Abstract P1-18-04: Phase 3 SOPHIA study of margetuximab + chemotherapy vs trastuzumab + chemotherapy in patients with HER2+ metastatic breast cancer after prior anti-HER2 therapies: Infusion time substudy results
Authors: Gradishar William J. , Im Seock-Ah , Cardoso Fatima , Cortes Javier , Curigliano Giuseppe , Pegram Mark D. , Musolino Antonino , Berardi Rosanna , De Laurentiis Michelino , Bahadur Shakeela W. , Im Young-Hyuck , Lynch Cynthia , Novik Yelena , Edlich Sutton , Rock Edwin , Hong Shengyan , Rugo Hope S. ,   SOPHIA Study Group
Published: March 2020

Abstract
Background: Margetuximab (M) is an investigational Fc-engineered anti-HER2 monoclonal antibody that targets the same epitope as trastuzumab (T) and exerts similar antiproliferative effects. Compared with T, M has higher affinity for both the 158V (high-binding) and 158F (low-binding) allotypes of the activating Fc receptor CD16A. M enhances innate immunity, including CD16A-mediated antibody-dependent cellular cytotoxicity, and does so more effectively than T in vitro. Based on ex vivo experiments with cells collected from patients (pts) before and after treatment, M induces adaptive immunity, including enhanced T-cell clonality and induction of HER2-specific T- and B-cell responses. The SOPHIA trial (NCT02492711) showed that in pts with pretreated HER2+ metastatic breast cancer (MBC), M+chemotherapy improved progression-free survival vs T+chemotherapy, with comparable safety. M is intended to be dosed at 15 mg/kg every 3 weeks, with infusions over 120 min at every cycle (C). A substudy of SOPHIA was conducted to evaluate the safety and tolerability of reduced infusion times from C2 onward. Methods: Eligible pts had HER2+ MBC after ≥4 lines of prior therapy for MBC, including prior T, pertuzumab, and ado-T emtansine. Enrolled pts received a 120-min M infusion, with or without chemotherapy, in C1, then either 60- or 30-min infusions in C2 and beyond. This single-arm substudy was unblinded, with no comparator. The primary objective was incidence of Grade 3 or greater infusion-related reactions (IRRs) by the end of C2. Incidence of all IRRs was a secondary objective. Results: Of 88 pts enrolled, 69 received M+chemotherapy and 19 received M alone. Mean age was 54.5 years; 99% were female and 71% white. The median number of cycles of M received was 3 (range 1-17). Overall, 7 pts were assigned to received 60-min M infusions starting at C2 (range 1-17 cycles), and 76 pts were assigned to received 30-min M infusions starting at C2 (range 1-14 cycles). Five pts did not receive C2 treatment due to non-radiologic progressive disease, unrelated adverse event (AE), patient or physician decision, or loss to follow-up. Eighty (91%) pts had premedication for IRRs. No pt had Grade ≥3 IRR. Overall, 18 (21%) had IRRs (2 Grade 1, 16 Grade 2), all but 1 of which occurred in C1 (120 min). Of the 18 pts with IRRs, 17 (94%) were premedicated and 10 (56%) were treated for IRRs. The overall rate of IRRs in premedicated pts was 21% (17/80) and in non-premedicated pts was 13% (1/8). One pt experienced IRRs in both C1 and C2 (Grade 2 in C1 and Grade 1 in C2); the same patient then received 6 additional cycles of M (30 min) with no IRRs after C2 (C3-8) and had no premedication after C1. No pt discontinued treatment due to an IRR. Of 88 pts enrolled, 85 (97%) pts experienced an AE, and 7 (8%) had Grade ≥3 AEs. Fifty (57%) pts had M-related AEs. The most common (&gt;5% of pts) M-related AEs were IRRs in 17 (19%), fatigue in 9 (10%), diarrhea in 5 (6%), and aspartate aminotransferase increase in 5 (6%). Serious AEs occurred in 13/88 pts (15%), none of which were considered M-related by the investigator. Conclusions: In this heavily pretreated population, shorter M infusion times did not lead to an increase in IRRs. IRRs were most likely to occur during C1 when the infusion time was 120 min. No Grade ≥3 IRRs were observed. Of 18 pts with Grade 1-2 IRRs, only 1 had an IRR after C1. These results showed that the acceptable safety and tolerability profile of M was maintained even after infusion time is reduced to 30-min from C2 onward. Shorter infusion times may reduce the burden of chronic M therapy on pts, caregivers, and clinic staff.
Citation Format: William J. Gradishar, Seock-Ah Im, Fatima Cardoso, Javier Cortes, Giuseppe Curigliano, Mark D. Pegram, Antonino Musolino, Rosanna Berardi, Michelino De Laurentiis, Shakeela W. Bahadur, Young-Hyuck Im, Cynthia Lynch, Yelena Novik, Sutton Edlich, Edwin Rock, Shengyan Hong, Hope S. Rugo, 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: Infusion time substudy results [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 P1-18-04.