Margetuximab

Patients who receive anthracyclines less than 4 months after stopping margetuximab may be at increased risk of cardiac dysfunction. While this interaction has not been studied with margetuximab, clinical data from other HER2-directed antibodies warrants consideration. Avoid anthracycline-based therapy for up to 4 months after stopping margetuximab. If concomitant use is unavoidable, closely monitor patient’s cardiac function.

Risk Summary

Based on findings in animals and mechanism of action, margetuximab can cause fetal harm when administered to a pregnant woman. There are no available data on use of margetuximab in pregnant women to inform the drug-associated risk. In postmarketing reports, use of a HER2-directed antibody during pregnancy resulted in cases of oligohydramnios and oligohydramnios sequence manifesting as pulmonary hypoplasia, skeletal abnormalities, and neonatal death. In an animal reproduction study, intravenous administration of margetuximab-cmkb to pregnant cynomolgus monkeys once every 3 weeks, starting at gestational day (GD) 20 until delivery, resulted in oligohydramnios and delayed infant kidney development. Animal exposures were ≥3 times the human exposures at the recommended dose, based on C_max (see Data). Advise patients of potential risks to a fetus. There are clinical considerations if margetuximab is used during pregnancy or within 4 months prior to conception (see Clinical Considerations).

Estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.

Clinical Considerations

Fetal/Neonatal Adverse Reactions

Monitor women who received margetuximab during pregnancy or within 4 months prior to conception for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care.

Data

Animal Data

In an enhanced pre- and post-natal development study, pregnant cynomolgus monkeys received intravenous doses of 50 or 100 mg/kg margetuximab-cmkb once every 3 weeks starting on GD 20 and until delivery. Animal exposures at doses of 50 and 100 mg/kg were 3 and 6 times, respectively, the human exposures at the recommended dose, based on C_max. Treatment with 50 and 100 mg/kg margetuximab-cmkb resulted in oligohydramnios beginning on GD 75.

An infant mortality occurred on post-natal day 63 following maternal exposure to 100 mg/kg margetuximab-cmkb. Clinical findings included tubular degeneration/necrosis and tubular dilatation in the kidney. Maternal doses of 50 and 100 mg/kg resulted in decreased infant kidney weights and histologic immature nephrons. Measurable serum concentrations of margetuximab-cmkb were observed in infant animals, which is consistent with margetuximab-cmkb crossing the placenta.

There is no information regarding presence of margetuximab in human milk, effects on the breastfed child, or effects on milk production. Published data suggest human IgG is present in human milk but does not enter neonatal or infant circulation in substantial amounts. Consider developmental and health benefits of breastfeeding along with the mother’s clinical need for margetuximab treatment and any potential adverse effects on the breastfed child from margetuximab or from the underlying maternal condition. This consideration should also take into account the margetuximab washout period of 4 months.

Studies have not been performed to evaluate carcinogenic or mutagenic potential of margetuximab-cmkb.

Animal fertility studies have not been conducted with margetuximab-cmkb. In repeat-dose toxicity studies of up to 13-week duration, margetuximab-cmkb had no effect on male and female reproductive organs in sexually mature cynomolgus monkeys.

Margetuximab has a minor influence on the ability to drive or use machines. Dizziness and somnolence may occur during treatment with margetuximab. Patients experiencing infusion-related symptoms should be advised not to drive and use machines until symptoms abate.

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 margetuximab was evaluated in HER2-positive breast cancer patients who received two or more prior anti-HER2 regimens in SOPHIA.

Patients were randomized (1:1) to receive either margetuximab 15 mg/kg every 3 weeks plus chemotherapy or trastuzumab plus chemotherapy. Among patients who received margetuximab, 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 margetuximab. 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 margetuximab, including viral pneumonia (0.8%) and aspiration pneumonia (0.4%).

Permanent discontinuation due to an adverse reaction occurred in 3% of patients who received margetuximab. Adverse reactions which resulted in permanent discontinuation in >1% of patients who received margetuximab included left ventricular dysfunction and infusion-related reactions.

Dosage interruptions due to an adverse reaction occurred in 11% of patients who received margetuximab. Adverse reactions which required dosage interruption in >5% of patients who received margetuximab 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 Margetuximab in SOPHIA:

^* 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.

Clinically relevant adverse reactions in ≤10% of patients who received margetuximab 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 Margetuximab in SOPHIA:

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.

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity with margetuximab. The detection of antibody formation is highly dependent on assay sensitivity and specificity. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to margetuximab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In SOPHIA, samples were obtained from patients on margetuximab for immunogenicity testing at baseline, every 2 cycles, and at end of study therapy. All patients enrolled in SOPHIA received trastuzumab previously, and treatment-emergent anti-margetuximab antibodies were observed in 4 patients (1.7%). Of these 4 patients, anti-margetuximab antibodies were detected prior to Cycle 7 of margetuximab dosing in 1 patient, and more than 2 months after the last margetuximab dose in 3 patients. In the infusion substudy, treatment-emergent anti-margetuximab antibodies were observed in 2 patients (3.8%). Of these 2 patients, anti-margetuximab antibodies were detected prior to Cycle 3 of margetuximab dosing in 1 patient, and more than 6 months after the last margetuximab dose in 1 patient. Due to the limited number of patients who developed anti-margetuximab antibodies during treatment with margetuximab, the impact of anti-margetuximab antibodies on the PK, safety and efficacy of margetuximab is unknown.