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Clinical benefit over trastuzumab for margetuximab in HER2 breast cancer

SABCS 2019
Phase 3, SOPHIA

When combined with chemotherapy, margetuximab has shown to improve progression-free survival (PFS) over trastuzumab in pretreated patients with human epidermal growth factor 2 (HER2)-positive metastatic breast cancer. Safety of the two agents was comparable.

Pretreated HER2-positive metastatic breast cancer lacks a defined standard of care, although trastuzumab is commonly used. Margetuximab is an antibody designed to activate an immune response which has a similar HER2-binding and antiproliferative effects as trastuzumab. One difference is that its Fcγ region is engineered to increase affinity for both alleles of the activating Fc receptor CD16A and to decrease affinity for the inhibitory Fc receptor CD32B. The low affinity CD16A-158F allele (~85% of population) has been associated with diminished clinical response to trastuzumab.

The SOPHIA trial was a randomised, open-label phase 3 trial which enrolled 536 patients with HER2-positive metastatic breast cancer who had been treated with at least 2 prior lines of anti-HER2 therapy, including pertuzumab, and 1-3 prior lines in the metastatic setting [1]. Patients were randomly assigned 1:1 to margetuximab (15 mg/kg intravenously every 3 weeks) or trastuzumab (6 mg/kg [8-mg/kg loading dose]). In both arms, anti-HER2 therapy was given with physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). The primary endpoints were PFS and overall survival (OS). A secondary endpoint was objective response rate (ORR).

The results showed that the intention-to-treat analysis occurred after 265 PFS events. Margetuximab prolonged PFS over trastuzumab (median 5.8 vs 4.9 months, HR 0.76; 95% CI 0.59-0.98; P=0.033). Treatment effects were more pronounced in patients who harboured CD16A genotypes containing a 158F allele (median PFS 6.9 vs 5.1 months, HR 0.68; 95% CI 0.52-0.90; P=0.005). In patients who had baseline measurable disease (margetuximab n=262; trastuzumab n=262), ORR was higher with margetuximab (22%; 95% CI 17.3-27.7%) than with trastuzumab (16%; 95% CI 11.8-21.0%).

Safety profiles were comparable in 529 patients who received study therapy. Grade ≥3 adverse events and serious adverse events occurred in 52% and 15% of patients who received margetuximab versus 48% and 17% of patients receiving trastuzumab, respectively.

1. Rugo HS, et al. GS1-02. SABCS 2019.

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