1 INDICATIONS AND USAGE MARGENZA is indicated, in combination with chemotherapy, for the treatment of adult patients with metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease [see Dosage and Administration (2.1) and Clinical Studies (14.1) ].

MARGENZA is a HER2/neu receptor antagonist indicated, in combination with chemotherapy, for the treatment of adult patients with metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease.

( 1 , 2.1 , 14.1 )

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: Left Ventricular Dysfunction [see Warnings and Precautions (5.1) ] Embryo-Fetal Toxicity [see Warnings and Precautions (5.2) ] Infusion-Related Reactions [see Warnings and Precautions (5.3) ] The most common adverse drug reactions (>10%) with MARGENZA in combination with chemotherapy are fatigue/asthenia, nausea, diarrhea, vomiting, constipation, headache, pyrexia, alopecia, abdominal pain, peripheral neuropathy, arthralgia/myalgia, cough, decreased appetite, dyspnea, infusion-related reactions, palmar-plantar erythrodysesthesia, and extremity pain.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact TerSera Therapeutics LLC at 1-844-334-4035 or medicalinformation@tersera.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice.

The safety of MARGENZA was evaluated in HER2-positive breast cancer patients who received two or more prior anti-HER2 regimens in SOPHIA [see Clinical Studies (14.1) ].

Patients were randomized (1:1) to receive either MARGENZA 15 mg/kg every 3 weeks plus chemotherapy or trastuzumab plus chemotherapy.

Among patients who received MARGENZA, 40% were exposed for 6 months or longer and 11% were exposed for greater than one year.

Serious adverse reactions occurred in 16% of patients who received MARGENZA.

Serious adverse reactions in > 1% of patients included febrile neutropenia (1.5%), neutropenia/neutrophil count decrease (1.5%) and infusion related reactions (1.1%).

Fatal adverse reactions occurred in 1.1% of patients who received MARGENZA, including viral pneumonia (0.8%) and aspiration pneumonia (0.4%).

Permanent discontinuation due to an adverse reaction occurred in 3% of patients who received MARGENZA.

Adverse reactions which resulted in permanent discontinuation in > 1% of patients who received MARGENZA included left ventricular dysfunction and infusion-related reactions.

Dosage interruptions due to an adverse reaction occurred in 11% of patients who received MARGENZA.

Adverse reactions which required dosage interruption in > 5% of patients who received MARGENZA included infusion-related reactions.

Table 1 summarizes the adverse reactions in SOPHIA.

Table 1 Adverse Reactions (>10%) in Patients with Metastatic HER2-Positive Breast Cancer Who Received MARGENZA in SOPHIA Adverse Reaction MARGENZA + Chemotherapy (n = 264) Trastuzumab + Chemotherapy (n = 266) All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) General disorders and administration site conditions Fatigue/Asthenia 57 7 47 4.5 Pyrexia 19 0.4 14 0.4 Gastrointestinal disorders Nausea 33 1.1 32 0.4 Diarrhea 25 2.3 25 2.3 Vomiting 21 0.8 14 1.5 Constipation 19 0.8 17 0.8 Abdominal pain Includes abdominal pain, abdominal discomfort, lower abdominal pain and upper abdominal pain 17 1.5 21 1.5 Skin and Subcutaneous tissue Alopecia 18 0 15 0 Palmar-plantar erythrodysesthesia 13 0 15 3 Nervous System Disorders Headache Includes headache and migraine 19 0 16 0 Peripheral neuropathy Includes peripheral neuropathy, peripheral sensory neuropathy, peripheral motor neuropathy, and neuropathy 16 1.1 15 2.3 Respiratory, thoracic and mediastinal disorders Cough 14 0.4 12 0 Dyspnea 13 1.1 11 2.3 Metabolism and nutrition disorders Decreased appetite 14 0.4 14 0.4 Musculoskeletal and connective tissue disorders Arthralgia/Myalgia 14 0.4 12 0.8 Extremity pain 11 0.8 9 0 Injury, poisoning and procedural complications Infusion-related reaction 13 1.5 3 0 Clinically relevant adverse reactions in ≤10% of patients who received MARGENZA in combination with chemotherapy included: dizziness and stomatitis (10%) each, decreased weight, dysgeusia, rash, and insomnia (6%) each, hypertension (5%), and syncope (1.5%).

Table 2 summarizes the laboratory abnormalities in SOPHIA.

Table 2 Select Laboratory Abnormalities (≥20%) That Worsened from Baseline in Patients with Metastatic HER2-Positive Breast Cancer Who Received MARGENZA in SOPHIA Laboratory Abnormality MARGENZA + Chemotherapy The denominator used to calculate the rate varied from 229 to 253 based on the number of patients with a baseline value and at least one post-treatment value.

Trastuzumab + Chemotherapy All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) aPTT: activated partial thromboplastin time; INR: prothrombin international normalized ratio; ALT: alanine aminotransferase; AST: aspartate aminotransferase Hematology Decreased hemoglobin 52 3.2 43 2.4 Decreased leukocytes 40 5 36 3.2 Decreased neutrophils 34 9 28 9 Increased aPTT 32 3.4 34 4.3 Decreased lymphocytes 31 4.4 38 4.4 Increased INR 24 1.2 25 0.4 Chemistry Increased creatinine 68 0.4 60 0 Increased ALT 32 2 30 0.8 Increased lipase 30 6 24 3.2 Increased AST 23 2 22 0.8 Increased alkaline phosphatase 21 0 23 0.8