The following article features coverage from the American Society of Clinical Oncology 2019 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.

Results of the phase 3 SOPHIA trial ( Identifier: NCT02492711) showed significantly improved progression-free survival (PFS) in patients with previously treated metastatic HER2-positive breast cancer receiving margetuximab, an investigational anti-HER2 antibody, compared with trastuzumab, both in combination with chemotherapy. The findings from this study were presented at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois.1

While the current standard of care for the treatment of patients with HER2-positive metastatic breast cancer involves first-line trastuzumab/pertuzumab/chemotherapy and second-line trastuzumab emtansine (T-DM1), no standard has been identified beyond the second-line setting, although sequential chemotherapy with trastuzumab or lapatinib is frequently used.

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Hope Rugo, MD, University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, who presented the results of the SOPHIA study, explained that margetuximab has been engineered to have a higher affinity for the activating FcϒR, CD16A, a protein found on the surface of many immune cells, compared with trastuzumab. Hence, antibody-dependent cell-mediated cytotoxicity (ADCC) may be potentiated with margetuximab. A study hypothesis was that margetuximab would show greater benefit in patients with 1 or more alleles encoding for CD16A, with lower Fc binding.

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In the large, open-label SOPHIA trial, patients were randomly assigned in a 1:1 ratio to receive the combination of margetuximab plus chemotherapy (ie, capecitabine, eribulin, vinorelbine, or gemcitabine) or the combination of trastuzumab with chemotherapy in patients with metastatic breast cancer who had received prior therapy with 2 or more anti-HER2 therapies, including pertuzumab, along with 1 to 3 lines of prior therapy in the metastatic setting. Progression-free survival (PFS) and overall survival (OS) were primary end points of the study; overall response rate (ORR) was a secondary study end point. 

Of the 536 patients enrolled in the study, 266 and 270 were randomly assigned to margetuzimab and trastuzumab treatment arms, respectively. Median PFS was 5.8 months and 4.9 months in patients treated with margetuximab and trastuzumab, respectively (hazard ratio [HR], 0.76; 95% CI, 0.59–0.98; P= .033).

A prespecified, exploratory subgroup analysis showed a more marked difference in PFS for the 192 patients with disease characterized by 1 or 2 alleles encoding for the lower-affinity form of CD16A, with median PFS of 6.9 months and 5.1 months (HR, 0.68; 95% CI, 0.52-0.90; P =.005) for those receiving margetuximab and trastuzumab, respectively. Furthermore, a PFS difference in favor of margetuximab was not observed in the 62 patients with homozygous alleles encoding for the higher-affinity form of CD16A (4.8 months vs 5.6 months; HR, 1.78, 95% CI, 0.87-1.62; P =.110)

The overall ORR in the 524 patients with measurable disease at baseline was 22.1% for the patients in the margetuximab-containing arm and 16.0% for those treated with trastuzumab plus chemotherapy (P =.060). Although a higher clinical benefit rate was observed in patients receiving margetuximab (36.6% vs 24.8%; P =.003), there was no difference in the duration of response when the 2 study arms were compared.   

While data on OS were considered to be immature, Dr Rugo mentioned that a second interim analysis is expected in late 2019.

In general, rates of grade 3 or higher adverse events (52.3% vs 48.3%) and serious adverse events (14.8% vs 17.4%) were similar for patients in the margetuximab- and trastuzumab-containing study arms, respectively, and the safety profiles of these 2 treatments were also similar. However, rates of infusion reactions were higher in patients receiving margetuximab (12.9%) compared with trastuzumab (3.8%).

In her concluding remarks, Dr Rugo stated that “this is the first prospective study of CD16A genotype as a predictor of efficacy from anti-HER2 therapy.”


Rugo HS, Im S-A, Shaw Wright GL, et al. SOPHIA primary analysis: A phase 3 (P3) study of margetuximab (M) + chemotherapy (C) versus trastuzumab (T) + C in patients (pts) with HER2+ metastatic (met) breast cancer (MBC) after prior anti-HER2 therapies (Tx). Presented at: 2019 American Society of Clinical Oncology (ASCO) Annual Meeting; Chicago, IL; May 31-June 4, 2019. Abstract 1000.