ONTRUZANT®

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

Biosimilar Data

Safety

Safety and immunogenicity profiles of ONTRUZANT and Herceptin (trastuzumab)1

  • Treatment-emergent adverse events (TEAEs) were reported by 96.6% of patients (422 of 437 patients) in the ONTRUZANT group and 95.2% of patients (417 of 438 patients) in the Herceptina group
  • The most common TEAEs in both groups were neutropenia, alopecia, nausea, and leukopenia
  • Patients with ≥1 serious TEAE included 46 (10.5%) in the ONTRUZANT group (n = 437) and 47 (10.7%) in the Herceptin group (n = 438)
  • TEAEs resulted in the death of 4 patients; 1 in the ONTRUZANT group, 3 in the Herceptina group—none of these events were considered to be related to study drugs

Immunogenicity1

  • Up to cycle 9, the overall incidence of anti-drug antibodies (ADAs) was 3 (0.7%) in the ONTRUZANT group and 0 (0.0%) in the Herceptina group (the clinical relevance is unclear)
  • None of the 3 ADA-positive patients presented significant TEAEs related to immunogenicity
TEAEs OF SPECIAL INTEREST1 ONTRUZANT
(n = 437)
n (%)
Herceptin a
(n = 438)
n (%)
Infusion-related reaction 36 (8.2) 44 (10.0)
Left ventricular systolic dysfunction (asymptomatic) 4 (0.9) 3 (0.7)
Congestive heart failure 2 (0.5) 0 (0.0)
ADVERSE EVENT1 ONTRUZANT
(n = 437)
n (%) ≥10%
Herceptin a
(n = 438)
n (%) ≥10%
Neutropenia 293 (67.0) 279 (63.7)
Alopecia 293 (67.0) 277 (63.2)
Nausea 136 (31.1) 133 (30.4)
Leukopenia 122 (27.9) 107 (24.4)
Diarrhea 88 (20.1) 66 (15.1)
ALT increased 81 (18.5) 76 (17.4)
Anemia 80 (18.3) 89 (20.3)
Fatigue 63 (14.4) 67 (15.3)
Myalgia 63 (14.4) 64 (14.6)
AST increased 61 (14.0) 56 (12.8)
Stomatitis 60 (13.7) 49 (11.2)
Vomiting 59 (13.5) 49 (11.2)
Neutrophil count decreased 55 (12.6) 56 (12.8)
Asthenia 51 (11.7) 48 (11.0)

Definitions

ADAs = antidrug antibodies
ALT = alanine aminotransferase
AST = aspartate aminotransferase
TEAE = treatment-emergent adverse event

Study design1

Results from a large, phase 3, randomized, double-blind study (N = 875) comparing the efficacy, safety, and immunogenicity of ONTRUZANT with Herceptina in patients with HER2+ early BC or locally advanced BC in the neoadjuvant setting. Patients were assigned to receive neoadjuvant ONTRUZANT or Herceptina for 8 cycles concurrently with chemotherapy (4 cycles of docetaxel followed by 4 cycles of fluorouracil, epirubicin, and cyclophosphamide) followed by surgery, and then 10 cycles of adjuvant ONTRUZANT or Herceptin.a The primary objective was comparison of breast pathologic complete response (bpCR) rate in the per-protocol set. The secondary end points included comparisons of safety and immunogenicity. There was no prespecified equivalence margin to analyze any of the secondary end points. This study was not designed to determine equivalence between ONTRUZANT and Herceptina on any of the secondary end points.

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

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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REFERENCE: 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.
US-SBF-0014309/20