Phase III SOPHIA Trial Evaluates Margetuximab/Chemotherapy vs Trastuzumab/Chemotherapy for HER2-Positive Breast Cancer

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The second interim analysis of the phase III SOPHIA trial demonstrated a significant, though modest, improvement in progression-free survival, response rate, and clinical benefit with the addition of margetuximab to chemotherapy vs trastuzumab plus chemotherapy in patients with HER2-positive pretreated metastatic breast cancer. The benefits were enhanced in patients with low-affinity CD16A genotypes. (Also known as FCGR3A, CD16A is a cluster-of-differentiation molecule with a role in signal transduction and is found on the surface of natural killer cells, neutrophils, monocytes, and macrophages.) The data also indicated a trend for improved overall survival with margetuximab, but this finding was not statistically significant.

Hope S. Rugo, MD, FASCO

Hope S. Rugo, MD, FASCO

“The current standard of care for the treatment of HER2-positive metastatic breast cancer is trastuzumab, pertuzumab, and ado-trastuzumab emtansine (T-DM1) given sequentially. The results of this analysis are not likely to change the standard of care,” said lead author Hope S. Rugo, MD, FASCO, Director of Breast Oncology and Clinical Trials Education at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center, at the 2019 San Antonio Breast Cancer Symposium.1

Phase III SOPHIA Trial

Margetuximab, a novel investigational antibody, differs from trastuzumab in that it is designed to alter Fc-gamma receptor affinities—in particular, the drug increases affinity to variants of the CD16A receptor—and to decrease affinity for the CD20 “dimmer switch,” Dr. Rugo told the audience. These alterations are aimed at enhancing innate immunity and adaptive HER2-targeted immunity.

SOPHIA enrolled 538 patients with advanced pretreated HER2-positive metastatic breast cancer and randomly assigned them 1:1 to margetuximab plus chemotherapy or trastuzumab plus chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine) given every 3 weeks. All patients had received at least two prior anti-HER2 therapies. Patients were stratified according to choice of chemotherapy, prior therapies, and extent of disease. The last patient was assigned to treatment in October 2018.

The results that Dr. Rugo presented in San Antonio were focused on the intent-to-treat population of 536 patients. At baseline, more than 50% of patients had received prior treatment in the early breast cancer setting; 100% received trastuzumab, and more than 90% received T-DM1.

Primary progression-free survival results, presented at the 2019 ASCO Annual Meeting,2 showed a 24% decrease in the risk of disease progression or death when margetuximab was added to chemotherapy. Mature data will be analyzed in the future.

In the current update, based on investigator-assessed progression-free survival, the data showed an absolute benefit of about 1 month for patients who received margetuximab. This reflected a significant 29% improvement with margetuximab over trastuzumab when added to chemotherapy (P = .0006).

At the time of SABCS, 20 patients remained on margetuximab, and 10 remained on

Objective response rates were higher with margetuximab: 25.2% vs 13.7%, improving the clinical benefit rate (ie, response plus stable disease) from 35.6% with trastuzumab to 48.1% with margetuximab (P = .0025). The median duration of response was similar in both arms.

Dr. Rugo commented: “The subgroup analysis for overall survival shows no real differences between the two study arms, with the exception of HER2-positive patients who have an immunohistochemistry score of 2+, which aligns with the mechanism of margetuximab.”

Impact of CD16A Allele

SOPHIA is the first prospective trial to explore the impact of these Fc-gamma receptor alleles. In an exploratory analysis, investigators found that the CD16A allele appears to impact survival for patients on margetuximab. Median overall survival at the second interim analysis was prolonged by 4.3 months in the margetuximab arm for those who carried the CD16A-158F allele (85% of participants): 23.7 months vs 19.4 months with trastuzumab (P = .087). Patients who were homozygous for the CD16A-158VV allele (15% of participants) experienced no benefit from margetuximab, she said.


  • Margetuximab combined with chemotherapy led to significant, though modest, improvement in progression-free survival, response rate, and clinical benefit compared with trastuzumab/chemotherapy.
  • No significant improvement in overall survival was reported.
  • Margetuximab is designed to increase affinity to the CD16A-158F allele.

“The results may have been affected by more visceral metastasis, brain metastasis, and older age in patients randomly assigned to margetuximab,” Dr. Rugo said. “More data are needed. At present, it is reasonable to conclude that there is no evidence to support a benefit of margetuximab over trastuzumab in the homozygous-dominant population.”

A neoadjuvant trial is being planned to study margetuximab in patients with HER2-positive disease who carry the CD16A-158F allele. The final analysis of SOPHIA is expected late in 2020. 

DISCLOSURE: SOPHIA was supported by MacroGenics. For a complete list of study authors’ disclosures, please view the online version of this article on


1. Rugo HS, Im SA, Cardoso F, et al: Phase III SOPHIA study of margetuximab + chemotherapy vs trastuzumab + chemotherapy in patients with HER2+ metastatic breast cancer after prior anti-HER2 therapies: Second interim overall survival analysis. 2019 San Antonio Breast Cancer Symposium. Abstract GS1-02. Presented December 11, 2019.

2. Rugo HS, Im SA, Shaw Wright GL, et al: SOPHIA primary analysis: A phase 3 study of margetuximab + chemotherapy (C) versus trastuzumab + C in patients with HER2+ metastatic breast cancer after prior anti-HER2 therapies. 2019 ASCO Annual Meeting. Abstract 1000. Presented June 4, 2019.

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