Background: Human epidermal growth factor receptor 2 (HER2)-targeting monoclonal antibodies (mAb) are the standard of care in early-to-advanced HER2+ breast cancer. However, for relapsed/refractory disease, limited options exist after progression on trastuzumab (T), pertuzumab (P), and ado-trastuzumab emtansine. Margetuximab (M) is an Fc-engineered anti-HER2 mAb that targets the same epitope as T and exerts similar antiproliferative effects. Compared with T, M has higher affinity for both 158V (high binding) and 158F (low binding) alleles of the activating Fc receptor, CD16A. M enhances innate immunity, including CD16A-mediated antibody-dependent cellular cytotoxicity, more effectively than T. M also potentiates adaptive immunity in treated patients (pts), including enhanced clonality of the T-cell repertoire and induction of HER2-specific T- and B-cell responses. SOPHIA (NCT02492711) is a phase 3 trial that demonstrated the benefit of M vs T, both with chemotherapy, in pts with HER2+ metastatic breast cancer (MBC). This trial is the first prospective analysis of the effect of CD16A genotype on anti-HER2 antibody efficacy.

Methods: Pts with disease progression after at least 2 lines of anti-HER2 therapy, including P, and 1-3 lines of therapy for HER2+ MBC were randomized 1:1 to chemotherapy + either M (15 mg/kg intravenously every 3 wk) or T. Randomization was stratified by number of metastatic sites (≤2, >2), lines of treatment for MBC (≤2, >2), and chemotherapy choice (capecitabine, eribulin, gemcitabine, or vinorelbine). Primary endpoints were central-blinded review of progression-free survival (PFS) and overall survival (OS). The first interim OS analysis at time of PFS analysis (October 10, 2018) was immature, with 158 of 385 deaths (41%) needed for final OS analysis. The stopping boundary was not crossed. A second interim OS analysis was planned after 270 deaths and will be reported here.

Results: The intent-to-treat (ITT) population comprised 536 pts (M, 266; H, 270). M + chemotherapy prolonged PFS vs T + chemotherapy (median PFS, 5.8 vs 4.9 mo; hazard ratio [HR], 0.76; 95% confidence interval [CI]: 0.59-0.98; P=0.033). Results were more pronounced in pts with CD16A genotypes containing a 158F allele (median PFS, 6.9 vs 5.1 mo; HR, 0.68; 95% CI: 0.52-0.90; nominal P=0.005). OS at the first interim analysis demonstrated a HR (95% CI) of 0.95 (0.69-1.31) for the ITT population (n=536) and an HR of 0.82 (95% CI: 0.58-1.17) for the CD16A/FF or FV genotype population (n=457). Grade ≥3 adverse events (AEs) occurred in 138 pts (52%) receiving M vs 128 pts (48%) receiving T. Serious AEs were seen in 39 (15%) receiving M vs 46 (17%) receiving T. The second planned interim analysis of OS (at n=270), as well as updated safety, will be presented.

Conclusions: M + chemotherapy in pts with treated HER2+ MBC improves PFS vs T. Safety was comparable. CD16A genotyping suggests a greater benefit in pts with a 158F allele. Maturing data comparing the OS of pts treated with M vs T with chemotherapy will provide important new insights in characterizing clinical activity of this regimen in pts with MBC.

Citation Format: Hope S. Rugo, Seock-Ah Im, Fatima Cardoso, Javier Cortes, Giuseppe Curigliano, Mark D. Pegram, Antonino Musolino, Thomas Bachelot, Gail S. Wright, Michelino De Laurentiis, Peter A. Kaufman, Timothy Pluard, Francesco Ricci, Lupe G. Salazar, Denise A. Yardley, Sutton Edlich, Shengyan Hong, Edwin Rock, William J. Gradishar, SOPHIA Study Group. Phase 3 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 [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS1-02.