Final overall survival (OS) data from the phase 3 SOPHIA trial indicate that margetuximab-cmkb (Margenza) in combination with chemotherapy did not significantly improve survival outcomes compared to trastuzumab plus chemotherapy in patients with HER2-positive advanced breast cancer. The study, which enrolled patients who had progressed on prior HER2-targeted therapies, revealed similar median OS and survival rates between the two treatment arms.
The SOPHIA trial was a randomized, open-label study involving adult patients with HER2-positive advanced breast cancer who had experienced disease progression following at least two prior lines of HER2-targeted therapy, including pertuzumab, and one to three lines of nonhormonal therapy. Patients were randomized 1:1 to receive either margetuximab at 15 mg/kg intravenously every 21 days or trastuzumab at 6 mg/kg intravenously every 21 days (following an 8 mg/kg loading dose), both in combination with chemotherapy.
Survival Outcomes
At a median follow-up of 20.2 months, the median OS was 21.6 months (95% CI, 18.89-25.07) in the margetuximab arm (n = 266) compared to 21.9 months (95% CI, 18.69-24.18) in the trastuzumab arm (n = 270), with a hazard ratio of 0.95 (95% CI, 0.77-1.17; P = .620). The 12-, 18-, and 24-month OS rates were also similar between the two arms: 75% vs 76%, 60% vs 57%, and 46% vs 44%, respectively.
The primary endpoints of the trial were progression-free survival (PFS) and OS. Secondary endpoints included investigator-assessed PFS and overall response rate. The final OS analysis was triggered by 385 pre-specified events.
Subgroup Analysis
While HER2 status and chemotherapy backbone did not significantly impact survival, a subgroup analysis showed that patients carrying the CD16A-158F low-affinity allele who were treated with margetuximab (n = 221) experienced a median OS of 23.3 months (95% CI, 18.9-29.4) compared to 20.8 months (95% CI, 18-23.9) for those treated with trastuzumab (n = 216; HR, 0.86; 95% CI, 0.69-1.08). Similarly, among patients with the CD16A-158FF allele, the median OS was 23.6 months with margetuximab (n = 102) versus 19.2 months with trastuzumab (n = 90; HR, 0.72; 95% CI, 0.52-1.00).
Safety Profile
The safety profiles of both treatments were comparable. Any-grade adverse events (AEs) occurred in 98.5% of patients in the margetuximab arm and 98.1% in the trastuzumab arm. Infusion-related AEs were more frequent with margetuximab (13.6%) compared to trastuzumab (3.4%). Serious AEs were reported in 17.8% and 19.2% of patients in the margetuximab and trastuzumab arms, respectively. The most common AEs in both arms included fatigue, nausea, and diarrhea.
Clinical Implications
Despite a PFS advantage observed in a previous analysis, the final OS results from the SOPHIA trial did not demonstrate a significant difference in overall survival between margetuximab plus chemotherapy and trastuzumab plus chemotherapy in the intention-to-treat population. However, margetuximab remains an available treatment option for patients with pretreated HER2-positive advanced breast cancer, and further studies are warranted to explore its potential benefits in specific patient subgroups based on CD16A allelic variants.
