1000 Background: Pretreated HER2+ MBC lacks a defined standard of care, although T is commonly used. M has similar HER2 binding and antiproliferative effects as T. By contrast, M’s Fc region is engineered to increase affinity for both alleles of the activating Fc receptor (FcR), CD16A, and decrease affinity for the inhibitory FcR, CD32B. The low affinity CD16A-158F allele (~85% of population) has been associated with diminished clinical response to T. In a Phase 1 trial, M demonstrated acceptable safety, anti-tumor activity, and evidence of HER2-specific antibody and T-cell responses. Methods: SOPHIA (NCT02492711), a randomized, open-label P3 trial, enrolled pts with HER2+ MBC after pertuzumab and 1–3 lines of prior Tx for MBC. Pts were randomized 1:1 to M (15 mg/kg IV q3w + C) or T (6 [8 for loading dose] mg/kg IV q3w + C), stratified by met sites (≤2, > 2), lines of Tx for met disease (≤2, > 2), and C choice (standard dose capecitabine, eribulin, gemcitabine, or vinorelbine). Primary endpoints are central blinded PFS and OS, assessed sequentially using the stratified log-rank test. Objective response rate (ORR) was a secondary endpoint. 257 PFS events were required to provide 90% power to show PFS superiority at 2-sided α = 0.05. Results: Intent-to-treat analysis (536 pts: M 266; T 270) occurred after 265 PFS events. M prolonged PFS over T (median 5.8 vs 4.9 mo, hazard ratio [HR], 0.76; 95% CI, 0.59–0.98; P= 0.033). Treatment effects 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; P= 0.005). In 524 pts with baseline measurable disease (M 262; T 262), ORR was higher with M (22%; 95% CI, 17.3-27.7%) vs T (16%; 95% CI 11.8-21.0%). Safety profiles were comparable in 529 pts who received study therapy. Grade ≥3 AEs and serious AEs occurred in 138 (52%) and 39 (15%) vs 128 (48%) and 46 (17%) pts on M vs T, respectively. PFS data cutoff: 10/10/18. Conclusions: In combination with chemotherapy in pretreated HER2+ MBC, M improves PFS over T with comparable safety. CD16A genotyping suggests a differential benefit in patients with a 158F allele. OS data are maturing. Clinical trial information: NCT02492711.

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.

501 Background: 1-year trastuzumab with chemotherapy is the standard adjuvant treatment for HER2+ breast cancer patients (pts). The efficacy of less extended trastuzumab exposure is still under investigation. The Short-HER study is an independent, non-profit study aimed to test the non-inferiority of 9 weeks vs 1 year of adjuvant trastuzumab. Methods: This is a phase III, multicenter, Italian trial where pts with HER2+ breast cancer were randomly assigned to: Arm A (Long) AC or ECx4 followed by 4 courses of 3-weekly docetaxel in combination with trastuzumab, followed by 14 additional courses of 3-weekly trastuzumab; or Arm B (Short) 3 courses of 3-weekly docetaxel plus weekly trastuzumab for 9 doses followed by FEC x3. When indicated, radiation therapy was administered after the completion of chemotherapy. Hormonal therapy started at the completion of chemotherapy for pts with hormone receptor positive tumors. This is a non-inferiority trial with disease-free survival (DFS) as primary end-point.Overall survival (OS) is evaluated as second primary analysis outcome. The sample size of 1250 pts has been estimated based on a hazard ratio <1.29 for the short arm to be non-inferior. The definitive analysis will take place after 198 DFS events. Secondary aims include 2-yrs failure rate, cardiac toxicity, correlative biomarkers analyses. Hazard ratio for DFS and OS (90% CI) will be estimated according to the Cox model. Data will also be analyzed by the Bayesian approach. Results: from Dec-2007 to Oct-2013, 1254 pts from 82 centers have been randomized. Pts characteristics are the following: median age 55 yrs (25-78), stage I 37.3%, IIA 40%, IIB 20.6%, III 2.1%. 30% of the pts had 1-3 positive nodes, 16% >=4. Sixty-eight% of the pts had ER+ tumors. Characteristics were balanced between the two arms. At the time of this writing, 95% of the planned DFS events have been reported. 105 Grade ≥2 cardiac events have been reported, 78 in arm A (long) and 27 in arm B (short). Grade 3-4 cardiac events were 20 in arm A and 11 in arm B. Conclusions: Shorter trastuzumab administration almost halves the rate of severe cardiac toxicity. Final DFS data will be available at the time of the meeting. Clinical trial information: NCT00629278.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Final overall survival (OS) in SOPHIA (ClinicalTrials.gov identifier: NCT02492711 ), a study of margetuximab versus trastuzumab, both with chemotherapy, in patients with previously treated human epidermal growth factor receptor 2–positive advanced breast cancer, is reported with updated safety. Overall, 536 patients in the intention-to-treat population were randomly assigned to margetuximab (15 mg/kg intravenously once every 3 weeks; n = 266) plus chemotherapy or trastuzumab (6 mg/kg intravenously once every 3 weeks after a loading dose of 8 mg/kg; n = 270) plus chemotherapy. Primary end points were progression-free survival, previously reported, and OS. Final OS analysis was triggered by 385 prespecified events. The median OS was 21.6 months (95% CI, 18.89 to 25.07) with margetuximab versus 21.9 months (95% CI, 18.69 to 24.18) with trastuzumab (hazard ratio [HR], 0.95; 95% CI, 0.77 to 1.17; P = .620). Preplanned, exploratory analysis of CD16A genotyping suggested a possible improvement in OS for margetuximab in CD16A-158FF patients versus trastuzumab (median OS, 23.6 v 19.2 months; HR, 0.72; 95% CI, 0.52 to 1.00) and a possible improvement in OS for trastuzumab in CD16A-158VV patients versus margetuximab (median OS, 31.1 v 22.0 months; HR, 1.77; 95% CI, 1.01 to 3.12). Margetuximab safety was comparable with trastuzumab. Final overall OS analysis did not demonstrate margetuximab advantage over trastuzumab. Margetuximab studies in patients with human epidermal growth factor receptor 2–positive breast cancer with different CD16A allelic variants are warranted.