What is the recommended use of Margetuximab (margetuximab) in patients with HER2-positive metastatic breast cancer?

Use of Margetuximab in HER2-Positive Metastatic Breast Cancer

Margetuximab should be used in combination with chemotherapy as a fourth-line or later treatment option for patients with HER2-positive metastatic breast cancer who have received at least two prior anti-HER2 regimens, with at least one for metastatic disease. 1

Positioning in Treatment Sequence

The current treatment sequence for HER2-positive metastatic breast cancer follows a clear algorithm:

1. First-line therapy: Pertuzumab + trastuzumab + taxane (docetaxel, paclitaxel, or nab-paclitaxel) 1
2. Second-line therapy: Trastuzumab deruxtecan (T-DXd) 1
3. Third-line therapy: Tucatinib + trastuzumab + capecitabine (especially for patients with brain metastases) or T-DM1 (if not previously used) 1
4. Fourth-line and beyond: Margetuximab + chemotherapy, lapatinib + trastuzumab, trastuzumab + chemotherapy, or neratinib + chemotherapy 1

Efficacy Data

Margetuximab's approval is based on the SOPHIA trial, which demonstrated:

• Modest improvement in progression-free survival (PFS) compared to trastuzumab when combined with chemotherapy (5.8 vs 4.9 months; HR 0.76; p=0.03) 2
• ESMO-MCBS score of 1B, indicating limited clinical benefit 1
• FDA approval in December 2020, though not currently approved by the European Medicines Agency (EMA) 1, 2

Mechanism of Action

Margetuximab is an Fc-modified anti-HER2 monoclonal antibody with:

• Enhanced binding to CD16A (activating Fcγ receptor)
• Decreased binding to CD32B (inhibitory Fcγ receptor)
• Improved antibody-dependent cell-mediated cytotoxicity (ADCC) compared to trastuzumab 3

Patient Selection

• Confirmed HER2-positive status (3+ by IHC or FISH-positive)
• Prior treatment with at least two anti-HER2 regimens
• An exploratory analysis suggested that patients with an F-allele for the Fc-gamma receptor IIIA gene may derive greater benefit 1

Administration and Dosing

Margetuximab is administered intravenously in combination with chemotherapy. Common chemotherapy partners include:

• Vinorelbine
• Capecitabine
• Other standard chemotherapy agents 4

Safety Profile

The most common adverse events (>10%) include:

• Fatigue/asthenia
• Nausea, diarrhea, vomiting, constipation
• Infusion-related reactions (13% of patients, 1.5% grade 3)
• Headache, pyrexia
• Peripheral neuropathy 2

Special Considerations

Brain Metastases

• For patients with active brain metastases, tucatinib-based regimens are preferred over margetuximab 1, 5
• Local therapies (surgery, stereotactic radiotherapy) should be considered first for brain metastases 1

Treatment Sequencing

• The optimal sequence after progression on third-line therapy is not firmly established
• In patients who have exhausted preferred options (pertuzumab/trastuzumab, T-DXd, tucatinib-based therapy, T-DM1), margetuximab plus chemotherapy represents a reasonable option 5

Clinical Pearls

• Continued HER2 blockade beyond progression is considered standard clinical practice 1
• The clinical benefit of margetuximab is modest compared to earlier-line HER2-targeted therapies
• Consider CD16A genotype testing if available, as this may predict greater benefit from margetuximab 1
• Monitor for infusion-related reactions, which occur in approximately 13% of patients 2

Margetuximab represents an additional option in the growing armamentarium against HER2-positive metastatic breast cancer, particularly for heavily pretreated patients who have progressed on standard therapies.