Margetuximab Does Not Surpass Trastuzumab in Terms of Survival in HER2+ Breast Cancer

Margetuximab did not deliver a significant survival benefit in patients with HER2-positive advanced breast cancer compared with trastuzumab.

Hope S. Rugo, MD, FASCO

Patients with HER2-positive advanced breast cancer who received the anti-HER2 IgG monoclonal antibody margetuximab-cmkb (Margenza) plus chemotherapy did not experience a significant survival benefit compared with those treated with trastuzumab (Herceptin) plus chemotherapy, according to final overall survival (OS) findings from the phase 3 SOPHIA trial (NCT02492711).1

Data from the study showed that, at a median follow-up of 20.2 months, patients in the margetuximab arm (n = 266) had a median OS of 21.6 months (95% CI, 18.89-25.07) vs 21.9 months (95% CI, 18.69-4.18) in the 270-patient trastuzumab arm (HR 0.95; 95% CI, 0.77-1.17; P = .620). Additionally, the 12-, 18-, and 24-months OS rates were similar between the 2 arms, at 75% (95% CI, 70%-80%) vs 76% (95% CI, 70%-80%), 60% (95% CI, 54%-66%) vs 57% (95% CI, 51%-63%), and 46% (95% CI, 40%-52%) vs 44% (95% CI, 38%-50%), respectively.

SOPHIA was a randomized, open-label trial that enrolled adult patients with HER2-positive advanced breast cancer. Eligible patients must have experienced progression following treatment with at least 2 prior lines of HER2-target therapy, including pertuzumab, and 1 to 3 lines of nonhormonal therapy. Patients with prior brain metastases were permitted to enroll.2

Patients were randomly assigned 1:1 to the margetuximab arm or the trastuzumab arm. Stratification occurred based on metastatic sites (≤ 2 vs > 2), prior lines of therapy for metastatic disease (≤ 2 vs > 2), and chemotherapy backbone. Chemotherapy selection was determined by the investigator’s choice of either capecitabine, eribulin, gemcitabine, or vinorelbine.

Margetuximab at 15 mg/kg was administered intravenously over 2 hours on day 1 of each 21-day cycle. Trastuzumab was given intravenously at 6 mg/kg on day 1 of each cycle following a loading dose of 8 mg/kg.

The primary end points were progression-free survival (PFS) and OS. Secondary end points included investigator-assessed PFS and overall response rate. The final OS analysis was triggered by the occurrence of 385 prespecified events.

The median age of patients included in the final OS analysis was 55 years (range, 29-83) and 56 years (range, 27-86) in the margetuximab arm and the trastuzumab arm, respectively. Most patients in both arms were White (77.1% vs 82.2%), had an ECOG performance status of 0 (56% vs 59.6%), and received taxane chemotherapy (94.7% vs 92.2%). A majority of patients in both arms received 2 or less prior lines of therapy in the metastatic setting, 65.8% vs 66.7% respectively.

Additional findings from the trial showed that HER2 status or chemotherapy backbone had no significant effect on survival. However, patients who carried the CD16A-158F low-affinity allele who were treated with margetuximab (n = 221) experienced an OS benefit of 23.3 months (95% CI, 18.9-29.4) compared with 20.8 months (95% CI, 18-23.9) for the 216 patients with the allele who were treated with trastuzumab (HR, 0.86; 95% CI, 0.69-1.08). Similarly, the median OS was 23.6 months (95% CI, 18.6-32.8) with margetuximab vs 19.2 months (95% CI, 15.4-24.25) with trastuzumab (HR, 0.72; 95% CI, 0.52-1.00) among patients with the CD16A-158FF allele who were treated with margetuximab (n =102) and trastuzumab (n = 90), respectively.

Regarding safety, any-grade adverse effects (AEs) occurred at a rate of 98.5% and 98.1% in the margetuximab (n = 264) and trastuzumab (n = 266) safety populations, respectively. Infusion-related AEs of any grade were rare at 13.6% vs 3.4%, respectively. Ten patients in each arm experienced an AE that led to study discontinuation.

Serious AEs were reported in 17.8% of patients treated with margetuximab and 19.2% of patients who received trastuzumab. The most common any-grade AEs in the margetuximab arm included fatigue (42.4%), nausea (33.3%), and diarrhea (26.1%). In the trastuzumab arm, the most common AEs of any grade also included fatigue (35.7%), nausea (32.7%), and diarrhea (25.2%).

“PFS advantage with margetuximab plus chemotherapy observed in the previous analysisand confirmed in this analysis did not translate into a significant difference in OS in the [intention]-to-treat population of SOPHIA,” study authors wrote in conclusion. “However, margetuximab plus chemotherapy is an available treatment option for patients with pretreated HER2-positive advanced breast cancer. Studies of margetuximab in patients with HER2-positive breast cancer with different CD16A allelic variants are warranted.”


  1. Rugo HS, Im SA, Cardoso F, et al. Margetuximab versus trastuzumab in patients with previously treated HER2-positive advanced breast cancer (SOPHIA): final overall survival results from a randomized phase 3 trial. J Clin Oncol. Published online November 4, 2022. doi:10.1200/JCO.21.02937
  2. Rugo HS, Im SA, Cardoso F, et al. Efficacy of margetuximab vs trastuzumab in patients with pretreated ERBB2-positive advanced breast cancer: a phase 3 randomized clinical trial. JAMA Oncol. 2021;7(4):573-584. doi:10.1001/jamaoncol.2020.7932
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