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Several anti-HER2 agents are approved for third-line treatment and beyond (after first-line and second-line); however, no specific treatment strategy is recommended for third-line and beyond. Although these agents improve disease outcomes, HER2-positive metastatic breast cancer remains incurable and there is an unmet need for effective therapies in the later line setting. This review focuses on the development of margetuximab-cmkb, a novel, Fc-engineered, anti-HER2 monoclonal antibody, and its role in the systemic treatment of adult patients with metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 regimens, at least one of which was for metastatic disease.

Purpose: To assess the ability of circulating tumor DNA (ctDNA)-based testing to identify patients with HER2 (encoded by ERBB2)-positive gastric/gastroesophageal adenocarcinoma (GEA) who progressed on or after trastuzumab-containing treatments were treated with combination therapy of anti-HER2 and anti-PD-1 agents., Methods: ctDNA analysis was performed retrospectively using plasma samples collected at study entry from 86 patients participating in the phase 1/2 CP-MGAH22-05 study (NCT02689284)., Results: Objective response rate (ORR) was significantly higher in evaluable ERBB2 amplification-positive vs - negative patients based on ctDNA analysis at study entry (37% vs 6%, respectively; P = .00094). ORR was 23% across all patients who were evaluable for response. ERBB2 amplification was detected at study entry in 57% of patients (all HER2 positive at diagnosis), and detection was higher (88%) when HER2 status was determined by immunohistochemistry fewer than 6 months before study entry. ctDNA was detected in 98% (84/86) of patients tested at study entry. Codetected ERBB2-activating mutations were not associated with response., Conclusions: Current ERBB2 status may be more effective than archival status at predicting clinical benefit from margetuximab plus pembrolizumab therapy. ctDNA testing for ERBB2 status prior to treatment will spare patients from repeat tissue biopsies, which may be reserved for reflex testing when ctDNA is not detected.

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.

Background: Human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric and gastroesophageal adenocarcinoma (GEA) is globally treated with chemotherapy plus trastuzumab. Novel therapeutic strategies strive to not only optimize efficacy, but also limit toxicities. In MAHOGANY cohort A, margetuximab, an Fc-engineered, anti-HER2 monoclonal antibody (mAb) was combined with retifanlimab, an anti-programmed cell death protein 1 mAb, in the first-line HER2-positive/programmed death-ligand 1 (PD-L1)-positive GEA., Patients and Methods: MAHOGANY cohort A part 1 is a single-arm trial to evaluate margetuximab plus retifanlimab in patients with HER2 immunohistochemistry 3+, PD-L1-positive (combined positive score ≥1%), and non-microsatellite instability-high tumors. Primary objectives for cohort A were safety/tolerability and the confirmed objective response rate (ORR)., Results: As of 3 August 2021, 43 patients were enrolled and received margetuximab/retifanlimab. Nine grade 3 treatment-related adverse events (TRAEs) were reported in eight (18.6%) patients and eight serious TRAEs in seven (16.3%) patients. There were no grade 4/5 TRAEs. Three patients discontinued margetuximab/retifanlimab because of immune-related adverse events. The ORR by independent assessment was 53% [21/40 (95% confidence interval (CI) 36.1-68.5)], with a median duration of response of 10.3 months (95% CI 4.6-not evaluable); disease control rate was 73% [29/40 (95% CI 56.1-85.4)]. The study sponsor discontinued the study in advance of the planned enrollment when it became apparent that the study design would no longer meet the requirements for drug approval because of recent advances in the treatment of GEA., Conclusions: The chemotherapy-free regimen of combined margetuximab/retifanlimab as first-line treatment in double biomarker-selected patients demonstrated a favorable toxicity profile compared with historical outcomes using chemotherapy plus trastuzumab. The ORR observed in this study compares favorably versus ORR observed with other chemotherapy-free approaches., Competing Interests: Disclosure DVTC has received personal fees from Archer, Astellas Pharma, Bristol Myers Squibb, Daiichi Sankyo, Five Prime Therapeutics, Foundation Medicine, Guardant Health, Tempus Labs, Genentech/Roche, Gritstone Oncology, Lilly, Merck, Novartis, AstraZeneca, Natera, Pieris Pharmaceuticals, QED Therapeutics, Seattle Genetics, Taiho Pharmaceutical, and Zymeworks. YKK has received consulting fees from ALX Oncology, Amgen, Blueprint Medicines, Bristol Myers Squibb, Daehwa Pharmaceutical, MacroGenics, Merck & Co., Inc., Novartis, Roche, Surface Oncology, and Zymeworks. HHY has received payments to the institution for grants from Bristol Myers Squibb and Merck & Co., Inc.; consulting fees from ALX Oncology, Astellas Pharma, AstraZeneca, BeiGene, Bristol Myers Squibb, MacroGenics, Merck & Co, Inc., Novartis, OncXerna Therapeutics, and Zymeworks; honoraria from BeiGene; and advisory board or data safety monitoring board payments from ALX Oncology, Astellas Pharma, AstraZeneca, BeiGene, Bristol Myers Squibb, MacroGenics, Merck & Co., Inc., Novartis, OncXerna Therapeutics, and Zymeworks. DYO has received grants from Array BioPharma, AstraZeneca, BeiGene, Lilly, HANDOK, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Novartis, and Servier Pharmaceuticals; and participated in advisory boards for ASLAN Pharmaceuticals, AstraZeneca, Basilea Pharmaceutica, Bayer, BeiGene, Celgene, a Bristol-Myers Squibb Company, Genentech/Roche, Halozyme, Merck Serono, Novartis, Taiho Pharmaceutical, Turning Point Therapeutics, and Zymeworks. AIS has received stock payments from Lilly; payments for leadership role from NEXT Oncology; honoraria from Amgen, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, CytomX Therapeutics, Janssen Oncology, Merck, Novartis, and Takeda; and personal and institutional payments for advisory boards from Amgen, Array BioPharma, AstraZeneca, Bristol Myers Squibb, Gritstone Oncology, Incyte, Janssen Research and Development, Merck & Co., Inc., Mirati Therapeutics, Novartis, and Takeda; consulting fees from Amgen, Array BioPharma, AstraZeneca, Bristol Myers Squibb, Gritstone Oncology, Janssen Research and Development, Jazz Pharmaceuticals, Incyte, Merck & Co., Inc., Mirati Therapeutics, Novartis, and Takeda; and grants and other support from AbbVie, ADC Therapeutics, Amgen, Arch Therapeutics, Astellas Pharma, Astex Pharmaceuticals, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, CytomX Therapeutics, Daiichi Sankyo, Gritstone Oncology, Ignyta, Incyte, Janssen Oncology, LAM Therapeutics, Loxo Oncology, MacroGenics, MedImmune, Mirati Therapeutics, NewLink Genetics, Novartis, Plexxikon, Roche, Rubius Therapeutics, Takeda, and TrovaGene. SVU has participated in advisory boards for Array BioPharma, Bayer, Eisai, Exelixis, Incyte, and Syros Pharmaceuticals; and grants to institution from AbbVie, ArQule, AstraZeneca, Atreca, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, a Bristol-Myers Squibb Company, CicloMed, Evelo Biosciences, Exelixis, G1 Therapeutics, GlaxoSmithKline, IGM Biosciences, Incyte, Isofol Medical, KLUS Pharma, MacroGenics, Merck & Co., Inc., Mersana Therapeutics, OncoMed Pharmaceuticals, Pfizer, Regeneron Pharmaceuticals, Revolution Medicines, Synermore Biologics, Takeda, Tarveda Therapeutics, Tesaro, Tempest Therapeutics, and Vigeo Therapeutics. EJA has received research funding from Bristol Myers Squibb, AstraZeneca, Seagen, AbbVie, and Lilly; consulting fees from AstraZeneca, Janssen Biotech, and McKesson. PMB has received consulting fees from Bristol Myers Squibb and Merck; grants/research support to institution from Ipsen, Processa Pharmaceuticals, AbbVie, MacroGenics, Merck, Taiho Pharmaceutical, and Athenex. JC has received consulting fees from Amgen, Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Foundation Medicine, Lilly, MacroGenics, Merck & Co., Inc., Novartis, Ono Pharmaceutical, Silverback Therapeutics, and Turning Point Therapeutics; speaker’s bureau honorarium from Bristol Myers Squibb and Merck and Co., Inc.; data safety monitoring board member fees from Yiviva; and research payments to the institution from Brooklyn ImmunoTherapeutics, MacroGenics, and Merck & Co., Inc. HCC received grants/research support from Lilly, GlaxoSmithKline, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Merck Serono, Bristol Myers Squibb/Ono Pharmaceutical, Taiho Pharmaceutical, Amgen, BeiGene, Incyte, and Zymeworks; received honoraria from Lilly and Merck Serono; and did consultation for Amgen, BeiGene, Bristol Myers Squibb, Celltrion, Gloria Therapeutics, Lilly, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Merck Serono, Taiho Pharmaceutical, and Zymeworks. FG has received consulting fees for participating on advisory boards from Janssen, Epizyme, and Regeneron/Sanofi; speaker’s bureau honorarium from Epizyme, Regeneron/Sanofi, and Pfizer. SJK has received consulting fees for participating on advisory boards from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Lilly, Merck & Co., Inc., Natera, and Pieris Pharmaceuticals; and stock options from Turning Point Therapeutics. KWL has received consulting fees from Bayer, Bristol Myers Squibb, Daiichi Sankyo, and ISU ABXIS; honorarium from Boryung Pharmaceutical and Ono Pharmaceutical; and research grants to the institution from ABL Bio, ALX Oncology, Astellas Pharma, AstraZeneca, BeiGene, Bolt Biotherapeutics, Daiichi Sankyo, Five Prime Therapeutics, Genexine, Green Cross Corp, InventisBio, Leap Therapeutics, LSK BioPharma, MacroGenics, MedPacto, Merck KGaA, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Oncologie, Pharmacyclics, Ono Pharmaceutical, Pfizer, Seagen, Taiho Pharmaceutical, Trishula Therapeutics, Y-Biologics, and Zymeworks for conducting clinical trials. JP has received honoraria from Agendia, Guardant Health, and Tempus; consulting fees from TerSera Therapeutics; research funding for clinical trials from AbbVie, BerGenBio, Calithera Biosciences, Inc, eFFECTOR Therapeutics, EMD Serono, Epizyme, Genentech/Roche, Immunity Bio, Immutep S.A.S., Incyte, Janssen Pharmaceuticals, Jounce Therapeutics, Lilly, KeChow Pharma, Loxo Oncology, MacroGenics, Inc., Merck, Mirati, Natera, Novocure Ltd, Sermonix Pharmaceuticals, TerSera Therapeutics, Turning Point Therapeutics, Salarius Pharmaceuticals, Immunomedics, Pfizer, and Kyowa Kirin; and owns stocks of Oncology Consultants, Zogen, Spectrum Pharmaceuticals, Roche, TerSera Therapeutics. LS has received consulting fees from Boehringer Ingelheim, Haichuang Pharmaceutical, Harbour BioMed, Merck & Co., Inc., Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., and Mingji Biopharmaceutical; speaker’s bureau fees from CStone Pharmaceuticals, Jiangsu Hengrui Pharmaceuticals, Hutchison Whampoa, and Zai Lab; participated on advisory boards for Bristol Myers Squibb, CStone Pharmaceuticals, Rongchang Pharmaceuticals, and Zai Lab; and grants to the institution from Beihai Kangcheng (Beijing) Medical Technology, Beijing Xiantong Biomedical Technology, Jacobio Pharmaceuticals, Qilu Pharmaceutical, and Zai Lab. MM has received grants and nonfinancial support from the AIO, BMBF, EORTC, and German Cancer Aid; personal fees from Amgen, Bristol Myers Squibb, Falk Foundation, Lilly, MGI Group, Merck Serono, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Pfizer, Roche, and Taiho Pharmaceutical; grants to the institution from Amgen, Bristol Myers Squibb, Merck Serono, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., and Pfizer; and nonfinancial support from Amgen and Bristol Myers Squibb paid to the institution. JS, DL, and MKR are/were employees of MacroGenics and hold stock in the company. HP has received grants to institution from Adlai Nortye USA, Alpine Immune Sciences, Ambrx, Amgen, Aprea Therapeutics AB, Array BioPharma, Bayer, BeiGene, BJ Bioscience Inc., Bristol Myers Squibb, Daiichi Sankyo, Lilly, Elicio Therapeutics, EMD Serono, Exelixis, Genentech, Gilead Sciences, GlaxoSmithKline, Gossamer Bio, Hoffman-La Roche, Hutchison MediPharma, ImmuneOncia Therapeutics, Incyte, Jounce Therapeutics, MabSpace Biosciences, MacroGenics, MedImmune, Medivation, Merck & Co., Inc., Millennium Pharmaceuticals, Mirati Therapeutics, Novartis, Oncologie, Pfizer, PsiOxus Therapeutics, Puma Biotechnology, Regeneron Pharmaceuticals, Repare Therapeutics, Seattle Genetics, Synermore Biologics, Taiho Pharmaceutical, TopAlliance Biosciences, Turning Point Therapeutics, Vedanta Biosciences, and Xencor; writing support from MacroGenics; and participated in advisory boards for Jacobio Pharmaceuticals. BYS, STK, SCO, and MBS have declared no conflicts of interest. Data sharing The data collected for the study will not be made available to others., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Since completion of the Trastuzumab for Gastric Cancer study, trastuzumab with doublet chemotherapy (a fluoropyrimidine and a platinum) has been the gold-standard first-line therapy for patients with locally advanced unresectable or metastatic human epidermal growth factor receptor 2-positive (HER2+) gastroesophageal adenocarcinoma (GEA). The safety and efficacy of 23 studies of first-line trastuzumab plus doublet chemotherapy, without checkpoint inhibitors (n = 19) or with checkpoint inhibitors (n = 4), conducted in patients with locally advanced unresectable or metastatic HER2+ GEA, including phase II/III, prospective, and retrospective observational studies, were summarized. In studies without checkpoint inhibitors, the median duration of trastuzumab treatment ranged from 19.5 to 39.0 weeks and from 15.3 to 30.0 weeks for chemotherapy. In studies with checkpoint inhibitors, the median duration of pembrolizumab/trastuzumab/chemotherapy was 30 weeks, and 18 weeks for chemotherapy. In studies without checkpoint inhibitors, treatment-emergent adverse events (TEAEs) of grade ≥3 ranged from 32% to 84%. Serious adverse events (SAEs) ranged from 15% to 39%. Adverse events resulting in discontinuation ranged from 0% to 30%. Treatment-related deaths occurred in 0%-9% of patients. In studies with checkpoint inhibitors, TEAEs of grade ≥3 were 57%. SAEs ranged from 31% to 38%. Adverse events resulting in discontinuation ranged from 5% to 24%. Treatment-related deaths occurred in 0%-3% of patients. In studies without checkpoint inhibitors, objective response rate (ORR) ranged from 39% to 82%, median progression-free survival (PFS) from 5.7 to 11.6 months, and median overall survival (OS) from 11.2 to 27.6 months. In studies with checkpoint inhibitors, ORR ranged from 39% to 86%, median PFS from 8.0 to 13.0 months, and median OS from 19.3 to 27.3 months. This review provides a historical benchmark on safety and efficacy of available first-line chemotherapy-based standard of care for patients with locally advanced unresectable or metastatic HER2+ GEA., Competing Interests: Disclosure DVTC reports personal fees from Archer, Astellas Pharma, Bristol-Myers Squibb, Daiichi Sankyo, Five Prime, Foundation Medicine, Guardant Health, Genentech/Roche, Gritstone Oncology, Lilly, Merck, Natera, Pieris Pharmaceuticals, QED Therapeutics, Seattle Genetics, Taiho Pharmaceutical, Tempus Labs, and Zymeworks; HCC has received consultation fees from Taiho Pharmaceutical, Celltrion, Merck Sharpe & Dohme, Eli Lilly, Bristol Myers Squibb, Merck-Serono, Gloria Pharmaceuticals, BeiGene, Amgen, and Zymeworks; grants to institution for clinical trial from Eli Lilly, GlaxoSmithKline, Merck Sharpe & Dohme, Merck-Serono, Bristol Myers Squibb/Ono Pharmaceutical, Taiho Pharmaceutical, Amgen, BeiGene, and Incyte; and honoraria from Merck-Serono and Eli Lilly; LS reports grants from Beijing Xiantong Biomedical Technology, Beihai Kangcheng (Beijing) Medical Technology, Boehringer Ingelheim, Jacobio Pharmaceuticals, Qilu Pharmaceutical, and Zaiding Pharmaceutical (Shanghai); and consulting fees from Harbour BioMed and Merck; MM reports grants and nonfinancial support from Arbeitsgemeinschaft Internistische Onkologie, German Ministry of Education and Research, the European Organisation for Research and Treatment of Cancer, and German Cancer Aid; personal fees from Amgen, Bristol-Myers Squibb, Falk Foundation, Lilly, MCI Group, Merck Serono, Merck Sharp & Dohme Corp., Pfizer and Roche; grants to the university from Amgen, Bristol-Myers Squibb, Merck Serono, Merck Sharp & Dohme Corp., and Pfizer; and nonfinancial support from Amgen and Bristol-Myers Squibb; HHY reports honoraria for advisory board and steering committee from MacroGenics, honoraria for advisory boards from Bristol-Myers Squibb and Zymeworks, and honoraria for steering committees from BeiGene and Merck; Y-KK reports consulting fees from ALX Oncology, Amgen, Astellas Pharma, Bristol-Myers Squibb, Daehwa Pharmaceutical, MacroGenics, Merck, Novartis, Ono Pharmaceutical, Surface Oncology, Taiho Pharmaceutical, and Zymeworks; MKR is a full-time employee of MacroGenics., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The high-probability (high-p) instructional sequence typically consists of the delivery of a series of high-p instructions immediately followed by the delivery of a low-probability (low-p) instruction and is a commonly used procedure to increase compliance among children with intellectual disabilities. In the current study, we used withdrawal designs to evaluate the use of the high-p sequence to increase compliance with a series of 2 or 3 low-p instructions among 3 children with autism. The sequence was moderately effective in increasing compliance with all low-p instructions for 2 participants. Compliance exhibited by the 3rd participant, for whom the high-p sequence was ineffective, increased when differential reinforcement was delivered. We discuss the utility of the high-p sequence to increase compliance with multiple instructions and the putative mechanisms responsible for the effects of the sequence., (© 2020 Society for the Experimental Analysis of Behavior (SEAB).)

Background: Margetuximab, a novel, investigational, Fc-engineered, anti-HER2 monoclonal antibody, is designed to more effectively potentiate innate immunity than trastuzumab. We aimed to evaluate the safety, tolerability, and antitumour activity of margetuximab plus pembrolizumab (an anti-PD-1 monoclonal antibody) in previously treated patients with HER2-positive gastro-oesophageal adenocarcinoma., Methods: CP-MGAH22-05 was a single-arm, open-label, phase 1b-2 dose-escalation and cohort expansion study done at 11 academic centres in the USA and Canada and 15 centres in southeast Asia (Korea, Taiwan, and Singapore) that enrolled men and women aged 18 years or older with histologically proven, unresectable, locally advanced or metastatic, HER2-positive, PD-L1-unselected gastro-oesophageal adenocarcinoma, with an Eastern Cooperative Oncology Group performance status of 0 or 1, who had progressed after at least one previous line of therapy with trastuzumab plus chemotherapy in the locally advanced unresectable or metastatic setting. In the dose-escalation phase, nine patients were treated: three received margetuximab 10 mg/kg intravenously plus pembrolizumab 200 mg intravenously every 3 weeks and six received the recommended phase 2 dose of margetuximab 15 mg/kg plus pembrolizumab 200 mg intravenously every 3 weeks. An additional 86 patients were enrolled in the phase 2 cohort expansion and received the recommended phase 2 dose. The primary endpoints were safety and tolerability, assessed in the safety population (patients who received at least one dose of either margetuximab or pembrolizumab) and the objective response rate as assessed by the investigator according to both Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, in the response-evaluable population (patients with measurable disease at baseline and who received the recommended phase 2 dose of margetuximab and pembrolizumab). This trial is registered with ClinicalTrials.gov, NCT02689284. Recruitment for the trial has completed and follow-up is ongoing., Findings: Between Feb 11, 2016, and Oct 2, 2018, 95 patients were enrolled. Median follow-up was 19·9 months (IQR 10·7-23·1). The combination therapy showed acceptable safety and tolerability; there were no dose-limiting toxicities in the dose-escalation phase. The most common grade 3-4 treatment-related adverse events were anaemia (four [4%]) and infusion-related reactions (three [3%]). Serious treatment-related adverse events were reported in nine (9%) patients. No treatment-related deaths were reported. Objective responses were observed in 17 (18·48%; 95% CI 11·15-27·93) of 92 evaluable patients., Interpretation: These findings serve as proof of concept of synergistic antitumour activity with the combination of an Fc-optimised anti-HER2 agent (margetuximab) along with anti-PD-1 checkpoint blockade (pembrolizumab)., Funding: MacroGenics., (Copyright © 2020 Elsevier Ltd. All rights reserved.)