| Coverage Policy Manual | |
| Policy #: | 1998158 |
| Category: | Pharmacy |
| Initiated: | October 1998 |
| Last Review: | April 2024 |
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| Trastuzumab AND Trastuzumab and Hyaluronidase-oysk | |
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| Description: |
Trastuzumab is a monoclonal antibody, one of a group of drugs designed to attack specific cancer cells. Trastuzumab binds to a protein called HER2/ErbB2 or HER2/neu, which is found on the surface of some normal cells and plays a role in regulating cell growth. It is estimated that in the United States approximately 20% of women diagnosed with metastatic breast cancer have tumors that produce excessive amounts of (over express) the ER2/ErbB2 protein.
Individual selection, determining who are most likely to benefit from trastuzumab, is important as the drug also has serious risks. The use of trastuzumab alone or in combination with chemotherapy can result in a weakening of the heart muscle that can lead to congestive heart failure. This was seen more often in individuals who received trastuzumab in combination with chemotherapy consisting of anthracyclines. Because the benefit is not great enough to overcome this serious risk, Herceptin is not approved to be used with anthracyclines. All individuals receiving trastuzumab should have their heart function assessed (ejection fraction) before starting treatment and must be carefully monitored during treatment.
Other side effects, which were more frequent with trastuzumab plus chemotherapy as compared to chemotherapy alone, include leukopenia, anemia, diarrhea, abdominal pain and infections. Side effects associated with Herceptin infusion are seen in about half of the individuals and include chills, fever, pain, weakness, nausea, vomiting and headache. Symptoms were much less likely to occur with subsequent infusions.
Trastuzumab will only benefit those individuals who have HER2/ErbB2 over expression and individual selection is critical. See policy #2007024 for discussion and coverage of HER2/ErbB2 testing.
Regulatory Status
Trastuzumab (e.g., Herceptin®) is a humanized monoclonal antibody against the extracellular domain of HER2. Trastuzumab has received FDA marketing approval for treatment of HER2-positive breast cancer in both the adjuvant and metastatic settings. 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.
In November 2006, trastuzumab received FDA marketing approval as part of a treatment regimen containing doxorubicin, cyclophosphamide, and paclitaxel (AC→P) for the adjuvant treatment of HER2-positive, node-positive early-stage breast cancer.
In January 2008, FDA granted marketing approval for trastuzumab as a single agent for the adjuvant treatment of early-stage HER2-positive node-positive breast cancer or node-negative (ER/PR-negative or with one high-risk feature) disease following multi-modality, anthracycline-based therapy. Trastuzumab also was approved to be administered as a single agent in an every-3-week dosing schedule for 1 year.
In May 2008, the FDA approved two new trastuzumab-containing regimens for the adjuvant treatment of early-stage HER2-positive node-positive or node-negative (ER/PR-negative or with one high-risk feature) breast cancer. The first regimen is in combination with docetaxel and carboplatin (also known as TCH for Taxotere®, carboplatin, and Herceptin®), which does not contain an anthracycline (doxorubicin) component. The second is part of a treatment regimen containing anthracycline (doxorubicin), cyclophosphamide, and docetaxel (AC-TH).
On June 8, 2012, Food and Drug Administration approved pertuzumab injection (e.g., Perjeta™, made by Genentech, Inc.) for use in combination with trastuzumab and docetaxel for the treatment of individuals with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. Pertuzumab is a recombinant humanized monoclonal antibody that targets the extracellular dimerization domain (subdomain II) of HER2 and thereby blocks ligand-dependent heterodimerization of HER2 with other HER family members, including EGFR, HER3, and HER4. Pertuzumab is being approved with a BOXED WARNING regarding embryo-fetal toxicity and birth defects, based on observations of oligohydramnios, delayed renal development and embryo-fetal death in animal studies. Individuals should be advised of these risks and the need for effective contraception prior to starting pertuzumab.
On 12/1/2017, U.S. Federal Drug Administration approved Trastuzumab-dkst(e.g., Ogivri), biosimilar to Trastuzumab (e.g., Herceptin) for the treatment individuals with breast or gastric cancer who have a positive HER2/ErbB2 test.
On December 14, 2018, the Food and Drug Administration approved biosimilar trastuzumab-pkrb (e.g., Herzuma) for adjuvant treatment of HER2-overexpressing node positive or node negative breast cancer and HER2-overexpressing metastatic breast cancer.
On January 18, 2019, the Food and Drug Administration approved biosimilar trastuzumab-dttb (e.g., Ontruzant) for adjuvant treatment of HER2-overexpressing node positive or node negative breast cancer, HER2-overexpressing metastatic breast cancer, and HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma.
On February 28, 2019, Food and Drug Administration approved Trastuzumab and Hyaluronidase-oysk (e.g., Herceptin Hylecta) injection, for subcutaneous use for the treatment of HER2-overexpressing breast cancer. Herceptin Hylecta is a combination of trastuzumab, a HER2/neu receptor antagonist, and hyaluronidase, an endoglycosidase, indicated in adults for the treatment of HER2-overexpressing breast cancer. Trastuzumab and Hyaluronidase-oysk is approved with a BOXED WARNING regarding cardiomyopathy, pulmonary toxicity, and embryo-fetal toxicity. Individuals should be advised of these risks and the need for effective contraception prior to starting Trastuzumab and Hyaluronidase-oysk .
On March 11, 2019, the Food and Drug Administration approved Trazimera, biosimilar to trastuzumab (e.g., Herceptin) for the treatment of HER2-overexpressing breast cancer, and HER2- overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma.
On May 16, 2019, the Food and Drug Administration approved biosimilar Trastuzumab-pkrb (e.g., Herzuma) for treatment of HER2-overexpressing metastatic gastric cancer or gastroesophageal junction adenocarcinoma.
On June 13, 2019, the Food and Drug Administration approved biosimilar trastuzumab-anns (e.g., Kanjinti) for adjuvant treatment of HER2-overexpressing node positive or node negative breast cancer, HER2-overexpressing metastatic breast cancer, and HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma.
Coding
See CPT/HCPCS Code section below.
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Policy/ Coverage: |
For members of plans that utilize a prescription drug program vendor (i.e., Arkansas State Employees and Public School Employees, Arkansas State Police and Arkansas State University) for preferred products under the medical benefit, the preferred products contained in this policy are NOT applicable. Please contact the member’s prescription drug program vendor.
Effective January 1, 2024, Prior Approval is required for trastuzumab.
The Step Therapy Medication Act is applicable to fully insured (Arkansas Blue Cross, Health Advantage, and Exchange) and specified governmental (ASE/PSE and ASP) health plans. The law is not applicable to FEP or self-insured ERISA groups (including but not limited to Walmart or other Blue Advantage groups). Initial approval for exigent request is 28 days. Otherwise, initial approval for standard review is up to 1 year.
Effective August 1, 2021, for members of plans that utilize an oncology benefits management program, Prior Approval is required for this service and is managed through the oncology benefits management program.
Effective April 17, 2024
TRASTUZUMAB (e.g., HERCEPTIN): BIOSIMILARS: TRASTUZUMAB-QYYP (E.G., TRAZIMERA), TRASTUZUMAB-DKST (E.G., OGIVRI), TRASTUZUMAB-PKRB (E.G., HERZUMA), TRASTUZUMAB-DTTP (E.G., ONTRUZANT), TRASTUZUMAB-ANNS (E.G., KANJINTI)
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Trastuzumab meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when the preferred product criteria and ALL the following clinical criteria are met:
PREFERRED PRODUCT CRITERIA
Select products (e.g., Ontruzant, Ogivri, and Kanjinti) are preferred where there is an FDA approved indication for the biosimilar product and for all off-label uses of the reference product. According to the United States FDA “a biosimilar is a biological product that has no clinically meaningful differences from the existing FDA-approved reference product. All biosimilar products meet the FDA’s rigorous standards for approval for the indications described in the product labeling. Once a biosimilar has been approved by the FDA, the safety and effectiveness of these products have been established, just as they have been for the reference product.”
Preferred Products:
HCPCS Brand Name Generic Name
Q5112 Ontruzant Trastuzumab dttb
Q5114 Ogivri Trastuzumab dkst
Q5117 Kanjinti Trastuzumab anna
Non-Preferred Products:
HCPCS Brand Name Generic Name
J9355 Herceptin Trastuzumab
J9356 Herceptin Hylecta Trastuzumab and hyaluronidase oysk
Q5113 Herzuma Trastuzumab pkrb
Q5116 Trazimera Trastuzumab qyyp
If the request is for a non-preferred product, one of the following criteria must be met for the non-preferred product to be covered:
CLINICAL CRITERIA
FDA Labeled Indications
For FDA labeled indications, all products must be dosed in accordance with the FDA label unless otherwise specified.
STANDARD REVIEW for up to 12 months:
Off Label Indications
For Off Label indications, authorizations will not exceed 8 mg/kg IV initially, then 6 mg/kg IV every 3 weeks unless medical literature supports a higher dose.
STANDARD REVIEW for up to 12 months:
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and administration
Dosing per FDA Guidelines where applicable. For Off Label indications, authorizations will not exceed 8 mg/kg IV initially, then 6 mg/kg IV every 3 weeks unless medical literature supports a higher dose.
Do not substitute trastuzumab and biosimilars (e.g., Herceptin, Herzuma, Kanjinti, Ogivri, Ontruzant, Trazimera) for or with ado-trastuzumab emtansine (e.g., Kadcyla) and fam-trastuzumab deruxtecan (e.g., Enhertu) due to different action of the derivative products. Substitution with trastuzumab and hyaluronidase-oysk (e.g., Herceptin Hylecta) requires dosing change.
Trastuzumab (e.g., Herceptin) and biosimilars
Trastuzumab is available as 150 mg lyophilized powder in a single-dose vial for reconstitution and 420 mg lyophilized powder in a multiple-dose vial for reconstitution.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
TRASTUZUMAB AND HYALURONIDASE-OYSK (E.G., HERCEPTIN HYLECTA™)
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Trastuzumab and Hyaluronidase-oysk meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when the preferred product criteria and ALL the following clinical criteria are met:
PREFERRED PRODUCT CRITERIA
Select products (e.g., Ontruzant, Ogivri, and Kanjinti) are preferred where there is an FDA approved indication for the biosimilar product and for all off-label uses of the reference product. According to the United States FDA “a biosimilar is a biological product that has no clinically meaningful differences from the existing FDA-approved reference product. All biosimilar products meet the FDA’s rigorous standards for approval for the indications described in the product labeling. Once a biosimilar has been approved by the FDA, the safety and effectiveness of these products have been established, just as they have been for the reference product.”
Preferred Products:
HCPCS Brand Name Generic Name
Q5112 Ontruzant Trastuzumab dttb
Q5114 Ogivri Trastuzumab dkst
Q5117 Kanjinti Trastuzumab anna
Non-Preferred Products:
HCPCS Brand Name Generic Name
J9355 Herceptin Trastuzumab
J9356 Herceptin Hylecta Trastuzumab and hyaluronidase oysk
Q5113 Herzuma Trastuzumab pkrb
Q5116 Trazimera Trastuzumab qyyp
If the request is for a non-preferred product, one of the following criteria must be met for the non-preferred product to be covered:
CLINICAL CRITERIA
FDA Labeled Indications:
Trastuzumab and Hyaluronidase-oysk (e.g., Herceptin Hylecta) may be substituted for intravenous trastuzumab and used as a single agent or in combination with other systemic therapies for breast cancer. (NCCN 2A)
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and administration
Dosing per FDA Guidelines
For subcutaneous use only. Trastuzumab and Hyaluronidase-oysk has different dosage and administration instructions than intravenous trastuzumab products.
Do not administer intravenously.
Do not substitute Trastuzumab and Hyaluronidase-oysk for or with ado-trastuzumab emtansine.
The recommended dose of Trastuzumab and Hyaluronidase-oysk is 600 mg/10,000 units (600 mg trastuzumab and 10,000 units hyaluronidase) administered subcutaneously over approximately 2-5 minutes once every three weeks.
Trastuzumab and hyaluronidase-oysk is available as 600 mg trastuzumab and 10,000 units hyaluronidase per 5 mL (120 mg/2,000 units per mL) solution in a single-dose vial.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Trastuzumab and Trastuzumab and Hyaluronidase-oysk, for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes including but not limited to:
For members with contracts without primary coverage criteria, Trastuzumab and Trastuzumab and Hyaluronidase-oysk, for any indication or circumstance not described above, is considered investigational for the treatment of:
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective January 1, 2024 to April 16, 2024
Select products (e.g., Ontruzant, Ogivri, and Kanjinti) are preferred where there is an FDA approved indication for the biosimilar product and for all off-label uses of the reference product. According to the United States FDA “a biosimilar is a biological product that has no clinically meaningful differences from the existing FDA-approved reference product. All biosimilar products meet the FDA’s rigorous standards for approval for the indications described in the product labeling. Once a biosimilar has been approved by the FDA, the safety and effectiveness of these products have been established, just as they have been for the reference product.”
Preferred Products:
HCPCS Brand Name Generic Name
Q5112 Ontruzant Trastuzumab dttb
Q5114 Ogivri Trastuzumab dkst
Q5117 Kanjinti Trastuzumab anna
Non-Preferred Products:
HCPCS Brand Name Generic Name
J9355 Herceptin Trastuzumab
J9356 Trastuzumab and hyaluronidase oysk
Q5113 Herzuma Trastuzumab pkrb
Q5116 Trazimera Trastuzumab qyyp
If the request is for a non-preferred product, one of the following criteria must be met for the non-preferred product to be covered:
Trastuzumab (e.g., Herceptin)
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
BREAST CANCER
Trastuzumab meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for individuals with breast cancer who have a positive HER2/ErbB2 test (immunohistochemistry test of 3+ or greater, or a positive appropriate in-situ hybridization) in the following individual populations:
CENTRAL NERVOUS SYSTEM CANCERS
COLON CANCER
GASTRIC CANCER
ESOPHAGEAL AND ESOPHAGOGASTRIC JUNCTION CANCER
HEAD AND NECK CANCER – SALIVARY GLAND TUMORS
RECTAL CANCER
UTERINE CANCER
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and administration
Dosing per FDA Guidelines
Trastuzumab is available as 150 mg lyophilized powder in a single-dose vial for reconstitution or 420 mg lyophilized powder in a multiple-dose vial for reconstitution.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Biosimilars
Trastuzumab-qyyp (e.g., Trazimera)
Trastuzumab-dkst (e.g., Ogivri)
Trastuzumab-pkrb (e.g., Herzuma)
Trastuzumab-dttp (e.g., Ontruzant)
Trastuzumab-anns (e.g., Kanjinti)
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Trastuzumab-qyyp (e.g., Trazimera), Trastuzumab-dkst (e.g., Ogivri), Trastuzumab-pkrb (e.g., Herzuma), Trastuzumab-dttp (e.g., Ontruzant), and Trastuzumab-anns (e.g., Kanjinti) meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following:
ADUJVANT BREAST CANCER
METASTATIC BREAST CANCER
METASTATIC GASTRIC CANCER
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and administration
Dosing per FDA Guidelines
Do not substitute Trazimera or Ogivri for or with ado-trastuzumab emtansine.
Trastuzumab-qyyp is available as 420 mg lyophilized powder in a multiple-dose vial for reconstitution.
Trastuzumab-dkst is available as 420 mg lyophilized powder in a multiple-dose vial for reconstitution.
Trastuzumab-pkrb is available as 150 mg lyophilized powder in a single-dose vial for reconstitution or 420 mg lyophilized in a multiple-dose vial for reconstitution.
Trastuzumab-dttb is available as 150 mg lyophilized powder in a single-dose vial for reconstitution or 420 mg lyophilized powder in a multiple-dose vial for reconstitution.
Trastuzumab-anns is available as 150 mg lyophilized powder in a single-dose vial for reconstitution or 420 mg lyophilized powder in a multiple-dose vial for reconstitution.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Trastuzumab and Hyaluronidase-oysk (e.g., Herceptin Hylecta™)
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Trastuzumab and Hyaluronidase-oysk meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for individuals with HER2-overexpressing breast cancer: (FDA 2019)
May be substituted for intravenous trastuzumab and used as a single agent or in combination with other systemic therapies for breast cancer. (NCCN 2A)
The use of this drug is covered if an FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and administration
Dosing per FDA Guidelines
Trastuzumab and hyaluronidase-oysk is available as 600 mg trastuzumab and 10,000 units hyaluronidase per 5 mL (120 mg/2,000 units per mL) solution in a single-dose vial.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Trastuzumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the treatment of:
For members with contracts without primary coverage criteria, Trastuzumab is considered investigational for the treatment of:
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Due to the detail of the policy statement, the document containing the coverage statements for dates prior to January 1, 2024 are not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com
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| Rationale: |
Trastuzumab was originally FDA approved September 25, 1998, for two indications, and this policy was initially developed in October 1998, for coverage in patients 1) with metastatic breast cancer whose tumors overexpress HER2 protein and who have received one or more chemotherapy regimens for their metastatic disease, and 2) in combination with paclitaxel in patients with metastatic breast cancer whose tumors overexpress HER2 protein and who have not received chemotherapy for their metastatic disease. The policy has been reviewed biennially or whenever new information is available. Some of the initial rationale has been removed for brevity.
2004 Update
A September 2004 review of the literature identified no new published clinical trials to alter the above conclusions. Several studies on trastuzumab plus docetaxel for metastatic breast cancer reported positive results in 2003 and 2004 (Pegram, 2004; Julka, 2004; Montemurro, 2004). An uncontrolled study was published on trastuzumab plus paclitaxel as neoadjuvant therapy for stage II or stage III breast cancer (Burstein, 2003). The authors of this study reported clinical responses in 75% and complete pathologic responses in 18% of the 40 patients evaluated.
2006 Update
Interim analyses from 3 large randomized trials of adjuvant trastuzumab were first reported at the 2005 annual meeting of the American Society of Clinical Oncology (ASCO). Presentations included a combined analysis of 2 trials sponsored by the National Cancer Institute (NSABP B-31 and NCCTG N9831), plus the international HERA trial. These interim analyses were subsequently published in peer-reviewed journals (Romond, 2005; Piccart-Gebhart, 2005), but final results are not yet available. Two other trials, reported elsewhere, include BCIRG 006, presented at a meeting but not yet published in full, and the FinHer trial (Joesuu, 2006), with the smallest sample (n=232) but longest follow-up (median, 36 months) among the 5 reports. In November 2006 the FDA added adjuvant therapy with AC--> paclitaxel plus trastuzumab as an approved indication for patients with HER2-overexpressing node-positive breast cancer, based on the combined interim analysis of NSABP B-31 and NCCTG N9831. The discussion below summarizes evidence from the 5 available trials on outcomes of off-label adjuvant trastuzumab: i.e., combined with regimens other than AC-->paclitaxel, or for node-negative breast cancer patients.
NSABP B-31 was a 2-arm trial that administered four 3-week cycles of doxorubicin plus cyclophosphamide (AC), followed by four 3-week cycles of paclitaxel. Half the patients were randomized to receive trastuzumab weekly for 1 year beginning with the first cycle of paclitaxel. The other half was followed with no additional therapy after 4 cycles of paclitaxel. NCCTG N9831 used the same AC regimen, gave paclitaxel on a slightly different schedule, but also for 12 weeks, with or without trastuzumab for 1 year, and included a third arm that did not start trastuzumab (also for 1 year) until after 12 weeks of paclitaxel. The combined analysis omitted this sequential arm. Final results for the comparison of concurrent versus sequential therapy are expected in mid-2007. Eligible patients in each trial had invasive breast cancer resected by mastectomy or lumpectomy plus axillary dissection, with pathologically clear margins, and without distant metastasis or locally advanced disease. In both trials, patients were required to have HER-2-positive tumors by fluorescence in-situ hybridization (FISH) or immunohistochemistry (IHC; 3+ score). Those previously exposed to anthracyclines or taxanes and those with current or prior cardiac disease were excluded. Initially, both trials were limited to node-positive patients, but N9831 was amended in May 2003 to include high-risk, node-negative disease (defined as tumors larger than 1 cm if estrogen receptor negative [ER-] or larger than 2 cm if ER+). This node-negative group (n=194) was 5.8% of patients in the pooled analysis and 12% of those randomized in N9831. While subgroup analyses demonstrated that trastuzumab significantly improved disease-free and overall survival for those with 1-3, 3-10, or >10 positive nodes, the sample size and number of events was inadequate to determine whether node-negative patients benefited from adjuvant trastuzumab. (Romond, 2004)
Interim results from the international HERA trial (5,081 patients treated at 478 centers in 39 countries) were published in 2005 (Piccart-Gebhart, 2005). Eligibility required completely resected, non-metastatic, HER2-positive primary breast cancer that was node-positive or 1 cm or larger if node-negative, and with known hormone receptor status. Patients were excluded for significant cardiac risk factors or measurable cardiac dysfunction. After completing all local therapy (surgery with or without radiation) and at least 4 cycles of an approved adjuvant chemotherapy regimen, patients were randomized to either observation (controls), 1 year, or 2 years of adjuvant trastuzumab given once every 3 weeks. The HERA trial is distinct since trastuzumab was given only after completion of all other adjuvant chemotherapy. Also, this study focused on the important issue of trastuzumab duration. However, results reported from the interim analysis compared only the patients given 1 year of trastuzumab (n=1,694) versus controls (n=1,693). The HERA trial will continue to follow up patients in the arms randomized to 1 year versus 2 years of trastuzumab, but patients in the control arm were offered trastuzumab off-study once interim results were available. Results comparing treatment durations are expected in 2008.
Patients enrolled in HERA were stratified at randomization by several characteristics, including nodal status and type of adjuvant chemotherapy received (Piccart-Gebhart, 2005). The trastuzumab and control arms included 543 (32.1%) and 557 (32.9%) node-negative patients, respectively, all with tumors >1 cm diameter. Subgroup analysis showed that 1 year of adjuvant trastuzumab significantly improved disease-free survival (DFS) of node-negative patients (hazard ration [HR] =0.51; 95% CI: 0.30, 0.87). Trastuzumab also significantly improved DFS among 358 patients with unknown nodal status who received neoadjuvant chemotherapy before resection (HR=0.53; 95% CI: 0.32, 0.88). The benefit for these subgroups was indistinguishable from the benefit for all patients randomized to 1 year of trastuzumab versus control (HR=0.54; 95% CI: 0.43, 0.67). The difference between arms in overall survival (OS) was not statistically significant in this interim analysis, and was not analyzed separately for any subgroups.
For most HERA patients (n=2,307), adjuvant chemotherapy included an anthracycline (doxorubicin or epirubicin) but not a taxane (paclitaxel or docetaxel) (Piccart-Gebhart, 2005). One year of adjuvant trastuzumab significantly improved DFS for these patients, whose adjuvant chemotherapy regimen differed from the AC paclitaxel regimen used in NSABP B-31 and NCCTG N9831 (HR=0.43; 95% CI: 0.32, 0.57). However, improved DFS was not statistically significant in this interim analysis for subgroups given adjuvant chemotherapy without an anthracycline (N=206; HR=0.63; 95% CI: 0.27, 1.47) or with both an anthracycline and a taxane (N=873; HR=0.77; 95% CI: 0.53, 1.13) as in B31 and N9831.
The BCIRG 006 trial randomized 3,222 patients to 1 of 3 arms: AC DOCetaxel without (controls) or with (arm 2) 1 year of trastuzumab started concurrently with docetaxel, or docetaxel plus carboplatin for 6 cycles plus 1 year of trastuzumab started concurrently (arm 3) (Slamon, 2005). Eligible patients had fully resected HER2-positive breast cancer that was either lymph-node positive or high-risk for recurrence if lymph node negative (29% of each arm), and were stratified by lymph node status (0, 1-3, or >=4). Those with significant cardiac risk factors or measurable cardiac dysfunction were excluded. At 23 months median follow-up, DFS in arm 2 (HR=0.49; 95% CI: 0.37, 0.65) and in arm 3 (HR=0.61; 95% CI: 0.47, 0.79) were superior to DFS in the control arm. The difference in DFS between arms 2 and 3 was not statistically significant. Subgroup analyses by nodal status were not presented. At the time of this interim analysis, the number of deaths was insufficient to compare arms for OS, a secondary outcome of the trial.
The FinHer trial randomized patients (n=1,010) with fully resected, lymph node positive or high risk (>20- mm diameter and progesterone-receptor negative) lymph-node negative breast cancer to three 21-day cycles of docetaxel or vinorelbine, each followed by fluorouracil, epirubicin, and cyclophosphamide (FEC) (Joensuu, 2006). Of these, 232 patients had an amplified HER2/ neu gene and were further randomized to receive or not receive trastuzumab for 9 weekly doses concurrent with docetaxel or vinorelbine (n=116 per group). Lymph nodes were negative in 10% of those randomized to trastuzumab and in 22% of HER2-positive controls. At a median follow-up of approximately 3 years, trastuzumab significantly improved recurrence-free survival (RFS, 89% vs. 78%; HR=0.42; 95% CI: 0.21. 0.83). Hazard ratios remained similar after adjustment for docetaxel versus vinorelbine chemotherapy (0.41; 95% CI: 0.21, 0.82), or for the number of positive nodes (HR=0.39; 95% CI: 0.20, 0.77).
In summary, 3 of 5 trials reported that trastuzumab improved DFS or RFS of breast cancer patients given adjuvant regimens other than AC-->T. In HERA, 1 year of trastuzumab increased DFS after adjuvant regimens that included an anthracycline but not a taxane. In BCIRG 006, 1 year of trastuzumab increased DFS after adjuvant regimens with docetaxel in place of paclitaxel, whether following AC or combined concurrently with carboplatin. In FinHer, 9 weeks of concurrent trastuzumab increased RFS after adjuvant regimens that began with docetaxel or vinorelbine monotherapy, then continued with FEC. Although only HERA reported that trastuzumab improved DFS in a subgroup with high-risk, node-negative disease, 3 other trials included similar patients and found better outcomes in the trastuzumab arm. While few patients were node negative in NCCTG N9831 and FinHer, 29% of each arm was node negative in BCIRG 006. Note that 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.
Each trial also excluded patients with significant cardiac risk factors or measurable cardiac dysfunction, since trastuzumab was associated with cardiac toxicity in earlier trials for patients with metastatic disease. However, the trials differed in the times at which they assessed cardiac function to exclude patients from trastuzumab. B31 and N9831 measured left ventricular ejection fraction (LVEF) before patients were randomized, and again after 12 weeks of AC. HERA measured LVEF after patients completed all local therapy (surgery with or without radiation) and adjuvant chemotherapy. The BCIRG 006 presentation did not report when LVEF was measured, while the FinHer trial measured LVEF between surgery and the start of adjuvant chemotherapy. Each trial with planned trastuzumab duration of at least 1 year monitored LVEF periodically and discontinued the antibody if LVEF fell below a protocol-specified threshold.
The effect of trastuzumab on incidence of New York Heart Association (NYHA) class III or IV congestive heart failure (CHF) or death varied in these trials (Romand, 2005; Piccart-Gebhart, 2005; Slamon 2005; Joensuu, 2006; Tan-Chiu, 2005; Winer, 2006). In NSABP B31, which published a separate report on cardiac toxicities (Tan-Chiu, 2005), trastuzumab increased the 3-year cumulative incidence of clinically significant cardiac events by an absolute 3.3% (0.8% in controls versus 4.1% in the trastuzumab arm; 95% CI for difference: 1.7%, 4.9%). While acknowledging problems with cross-trial comparisons (Winer, 2006), reviewers suggest three tentative conclusions. First, combining trastuzumab with a non-anthracycline containing adjuvant regimen apparently does not increase the risk of severe cardiac events (e.g., 0.3% in the carboplatin + docetaxel regimen in one arm of BCIRG 006). Second, sequential therapy with trastuzumab after an anthracycline followed by a taxane may be associated with less frequent severe cardiac events than concurrent therapy (2.4% in the concurrent arm of NCCTG N9831, compared with 1.4% in the sequential arm, and 0.5% in HERA which only gave trastuzumab after all adjuvant chemotherapy was completed). Third, concurrent trastuzumab plus a taxane after 4 cycles of AC varied from 1.5% with docetaxel (BCIRG 006) to 2.4% with weekly paclitaxel (N9831) and to 3.4% with paclitaxel every 3 weeks (B31). However, it is uncertain whether these outcome differences resulted from the regimens and schedules used, baseline risks of randomized patients, or from chance. Note also that the FinHer trial reported no NYHA class III or IV CHF. This study gave trastuzumab for only 9 weeks concurrent with docetaxel or vinorelbine, before patients received a combination regimen with an anthracycline (epirubicin in the FEC regimen).
2007 Update
A published update extended the initially reported results (Buzdar, 2005) from a randomized controlled trial (RCT) on benefits of adding trastuzumab to neoadjuvant chemotherapy (Buzdar, 2007). The study sequentially administered two neoadjuvant chemotherapy regimens followed by surgery to breast cancer patients with stage II to IIIA disease, and compared paclitaxel (four 3-week cycles) followed by fluorouracil, epirubicin, and cyclophosphamide (FEC; four 3-week cycles) with versus without trastuzumab. The trial originally targeted accrual of 164 patients, and had 80% power to detect an absolute improvement from 21% to 41% in pathologic complete response (pCR) rates when trastuzumab was added to each neoadjuvant regimen given sequentially. A data monitoring committee ended the trial after investigators randomized 42 patients, when a requested (but unplanned) analysis showed pCR rates of 25% in the arm without and 66.7% in the arm with trastuzumab. Approximately the same proportion of patients in each arm (52.6% without and 56.5% with trastuzumab) received breast-conserving surgery, but patient choice likely influenced these results.
The 2007 Buzdar report included longer follow-up for randomized patients, and additional nonrandomized patients. Results showed pCR in 26.3% (95% CI: 9% to 51%) of 19 patients randomized to neoadjuvant chemotherapy without trastuzumab, 65.2% (95% CI: 43% to 84%) of 23 patients randomized to the same neoadjuvant regimen plus trastuzumab, and 54.5% (95% CI: 32.2% to 75.6%) of 22 consecutive nonrandomized patients also given the same regimen plus trastuzumab. (Buzdar, 2007). At a median follow-up of 36.1 months for randomized patients, 3 in the chemotherapy-only arm experienced recurrence (one of whom died), and none in the arm with added trastuzumab.
Although few recurrences or deaths have occurred thus far in this terminated RCT, the 2-fold increase in pCR rate is unlikely to be a chance result. Analyses from RCTs (Fisher, 1998; Wolmark, 2001; Bear, 2006) showed that patients with pCR after neoadjuvant chemotherapy (determined postoperatively) had significantly longer overall, disease-free, and/or recurrence-free survival than those who did not achieve pCR. This also was true when those who achieved pCR were compared with those who achieved clinically complete responses but were subsequently shown by postoperative pathology to have residual (microscopic) invasive disease. Thus, improving pCR rate by adding trastuzumab to neoadjuvant chemotherapy for HER2 patients with high-risk, larger tumors predicts improved overall and disease-free survival.
Additional reasoning supports considering neoadjuvant trastuzumab medically necessary for HER2-positive patients undergoing neoadjuvant chemotherapy, even if the one available RCT did not show it increased the proportion of patients given breast-conserving surgery. When used to reduce risk of recurrence for patients with operable breast cancer, chemotherapy is either completed before surgery or not begun until after. Those given preoperative chemotherapy rarely receive additional chemotherapy after resection, unless their breast cancer recurs or progresses. Although hormone-receptor-positive patients given neoadjuvant chemotherapy are given tamoxifen or an aromatase inhibitor after resection, most HER2-positive patients are hormone-receptor negative and would not receive hormone therapy. Whether chemotherapy is used pre- or postoperatively, it is given for 18-24 weeks depending on the regimen, and trastuzumab currently is given for a full year. Trastuzumab administration was initiated concurrently with chemotherapy in most trials on adjuvant therapy.
2008 Update
The December 2008 San Antonio Breast Cancer Symposium included a paper from M.D. Anderson Hospital which reported worsened outcomes in women with HER-2-neu breast cancer in tumors of 1 cm or less in size. All previous trials all trials excluded patients with small (<1 cm) node-negative tumors. Hence, there is no evidence that adjuvant trastuzumab benefits this subgroup of HER2-positive patients, and current treatment guidelines do not recommend that the drug be given to women with HER2-positive tumors less than one-half centimeter in size. The guidelines also suggest only that doctors discuss Herceptin treatment with women who have tumors between one-half and one centimeter in size.
Researchers at the University of Texas M.D. Anderson Cancer Center reviewed data from 965 women treated from 1990 to 2002 who had tumors less than one centimeter in size. They also studied 350 patients from European institutions. They found that after five years, 23 percent of women with very small HER2-positive tumors experienced a return of the cancer, compared with 6 percent of similar women without HER2 disease. The finding indicates that even among women who detect their cancers early, the risk of recurrence is nearly three times greater if they test positive for HER2 than if they do not. None of the women in the study received Herceptin treatment.
Although the data on recurrence strongly suggest that women with early-stage HER2-positive cancer could benefit from aggressive treatment, the study did not examine the effectiveness of Herceptin in women with small tumors. Women with small but fast-growing tumors should be included in clinical trials comparing current practices with more aggressive treatment, said Dr. Ana M. Gonzalez-Angulo, an assistant professor at M.D. Anderson. The findings need to be tested in larger studies to see if women with small HER-2 tumors really are at greater risk, said Dr. Powel Brown of Baylor College of Medicine, Houston, TX. "The implication would be that they might benefit from treatment," but that wasn't tested in the Texas study, said Brown.
USE OF TRASTUZUMAB FOR DISEASES OTHER THAN BREAST CANCER
1999 Update
Trials are in progress on the use of trastuzumab in treating the following malignancies: non-small-cell lung, ovarian, prostate, head and neck, esophageal, gastric, pancreatic, and colorectal cancer. However, no results had yet been published.
2002 Update
A September 2002 literature review update did not identify any published reports that would change the conclusions of the TEC Assessment or the policy statement above.
Uncontrolled pilot studies reported preliminary results for outcomes of trastuzumab combined with chemotherapy for patients with advanced non-small-cell lung cancer (Azzoli, 2002; Zinner, 2002) and for advanced androgen dependent or androgen-independent prostate cancer (Small, 2001; Morris, 2002) that is positive for HER2 overexpression or amplification. However, results were unavailable from comparative trials.
2004 Update
Several studies reported low rates of HER2 overexpression for other cancers and poor results with trastuzumab treatment. A study of trastuzumab and docetaxel for HER-2/neu positive prostate cancer was closed as not feasible, since only 7 of 100 patients screened had 2+ or 3+ HER2 expression by immunohistochemistry, required for study eligibility (Lara, 2004). Another study reporting treatment with trastuzumab as a single agent demonstrated poor efficacy in 18 patients with advanced hormone-refractory prostate cancer (Ziada, 2004). A study to evaluate the use of trastuzumab in salivary gland cancer was closed early after it was found that the majority of salivary gland tumors did not overexpress HER2 (Haddad, 2003). In addition, a study of trastuzumab in patients with recurrent or refractory ovarian or primary peritoneal carcinoma found a low frequency of HER2 overexpression and a low rate of clinical response to treatment. The overall response rate of the 41 patients studied was 7.3% and included 1 complete and 2 partial responses (Bookman, 2003).
Three reports were identified from phase II trials of trastuzumab plus chemotherapy to treat non-small cell lung cancer (Zinner, 2004; Langer, 2004; Gatzemeier, 2004). Each of these studies reported that the addition of trastuzumab did not improve outcomes.
2006 Update
A November 2006 review of the literature identified no new published clinical trials to alter the conclusions or policy on trastuzumab for malignancies other than breast cancer. Only 4 new studies with 5 or more patients were reported; these are summarized below. Each lacked a comparison group managed without trastuzumab.
A randomized phase II comparison of docetaxel plus trastuzumab versus paclitaxel plus trastuzumab in chemotherapy-naive non-small cell lung cancer patients (n=65) reported no differences in objective response rates, median survival, or toxicity between arms (Krug, 2005). This study also reported no outcome differences between patients who tested positive versus negative for HER2 overexpression. Two uncontrolled small series were also reported on trastuzumab for metastatic transitional cell cancer of the bladder (n=7) or bladder and renal pelvis (n=6) (Salzberg, 2006; Peyromaure, 2005).
In November 2006, the National Cancer Institute’s database of clinical trials included no open phase III trials on the use of trastuzumab (alone or in combination) to treat malignancies other than breast cancer. Trials on breast cancer were comparing different chemotherapy regimens or different treatment durations, or were focused on neoadjuvant therapy. The 5 open phase II trials included 1 each on transitional cell bladder cancer (NCT00238420), endometrial cancer (NCT00006089), synovial sarcoma (NCT00104949), salivary gland carcinoma (NCT00126607), and ovarian cancer (NT00189579).
2007 Update
A November 2007 review of the literature identified no new published clinical trials to alter the conclusions or policy on trastuzumab for malignancies other than breast cancer. Two new reports were a phase II trial that treated 44 patients with HER2–positive, advanced urothelial carcinoma with a combination of trastuzumab, paclitaxel, carboplatin, and gemcitabine (Hussain, 2007). Thirty-one (70%) patients responded, including 5 complete and 26 partial responses. Median time to progression and survival were 9.3 and 14.1 months, respectively. However, the study lacked controls given the same chemotherapy without trastuzumab.
A second paper which described an uncontrolled phase I/II study of trastuzumab combined with paclitaxel, cisplatin and radiation for locally advanced, HER2 overexpressing esophageal cancer (Safran, 2007) found a median OS of 24 months, but no conclusions could be drawn from this study.
In November 2007, the National Cancer Institute’s database of clinical trials still included no open phase III trials on the use of trastuzumab (alone or in combination) to treat malignancies other than breast cancer. Only two open phase II trials were listed: one on transitional cell bladder cancer (NCT00238420) and one on gallbladder or bile duct cancer (NCT00478140).
As of November 2007, use of trastuzumab has not been addressed by any of the NCCN guidelines for malignancies other than breast cancer, including osteosarcoma or non-small-cell lung, ovarian, prostate, head and neck, esophageal, gastric, pancreatic, colon, rectal, endometrial, or urothelial cancers. Additionally, breast cancer is the only malignancy for which trastuzumab use is recommended in the NCCN Drugs and Biologics Compendium.
2009 Update
Gastric Carcinoma
HER-2 amplification occurs in 10%-20% of gastric adenocarcinomas (Marx, 2009). Kim at al. (2007) reported measurements of HER-2 expression by FISH and real-time q-PCR and of HER-2 protein by IHC were highly concordant at determining HER-2 status in gastric carcinoma.
An abstract by Van Cutsem et al. was presented at the 2009 ASCO Annual Meeting. This reported efficacy results from the ToGA trial. The preliminary results of this phase III randomized controlled trial comparing trastuzumab plus either capecitabine + cisplatin or 5FU + cisplatin versus either of the two chemotherapy regimens alone. There was a statistically significant overall survival response in the trastuzumab group. Based on this finding, and until a peer-reviewed paper is published, trastuzumab meets member certificate of benefit for treatment of adenocarcinoma of the stomach or gastroesophageal junction.
2010 Update
The final report of the “Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-esophageal junction cancer” trial was published in August 2010 (Bang YJ, et al). Central testing of tumors for 3,665 patients determined 22.1% of them were HER2 positive. 594 patients were randomized 1:1 at sites in Europe, Latin America and Asia (the patient’s region of origin was not stratified), and 584 patients received Herceptin and 5-fluorouracil or capecitabine and cisplatin (H+CT) or chemotherapy alone in an open-label trial sponsored by the manufacturer; the manufacturer was involved in the study design, data interpretation, and decision to submit the report for publication. The primary end-point was overall survival. High expression of HER2 protein was found in 446 of 584 tumors. Median OS for the trastuzumab group was 13.8 months versus 11.1 months for the chemotherapy alone group. Median PFS was 6.7 mos versus 5.5 mos. A post-hoc analysis divided patients into two large subgroups, with either high (immunohistochemistry testing of 2+ and FISH positive, or immunohistochemistry of 3+, n=446)) or low (immunochemistry 0 or 1+ and FISH positive, n = 131). The patients with the high levels of HER2 protein had an OS of 16 mos compared to 11.8 mos for the low HER2 protein level group. The number of patients receiving the capecitabine + cisplatin regimen versus 5FU plus cisplatin was not reported. A comment article which accompanied the report states, “Today’s study shows that the differences in outcomes when a targeted agent is combined with conventional treatment are, in absolute terms, small, even though with a modest added benefit. Such results are generally true for cetuximab in cancers of the head and neck, bevacizumab in colorectal cancer, trastuzumab in breast cancer, and now, for trastuzumab in tumors of the upper gastrointestinal tract. But the absolute benefits in ToGA are small; median survival was prolonged by 11 weeks and disease progression was delayed by a median of 5 weeks. Although improvement in overall survival for an individual patient (calculated from the difference in the areas under the overall survival curves) was about 3 months, the survival curves in today’s study do not indicate that the addition of trastuzumab saves lives. The longer-term survival rates in both groups were similar.” NCCN (Dec 2009) recommends trastuzumab plus chemotherapy for treatment of gastric adenocarcinoma or adenocarcinoma of the gastroesophageal junction.
Trastuzumab does not meet member certificate of benefit Primary Coverage Criteria for treatment of any malignancy other than 1) adenocarcinoma of the breast that is HER2 immunohistochemistry 2+ or greater, or is FISH +; and 2) adenocarcinoma of the stomach or gastroesophageal junction that is HER2 immunohistochemistry 2+ and FISH positive, or HER 2 immunohistochemistry 3+ or greater.
2011 Update
A literature search was conducted on the use of trastuzumab for the treatment of HER2-positive cancers. There was no literature identified that would support the use of trastuzumab for the treatment of any HER2-positive cancers other than breast and gastric/gastroesophageal cancers. In addition, there was a lack of evidence supporting the use of trastuzumab for periods longer than 12 months or for maintenance therapy. The coverage statement was revised to include a statement relating to use of trastuzumab for maintenance therapy.
2012 Update
On June 8, 2012, Food and Drug Administration approved pertuzumab injection (Perjeta™, made by Genentech, Inc.) for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease (FDA, 2012). The approval is based on a randomized double-blind placebo-controlled multicenter trial in patients with HER2-positive metastatic breast cancer. Breast tumor specimens were required to show HER2 overexpression, defined as 3+ IHC or FISH amplification ratio more than 2.0 using FDA-approved tests at a central laboratory. Patients with prior adjuvant or neoadjuvant therapy were required to have a disease-free interval of greater than 12 months before trial enrollment. The trial enrolled 808 patients who were randomly assigned (1:1) to receive pertuzumab in combination with trastuzumab and docetaxel (n=402) or placebo in combination with trastuzumab and docetaxel (n=406). A statistically significant 6.1-month improvement in median progression-free survival (PFS) was observed in patients in the pertuzumab group compared with patients in the placebo group.
A statement regarding the use of trastuzumab in combination with pertuzumab and docetaxel was added to the coverage statement.
Addendum to 2012 Update
According to the European Society for Medical Oncology (ESMO), updated results of the HERA study were reported at the ESMO 2012 Congress of the European Society for Medial Oncology in Vienna (www.ESMO.org). The updated results indicate that extending treatment with trastuzumab for 2 years does not improve outcomes over treatment for 1 year in women who have previously received treatment with surgery, chemotherapy or radiotherapy. These findings support our coverage statement.
2015 Update
A literature search conducted through February 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
Breast Cancer Metastatic
Balduzzi and colleagues included these and other trials in a Cochrane review of trastuzumab-containing regimens for metastatic breast cancer (Balduzziand, 2014). Overall methodologic quality was considered moderate; all trials were open-label, although this likely did not impact OS results, and 2 trials that permitted crossover to trastuzumab at progression did not censor OS results at the time of crossover. Trials varied in chemotherapy regimens and treatment line (ie, first- or subsequent-line in the metastatic setting). Median follow-up was 2 years. Meta-analyses favored trastuzumab-containing regimens for OS (5 trials, total N=1309; pooled HR for death, 0.82 [95% CI, 0.71 to 0.94], p=0.004; I2=0%) and for progression-free survival (7 trials, total N=1489; pooled HR for progression or disease-related death: 0.61 [95% CI, 0.54 to 0.70], p<0.001; I2=12%). Congestive heart failure (CHF) occurred more commonly with trastuzumab containing regimens (7 trials, total N=1459; pooled relative risk [RR], 3.49 [90% CI, 1.88 to 6.47]; p<0.001; I2=0%), although more than half of patients were in a single trial of anthracycline-containing regimens.
Sendur and colleagues retrospectively analyzed 271 patients with newly diagnosed HER2-positive breast cancer metastatic to axillary lymph nodes who were treated at 2 centers in Turkey with trastuzumab for 9 weeks (n=155) or 52 weeks (n=116) (Sendur, 2014). Overall, groups were similar in demographic characteristics, including comorbid disease, and tumor characteristics. However, in the 52-week group, more patients were younger than 50 years (63% vs 51% in the 9-week group), more patients were pre- or perimenopausal (70% vs 55%), and more patients received adjuvant anthracycline plus a taxane rather than either drug alone or other adjuvant chemotherapy (97% vs 89%). At median follow-up of 43 months in the 9-week group and 26 months in the 52-week group, estimated 1-, 3-, and 5-year DFS did not differ statistically between groups (97%, 85%, and 75%, respectively, in the 9-week group vs 94%, 80%, and 80%, respectively, in the 52-week group; log-rank test, p=0.76). Similarly, 1-, 3-, and 5-year OS did not differ statistically between groups (99%, 92%, and 88%, respectively, in the 9-week group vs 99%, 95%, and 78%, respectively, in the 52-week group; log-rank test, p=0.99). Due to baseline imbalances in prognostically relevant factors and differential follow-up, interpretation of these findings is limited. Asymptomatic decline in LVEF occurred in 2% of the 9-week group compared with 16% of the 52-week group; magnitude of LVEF declines was not reported. In 2015, this same group reported on a retrospective comparison of cardiac adverse events in patients with stage I-III breast cancer treated at the same 2 institutions in Turkey with adjuvant trastuzumab for 9 weeks (n=108) or 52 weeks (n=56) (Sendur, 2015). Groups differed in proportion of patients age 50 years or younger (60% in the 52-week group vs 34%), disease stage (stage 1: 5% vs 19%; stage III: 48% vs 33%), and adjuvant treatment received (anthracycline plus a taxane: 93% vs 63%; radiotherapy: 89% vs 69%). At median follow-up of 32 months, asymptomatic decline in LVEF (by 15% or more, or by more than 10% to below 50%) occurred in 2% and 30% of patients in the 9-week and 52-week groups, respectively (chi-square test, p<0.001). At median 24 months of follow-up from the last trastuzumab dose, mean (SD) LVEF was 64% (3) in both groups (t-test, p=0.29).
In 2014, de Azambuja and colleagues reported on cardiac AEs in the HERA trial at median 8 years of follow-up (de Azambuja, 2014). Incidence of severe CHF, defined as New York Heart Association class III or IV with significant decrease in LVEF, was 0.8% in both 1-year and 2-year trastuzumab groups. Although 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%; Wald test;p<0.001), more patients in the 2-year group achieved acute recovery, defined as 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) follow-up, approximately 35% of patients who achieved recovery in each group had a subsequent decline in LVEF to less than 50%. Like the previously reviewed Sendur and colleagues study, these results suggest that some effects of trastuzumab exposure on LVEF may be reversible after discontinuation of trastuzumab.
Neoadjuvant
In neoadjuvant therapy trials, patients continued trastuzumab after surgery to complete 1 year of treatment (Bonnefoi, 2014; Gianni, 2014). However, in a single-center, retrospective review (N=589), Gonzalez-Angulo and colleagues showed that, among patients who achieved pathologic CR after 24-weeks of trastuzumab-based neoadjuvant chemotherapy, adjuvant trastuzumab did not impact overall or recurrence-free survival (Gonzalez-Angulo, 2015). Prospective trials are needed to confirm this finding.
Bladder and Kidney Cancer
Oudard and colleagues in Europe conducted a phase 2, open-label, multicenter RCT of trastuzumab in patients with unresectable locally advanced (18%) or metastatic (82%) HER2-positive urothelial carcinoma (Oudard, 2015). HER2-positivity was defined as 2+ or 3+ on IHC confirmed by positive FISH. Of 563 patients screened, 61 were HER2-positive and met eligibility criteria. Most patients (89%) had urothelial carcinoma of the bladder, 5% had carcinoma of the renal pelvis, and 7% had carcinoma of the ureter. However, due to low enrollment, the trial was discontinued. Enrolled patients were randomized 1:1 to receive gemcitabine plus platinum chemotherapy with (n=32) or without (n=29) trastuzumab. Median duration of trastuzumab therapy was 10 months (range, 1-27); median number of chemotherapy cycles was 8 in the trastuzumab group and 6 in the chemotherapy-only group. There were no statistical differences in median PFS (the primary outcome; 8.2 [95% CI, 4.6 to 10.6] with trastuzumab vs 10.2 months [95% CI, 4.3 to 13.4] chemotherapy; log-rank test, p=0.69), ORR (53% with trastuzumab vs 66% chemotherapy; p=0.39), or median OS (14.1 months [95% CI, 9.3 to 28.0] with trastuzumab vs 15.7 [95% CI, 12.2 to 23.6] chemotherapy; log-rank test, p=0.684). Incidence of AEs was similar between groups.
Ongoing and Unpublished Clinical Trials
A search of online site ClinicalTrials.gov identified 37 active phase 3 trials using trastuzumab therapy Three phase 3 trials of trastuzumab for the treatment of malignancies other than breast cancer were identified.
American Society of Clinical Oncology
In 2014, ASCO published evidence-based guidelines on systemic therapy for patients with advanced
HER2-positive breast cancer (ACO, 2014).Trastuzumab is recommended in the first-line setting in combination with pertuzumab and a taxane, unless taxanes are contraindicated (strength of recommendation: strong; level of evidence: high); and in the second- or subsequent-line setting as an option in combination with chemotherapy with or without lapatinib in patients previously treated with trastuzumab, pertuzumab, or ado-trastuzumab emtansine (strength of recommendation: weak; level of evidence: insufficient (informal consensus).
2017 Update
A literature review conducted using the MEDLINE database did not reveal any new literature that would prompt a change in the coverage statement.
2018 Update
A literature review conducted using the MEDLINE database did not reveal any new literature that would prompt a change in the coverage statement.
2019 Update
A literature search conducted through March 2019 did not reveal any new information that would prompt a change in the coverage statement.
2019 Update (July)
Trastuzumab and Hyaluronidase-oysk (Herceptin Hylecta™)
The HannaH study (NCT00950300) was a randomized, multicenter, open-label, clinical trial in 596 patients with HER2-positive operable or locally advanced breast cancer (LABC), including inflammatory breast cancer. HER2positivity was defined as IHC 3+ or ISH+. Patients were randomized to receive 8 cycles of either HERCEPTIN HYLECTA or intravenous trastuzumab concurrently with chemotherapy (docetaxel followed by 5FU, epirubicin and cyclophosphamide), followed by surgery and continued therapy with HERCEPTIN HYLECTA or intravenous trastuzumab as treated prior to surgery, for an additional 10 cycles, to complete 18 cycles of therapy. HannaH demonstrated comparability between Herceptin Hylecta and intravenous trastuzumab based on co-primary endpoints of pathologic complete response and pharmacokinetics. Pathological complete response (pCR) was observed in 118 patients (45.4%) on the Herceptin Hylecta arm and in 107 patients (40.7%) receiving intravenous trastuzumab (95% CI for difference in pCR: -4.0; 13.4).
The SafeHER study (NCT01566721) was a prospective, two-cohort, non-randomized, multinational, open-label study designed to assess the overall safety and tolerability of HERCEPTIN HYLECTA with chemotherapy in 1864 patients with HER2-positive breast cancer. The secondary objectives include the evaluation of disease-free survival (DFS) and overall survival (OS). HER2-positivity was defined as IHC 3+ or ISH+. Patients received a fixed dose of 600 mg HERCEPTIN HYLECTA every 3 weeks for a total of 18 cycles throughout the study. HERCEPTIN HYLECTA treatment was initiated either sequentially with chemotherapy, concurrently with chemotherapy, or without adjuvant chemotherapy, or in combination
with neoadjuvant chemotherapy followed by trastuzumab therapy.
In the primary safety analysis, no new safety signals were identified for HERCEPTIN HYLECTA. Safety and tolerability results, including in lower weight patients, were consistent with the known safety profile for HERCEPTIN HYLECTA and intravenous trastuzumab.
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2020. No new literature was identified that would prompt a change in the coverage statement.
March 2021 Update
In an open-label, randomized controlled study, a treatment selection design in which a noninferiority criterion was predefined, patients aged 70-80 years with surgically treated human epidermal growth factor receptor 2-positive invasive breast cancer received trastuzumab monotherapy or trastuzumab + chemotherapy. The primary end point was disease-free survival (DFS) with assessment of prespecified hazard ratio (HR), relapse-free survival (RFS), adverse events (AEs), health-related quality of life (HRQoL), and restricted mean survival time (RMST).
The study involved 275 patients (mean age, 73.5 years) who were followed up for a mean of 4.1 years (range, 0.3-8.0 years). The percentages of patients by cancer stage were as follows: I (pT > 0.5 cm), 43.6%; IIA, 41.7%; IIB, 13.5%; and IIIA, 1.1%. Three-year DFS was 89.5% with trastuzumab monotherapy versus 93.8% with trastuzumab + chemotherapy (HR, 1.36; 95% CI, 0.72 to 2.58; P = .51). At 3 years, RMST differed by -0.39 months between arms (95% CI, -1.71 to 0.93; P = .56). Three-year RFS was 92.4% with trastuzumab monotherapy versus 95.3% with trastuzumab + chemotherapy (HR, 1.33; 95% CI, 0.63 to 2.79; P = .53). Common AEs were anorexia (7.4% v 44.3%; P < .0001) and alopecia (2.2% v 71.7%; P < .0001), and grade 3/4 nonhematologic AEs occurred in 11.9% versus 29.8% (P = .0003) for trastuzumab monotherapy versus trastuzumab + chemotherapy, respectively. Clinically meaningful HRQoL deterioration rate showed significant differences at 2 months (31% for trastuzumab monotherapy v 48% for trastuzumab + chemotherapy; P = .016) and at 1 year (19% v 38%; P = .009).
The primary objective of noninferiority for trastuzumab monotherapy was not met. However, the observed loss of survival without chemotherapy was < 1 month at 3 years. Therefore, and in light of the lower toxicity and more favorable HRQoL profile, trastuzumab monotherapy can be considered an adjuvant therapy option for selected older patients. (Sawaki M, Taira N, Uemura Y, et.al., 2020)
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2022. No new literature was identified that would prompt a change in the coverage statement.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2023. No new literature was identified that would prompt a change in the coverage statement.
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2024. No new literature was identified that would prompt a change in the coverage statement.
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