Margetuximab in HER2-Positive Breast Cancer
Margetuximab plus chemotherapy should be reserved as a fourth-line or later option for HER2-positive metastatic breast cancer patients who have exhausted preferred therapies including trastuzumab deruxtecan, tucatinib combinations, and trastuzumab emtansine. 1
Treatment Positioning in Current Guidelines
Third-Line and Beyond Hierarchy
The most recent ESMO guidelines (2025) clearly establish the treatment sequence for HER2-positive metastatic breast cancer after progression on first-line trastuzumab/pertuzumab and second-line trastuzumab deruxtecan 1:
Preferred third-line options:
- Tucatinib plus trastuzumab plus capecitabine (MCBS 1A) 1
- Trastuzumab deruxtecan if not previously used (MCBS 3A) 1
- Trastuzumab emtansine if not previously used (MCBS 1A) 1
Fourth-line and later options include:
- Lapatinib plus trastuzumab (MCBS 1B) 1
- Trastuzumab plus chemotherapy (MCBS 3A) 1
- Margetuximab plus chemotherapy (MCBS 1B) 1
- Neratinib plus chemotherapy (MCBS 1C) 1
ASCO Guidelines Alignment
The 2022 ASCO guidelines similarly position margetuximab as a third-line or later option, noting it as one of several reasonable choices after progression on preferred regimens 1. The guidelines explicitly state that other third-line regimens should be preferred over margetuximab due to its minimal clinical impact 1.
Clinical Evidence and Limitations
The SOPHIA Trial Results
The pivotal SOPHIA trial compared margetuximab plus chemotherapy versus trastuzumab plus chemotherapy in 536 patients who had received two or more prior anti-HER2 therapies 1, 2:
Efficacy outcomes:
- Median PFS: 5.8 months (margetuximab) vs 4.9 months (trastuzumab) 1, 2
- Hazard ratio: 0.76 (95% CI, 0.59-0.98; P = .03) 1, 2
- Median OS: 21.6 months vs 19.8 months (not statistically significant) 1, 2
- Objective response rate: 22% vs 16% 2
Critical interpretation: While statistically significant, the PFS improvement of approximately 0.9 months is clinically negligible 1. The ASCO Expert Panel explicitly noted this minimal clinical impact as the reason for recommending other third-line regimens be preferred 1.
Mechanism of Action
Margetuximab is an Fc-engineered anti-HER2 monoclonal antibody designed to enhance antibody-dependent cellular cytotoxicity (ADCC) 3, 4. It binds with elevated affinity to both low and high affinity forms of CD16A (an Fc receptor) while decreasing binding to the inhibitory CD32B receptor 3, 4. This modification theoretically enhances immune-mediated tumor cell killing compared to trastuzumab 3.
Regulatory Status and Geographic Considerations
A critical caveat: Margetuximab plus chemotherapy is FDA-approved in the United States but not currently licensed by the European Medicines Agency (EMA) 1. This significantly limits its availability in Europe and other regions following EMA guidance.
Safety Profile
Margetuximab demonstrates acceptable safety comparable to trastuzumab, with one notable exception 1, 2:
- Infusion-related reactions: 13.3% with margetuximab vs 3.4% with trastuzumab, mostly occurring in cycle 1 2
- Other adverse events were comparable between groups 1, 2
- Phase 1 data showed mostly Grade 1-2 toxicities including pyrexia, nausea, anemia, diarrhea, and fatigue 3
Clinical Decision Algorithm
When to consider margetuximab:
After progression on all preferred options: Patient must have received and progressed on trastuzumab/pertuzumab, trastuzumab deruxtecan, and tucatinib-based regimens 1
Geographic availability: Only in regions where it has regulatory approval (currently FDA-approved, not EMA-approved) 1
Patient factors: Acceptable cardiac function and performance status to tolerate combination chemotherapy 1
Biomarker consideration: Exploratory analysis suggested CD16A-158F allele carriers may derive greater benefit, though no validated biomarker exists for clinical use 1
Common Pitfalls to Avoid
Do not use margetuximab prematurely: The evidence clearly supports using trastuzumab deruxtecan, tucatinib combinations, and trastuzumab emtansine before margetuximab, as these agents demonstrate superior clinical benefit 1.
Do not expect substantial clinical benefit: The modest PFS improvement should be discussed transparently with patients when considering this option 1.
Do not assume EMA approval: Verify regulatory status in your region before planning treatment 1.
Practical Treatment Approach
When margetuximab is selected, combine it with chemotherapy (as studied in SOPHIA trial) at a dose of 15 mg/kg every 3 weeks 2. Continue treatment until disease progression or unacceptable toxicity 1. Monitor closely for infusion reactions during the first cycle 2.