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).

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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.