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)]

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 (%)
* Includes abdominal pain, abdominal discomfort, lower abdominal pain and upper abdominal pain † Includes headache and migraine ‡ Includes peripheral neuropathy, peripheral sensory neuropathy, peripheral motor neuropathy, and neuropathy
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*	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†	19	0	16	0
Peripheral 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*		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
* 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.
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