The efficacy of ENHERTU (fam-trastuzumab deruxtecan-nxki) was evaluated in study DESTINY-Breast01 (NCT03248492), a multicenter, single-arm, trial that enrolled 184 female patients with HER2-positive, unresectable and/or metastatic breast cancer who had received two or more prior anti-HER2 therapies. Patients were excluded for a history of treated ILD or current ILD at screening. Patients were also excluded for history of clinically significant cardiac disease, active brain metastases, and ECOG performance status >1. HER2 expression was based on archival tissue tested at a central laboratory prior to enrollment with HER2 positivity defined as HER2 IHC 3+ or ISH positive. Patients received ENHERTU (fam-trastuzumab deruxtecan-nxki) 5.4 mg/kg by intravenous infusion every 3 weeks until unacceptable toxicity or disease progression. Tumor imaging was obtained every 6 weeks and CT/MRI of the brain was mandatory for patients with brain metastases at baseline. The major efficacy outcomes were confirmed objective response rate (ORR) assessed by independent central review using RECIST v1.1 and duration of response (DOR). The median number of prior cancer regimens in the locally advanced/metastatic setting was 5 (range: 2-17). All patients received prior trastuzumab, ado-trastuzumab emtansine, and 66% had prior pertuzumab. 60.3% of patients observed a confirmed objective response rate of which 4.3% had a complete response and 56% had a partial response. The median duration of response was 14.8 months.

[INFORMATIONAL NOTES:
Trastuzumab (Herceptin) has the following BOXED WARNINGS::

• Cardiomyopathy – Herceptin can result in sub-clinical and clinical cardiac failure manifesting as CHF and decreased LVEF. The incidence and severity of left ventricular cardiac dysfunction was highest in patients who received Herceptin concurrently with anthracycline-containing chemotherapy regimens. Evaluate left ventricular function in all patients prior to and during treatment with Herceptin. Discontinue Herceptin treatment in patients receiving adjuvant therapy and strongly consider discontinuation of Herceptin treatment in patients with metastatic breast cancer for clinically significant decrease in left ventricular function.
• Infusion Reactions; Pulmonary Toxicity – Herceptin administration can result in serious infusion reactions and pulmonary toxicity. Fatal infusion reactions have been reported. In most cases, symptoms occurred during or within 24 hours of administration of Herceptin. Herceptin infusion should be interrupted for patients experiencing dyspnea or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve. Discontinue Herceptin for infusion reactions manifesting as anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome.
• Embryo-Fetal Toxicity - Exposure to trastuzumab during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death

• Do not substitute Kadcyla for or with trastuzumab
• Hepatoxicity, liver failure, and death have occurred in Kadcyla-treated patients. Monitor hepatic function prior to initiation and prior to each dose. Institute does modifications or permanently discontinue as appropriate
• Kadcyla may lead to reductions in left ventricular ejections fraction (LVEF). Assess LVEF prior to initiation. Monitor and withhold dosing or discontinue as appropriate.
• Can cause fetal harm. Advise women of potential risk to the fetus.

• Cardiomyopathy: trastuzumab products can result in subclinical and clinical cardiac failure manifesting as CHF, and decreased LVEF, with greatest risk when administered concurrently with anthracycline. Discontinue Ogivri for cardiomyopathy.
• Infusion Reactions, Pulmonary Toxicity: Discontinue Ogivri for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome.
• Embryo-Fetal Toxicity: Exposure to trastuzumab products during pregnancy can result in oligohydramnios, in some cases complicated by pulmonary hypoplasia and neonatal death. Advise patients of these risks and the need for effective contraception.]

• Cardiomyopathy: trastuzumab products can result in subclinical and clinical cardiac failure manifesting as CHF, and decreased LVEF, with greatest risk when administered concurrently with anthracycline. Evaluate cardiac function prior to and during treatment. Discontinue Herzuma for cardiomyopathy.
• Infusion Reactions, Pulmonary Toxicity: Discontinue Herzuma for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome.
• Embryo-Fetal Toxicity: Exposure to trastuzumab products during pregnancy can result in oligohydramnios, in some cases complicated by pulmonary hypoplasia and neonatal death. Advise patients of these risks and the need for effective contraception.

• Cardiomyopathy: trastuzumab products can result in subclinical and clinical cardiac failure manifesting as CHF, and decreased LVEF, with greatest risk when administered concurrently with anthracycline. Evaluate cardiac function prior to and during treatment. Discontinue Ontruzant for cardiomyopathy.
• Infusion Reactions, Pulmonary Toxicity: Discontinue Ontruzant for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome.
• Embryo-Fetal Toxicity: Exposure to trastuzumab products during pregnancy can result in oligohydramnios, in some cases complicated by pulmonary hypoplasia and neonatal death. Advise patients of these risks and the need for effective contraception.

• Cardiomyopathy: Herceptin Hylecta can result in subclinical and clinical cardiac failure manifesting as CHF, and decreased LVEF, with greatest risk when administered concurrently with anthracyclines. Evaluate cardiac function prior to and during treatment. Discontinue Herceptin Hylecta for cardiomyopathy.
• Infusion Reactions, Pulmonary Toxicity: Discontinue Herceptin Hylecta for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome.
• Embryo-Fetal Toxicity: Exposure to Herceptin Hylecta during pregnancy can result in oligohydramnios, in some cases complicated by pulmonary hypoplasia and neonatal death. Advise patients of these risks and the need for effective contraception.

• Cardiomyopathy: Trastuzumab products can result in subclinical and clinical cardiac failure manifesting as CHF, and decreased LVEF, with greatest risk when administered concurrently with anthracyclines. Evaluate cardiac function prior to and during treatment. Discontinue Trazimera (trastuzumab-qyyp) for cardiomyopathy
• Infusion Reactions, Pulmonary Toxicity: Discontinue Trazimera (trastuzumab-qyyp) for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome.
• Embryo-Fetal Toxicity: Exposure to trastuzumab products during pregnancy can result in oligohydramnios, in some cases complicated by pulmonary hypoplasia and neonatal death. Advise patients of these risks and the need for effective contraception

• Cardiomyopathy: Trastuzumab products can result in subclinical and clinical cardiac failure manifesting as CHF, and decreased LVEF, with greatest risk when administered concurrently with anthracyclines. Evaluate cardiac function prior to and during treatment. Discontinue Kanjinti (trastuzumab-anns) for cardiomyopathy
• Infusion Reactions, Pulmonary Toxicity: Discontinue Kanjinti (trastuzumab-anns) for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome.
• Embryo-Fetal Toxicity: Exposure to trastuzumab products during pregnancy can result in oligohydramnios, in some cases complicated by pulmonary hypoplasia and neonatal death. Advise patients of these risks and the need for effective contraception.

• Embryo-Fetal Toxicity: Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception.]

Pertuzumab is indicated in treatment for HER2-positive metastatic breast cancer, in combination with trastuzumab and docetaxel, who have not received prior anti-HER2 therapy or chemotherapy.

Regarding breast cancer, approximately 20% of all breast cancers have gene amplification or overexpression (or both) of HER2, resulting in a more aggressive phenotype and a poor prognosis. Pertuzumab prevents HER2 from dimerizing with other ligand-activated HER receptors like HER3.

Pertuzumab gained FDA approval, which was based on the CLEOPATRA Study Group, a phase III, randomized, double-blind trial, which looked the use of pertuzumab in junction with trastuzumab and docetaxel (pertuzumab group) versus placebo treatment with trastuzumab and docetaxel (control group). In order for patients to be eligible for the CLEOPATRA trial, they had to be 18 years or older, have a left ventricular ejection fraction (LVEF) of 50% or more at baseline, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1(with 0 stating that the patient is fully active and able to carry on pre-disease activities without restriction and 1indicating that the patient is restricted in physically strenuous active but is ambulatory and able to carry out work of a light or sedentary nature.

The results showed the medial progression-free survival was significantly improved in the pertuzumab group versus the control group (18.5 months vs. 12.4 months, respectively p < 0.001) with the hazard ratio of death, 0.62, a 95% CI of 0.75 vs. 0.51 respectively. The safety profile was generally similar in both groups with the main adverse effects cited as diarrhea, alopecia, neutropenia, nausea, fatigue, rash and peripheral neuropathy.

Pertuzumab also gained FDA approval on September 30, 2013 for neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer in combination with trastuzumab and docetaxel. This indication is based on demonstration of an improvement in pathological complete response rate in the phase II NEOSPHERE study, a randomized, open-label trial that compared safety and efficacy of trastuzumab plus docetaxel with combination of pertuzumab with either docetaxel or trastuzumab, or both in women with locally advanced, inflammatory, or early HER2-positive breast cancer. In order to be eligible for the NEOSPHERE trial, patients had to be 18 years or older, have a left ventricular ejection fraction (LVEF) of 55% or more at baseline, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (with 0 stating that the patient is fully active and able to carry on pre-disease activities without restriction and 1 indicating that the patient is restricted in physically strenuous active but is ambulatory and able to carry out work of a light or sedentary nature). Tumors had to be HER-2 immunohistochemistry 3+ or 2+ and positive for fluorescence or chromogenic in-situ hybridization. All eligible patient had centrally confirmed HER-2 positive, operable, locally advanced, or inflammatory breast cancer with primary tumors larger than 2 cm in diameter.

The results showed that pertuzumab and trastuzumab plus docetaxel had a significantly improved pathological complete response rate (49/107 patients, 45.8%, p=0.0141) compared with those given trastuzumab plus docetaxel (31/107 patients, 29.0%), pertuzumab plus docetaxel (23/96 patients, 24.0%), or pertuzumab plus trastuzumab (18/107 patients, 16.8%). The safety profile was similar between the four treatment arms, with the main adverse effects cited as neutropenia, febrile neutropenia, leukopenia and diarrhea.

Based on the immunohistochemical (IHC) assay, specimens are scored as 0, 1+, 2+ or 3+ (with 3+ indicating positive status) or fluorescence in situ hybridization (with an amplification ratio ≥ 2.0 indicating positive status). A level of 2+ or 3+ is considered positive for HER-2/neu overexpression. A ratio of HER2/CEP17 (chromosome enumeration probe) greater than or equal to 2 is considered FISH positive for HER-2/neu gene amplification.

Pertuzumab is marketed as Perjeta by Genentech, Inc., San Francisco, California, Pertuzumab was approved by the U.S. Food and Drug Administration (FDA) on June 8, 2012.

In December 2017, pertuzumab received FDA approval for adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence, in combination with trastuzumab and chemotherapy. The approval was based a multicenter, randomized, double-blind, placebo-controlled trial in 4804 patients with HER2-positive early breast cancer who had their primary tumor excised prior to randomization. Patients were then randomized to receive pertuzumab or placebo, in combination with adjuvant trastuzumab and chemotherapy. The main efficacy outcome was invasive disease-free survival (IDFS), defined as the time from randomization to first occurrence of ipsilateral local or regional invasive breast cancer recurrence, distant recurrence, contralateral invasive breast cancer, or death from any cause. The initial pertuzumab dose is 840 mg administered as a 60-minute intravenous infusion, followed every 3 weeks thereafter by 420 mg administered as a 30- to 60-minute intravenous infusion. After a median follow-up of 45.4 months, the proportion of IDFS events in the intent-to-treat population was 7.1% (n=171) in the pertuzumab arm and 8.7% (n=210) for those receiving placebo (HR 0.82; 95% CI: 0.67, 1.00; p=0.047). High-risk patients included patients such as those with hormone receptor negative or those with node positive breast cancer. The proportion of IDFS events in patients with hormone receptor negative disease was 8.2% (n=71) and 10.6% (n=91) in the pertuzumab and placebo arms, respectively (HR 0.76, 95% CI 0.56, 1.04). The proportion of IDFS events for patients with node positive disease was 9.2% (n=139) and 12.1% (n=181) in the pertuzumab and placebo arms, respectively (HR 0.77, 95% CI 0.62, 0.96).

Pertuzumab can cause fetal harm when administered to a pregnant woman (pregnancy category D). Decreases in LVEF have been reported with drugs that block HER2 activity and has been associated with infusion and hypersensitivity reactions.

[INFORMATIONAL NOTE: As per FDA-approved product labeling, pertuzumab (Perjeta) has the following BLACK BOX WARNING: Embryo-Fetal Toxicity - Exposure to pertuzumab during pregnancy can result in fetal harm. Cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death with use of another HER2/neu receptor antagonist (trastuzumab). 2. Left Ventricular Dysfunction: pertuzumab can result in subclinical and clinical cardiac failure manifesting as CHF, and decreased LVEF. Evaluate cardiac function prior to and during treatment. Discontinue pertuzumab treatment for a confirmed clinically significant decrease in left ventricular function.]


On June 29, 2020, the FDA approved a new fixed-dose combination of pertuzumab, trastuzumab, and hyaluronidase–zzxf (PHESGO, Genentech, Inc.) for subcutaneous injection for the following indications: 

• Use in combination with chemotherapy as: 
  • neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer;
  • adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence.
• Use in combination with docetaxel for treatment of patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

The safety profile of PHESGO is comparable to intravenous pertuzumab and trastuzumab, except for increased administration-related reactions.The most common adverse reactions in >30% patients receiving PHESGO were alopecia, nausea, diarrhea, anemia, and asthenia

The recommended initial dose of PHESGO is 1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase administered subcutaneously over approximately 8 minutes, followed every 3 weeks by a dose of 600 mg pertuzumab,
600 mg trastuzumab, and 20,000 units hyaluronidase administered subcutaneously over approximately 5 minutes. Phesgo contains a fixed-dose combination of pertuzumab and trastuzumab with hyaluronidase for injection under the skin. The therapeutic components in Phesgo are the same as those in FDA-approved intravenous (IV) pertuzumab and IV trastuzumab.

Prescribing information for Phesgo includes a boxed warning to advise health care professionals and patients about the risk of potential heart failure, fetal harm and lung toxicity. Health care professionals should use similar monitoring parameters as those used with IV pertuzumab and IV trastuzumab. Women who are pregnant should be advised that Phesgo may cause harm to a developing fetus or a newborn baby. The FDA advises health care professionals to inform females of reproductive age that exposure to Phesgo during pregnancy or within 7 months prior to conception can result in fetal harm.

[INFORMATIONAL NOTE: Pertuzumab, trastuzumab, and hyaluronidase-zzxf (PHESGO) has the following BOXED WARNINGS:

• Cardiomyopathy: PHESGO administration can result in subclinical and clinical cardiac failure manifesting as CHF, and decreased LVEF, with greatest risk when administered concurrently with anthracyclines. Evaluate cardiac function prior to and during treatment. Discontinue PHESGO for cardiomyopathy.
• Embryo-fetal Toxicity: Exposure to PHESGO can result in embryo-fetal death and birth defects. Advise patients of these risks and the need for effective contraception.
• Pulmonary Toxicity: Discontinue PHESGO for anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome.]

The requirements of the Horizon BCBSNJ Trastuzumab (Herceptin), Trastuzumab-dkst (Ogivri), Ado-trastuzumab emtansine (Kadcyla), Trastuzumab-pkrb (Herzuma), Trastuzumab-dttb (Ontruzant)Trastuzumab and Hyaluronidase-oysk (Herceptin Hylecta), trastuzumab-qyyp (Trazimera), trastuzumab-anns (Kanjinti), Fam-trastuzumab deruxtecan-nxki (Enhertu), Pertuzumab (Perjeta), and Pertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo) Program may require a precertification/prior authorization via MagellanRx Management. These requirements are member-specific: please verify member eligibility and requirements through the Horizon Provider Portal (www.horizonblue.com/provider). Ordering clinicians should request pre-certification from MagellanRx Management at ih.magellanrx.com or call 1-800-424-4508 (when applicable).

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

A. Trastuzumab (Herceptin), trastuzumab-dkst (Ogivri), trastuzumab-pkrb (Herzuma), trastuzumab-dttb (Ontruzant), trastuzumab-qyyp (Trazimera), and trastuzumab-anns (Kanjinti) therapy are medically necessary when ALL of the following criteria are met:

• Member is 18 years and older; AND
• Member's baseline left ventricular ejection fraction (LVEF) is within normal limit; AND
• If the request is for Herceptin, Herzuma, or Ontruzant, member have trial and failure, contraindication or allergy to Kanjinti, Trazimera, or Ogivri
• Member has one of the following diagnosis:
  • Adjuvant treatment of HER2 overexpressing node positive or node negative (ER/PR negative or with one high risk feature) breast cancer
    • As part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; (Herceptin, Ogivri, Herzuma, Ontruzant, Trazimera and Kanjinti) or
    • With docetaxel and carboplatin; (Herceptin, Ogivri, Herzuma, Ontruzant, Trazimera and Kanjinti) or
    • As a single agent following multi-modality anthracycline based therapy (Herceptin, Ogivri, Herzuma, Ontruzant, Trazimera, and Kanjinti)
  • Metastatic breast cancer
    • In combination with paclitaxel for first-line treatment of HER2-overexpressing metastatic breast cancer; (Herceptin, Ogivri, Herzuma, Ontruzant, Trazimera and Kanjinti) or
    • As a single agent for treatment of HER2-overexpressing breast cancer in patients who have received one or more chemotherapy regimens for metastatic disease (Herceptin, Ogivri, Herzuma, Ontruzant, Trazimera and Kanjinti).
  • Metastatic gastric cancer
    • In combination with cisplatin and capecitabine or 5- fluorouracil for the treatment of patients with HER2- overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma who have not received prior treatment for metastatic disease (Herceptin, Ogivri, Herzuma, Ontruzant, Trazimera and Kanjinti)
• The prescriber is a specialist in the area of the patient’s diagnosis (e.g. oncologist) or has consulted with a specialist in the area of the patient’s diagnosis
[INFORMATIONAL NOTES:

The P&T Committee at Horizon Blue Cross Blue Shield of New Jersey subjects each prescription drug being considered for formulary placement to a rigorous clinical analysis. Based on the clinical and effective analysis, the P&T Committee recommends the placement of commercially available biosimilar agents as preferred.

Select patients based on HER2 protein overexpression or HER2 gene amplification in tumor specimens. Assessment of HER2 protein overexpression and HER2 gene amplification should be performed using FDA-approved tests specific for breast or gastric cancers by laboratories with demonstrated proficiency. Information on the FDA-approved tests for the detection of HER2 protein overexpression and HER2 gene amplification is available at: http://www.fda.gov/CompanionDiagnostics.
Assessment of HER2 protein overexpression and HER2 gene amplification in metastatic gastric cancer should be performed using FDA-approved tests specifically for gastric cancers due to differences in gastric vs. breast histopathology, including incomplete membrane staining and more frequent heterogeneous expression of HER2 seen in gastric cancers.
Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results.
An immunohistochemical (IHC) assay level of 3+ is considered positive for HER2 protein overexpression. A fluorescence in-situ hybridization (FISH) assay is considered positive for HER2 gene amplification if the ratio of HER2/CEP17 (chromosome enumeration probe) is greater than 2.2.]
According to the National Comprehensive Cancer Network (NCCN), the optimal method of selecting the subset of patients most likely to benefit from trastuzumab is rapidly evolving. Currently, the NCCN Breast Cancer Panel recommends selecting patients for trastuzumab who have tumors either:
• Immunohistochemistry (IHC) assay 3+ ; OR
• Fluorescence in situ hybridization (FISH) assay ≥2.0 (HER2/CEP17 ratio); OR
• Average HER2 copy number ≥ 6 signals/cell]

• Adjuvant Treatment of HER2-Overexpressing Breast Cancer:
  • Initial dose of 4 mg/kg IV infusion, then 2 mg/kg IV infusion weekly for 12 weeks (with paclitaxel or docetaxel) or 18 weeks (with docetaxel/carboplatin). One week after the last weekly dose, administer 6 mg/kg as an IV infusion over 30−90 minutes every three weeks to complete a total of 52 weeks of therapy (Herceptin, Ogivri, Herzuma, Ontruzant, Trazimera, Kanjinti), or
  • Initial dose of 8 mg/kg IV infusion, then 6 mg/kg IV infusion every three weeks for 52 weeks (Herceptin, Ogivri, Herzuma, Ontruzant, Trazimera, and Kanjinti).
• Metastatic HER2-Overexpressing Breast Cancer:
  • Initial dose of 4 mg/kg IV infusion followed by subsequent weekly doses of 2 mg/kg IV infusions (Herceptin, Ogivri, Herzuma, Ontruzant, Trazimera, Kanjinti).
• Metastatic HER2-Overexpressing gastric or gastroesophageal junction adenocarcinoma
  • Initial dose of 8 mg/kg IV infusion followed by 6 mg/kg over IV infusion every 3 weeks (Herceptin, Ogivri, Herzuma, Ontruzant, Trazimera, and Kanjinti).
• Continuation of therapy will be approved if:
  • Member had a tumor response with stabilization of disease or decrease in tumor size or tumor spread; AND
  • Absence of unacceptable toxicity from the drug (e.g.: cardiomyopathy, infusion reactions, pulmonary toxicity [e.g., interstitial pneumonitis, respiratory distress syndrome, etc.], neutropenia); AND
  • Left ventricular ejection fraction (LVEF) has not had an absolute decrease16% or more from pre-treatment baseline and is within normal limits or has not had an absolute decrease of 10% or more from pre-treatment baseline and is below normal limits

A. Ado-trastuzumab emtansine (Kadcyla) is medically necessary for the following FDA approved indications when the following criteria are met:
• The prescriber is a specialist in the area of the patient’s diagnosis (e.g. oncologist) or has consulted with a specialist in the area of the patient’s diagnosis
a. As a single agent for the treatment of patients with HER2-positive metastatic breast cancer when ALL of the following criteria are met
• Member is 18 years or older; AND
• Member's baseline left ventricular ejection fraction is within normal limit; AND
• Member received prior therapy with trastuzumab and a taxane separately or in combination; AND
• Member received prior therapy for metastatic disease; or
• Member developed disease recurrence during or within six months of completing adjuvant therapy
b. As a single agent for the adjuvant treatment of patients with HER-2 positive early breast cancer when ALL of the following criteria are met:
· Member is 18 years or older, AND
· Member has histologically confirmed invasive breast cancer, AND
· Member does NOT have metastatic disease, AND
· Member has completed preoperative systemic chemotherapy and HER2-directed treatment, consisting of at least 6 cycles of chemotherapy with a total duration of at least 16 weeks, including at least 9 weeks of trastuzumab and at least 9 weeks of taxane-based therapy, AND
· Member has residual disease following completion of preoperative therapy, AND
· Member’s baseline left ventricular ejection fraction is within normal limit

• Tumor response with stabilization of disease or decrease in size of tumor; AND
• Absence of unacceptable toxicity from the drug. (e.g.: hepatotoxicity, left ventricular dysfunction, pulmonary toxicity (i.e. pneumonitis), thrombocytopenia, neurotoxicity, infusion-related and hypersensitivity reactions, hemorrhage); AND
• For the indication of metastatic breast cancer: Left ventricular ejection fraction (LVEF) is >45% OR LVEF is ≥40% and absolute decrease is <10% from baseline OR
• For the indication of early breast cancer:
  • Left ventricular ejection fraction (LVEF) is >50% or LVEF ≥45% and absolute decrease is <10% from baseline AND
  • Total duration of treatment does not exceed 14 cycles

D. Use of ado-trastuzumab emtansine (Kadcyla) is considered investigational for all other indications.

[INFORMATIONAL NOTES:
• As per the FDA approved package insert, platelet counts should be monitored with each dose due to risk of thrombocytopenia
• The following table was adopted from American Society of Clinical Oncology/College of American Pathologist Clinical Practice Guideline Focused Update from 2018.]

Summary of HER2 ISH Diagnostic Criteria
HER2 Positive		HER2 Negative
Dual Probe Assay
Group 1	Group 2 AND concurrent IHC 0-1+ or 2+
Group 2 AND concurrent IHC 3+	Group 3 AND concurrent IHC 0-1+
Group 3 AND concurrent IHC 2+ or 3+	Group 4 AND concurrent IHC 0-1+ or 2+
Group 4 AND concurrent IHC 3+	Group 5
Single Probe Assay
HER2 copy number ≥6.0 signals/cell		HER2 copy number <4.0 signals/cell
HER2 copy number ≥4.0 and <6.0 signals/cell AND concurrent IHC 3+		HER2 copy number ≥4.0 and <6.0 signals/cell AND concurrent IHC 0 or 1+
HER2 copy number ≥4.0 and <6.0 signals/cell AND concurrent dual probe Group 1		HER2 copy number ≥4.0 and <6.0 signals/cell AND concurrent dual probe Group 5

Group 1	Group 2	Group 3	Group 4	Group 5
Ratio ≥ 2.0 ≥4.0 signals/cell	Ratio ≥ 2.0 <4.0 signals/cell	Ratio <2.0 ≥6.0 signals/cell	Ratio < 2.0 ≥4.0 and <6.0 signals/cell	Ratio <2.0 <4.0 signals/cell

A. Trastuzumab and hyaluronidase-oysk (Herceptin Hylecta) is medically necessary for the treatment of patients with HER2-overexpressing breast cancer when ALL of the following criteria are met:
• Member is 18 years or older, AND
• Member’s baseline left ventricular ejection fraction is within normal limits, AND
  a. When used as an adjuvant treatment of HER2 overexpressing node positive or node negative (ER/PR negative or with one high risk feature) breast cancer, Herceptin Hylecta must be used
  • As a single agent following multi-modality anthracycline based therapy
  b. When used in metastatic breast cancer, Herceptin Hylecta must be used
  • As a single agent for in patients who have received one or more chemotherapy regimens for metastatic disease.
• The prescriber is a specialist in the area of the patient’s diagnosis (e.g. oncologist) or has consulted with a specialist in the area of the patient’s diagnosis
B. Trastuzumab and hyaluronidase-oysk (Herceptin Hylecta) is NOT medically necessary for the following:
a. When used as an adjuvant treatment of HER2 overexpressing node positive or node negative breast cancer, if used as ONE of the following:
· As part of a treatment regimen consisting of doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel, OR
· As part of a treatment regimen with docetaxel and carboplatin
b. When used in metastatic breast cancer, if used
· In combination with paclitaxel for first-line treatment

[INFORMATIONAL NOTE: – For combination use of Herceptin Hylecta, a member would be receiving an intravenous infusion for the other agent(s) and therefore Herceptin or a Herceptin biosimilar agent (IV) would be preferred over the SQ agent Herceptin Hylecta.]

C. Trastuzumab and hyaluronidase-oysk (Herceptin Hylecta) will be approved initially for 6 months and is subject to review on an annual basis thereafter at the FDA recommended dose of 600mg/10,000 units (600mg trastuzumab and 10,000 units hyaluronidase) administered subcutaneously over approximately 2-5 minutes once every three weeks.

[INFORMATIONAL NOTE:
• Assess left ventricular ejection fraction (LVEF) prior to initiation of Herceptin Hylecta and at regular intervals during treatment. Withhold Herceptin Hylecta dosing for at least 4 weeks for either of the following:
  • ≥16% absolute decrease in LVEF from pre-treatment values
  • LVEF below institutional limits of normal and ≥10% absolute decrease in LVEF from pretreatment values.
• Herceptin Hylecta may be resumed if, within 4−8 weeks, the LVEF returns to normal limits and the absolute decrease from baseline is ≤15%.
• Permanently discontinue Herceptin Hylecta for a persistent (>8 weeks) LVEF decline or for suspension of Herceptin Hylecta dosing on more than 3 occasions for cardiomyopathy)]

D. Trastuzumab and hyaluronidase-oysk (Herceptin Hylecta) is considered medically necessary for annual renewal if ALL of the following criteria are met:
• Tumor response with stabilization of disease or decrease in size of tumor; AND
• Absence of unacceptable toxicity from the drug. (e.g.: left ventricular dysfunction, pulmonary toxicity (i.e. pneumonitis), neutropenia, hypersensitivity reactions); AND
• LVEF has not had an absolute decrease ≥ 16% from baseline and is within normal limits or LVEF has not had an absolute decrease of ≥ 10% from baseline and is below normal limits, AND
• The member did not experience a persistent (> 8 weeks) decline in LVEF or suspension of Herceptin Hylecta dosing on more than 3 occasions for cardiomyopathy, AND
• Members with adjuvant breast cancer should be treated with Herceptin Hylecta for 52 weeks or until disease recurrence (whichever occurs first).
E. Trastuzumab and hyaluronidase-oysk (Herceptin Hylecta) is considered medically necessary for off-label indications that have in effect a rating of 'Category 1' or 'Category 2A' in the current recommendations in National Comprehensive Cancer Network (NCCN) compendium. Refer to National Comprehensive Cancer Network: Drugs and Biologics Compendium - trastuzumab and hyaluronidase-oysk. Available at: [https://www.nccn.org/professionals/drug_compendium/content/].
F. Use of trastuzumab and hyaluronidase-oysk (Herceptin Hylecta) is considered investigational for all other indications.

A. Fam-trastuzumab deruxtecan-nxki (ENHERTU) is medically necessary for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer when ALL of the following criteria are met:
• Member is 18 years or older, AND
• ECOG performance status of 0-1; AND
• Member’s baseline left ventricular ejection fraction is within normal limits, AND
• Member does not have a medical history of myocardial infarction, symptomatic congestive heart failure (CHF) (NYHA classes II-IV), unstable angina or serious cardiac arrhythmia; AND
• Member has received at least 2 prior anti-HER2-based regimens in the metastatic setting (including but not limited to trastuzumab, ado-trastuzumab emtansine, pertuzumab); AND
• Member does not have active brain metastases that is unstable and requires treatment
• The prescriber is a specialist in the area of the patient’s diagnosis (e.g. oncologist) or has consulted with a specialist in the area of the patient’s diagnosis
B. Fam-trastuzumab deruxtecan-nxki (ENHERTU) will be approved initially for 6 months and is subject to review on an annual basis thereafter at the FDA recommended dose of 5.4mg/kg administered intravenously once every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity.

[INFORMATIONAL NOTE: As per the FDA labeled package insert dosing section:

Table 1: Dose Reduction Schedule

Dose Reduction Schedule (Starting dose is 5.4 mg/kg.)	Dose to be administered
First dose reduction	4.4 mg/kg
Second dose reduction	3.2 mg/kg
Requirement for further dose reduction	Discontinue treatment

Refer to the FDA labeled package insert dosing section for the dose modifications for adverse reactions.]

C. Fam-trastuzumab deruxtecan-nxki (ENHERTU) is considered medically necessary for annual renewal if ALL of the following criteria are met:
· Tumor response with stabilization of disease or decrease in size of tumor; AND
· Absence of unacceptable toxicity from the drug. (e.g.: neutropenia, left ventricular dysfunction); AND
· Left ventricular ejection fraction (LVEF) is >45% OR LVEF is ≥40% and absolute decrease is <10% from baseline
D. Fam-trastuzumab deruxtecan-nxki (ENHERTU) is considered medically necessary for the following off-label indications:
• Breast Cancer
  • Single-agent therapy for recurrent or stage IV (M1) human epidermal growth factor receptor 2 (HER2)-positive disease, following two or more lines of prior HER2-targeted therapy that is
    • hormone receptor-negative
    • hormone receptor-positive

E. Use of Fam-trastuzumab deruxtecan-nxki (ENHERTU) is considered investigational for all other indications.

A. Prior to initiating Perjeta (pertuzumab), member needs to meet the following:
• Baseline measurement of 50% left ventricular ejection fraction (LVEF) prior to treatment
• Not pregnant due to the risk of embryo-fetal toxicity, including embryo-fetal death and birth defects
B. Perjeta (pertuzumab) is considered medically necessary for the FDA approved indication for:
• Treatment of adult members with human epidermal growth factor receptor 2 (HER2) positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease and to be used in combination with trastuzumab and docetaxel.
• Neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer in combination with trastuzumab and chemotherapy
• Adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence in combination with trastuzumab and chemotherapy
C. Perjeta (pertuzumab) is medically necessary at the FDA approved doses initially for 6 months in combination with trastuzumab and docetaxel or chemotherapy:
• Metastatic Breast Cancer:
  • Pertuzumab - 840 mg administered as a 60-minute intravenous (IV) infusion, followed every 3 weeks thereafter by a dose of 420 mg administered as an IV infusion over 30 to 60 minutes,
  • Trastuzumab - 8 mg/kg administered as a 90-minute IV infusion, followed every 3 weeks thereafter by a dose of 6 mg/kg administered as an IV infusion over 30 to 90 minutes, and
  • Docetaxel 75 mg/m² administered as an IV infusion and the dose may be escalated to 100 mg/m² administered every 3 weeks if the initial dose is well tolerated.
• Neoadjuvant Treatment of Breast Cancer
  • Pertuzumab - 840 mg administered as a 60-minute intravenous (IV) infusion, followed every 3 weeks for 3 to 6 cycles, as part of one of the following treatment regimens for early breast cancer, by a dose of 420 mg administered as an IV infusion over 30 to 60 minutes:
    • Four preoperative cycles of pertuzumab in combination with trastuzumab and docetaxel followed by 3 postoperative cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC)
    • Three or four preoperative cycles of FEC alone followed by 3 or 4 preoperative cycles of pertuzumab in combination with docetaxel and trastuzumab
    • Six preoperative cycles of pertuzumab in combination with docetaxel, carboplatin, and trastuzumab (TCH) (escalation of docetaxel above 75 mg/m2 is not recommended)
    • Four preoperative cycles of dose-dense doxorubicin and cyclophosphamide (ddAC) alone followed by 4 preoperative cycles of Pertuzumab in combination with paclitaxel and trastuzumab
  • Following surgery, patients should continue to receive pertuzumab and trastuzumab to complete 1 year of treatment (up to 18 cycles)
  • Trastuzumab - 8 mg/kg administered as a 90-minute IV infusion, followed every 3 weeks thereafter by a dose of 6 mg/kg administered as an IV infusion over 30 to 90 minutes
• Adjuvant Treatment of Breast Cancer
  • Pertuzumab - 840 mg administered as a 60-minute intravenous (IV) infusion, followed every 3 weeks thereafter up to 18 cycles by a dose of 420 mg administered as an IV infusion over 30 to 60 minutes, as part of a complete regimen for early breast cancer, including standard anthracyclineand/or taxane-based chemotherapy
  • Trastuzumab - 8 mg/kg administered as a 90-minute IV infusion, followed every 3 weeks thereafter by a dose of 6 mg/kg administered as an IV infusion over 30 to 90 minutes
[INFORMATIONAL NOTE:
As per the FDA approved package insert, dose reductions of pertuzumab are not recommended. Pertuzumab caused fetotoxicity in animal studies. Pregnancy status should be verified in women of child-bearing age before initiating pertuzumab. Effective contraception should be used before and during pertuzumab therapy. Pertuzumab should be withheld or discontinued if trastuzumab treatment is withheld or discontinued. If docetaxel is discontinued, treatment with pertuzumab and trastuzumab may continue.
As per the FDA approved package insert, pertuzumab, trastuzumab, and taxane should be administered sequentially. Pertuzumab and trastuzumab can be given in any order. Taxane should be administered after Pertuzumab and trastuzumab. An observation period of 30 to 60 minutes is recommended after each Pertuzumab infusion and before commencement of any subsequent infusion of trastuzumab or taxane. In patients receiving an anthracycline-based regimen, Pertuzumab and trastuzumab should be administered following completion of the anthracycline. ]
D. Perjeta (pertuzumab) is medically necessary for continued therapy annually for the treatment of metastatic breast cancer if:
• Patient continues to meet the initial review criteria; AND
• Tumor response with stabilization of disease or decrease in size of tumor or tumor spread; AND
• Absence of unacceptable toxicity from the drug (e.g.: hypersensitivity reactions, anaphylaxis, cardiotoxicity and infusion related-reactions); AND
• Either of the following:
  • Patients maintains an ejection fraction of > 45% OR
  • Patient has a LVEF of 40-45% with < 10% absolute decrease from pre-treatment values
E. Perjeta (pertuzumab) is considered medically necessary for off-label indications that have in effect a rating of ‘Category 1’ or ‘Category 2A’ in the current recommendations in the National Comprehensive Cancer Network (NCCN) compendium. Refer to National Comprehensive Cancer Network: Drugs and Biologics Compendium - pertuzumab. Available at: https://www.nccn.org/professionals/drug_compendium/content/.
F. Other uses of Perjeta (pertuzumab) are considered investigational.

A. Pertuzumab, trastuzumab and hyaluronidase-zzxf (Phesgo) is medically necessary for the treatment of patients with HER2-positive breast cancer when ALL of the following criteria are met:
• Member is 18 years or older, AND
• Member’s baseline left ventricular ejection fraction is ≥ 55% for early breast cancer indication or ≥ 50% for metastatic breast cancer and for patients who received anthracycline-based chemotherapy before starting the requested agent, AND
• The prescriber is a specialist in the area of the patient’s diagnosis (e.g. oncologist) or has consulted with a specialist in the area of the patient’s diagnosis, AND
• The requested drug is indicated for one of the following FDA labeled indications:
  • Use in combination with chemotherapy as: 
    • neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer;
    • adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence.
  • Use in combination with docetaxel for treatment of patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.
B. Pertuzumab, trastuzumab and hyaluronidase-zzxf (Phesgo) will be approved initially for 6 months and is subject to review on an annual basis thereafter at the FDA recommended doses:
• The initial dose of PHESGO is 1,200 mg pertuzumab, 600 mg trastuzumab, and 30,000 units hyaluronidase administered subcutaneously over approximately 8 minutes, followed every 3 weeks by a dose of 600 mg pertuzumab, 600 mg trastuzumab, and 20,000 units hyaluronidase administered subcutaneously over approximately 5 minutes. (
• Neoadjuvant: administer PHESGO by subcutaneous injection every 3 weeks and chemotherapy by intravenous infusion preoperatively for 3 to 6 cycles.
• Adjuvant: administer PHESGO by subcutaneous injection every 3 weeks and chemotherapy by intravenous infusion postoperatively for a total of 1 year (up to 18 cycles).
• Metastatic breast cancer: administer PHESGO by subcutaneous injection and docetaxel by intravenous infusion every 3 weeks.

C. Pertuzumab, trastuzumab and hyaluronidase-zzxf (Phesgo) is considered medically necessary for annual renewal if ALL of the following criteria are met:
• Tumor response with stabilization of disease or decrease in size of tumor; AND
• Absence of unacceptable toxicity from the drug. (e.g.: left ventricular dysfunction, neutropenia, hypersensitivity reactions); AND
• For early breast cancer: LVEF has not decreased to <50% with a fall of ≥10%-points below pre-treatment value; OR
• For metastatic breast cancer: either LVEF has not decreased <40% or decreased to 40%-45% with a fall of ≥ 10%-points below pre-treatment value
D. Use of Pertuzumab, trastuzumab and hyaluronidase-zzxf (Phesgo) is considered investigational for all other indications.

For Drugs Administered Subcutaneously

Per Local Coverage Article A53127, Drugs ADMINISTERED subcutaneously are considered to be usually SELF-ADMINISTERED. If a drug is SELF-ADMINISTERED by more than 50 percent of Medicare beneficiaries, the drug is excluded from coverage under Medicare Part B.

Per Local Coverage Article A53127 Self-Administered Drug Exclusion List, Medicare covers drugs that are furnished “incident to” a physician’s service provided that the drugs are medically reasonable and necessary, approved by the Food and Drug Administration (FDA) and are not usually administered by the patients who take them.

For members with a Medicare drug plan (Part D), self-administered drugs may be covered under that plan.
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Trastuzumab
Herceptin
HercepTest
Inform
PathVysion
Pathway
Ado-trastuzumab emtansine
Kadcyla
Trastuzumab-dkst
Ogivri
Trastuzumab-pkrb
Herzuma
Trastuzumab-dttb
Ontruzant
Trastuzumab and hyaluronidase-oysk
Herceptin Hylecta
Trastuzumab-qyyp
Trazimera
Trastuzumab-anns
Kanjinti
Fam-trastuzumab deruxtecan-nxki
Enhertu
Perjeta
Pertuzumab
Breast Cancer, Pertuzumab (Perjeta) for
HER2 Positive Breast Cancer, Pertuzumab (Perjeta) for
Pertuzumab, trastuzumab and hyaluronidase-zzxf
Phsego

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27. Leyland-Jones B. Trastuzumab: hopes and realities. Lancet Oncol 2002; 3(3):137-44.

28. Lewis R, Bagnall AM, Forbes C et al. The clinical effectiveness of trastuzumab for breast cancer: a systematic review. Health Technol Assess 2002; 6(13):1-71.

29. Thomssen C. Trials of new combinations of Herceptin in metastatic breast cancer. Anticancer Drugs 2001; 12 (Suppl 4):S19-25.

30. McKeage K, Perry CM. Trastuzumab: a review of its use in the treatment of metastatic breast cancer overexpressing HER2. Drugs 2002; 62(1):209-43.

31. Leyland-Jones B, Smith I. Role of Herceptin in primary breast cancer: views from North America and Europe. Oncology 2001; 61(Suppl 2):83-91.

32. Smith I. Future directions in the adjuvant treatment of breast cancer: the role of trastuzumab. Ann Oncol 2001; 12(Suppl 1):S75-9.

33. Piccart-Gebhart MJ. Herceptin: the future in adjuvant breast cancer therapy. Anticancer Drugs 2001; 12(Suppl 4):S27-33.

34. Hortobagyi GN, Perez EA. Integration of trastuzumab into adjuvant systemic therapy of breast cancer: ongoing and planned clinical trials. Semin Oncol 2001; 28(5 Suppl 16):41-6.

35. Azzoli CG, Krug LM, Miller VA et al. Trastuzumab in the treatment of non-small cell lung cancer. Semin Oncol 2002; 29(1 Suppl 4):59-65.

36. Zinner RG, Kim J, Herbst RS. Non-small cell lung cancer clinical trials with trastuzumab: their foundation and preliminary results. Lung Cancer 2002; 37(1):17-27.

37. Small EJ, Bok R, Reese DM et al. Docetaxel, estramustine, plus trastuzumab in patients with metastatic androgen-independent prostate cancer. Semin Oncol 2001; 28(4 Suppl 15):71-6.

38. Morris MJ, Reuter VE, Kelly WK et al. HER-2 profiling and targeting in prostate carcinoma. Cancer 2002; 94(4):980-6.

39. ECRI. Windows on Medical Technology. HER2/NEU Testing of Breast Tumors to Predict Tumor Recurrence and Response to Chemotherapy. Issue No. 103. November 2003.

40. ECRI. Windows on Medical Technology. Testing for HER2/Neu Status in Breast Cancer. Issue No. 94. May 2003.

41. Thomson/Micromedex: USP DI: Herceptin. 2006. [Available at http://www.thomsonhc.com/home/dispatch]

42. Herceptin (trastuzumab) [Package Insert]. Genentech, Inc. San Francisco, CA. November 2018.
43. U.S. Food and Drug Administration. CDRH Consumer Information: New Device Approval for DakoCytomation Her2 FISH pharmDx™ Kit – p040005. http://www.fda.gov/cdrh/mda/docs/p040005.html (Accessed 1/7/09)

44. U.S. Food and Drug Administration. DakoCytomation Her2 FISH pharmDx™ Kit Labeling http://www.fda.gov/cdrh/pdf4/p040005c.pdf (Accessed 1/7/09)

45. U.S. Food and Drug Administration. CDRH Consumer Information: New Device Approval for Invitrogen SPOT-Light® HER2 CISH™ Kit – p050040. http://www.fda.gov/cdrh/mda/docs/P050040.html (Accessed 1/7/09)

46. U.S. Food and Drug Administration. Invitrogen SPOT-Light® HER2 CISH™ Kit Labeling http://www.fda.gov/cdrh/pdf5/p050040c.pdf (Accessed 1/7/09)

47. NCCN Drugs and Biologics Compendium™. Trastuzumab. [Available at: http://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=102 ][ Accessed January 31, 2020.]

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49. Van Cutsem E, Kang Y, Chung L, et al. Efficacy results from the ToGA trial: A phase III study of trastuzumab added to standard chemotherapy in first line human epidermal growth factor receptor 2 (HER-2)- positive advanced gastric cancer. J Clin Oncol 27: 18s, 2009.

50. Kadcyla (ado-trastuzumab emtansine) Prescribing Information. Genentech, Inc. San Francisco, CA. May 2019.

51. NCCN Drugs and Biologics Compendium™. Ado-trastuzumab emtansine. [Available at: http://www.nccn.org/professionals/drug_compendium/MatrixGenerator/Matrix.aspx?AID=399][ Accessed January 10, 2020.]

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54. Ogivri. Clinical Pharmacology [Internet]. Tampa (FL): Elsevier. c2018- [cited 2019 January 4]. Available from: http://www.clinicalpharmacology.com

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56. Herzuma (trastuzumab-pkrb) [Package Insert]. Teva Pharmaceuticals. Petah TIkva, Israel. May 2019.

57. Ontruzant (trastuzumab-dttb) [package insert] Merck. Kenilworth NJ. January 2019.

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60. Trazimera (trastuzumab-qyyp) [prescribing information]. Pfizer Inc. New York, NY. 03/2019.

61. Kanjinti (trastuzumab-anns) [prescribing information]. Amgen Inc. Thousand Oaks, CA. 6/2019.

62. Enhertu (fam-trastuzumab deruxtecan-nxki). [prescribing information]. Daiichi Sankyo, Inc. Basking Ridge, NJ. 12/2019.

63. Clinicaltrials.gov. DS-8201a in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer [DESTINY-Breast01]. NCT03248492. Available at: https://clinicaltrials.gov/ct2/show/NCT03248492

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67. NCCN Drugs and Biologics Compendium™. Trastuzumab-pkrb. [Available at: https://www.nccn.org/professionals/drug_compendium/content/] Accessed: January 10, 2020.

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76. Gianni L, Pienkowski T, Im YH et al. Effi cacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory or early HER2-positive breast cancer (NeoSphere):a randomised multicentre, open-label, phase 2 trial. Lancet Oncol 2012; 13: 25–32

77. Schneeweiss A, Chia S, Hickish T et al. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Annals of Oncology;24: 2278–2284, 2013

78. US Food and Drug Administration: Press Release. FDA grants regular approval to pertuzumab for adjuvant treatment of HER2-positive breast cancer. December 2017. Available at: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm590005.htm. Accessed January 2018.

79. Von minckwitz G, Procter M, De azambuja E, et al. Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer. N Engl J Med. 2017.

80. Genentech: A Member of the Roche Group. Press Release. FDA Approves Genentech’s Perjeta (Pertuzumab) for Adjuvant Treatment of Specific Type of Early Breast Cancer. December 2017. Available at: https://www.gene.com/media/press-releases/14703/2017-12-20/fda-approves-genentechs-perjeta-pertuzum. Accessed January 2018.

81. ClinicalTrials.gov. Perjeta Available from: https://clinicaltrials.gov/ct2/results?cond=&term=perjeta&cntry=&state=&city=&dist=

82. Pertuzumab, trastuzumab and hyaluronidase-zzxf (Phesgo) [package insert]. Genentech, Inc. South San Francisco, CA. June 2020.

83. FDA approves combination of pertuzumab, trastuzumab, and hyaluronidase-zzxf for HER2-positive breast cancer. U.S. Food & Drug Administration - Drug Approvals and Databases. June 29, 2020. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-combination-pertuzumab-trastuzumab-and-hyaluronidase-zzxf-her2-positive-breast-cancer




Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*
96413

96415
96417

HCPCS
J9354
J9355
J9356
Q5112
Q5113
Q5114
Q5116
Q5117
J9306
J9358

* CPT only copyright 2020 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.