ONTRUZANT®

(trastuzumab-dttb) for injection,
for intravenous use 21 mg/mL

Biosimilar Data

Clinical efficacy

A head-to-head, comparative-equivalence clinical study supported equivalent clinical efficacy with Herceptin (trastuzumab)1

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Study design2

To support biosimilarity to Herceptin, ONTRUZANT was evaluated in the largest clinical trial among biosimilars1,2


Approval of ONTRUZANT is based on the rigorous evaluation of the “totality of evidence,” which included structural, functional, and clinical data.

Approval of ONTRUZANT® (trastuzumab-dttb) Is Based on the Rigorous Evaluation of the "Totality of Evidence" Which Included Structural, Functional, and Clinical Data.

European Union (EU)–sourced Herceptin was used for the purpose of this study.1

Definitions

EBC = early breast cancer
FEC = fluorouracil, epirubacin, and cyclophosphamide
HER2+ = HER2-positive
HER2 = human epidermal growth factor receptor 2
LABC = locally advanced breast cancer
LVEF = left ventricular ejection fraction

Key inclusion criteria1:

  • Female, aged 18–65 years
  • Eastern Cooperative Oncology Group performance status of 0 or 1
  • Nonmetastatic, unilateral, primary breast cancer
  • Stage II to III, including inflammatory breast cancer
  • Tumor size ≥2 cm
  • Primary invasive adenocarcinoma of the breast
  • HER2 positive
  • LVEF ≥55%

Key exclusion criteria3:

  • Metastatic (stage IV) or bilateral breast cancer or 2 clinically detectable separate masses
  • History of any prior invasive breast carcinomaf
  • Past or current history of malignant neoplasms within 5 years of randomizationg
  • Pregnant or lactating women
  • Concurrent hormonal therapy
  • Previous history of radiation therapy, immunotherapy, chemotherapy, or biotherapy
  • Major surgery within 4 weeks of randomization
  • Minor surgery within 2 weeks of randomization
  • Serious cardiac, pulmonary, or other illness or infection
  • Abnormal laboratory tests

aA common dosing schedule was used in the ONTRUZANT and Herceptin arms.1
bDocetaxel 75 mg/m2.1
cFluorouracil 500 mg/m2, epirubicin 75 mg/m2, and cyclophosphamide 500 mg/m2.1
dEuropean Union (EU)–sourced Herceptin was used for the purposes of this study.1
ePrimary end point was pathologic complete response (pCR) in breast tumor.1
fExcept for patients with a past history of ductal carcinoma in situ and/or lobular carcinoma in situ treated with surgery only.3
gExcept for curatively treated carcinoma in situ of uterine cervix, basal cell carcinoma of the skin, or squamous cell carcinoma of the skin (malignant neoplasms occurring >5 years before randomization were permitted if curatively treated with surgery only).3

Study purpose and end point1

A head-to-head study to demonstrate the equivalent clinical efficacy of ONTRUZANT to Herceptin

Primary end point1

Efficacy:
  • Breast pathologic complete response (bpCR): defined as no histologic evidence of residual invasive tumor cells in the breast
    • Demonstration of clinical efficacy equivalence required that the confidence intervals of either ratio or difference of bpCR rates fell within predefined equivalence margins

Pathologic complete response in the breast (bpCR) in the per-protocol seth


Pathologic Complete Response in the Breast (bpCR) in the Per-Protocol Set.
  • Demonstration of clinical efficacy equivalence required that the confidence intervals of either ratio or difference of bpCR rates fall within predefined equivalence margins, as defined by: 95% CI of the ratio of bpCR rates (0.785–1.546); 95% CI of the difference of bpCR rates (−13%, 13%)1
  • Adjusted difference: 10.7% (95% CI, 4.13%–17.26%)1

In the 95% confidence interval of adjusted difference, the lower margin was contained within and the upper margin was outside the predefined equivalence margin.1

  • Adjusted rate ratio: 1.259 (95% CI, 1.085–1.460)1

95% confidence interval of adjusted rate ratio was within the margin of predefined equivalence.

hPer-protocol set is defined as all randomized subjects who completed 8 cycles of neoadjuvant therapy and surgery without major prespecified protocol deviations.1iEuropean Union (EU)–sourced Herceptin was used for the purposes of this study.1

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Indications and Usage

Adjuvant Breast Cancer

ONTRUZANT is indicated for 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
  • As part of a treatment regimen with docetaxel and carboplatin
  • As a single agent following multi-modality anthracycline based therapy

Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product.

Metastatic Breast Cancer

ONTRUZANT is indicated:

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

Select patients for therapy based on an FDA-approved companion diagnostic for a trastuzumab product.

Definitions

ER = estrogen receptor
HER2 = human epidermal growth factor receptor 2
PR = progesterone receptor

Selected Safety Information

CARDIOMYOPATHY

  • Administration of trastuzumab products can result in subclinical and clinical cardiac failure. The incidence and severity was highest in patients receiving a trastuzumab product with anthracycline-containing chemotherapy regimens.
  • Evaluate left ventricular function in all patients prior to and during treatment with ONTRUZANT. Discontinue ONTRUZANT treatment in patients receiving adjuvant therapy and withhold ONTRUZANT in patients with metastatic disease for clinically significant decrease in left ventricular function.

INFUSION REACTIONS; PULMONARY TOXICITY

  • Administration of trastuzumab products can result in serious and fatal infusion reactions and pulmonary toxicity. Symptoms usually occur during or within 24 hours of administration. Interrupt ONTRUZANT infusion for dyspnea or clinically significant hypotension. Monitor patients until symptoms completely resolve. 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 and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Advise patients of these risks and the need for effective contraception.

WARNINGS AND PRECAUTIONS

CARDIOMYOPATHY

  • Administration of trastuzumab products can result in subclinical and clinical cardiac failure. The incidence and severity was highest in patients receiving trastuzumab with anthracycline-containing chemotherapy regimens. In a pivotal adjuvant breast cancer trial, one patient who developed congestive heart failure (CHF) died of cardiomyopathy.
  • Trastuzumab products can cause left ventricular cardiac dysfunction, arrhythmias, hypertension, disabling cardiac failure, cardiomyopathy, and cardiac death.
  • Trastuzumab products can also cause asymptomatic decline in left ventricular ejection fraction (LVEF).
  • Discontinue ONTRUZANT treatment in patients receiving adjuvant breast cancer therapy and withhold ONTRUZANT in patients with metastatic disease for clinically significant decrease in left ventricular function.

CARDIAC MONITORING

  • Evaluate cardiac function prior to and during treatment. For adjuvant breast cancer therapy, also evaluate cardiac function after completion of ONTRUZANT.
  • Conduct thorough cardiac assessment, including history, physical examination, and determination of LVEF by echocardiogram or MUGA scan.
  • Monitor frequently for decreased left ventricular function during and after ONTRUZANT treatment.
  • Monitor more frequently if ONTRUZANT is withheld for significant left ventricular cardiac dysfunction.

INFUSION REACTIONS

  • Administration of trastuzumab products can result in serious and fatal infusion reactions.
  • Symptoms usually occur during or within 24 hours of ONTRUZANT administration.
  • Interrupt ONTRUZANT infusion for dyspnea or clinically significant hypotension.
  • Monitor patients until symptoms completely resolve.
  • Discontinue ONTRUZANT for infusion reactions manifesting as anaphylaxis, angioedema, interstitial pneumonitis, or acute respiratory distress syndrome. Strongly consider permanent discontinuation in all patients with severe infusion reactions.
  • Infusion reactions consist of a symptom complex characterized by fever and chills, and on occasion include nausea, vomiting, pain (in some cases at tumor sites), headache, dizziness, dyspnea, hypotension, rash, and asthenia.

EMBRYO-FETAL TOXICITY

  • Exposure to trastuzumab products during pregnancy can result in oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. Advise patients of these risks and the need for effective contraception.
  • Verify the pregnancy status of females of reproductive potential prior to the initiation of ONTRUZANT.
  • Advise pregnant women and females of reproductive potential that exposure to ONTRUZANT during pregnancy or within 7 months prior to conception can result in fetal harm.
  • Advise females of reproductive potential to use effective contraception during treatment and for at least 7 months following the last dose of ONTRUZANT.
  • Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for ONTRUZANT treatment and any potential adverse effects on the breastfed child from ONTRUZANT or from the underlying maternal condition.

PULMONARY TOXICITY

  • Administration of trastuzumab products can result in serious and fatal pulmonary toxicity, which includes dyspnea, interstitial pneumonitis, pulmonary infiltrates, pleural effusions, noncardiogenic pulmonary edema, pulmonary insufficiency and hypoxia, acute respiratory distress syndrome, and pulmonary fibrosis. Such events can occur as sequelae of infusion reactions.
  • Patients with symptomatic intrinsic lung disease or with extensive tumor involvement of the lungs, resulting in dyspnea at rest, appear to have more severe toxicity.
  • Discontinue ONTRUZANT in patients experiencing pulmonary toxicity.

EXACERBATION OF CHEMOTHERAPY-INDUCED NEUTROPENIA

  • In randomized, controlled clinical trials, the per-patient incidences of NCI-CTC grade 3-4 neutropenia and of febrile neutropenia were higher in patients receiving trastuzumab in combination with myelosuppressive chemotherapy as compared to those who received chemotherapy alone. The incidence of septic death was similar among patients who received trastuzumab and those who did not.

DRUG INTERACTIONS

  • Patients who receive anthracycline after stopping trastuzumab products may be at increased risk of cardiac dysfunction because of trastuzumab's long washout period based on population PK analysis. If possible, physicians should avoid anthracycline-based therapy for up to 7 months after stopping trastuzumab products. If anthracyclines are used, the patient's cardiac function should be monitored carefully.

ADVERSE REACTIONS

ADVERSE REACTIONS

  • The most common adverse reactions associated with trastuzumab products in the adjuvant and metastatic breast cancer setting are fever, nausea, vomiting, infusion reactions, diarrhea, infections, increased cough, headache, fatigue, dyspnea, rash, neutropenia, anemia, and myalgia.

Before prescribing ONTRUZANT, please read the accompanying Prescribing Information, including the Boxed Warning about cardiomyopathy, infusion reactions (pulmonary toxicity), and embryo-fetal toxicity.

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REFERENCES: 1. Pivot X, Bondarenko I, Nowecki Z, et al. Phase III, randomized, double-blind study comparing the efficacy, safety, and immunogenicity of SB3 (trastuzumab biosimilar) and reference trastuzumab in patients treated with neoadjuvant therapy for human epidermal growth factor receptor 2–positive early breast cancer. J Clin Oncol. 2018;36:968–974.
2. Data available on request from Merck, Professional Services-DAP, WP1-27, PO Box 4, West Point, PA 19486-0004. Please specify information package US-SBF-00344.
3. Pivot X, Bondarenko I, Nowecki Z, et al. Phase III, randomized, double-blind study comparing the efficacy, safety, and immunogenicity of SB3 (trastuzumab biosimilar) and reference trastuzumab in patients treated with neoadjuvant therapy for human epidermal growth factor receptor 2–positive early breast cancer. J Clin Oncol. 2018;36 (suppl) https://ascopubs.org/doi/suppl/10.1200/JCO.2017.74.0126 Accessed August 5, 2020.
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