Abstract PS10-12: Integrated safety summary of single agent and combination margetuximab in phase 1, 2, and 3 studies of HER2-positive advanced cancers and metastatic breast cancer (MBC)
Authors: Im Seock-Ah , Cardoso Fatima , Cortes Javier , Curigliano Giuseppe , Pegram Mark D. , Rugo Hope S. , Brown-Glaberman Ursa , Yardley Denise A. , Kim Sung-Bae , de Boer Maaike , Nowecki Zbigniew , Glavicic Vesna , Wolf Ido , Claes Nele , Sohn Joo Hyuk , Bachelot Thomas , Kaufman Peter A. , Baughman Jan , Hong Shengyan , Jacobs Kenneth , Rock Edwin , Gradishar William J. 
Published: February 2021

Abstract
Background Margetuximab (M) is an investigational Fc-engineered anti-HER2 monoclonal antibody that targets the same epitope as trastuzumab (T). 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 more effectively than T in vitro, including CD16A-mediated antibody-dependent cellular cytotoxicity. Samples collected from patients (pts) before and after single-agent treatment also demonstrate that M induces HER2-specific adaptive immune responses, including both T- and B-cell responses. The SOPHIA trial (NCT02492711) in pts with pretreated HER2+ MBC showed that M+chemotherapy (chemo) improved progression-free survival vs T+chemo, with comparable safety. A pooled analysis of M safety across 3 clinical trials is presented. Methods Study 01 (NCT01148849), an ongoing Phase 1 dose-finding/safety study of M monotherapy, enrolled 66 pts with advanced HER2+ carcinomas, including 27 with MBC. Study 02 (NCT01828021), a completed Phase 2 study of M monotherapy in low-expressing HER2+ MBC, enrolled 25 pts. Study 04 (NCT02492711), an ongoing Phase 3 study in pts with pretreated HER2+ MBC to compare M + chemo vs T + chemo, randomized 536 pts, of whom 264 and 265 received M and T, respectively. The pooled safety population includes all pts who received any M in Study 01 (cutoff 01Oct2015), Study 02 (cutoff 02Aug2017), and Study 04 (cutoff 10OCT2018). Treatment-emergent adverse events (AEs), defined as AEs that began or worsened in severity on or after first dose of study drug through an End of Treatment Visit or 28 days after last study treatment, are reported. Results Of 355 pts that received at least 1 dose of M, 295 received 15 mg/kg Q3W, and 60 received other doses from 0.1 - 18 mg/kg. Median (mean, range) number of cycles for all dose levels was 5.0 (6.6, 1-43), higher on Study 04 (6.0) than Study 01 (1-3 across dose groups) or Study 02 (2.0). Most pts (347 [97.7%]) experienced at least 1 AE, and about half (173 [48.7%]) had at least 1 Grade &gt;/= 3 AE. Serious AE (SAE) incidence across studies was low (58 [16.3%]), and 21 pts (5.9%) discontinued M due to AEs. Most frequently reported AEs (&gt;/= 20%) were fatigue (124 [34.9]), nausea (103 [29.0%]), diarrhea (75 [21.1%]), and neutropenia (75 [21.1%]). Blood/lymphatic system disorders were the most frequent events by SOC, and largely restricted to Study 04. Increased neutropenia on M (26.1%), relative to T (20.4%), was observed in Study 04 yet both febrile neutropenia (M 3.0%, T 4.5%) and infections (M 36.4%, T 39.6%) were higher on T. By contrast, Study 01 and Study 02 revealed no tendency of M monotherapy to cause neutropenia. Overall, infusion related reactions (IRRs) were observed in 51 pts (14.4%), primarly at first infusion, including serious IRRs in 5 (1.4%). Also, 34 pts (9.6%) had &gt; 15% reduction in LVEF with a median time to &gt; 15% reduction of 49 days. In all pts with complete follow-up, these LVEF reductions were asymptomatic and reversible. No M-induced cardiac conduction abnormalities were noted. In Study 04, similar proportions in both groups experienced AEs (M 97.7%, T 96.2%), including Grade &gt;/= 3 AEs (M 52.3%, T 48.3%), SAEs (M 14.8%, T 17.4%), discontinuations due to AEs (M 3.0%, T 2.6%), and deaths due to AEs (M 0.8%, T 0.8%). As of the 23Feb2020 safety update, 2 pts remain on M in Study 01, after 116 and 109 cycles (6.7 and 6.3 years), respectively. In Study 04, 16 pts (6%) continued on M, and 7 (2.6%) remained on T. Discussion M has demonstrated an acceptable safety profile across Phase 1, 2, and 3 studies. It has been administered for over 6 years without long-term cumulative safety issues. Combined M plus chemotherapy Q3W demonstrated acceptable safety and tolerability, similar to that for T plus chemotherapy Q3W in Study 04.
Citation Format: Seock-Ah Im, Fatima Cardoso, Javier Cortes, Giuseppe Curigliano, Mark D. Pegram, Hope S. Rugo, Ursa Brown-Glaberman, Denise A. Yardley, Sung-Bae Kim, Maaike de Boer, Zbigniew Nowecki, Vesna Glavicic, Ido Wolf, Nele Claes, Joo Hyuk Sohn, Thomas Bachelot, Peter A. Kaufman, Jan Baughman, Shengyan Hong, Kenneth Jacobs, Edwin Rock, William J. Gradishar. Integrated safety summary of single agent and combination margetuximab in phase 1, 2, and 3 studies of HER2-positive advanced cancers and metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-12.