The combination of margetuximab and chemotherapy induced a 1.8-month median overall survival increase in patients with pretreated HER2-positive metastatic breast cancer compared with trastuzumab (Herceptin) and chemotherapy.
The combination of margetuximab and chemotherapy induced a 1.8-month median overall survival (OS) increase in patients with pretreated HER2-positive metastatic breast cancer compared with trastuzumab (Herceptin) and chemotherapy, according to topline findings of a second prespecified interim OS analysis of the phase III SOPHIA trial.1
Updated results showed that in the intent-to-treat (ITT) population, the median OS in patients treated with the novel Fc-engineered HER2-targeted antibody and chemotherapy was 21.6 months compared with 19.8 months for those who had trastuzumab/chemotherapy (HR, 0.885; 95% CI, 0.693-1.130; P = .326). The second interim OS analysis was based on 270 events.
Moreover, a prespecified exploratory objective was to evaluate the effect of CD16A allelic variation on margetuximab activity. In the estimated 85% of patients carrying a CD16A 158F allele, the median OS was 23.7 months in the margetuximab arm versus 19.4 months in the trastuzumab arm (HR, 0.793; 95% CI, 0.607-1.035; P = .087).
However, in the estimated 15% of patients who were homozygous for the CD16A 158V allele, the trastuzumab regimen performed better than those on margetuximab/chemotherapy.
Margetuximab combined with chemotherapy also showed a safety profile that was generally comparable with trastuzumab plus chemotherapy, and was also consistent with previously reported data. Grade ≥3 adverse events (AEs) occurred in 145 (55%) patients on the margetuximab arm compared with 140 (53%) patients on the trastuzumab arm.
Serious AEs occurred in 45 (17%) patients on the margetuximab arm compared with 50 (19%) patients on the trastuzumab arm. Infusion-related reactions were more common with margetuximab treatment than with trastuzumab (13% vs 3%) and were mostly grade 1/2 and were associated with the first dose.
Detailed results from the second interim OS analysis from SOPHIA study will be presented at the 2019 San Antonio Breast Cancer Symposium, and MacroGenics, the developer of margetuximab, expects to submit a biologics license application to the FDA before the end of 2019. The final prespecified OS analysis is planned after 385 events have accrued, which is projected for 2020.
In SOPHIA, 536 patients with HER2-positive metastatic breast cancer despite ≥2 prior anti-HER2 therapies, including pertuzumab, and who received 1 to 3 prior lines of treatment in the metastatic setting, were randomized to margetuximab, 15 mg/kg every 3 weeks, or trastuzumab, using an 8 mg/kg loading dose followed by 6 mg/kg every 3 weeks. All patients also received investigator’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine). Sequential primary endpoints are PFS and OS. A preplanned exploratory secondary endpoint included evaluation of the effect of margetuximab by Fc-gamma receptor alleles.
Baseline characteristics were balanced between the arms, with a median age of 55 years in the margetuximab arm and 56 years in the trastuzumab arm. The backbone chemotherapy regimens were capecitabine in 27% in each arm, eribulin in about one-fourth, gemcitabine in 12%, and vinorelbine in about one-third of patients. More than 90% of patients received prior T-DM1 (ado-trastuzumab emtansine; Kadcyla), and 59% in the margetuximab arm and 54% in the trastuzumab arm received prior adjuvant and/or neoadjuvant therapy. About one-third in each arm received >2 lines of prior therapy in the metastatic setting.
Earlier data of the SOPHIA trial were presented during the 2019 ASCO Annual Meeting. By central blinded analysis, PFS was prolonged in patients randomized to margetuximab (HR, 0.76; P = .033).2 The median PFS was 5.8 months in the margetuximab arm compared with 4.9 months in the trastuzumab arm. Investigator-assessed PFS was also longer in the margetuximab arm (HR, 0.70; P = .001).
Additionally, in a planned exploratory PFS analysis by Fc-gamma receptor genotype, in patients with the CD16A-F allele, the median PFS was 6.9 months in patients randomized to margetuximab compared with 5.1 months in those who received trastuzumab (HR, 0.68; P = .005).
At the first interim OS analysis in the ITT population, the median OS was 18.9 months in the margetuximab arm versus 17.2 months in the trastuzumab arm (HR, 0.95; 95% CI, 0.69-1.31). In patients carrying at least 1 F allele, median PFS was 23.6 months in patients randomized to margetuximab compared with 16.9 months in those assigned to trastuzumab, an absolute difference of 6.7 months favoring margetuximab (HR, 0.82; 95% CI, 0.58-1.17).