819 | Malignant neoplasm of overlapping sites of unspecified female breast | |
| C50.821 | Malignant neoplasm of overlapping sites of right male breast | |
| C50.822 | Malignant neoplasm of overlapping sites of left male breast | |
| C50.829 | Malignant neoplasm of overlapping sites of unspecified male breast | |
| C50.911 | Malignant neoplasm of unspecified site of right female breast | |
| C50.912 | Malignant neoplasm of unspecified site of left female breast | |
| C50.921 | Malignant neoplasm of unspecified site of right male breast | |
| C50.922 | Malignant neoplasm of unspecified site of left male breast | |
| C50.929 | Malignant neoplasm of unspecified site of unspecified male breast | |
| C54.0-C54.9 | Malignant neoplasm of corpus uteri code range | |
| C55 | Malignant neoplasm of uterus, part unspecified | |
| C79.32 | Secondary malignant neoplasm of cerebral meninges | |
| D37.1 | Neoplasm of uncertain behavior of stomach | |
| D37.8 | Neoplasm of uncertain behavior of other specified digestive organs | |
| D37.9 | Neoplasm of uncertain behavior of digestive organ, unspecified | |
| Z80.49 | Family history of malignant neoplasm of other genital organs | |
| Z85.00 | Personal history of malignant neoplasm of unspecified digestive organ | |
| Z85.028 | Personal history of other malignant neoplasm of stomach | |
| Z85.3 | Personal history of malignant neoplasm of breast | |
| ICD-10-PCS | | ICD-10-PCS codes are only used for inpatient services |
| | 3E0330M | Introduction of antineoplastic antibody, peripheral vein |
| | 3E0430M | Introduction of antineoplastic antibody, central vein |
| Type of service | Prescription Drug | |
| Place of service | Physician’s Office Outpatient |
|
N/A
| Date | Action | Description |
|---|---|---|
| 09/11/2024 | Annual Review | Policy updated with literature review through July 9, 2024; no references added. Guidelines updated. Minor editorial refinements and an update to the boxed warning within policy guidelines for clarity. |
| 09/12/2023 | Annual Review | Policy updated with literature review through June 29, 2023; references added. Policy statements unchanged. |
| 08/28/2023 | Policy Review | Update policy with deletion of reference to naive patients in Benefit Application section. |
| 12/29/2022 | Preferred agent determination | Ogivri is removed as preferred agent. Trazimera is added as preferred agent. |
| 09/07/2022 | Annual Review | Policy updated with literature review through June 27, 2022; references added. Minor editorial refinements to policy statements; intent unchanged. |
| 09/07/2021 | Annual Review | Policy updated with literature review through June 17, 2021; references added. Policy statements unchanged. |
| 11/16/2020 | Replaced Policy | Policy updated. Biosimilar HCPCS Code added J9356, J9358, Q5112, Q5113. Policy updated with literature review through June 30, 2020; no references added. Policy statements unchanged. |
| 06/24/2020 | Annual Review | Biosimilars Preferred, Kanjinti, added |
| 06/24/2019 | Policy reviewed | Policy unchanged |
| 07/12/2018 | Policy reviewed | Policy unchanged |
| 11/15/2016 | Policy reviewed | Policy unchanged |
| 03/11/2015 | Policy reviewed | Policy unchanged |
| 03/27/2014 | Policy reviewed | Policy unchanged |
| 07/15/2013 | Policy reviewed | Policy unchanged |
| 03/04/2013 | Policy reviewed | Policy unchanged |
| 05/11/2009 | Policy replaced | ICES |
| 12/02/2007 | Policy reviewed | Policy unchange |
| 11/22/2005 | Policy created | New policy |