Margetuximab plus pembrolizumab in patients with previously treated, HER2-positive gastro-oesophageal adenocarcinoma (CP-MGAH22–05): a single-arm, phase 1b–2 trial

Catenacci, Daniel V.T.; Kang, Yoon‐Koo; Park, Haeseong; Uronis, Hope E.; Lee, Keun-Wook; Ng, Matthew; Enzinger, Peter C.; Park, Se Hoon; Gold, Philip J.; Lacy, Jill; Hochster, Howard S.; Oh, Sang Cheul; Kim, Yeul Hong; Marrone, Kristen A.; Kelly, Ronan J.; Juergens, Rosalyn A.; Kim, Jong Gwang; Bendell, Johanna C.; Alcindor, Thierry; Sym, Sun Jin; Song, Eun-Kee; Chee, Cheng Ean; Chao, Yee; Kim, Sunnie S. Y.; Lockhart, A. Craig; Knutson, Keith L.; Yen, Jennifer; Franovic, Aleksandra; Nordstrom, Jeffrey L.; Li, Daner; Wigginton, Jon M.; Davidson-Moncada, Jan K.; Rosales, Minori Koshiji; Bang, Yung‐Jue

doi:10.1016/s1470-2045(20)30326-0

Cited by 154 publications

(123 citation statements)

References 27 publications

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“…Margetuximab is an Fc (fragment crystallizable region) engineered HER2 -directed monoclonal antibody with enhanced ADCC activity [ 38 ]; notably enough, promising antitumor activity has been reported in early-phase clinical trials on HER2-positive cancer patients, including low HER2 -expressing GC [ 39 ]. In particular, the combination of the PD-1 inhibitor pembrolizumab plus margetuximab has shown promising levels of activity in a phase Ib-II trial in HER2 -positive GCs and GEJ cancers, with an ORR of 35.7% and a DCR of 67.9% in the HER2 3+ and PD-L1 positive patient population [ 40 ]. Based on this biological rationale and this preliminary evidence, the combination of the PD-1 inhibitor plus margetuximab seems to show a synergistic activity, with a favorable safety profile.…”

Section: Margetuximabmentioning

confidence: 99%

Novel HER2-Directed Treatments in Advanced Gastric Carcinoma: AnotHER Paradigm Shift?

Ricci

Rizzo

Llimpe

et al. 2021

Cancers

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Human epidermal growth factor receptor 2 (HER2) is overexpressed and/or amplified in approximately 15–20% of gastric adenocarcinoma (GC) patients. In 2010, the landmark ToGA trial established the combination of trastuzumab plus chemotherapy as the first-line standard of care for HER2-positive GC patients with advanced disease. However, subsequent studies on HER2 targeted therapies in this setting failed to meet their primary endpoints, and not all HER2-positive GC patients benefit from targeted approaches. More recently, novel HER2-directed treatments have been investigated, including trastuzumab deruxtecan (T-Dxd); following the results of the DESTINY-Gastric01 study, T-Dxd received its first U.S. Food and Drug Administration (FDA) approval on 15 January 2021 for the treatment of adults with unresectable, locally advanced, or metastatic GC who have received a prior trastuzumab-based regimen. In this review, we discuss the current HER2-targeted treatments for GC in the advanced disease setting, mainly focusing on emerging new treatments and future research directions.

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Section: Margetuximabmentioning

confidence: 99%

Novel HER2-Directed Treatments in Advanced Gastric Carcinoma: AnotHER Paradigm Shift?

Ricci

Rizzo

Llimpe

et al. 2021

Cancers

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“…The HER-2 inhibitor trastuzumab has immune mechanisms of action involving innate and adaptative immunity through antibody-dependent cellular cytotoxicity, upregulation of PD-L1 and promotion of immune infiltration [127,128]. In the global phase I-II CP-MGAH22-05 trial, the association of the novel anti-HER2 mAb margetuximab and pembrolizumab provided positive results in terms of safety and efficacy (ORR 18%, DCR 53%) in 95 pre-treated HER2-positive mGC patients [129].…”

Section: Metastatic Disease: Second Line Treatment and Beyondmentioning

confidence: 99%

How to Best Exploit Immunotherapeutics in Advanced Gastric Cancer: Between Biomarkers and Novel Cell-Based Approaches

Ghidini

Petrillo²,

Botticelli

et al. 2021

JCM

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Despite extensive research efforts, advanced gastric cancer still has a dismal prognosis with conventional treatment options. Immune checkpoint inhibitors have revolutionized the treatment landscape for many solid tumors. Amongst gastric cancer subtypes, tumors with microsatellite instability and Epstein Barr Virus positive tumors provide the strongest rationale for responding to immunotherapy. Various predictive biomarkers such as mismatch repair status, programmed death ligand 1 expression, tumor mutational burden, assessment of tumor infiltrating lymphocytes and circulating biomarkers have been evaluated. However, results have been inconsistent due to different methodologies and thresholds used. Clinical implementation therefore remains a challenge. The role of immune checkpoint inhibitors in gastric cancer is emerging with data from monotherapy in the heavily pre-treated population already available and studies in earlier disease settings with different combinatorial approaches in progress. Immune checkpoint inhibitor combinations with chemotherapy (CT), anti-angiogenics, tyrosine kinase inhibitors, anti-Her2 directed therapy, poly (ADP-ribose) polymerase inhibitors or dual checkpoint inhibitor strategies are being explored. Moreover, novel strategies including vaccines and CAR T cell therapy are also being trialed. Here we provide an update on predictive biomarkers for response to immunotherapy with an overview of their strengths and limitations. We discuss clinical trials that have been reported and trials in progress whilst providing an account of future steps needed to improve outcome in this lethal disease.

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“…The hiPSC models are a promising development in this space that will allow study groups to more clearly identify specific cardiotoxic mechanisms of HER2-mAb therapies and could enable the prediction of susceptibility to cardiotoxicity or offer potential therapies for cardioprotection [87]. Toxicity and adverse effects of margetuximab are still under investigation, though promising clinical trials in patients report little to no adverse effects with the most serious being anemia or infusion-related reactions [88]. Table 1 provides a summary of studies that attempt to identify specific cardiotoxic mechanisms of trastuzumab and predict susceptibility to cardiovascular toxicity.…”

Section: Modeling Her2 Monoclonal Antibodiesmentioning

confidence: 99%

Modeling Precision Cardio-Oncology: Using Human-Induced Pluripotent Stem Cells for Risk Stratification and Prevention

et al. 2021

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Purpose of Review Cardiovascular toxicity is a leading cause of mortality among cancer survivors and has become increasingly prevalent due to improved cancer survival rates. In this review, we synthesize evidence illustrating how common cancer therapeutic agents, such as anthracyclines, human epidermal growth factors receptors (HER2) monoclonal antibodies, and tyrosine kinase inhibitors (TKIs), have been evaluated in cardiomyocytes (CMs) derived from human-induced pluripotent stem cells (hiPSCs) to understand the underlying mechanisms of cardiovascular toxicity. We place this in the context of precision cardio-oncology, an emerging concept for personalizing the prevention and management of cardiovascular toxicities from cancer therapies, accounting for each individual patient’s unique factors. We outline steps that will need to be addressed by multidisciplinary teams of cardiologists and oncologists in partnership with regulators to implement future applications of hiPSCs in precision cardio-oncology. Recent Findings Current prevention of cardiovascular toxicity involves routine screenings and management of modifiable risk factors for cancer patients, as well as the initiation of cardioprotective medications. Despite recent advancements in precision cardio-oncology, knowledge gaps remain and limit our ability to appropriately predict with precision which patients will develop cardiovascular toxicity. Investigations using patient-specific CMs facilitate pharmacological discovery, mechanistic toxicity studies, and the identification of cardioprotective pathways. Studies with hiPSCs demonstrate that patients with comorbidities have more frequent adverse responses, compared to their counterparts without cardiac disease. Further studies utilizing hiPSC modeling should be considered, to evaluate the impact and mitigation of known cardiovascular risk factors, including blood pressure, body mass index (BMI), smoking status, diabetes, and physical activity in their role in cardiovascular toxicity after cancer therapy. Future real-world applications will depend on understanding the current use of hiPSC modeling in order for oncologists and cardiologists together to inform their potential to improve our clinical collaborative practice in cardio-oncology. Summary When applying such in vitro characterization, it is hypothesized that a safety score can be assigned to each individual to determine who has a greater probability of developing cardiovascular toxicity. Using hiPSCs to create personalized models and ultimately evaluate the cardiovascular toxicity of individuals’ treatments may one day lead to more patient-specific treatment plans in precision cardio-oncology while reducing cardiovascular disease (CVD) morbidity and mortality.

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Margetuximab plus pembrolizumab in patients with previously treated, HER2-positive gastro-oesophageal adenocarcinoma (CP-MGAH22–05): a single-arm, phase 1b–2 trial

Cited by 154 publications

References 27 publications

Novel HER2-Directed Treatments in Advanced Gastric Carcinoma: AnotHER Paradigm Shift?

Novel HER2-Directed Treatments in Advanced Gastric Carcinoma: AnotHER Paradigm Shift?

How to Best Exploit Immunotherapeutics in Advanced Gastric Cancer: Between Biomarkers and Novel Cell-Based Approaches

Modeling Precision Cardio-Oncology: Using Human-Induced Pluripotent Stem Cells for Risk Stratification and Prevention

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