Liquid Chromatography Tandem Mass Spectrometric Method for Quantification of Margetuximab in Rat Plasma and Application to a Pharmacokinetic Study.

Margetuximab was approved for the treatment of advanced HER2+ breast cancer. A feasible analytical technique that can measure this drug was obligatory. In light of this, a novel and thoroughly validated liquid chromatographic (LC)-tandem mass spectrometric (MS/MS) approach was developed for the quantification of margetuximab in rat plasma. The liquid-liquid extraction method was used to extract the analyte from rat plasma. The analyte was separated using acetonitrile and formic acid buffer (30:70) as a mobile phase on Waters, alliance e-2695 model HPLC having Symmetry C18 column, 150 mm × 4.6 mm, 3.5-µm column. The overall runtime was 6 min at a flow rate of 1.0 ml/min. The method showed significant sensitivity and acceptable linearity over the concentration range of 6-120 ng/ml. Accuracy was within 98.51-99.92%. The intraday precision ranged between 0.41 and 8.98% CV. Also, the findings of pharmacokinetic parameters such as Cmax, tmax, AUC0-∞, AUC0-t, and half-life results of margetuximab showed that the technique was helpful for accurately measuring drug concentrations in rat plasma. The method that was developed was useful and effective for quantifying margetuximab.

Human Epidermal Growth Factor Receptor-2 Gastric Adenocarcinoma: Expanding Therapy of a Recognized Target.

Human epidermal growth factor receptor-2 (HER2) is a well-known cancer target. Many HER2-targeted agents are marketed and being investigated. Unfortunately, these therapies lack consistent responses and outcomes amongst different tumors. Questions remain as to why HER2 biology is different in different tumor types. Gastric adenocarcinomas (GACs) demonstrate both intra- and inter-tumor HER2 expression heterogeneity and show discordance amongst primary and metastatic disease sites. This creates barriers in determining HER2 agents' effectiveness and contributes to the failure of some HER2-targeted agents in the treatment of HER2-positive advanced GACs. Trastuzumab deruxtecan, an antibody drug conjugate of trastuzumab with a topoisomerase inhibitor, was recently approved for the treatment of refractory HER2-positive advanced GAC patients. There are exciting and newer therapies under investigation. Examining resistance patterns (both adaptive and acquired) along with establishing a better understanding of the intra- and inter-tumor heterogeneity is necessary to ensure successful progress. Here we review the current status of HER2-targeted therapy in GACs. We additionally review newer therapies under investigation and their potential role in HER2 GACs.

Metastatic HER2-Positive Breast Cancer: Is There an Optimal Sequence of Therapy?

OPINION STATEMENT: Approximately 20% of breast cancers overexpress human epidermal growth factor receptor 2 (HER2+), conferring a particularly aggressive subtype of the disease with an increased risk for the development of systemic and brain metastases. However, the advent of trastuzumab and more recently several other HER2-targeting novel therapies has led to significant improvements in the prognosis, making the diagnosis a "double-edged sword." The current standard first-line therapy for patients with HER2+ metastatic breast cancer (MBC) is a taxane combined with trastuzumab and pertuzumab. Trastuzumab deruxtecan should be used preferentially in the second line, with the only caveat being patients with CNS involvement where the tucatinib, capecitabine, and trastuzumab regimen could be considered. In the third line setting, given the survival benefits demonstrated with the tucatinib regimen in patients with and without CNS metastases, this is the preferred strategy. In the fourth line and beyond, there is no clear standard. Options include margetuximab in combination with chemotherapy, neratinib + capecitabine, or trastuzumab + chemotherapy. There are several novel therapies under investigation reporting promising results in the late-line setting. The treatment landscape of HER2-positive advanced disease is evolving constantly, with several active therapies being moved to the early-stage setting. Accordingly, it will be critical to identify biomarkers and mechanisms of resistance to optimize therapy selection and maximize patient outcomes and quality of life. Here, we provide an overview of the current and future management of HER2-positive advanced breast cancer and address the specific scenarios which may impact treatment selection including triple-positive breast cancer and the presence of brain metastases. Finally, we highlight promising novel treatments and ongoing trials that may impact future treatment sequencing.

Margetuximab in HER2-positive metastatic breast cancer.

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.

In about 20% of patients with breast cancer, their tumor cells make too many copies of a protein called HER2. We call them HER2-positive breast cancer cells. HER2 is a protein that signals to breast cancer cells to make them grow. Certain drugs, known as antibodies, are able to bind to the HER2 proteins on the surface of the tumor cells. This stops their signaling and slows down the growth of the tumor cells. These antibodies are called anti-HER2 antibodies. In addition to its 'head' region binding to HER2, the 'tail' region of the anti-HER2 antibody can bind to certain other proteins (receptors) found on the surface of immune cells. When the anti-HER2 antibodies bind to the receptors on immune cells, this starts an anticancer immune response against the HER2-positive breast cancer cells and kills them. This review explains how anti-HER2 antibodies may block and destroy HER2-positive breast cancer cells. In particular, we focus on the beneficial and adverse effects of margetuximab, an anti-HER2 antibody. The tail region of margetuximab has been changed to boost the immune responses against HER2-positive cancer cells. Margetuximab is approved in the USA for patients with HER2-positive metastatic breast cancer after they have already received two or more anti-HER2 therapies. The decision to approve this was based on the pivotal clinical trial SOPHIA.

Circulating Tumor DNA as a Predictive Biomarker for Clinical Outcomes With Margetuximab and Pembrolizumab in Pretreated HER2-Positive Gastric/ Gastroesophageal Adenocarcinoma.

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.

Margetuximab and trastuzumab deruxtecan: New generation of anti-HER2 immunotherapeutic agents for breast cancer.

Advances in the development of anti-HER2 monoclonal antibodies (mAbs) represent one of the most significant milestones in the treatment of HER2+ breast cancer patients. However, HER2+ metastatic breast cancer (MBC) patients display resistance towards first-generation anti-HER2 mAbs or antibody-drug conjugate (ADC) treatment. In recent years, new generation of anti-HER2 mAb and ADC including margetuximab and trastuzumab deruxtecan (T-DXd), respectively, have been approved for the treatment of previously treated HER2+ MBC patients. The successes of margetuximab and T-DXd have renewed the interest in the research and development of anti-HER2 immunotherapies for both HER2+ and HER2-low breast cancer patients. In this review, we focus on these two immunotherapeutics in terms of their mechanisms of action, preclinical findings and clinical trials leading to their approval, as well as the mechanisms of resistance to conventional anti-HER2 immunotherapies (i.e. trastuzumab, pertuzumab and T-DM1). In the future, combination of either margetuximab or T-DXd with small molecule inhibitors such as tyrosine kinase inhibitors that elicit anticancer immunogenicity may further enhance the efficacy of margetuximab or T-DXd in the treatment of HER2+ MBC patients.

Economic evaluation of margetuximab vs. trastuzumab for pretreated ERBB2-positive advanced breast cancer in the US and China.

Objective: To assess the economic evaluation of margetuximab plus chemotherapy over trastuzumab plus chemotherapy for women with pretreated ERBB2-positive advanced breast cancer in the United States (US) and China. Methods: Based on the SOPHIA trial, a three-state Markov model was developed to compare the cost and efficacy of margetuximab to trastuzumab for previously treated women with ERBB2-positive advanced breast cancer. The model inputs were derived from existing literature and the US life table. Primary outcomes included lifetime costs in US dollars, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). Deterministic and probabilistic sensitivity analyses were conducted to evaluate the impact of uncertainty. Results: The base case analyses demonstrated that margetuximab plus chemotherapy had an increasing cost of $68,132 and $20,540 over trastuzumab plus chemotherapy in the US and China, respectively, with a gain of 0.11 and 0.09 QALYs both favored margetuximab. The ICERs for two treatment strategies were $260,176 in the US and $630,777 in China, resulting in a poor cost-effectiveness at their respective threshold of willingness to play. One-way sensitivity analyses showed that the results to be most sensitive to the price of margetuximab and that of trastuzumab. And an 11 and 82% price reduction of margetuximab would make this regimen cost-effective in the US and China, respectively. Conclusion: In the US and China, margetuximab plus chemotherapy is not likely to be cost-effective for women with pretreated ERBB2-positive advanced breast cancer, whereas price reduction effectively improves insufficient cost-effectiveness.

Margetuximab with retifanlimab as first-line therapy in HER2+/PD-L1+ unresectable or metastatic gastroesophageal adenocarcinoma: MAHOGANY cohort A.

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.

Margetuximab conjugated-PEG-PAMAM G4 nano-complex: a smart nano-device for suppression of breast cancer.

Abstract: Breast cancer due to its high incidence and mortality is the second leading cause of death among females. On the other hand, nanoparticle-based drug delivery is one of the most promising approaches in cancer therapy, nowadays. Hence, margetuximab- and polyethylene glycol-conjugated PAMAM G4 dendrimers were efficiently synthesized for targeted delivery of quercetin (therapeutic agent) to MDA-MB-231 breast cancer cells. Synthesized nano-complexes were characterized using analytical devices such as FT-IR, TGA, DLS, Zeta potential analyzer, and TEM. The size less than 40 nm, - 18.8 mV surface charge, efficient drug loading capacity (21.48%), and controlled drug release (about 45% of drug release normal pH after 8 h) were determined for the nano-complex. In the biomedical test, the cell viability was obtained 14.67% at 24 h of post-treatment for 800 nM concentration, and IC50 was ascertained at 100 nM for the nano-complex. The expression of apoptotic Bax and Caspase9 genes was increased by more than eightfolds and more than fivefolds after treatment with an optimal concentration of nanocarrier. Also, more than threefolds of cell cycle arrest was observed at the optimal concentration synthetics, and 27.5% breast cancer cell apoptosis was detected after treatment with 100 nM nano-complex. These outputs have been indicating the potential capacity of synthesized nano-complex in inhibiting the growth of breast cancer cells.

Profile of Margetuximab: Evidence to Date in the Targeted Treatment of Metastatic HER2-positive Breast Cancer.

Human epidermal growth factor receptor 2 (HER2) positive breast cancer accounts for about 20% of all breast cancers and this subtype has been historically associated with worse prognosis. Margetuximab is a chimeric and Fc-engineered monoclonal antibody directed to HER2 that can enhance the activation of the innate and adaptive immune responses while maintaining trastuzumab's antiproliferative effects. Margetuximab in combination with chemotherapy was approved by the US FDA in December 2020 for patients with metastatic HER2+ breast cancer who have received two or more HER2-targeted regimens. This approval was based on the results of the SOPHIA trial that showed a modest improvement in progression-free survival with margetuximab and chemotherapy compared to trastuzumab and chemotherapy. Ongoing studies are assessing the role of margetuximab in other settings and diseases such as early stage breast cancer and gastrointestinal malignancies. Here we review the rationale for the development of margetuximab, previous and ongoing clinical trials and current role in clinical practice.

A Review of Margetuximab-Based Therapies in Patients with HER2-Positive Metastatic Breast Cancer.

Breast cancer (BC) is the most commonly diagnosed cancer globally, with high mortality rates. Targeted drug therapies have revolutionized cancer treatment. For example, treatment with human epidermal receptor 2 (HER2) antagonists has markedly improved the prognosis of patients with HER2-positive BC (HER2 + BC). However, HER2+ metastatic BC (MBC) remains prevalent owing to its resistance to conventional anti-HER2 drugs. Therefore, novel agents are needed to overcome the limitations of existing cancer treatments and to enhance the progression-free and overall survival rates. Progress has been made by optimizing the fragment crystallizable (Fc) domain of trastuzumab, an IgG1 monoclonal, chimeric anti-HER2 antibody, to develop margetuximab. The modified Fc domain of margetuximab enhances its binding affinity to CD16A and decreases its binding affinity to CD32B, thereby promoting its antitumor activity. This review summarizes studies on the efficacy of margetuximab, discusses its utility as an anti-HER2 monoclonal antibody drug for the treatment of HER2 + BC, and presents the latest advances in the treatment of BC. This review provides insights into the clinical implication of margetuximab in HER2 + MBC treatment.

Efficacy and safety of margetuximab plus chemotherapy vs. trastuzumab plus chemotherapy in Chinese patients with pretreated HER2-positive advanced metastatic breast cancer: results from a randomized, open-label, multicenter, phase II bridging study.

Background: Trastuzumab is the recommended first-line treatment for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) patients in China, but therapeutic resistance to trastuzumab and other early-line treatments is common and late-line treatment options are limited. Derived from the same murine precursor antibody, margetuximab has enhanced anti-tumor activity compared with trastuzumab and may be an effective late-line treatment. However, data regarding the use of margetuximab in pre-treated Chinese patients are scarce. This study aimed to evaluate the efficacy and safety of margetuximab plus chemotherapy vs. trastuzumab plus chemotherapy in Chinese patients, and to determine whether the results are consistent with the clinical benefit of margetuximab observed in the pivotal global phase III study. Methods: In this randomized, open-label, multicenter, phase II bridging study, eligible Chinese patients pretreated with ≥2 lines of anti-HER2 therapies were randomized 1:1 by stratified block randomization to margetuximab (15 mg/kg over at least 120 minutes) or trastuzumab (6 mg/kg over at least 30 minutes), each administered intravenously once every 21-day cycle and plus chemotherapy. Disease assessment was conducted once every two treatment cycles (6 weeks ± 7 days). The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR). Secondary endpoints included overall survival (OS), investigator-assessed PFS, objective response rate (ORR), duration of response (DoR), clinical benefit rate (CBR), and the incidence and severity of treatment-emergent adverse events (TEAEs). Results: Between February 4, 2020 and February 23, 2021, 123 patients were randomized to the margetuximab (n=62) and trastuzumab (n=61) arms. Among them, 15 and 7 patients, respectively, were still on study treatment as of data cut-off (September 3, 2021). Overall, 99.2% were female, median age was 53 years old. All patients were pretreated with trastuzumab, and 83.7% and 25.2%, respectively, were pretreated with tyrosine kinase inhibitors (TKIs) and pertuzumab. Baseline characteristics were numerically balanced between arms. BICR-assessed median PFS (mPFS) was 5.5 months in the margetuximab arm and 4.1 months in the trastuzumab arm, with a hazard ratio (HR) of 0.69 [95% confidence interval (CI): 0.43-1.12], which met the consistency criterion (HR <0.88) for bridging success. Median investigator-assessed PFS was 5.5 months in the margetuximab arm and 4.0 months in the trastuzumab arm (HR =0.63; 95% CI: 0.41-0.96). Median OS (mOS) was not yet reached. Both ORR and CBR were greater in the margetuximab arm (25.5% vs. 12.5%; 32.7% vs. 14.3%). Safety results were numerically comparable between the two arms. Anti-HER2 treatment-related infusion-related reactions (IRRs) were more common in the margetuximab arm than in the trastuzumab arm (12.9% vs. 1.7%). All IRRs could be resolved. Conclusions: Margetuximab was effective and well-tolerated in this study, supporting its clinical use in pretreated HER2-positive MBC patients in China. Trial Registration: ClinicalTrials.gov Identifier: NCT04262804.

Strategies for the treatment of HER2+ advanced breast cancer based on clinical practice in Chinese patients: a roundtable discussion.

Human epithelial growth factor receptor 2-positive (HER2+) breast cancer is easy to relapse and metastasize in the early stage, and usually has more aggressive clinical behavior and worse patient survival outcomes as compared with estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancer. The HER2+ breast cancer has been significantly enhanced by trastuzumab and other multiple novel HER2 anti-tumor drugs. The dual combination regimen of trastuzumab + pertuzumab has been established as the standard first-line therapy for advanced HER2+ patients, and pyrotinib with capecitabine is the preferred second-line treatment in Chinese patients. However, no third- or later-line regimens are currently recommended, and thus, the treatment needs of these patients remain unmet. Margetuximab is a human/mouse chimeric anti-HER2 immunoglobulin G1 (IgG1) monoclonal antibody (mAb) based on the murine precursor of trastuzumab, has shown greater efficacy than trastuzumab in terms of its natural killer (NK) cell-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) effect and may become the preferred solution for HER2+ metastatic breast cancer (mBC) following progression on second-line therapy with small molecule tyrosine kinase inhibitors (TKIs). This paper explores discussion of therapeutic strategies of anti-HER2 drugs based on Chinese clinical practice, and summarizes the consensus and controversy in the post-anti-HER2 TKIs guideline recommendations, so as to provide certain guidance to HER2+ mBC patients pretreated with TKIs in the third or later lines.

Neu Perspectives, Therapies, and Challenges for Metastatic HER2-Positive Breast Cancer.

Even though gene amplification or protein overexpression occurs in approximately one-fifth of all breast cancers, the discovery of HER2 has, nevertheless, had profound implications for the disease. Indeed, the characterization of the receptor resulted in a number of significant advances. Structurally, unique features provided avenues for the development of numerous compounds with target-specificity; molecularly, biological constructs revealed a highly complex, internal signal transduction pathway with regulatory effects on tumor proliferation, survival, and perhaps, even resistance; and clinically, disease outcomes manifested its predictive and prognostic value. Yet despite the receptor's utility, the beneficial effects are diminished by tumor recurrence after neo- or adjuvant therapy as well as losses resulting from the inability to cure patients with metastatic disease. What these observations suggest is that while tumor response may be partially linked to uncoupling cell surface message reception and nuclear gene expression, as well as recruitment of the innate immune system, disease progression and/or resistance may involve a reprogrammable signaling mainframe that elicits alternative growth and survival signals. This review attempts to meld current perceptions related to HER2-positive metastatic breast cancer with particular attention to current biological insights and therapeutic challenges.

Clinical development and current role of margetuximab for the treatment of breast cancer.

Up to 20% of breast cancers overexpress HER2, a molecular alteration conferring these tumors a particularly aggressive behavior. However, targeting HER2 has radically changed the prognosis of this disease in the last 2 decades, with multiple anti-HER2 compounds shown to improve disease outcomes both in the early and advanced setting. The latest anti-HER2 compound to be approved by the U.S. Food and Drug Administration (FDA) was margetuximab, an Fc-engineered monoclonal antibody with an improved binding to FcγRIIIA receptor, which leads to a greater antibody-dependent cellular cytotoxicity (ADCC) activation compared with trastuzumab. Margetuximab was shown to slightly improve progression-free survival compared with trastuzumab when combined with chemotherapy for the treatment of advanced HER2-positive breast cancer patients, and is now included among the available treatment options for pretreated HER2-positive breast cancer patients. In this monograph we recapitulate the clinical development, current role and future perspectives of margetuximab for the treatment of breast cancer.

Targeting ADCC: A different approach to HER2 breast cancer in the immunotherapy era.

The clinical outcome of patients with human epidermal growth factor receptor 2 (HER2) amplified breast carcinoma (BC) has improved with the development of anti-HER2 targeted therapies. However, patients can experience disease recurrence after curative intent and disease progression in the metastatic setting. In the current era of evolving immunotherapy agents, the understanding of the immune response against HER2 tumor cells developed by anti-HER2 antibodies (Abs) is rapidly evolving. Trastuzumab therapy promotes Natural Killer (NK) cell activation in patients with BC overexpressing HER2, indicating that the efficacy of short-term trastuzumab monotherapy, albeit direct inhibition of HER, could also be related with antibody-dependent cell-mediated cytotoxicity (ADCC). Currently, dual HER2 blockade using trastuzumab and pertuzumab is the standard of care in early and advanced disease as this combination could confer an additive effect in ADCC. In patients with disease relapse or progression, ADCC may be hampered by several factors such as FcγRIIIa polymorphism and an immunosuppressive environment, among others. Hence, new drug development strategies are being investigated aiming to boost the ADCC response triggered by anti-HER2 therapy. In this review, we summarize these strategies and the rationale, through mAbs engineering and combinatorial strategies, focusing on clinical results and ongoing trials.

Trastuzumab-induced cardiotoxicity: a review of clinical risk factors, pharmacologic prevention, and cardiotoxicity of other HER2-directed therapies.

PURPOSE: Despite great success as a targeted breast cancer therapy, trastuzumab use may be complicated by heart failure and loss of left ventricular contractile function. This review summarizes the risk factors, imaging, and prevention of cardiotoxicity associated with trastuzumab and other HER2-targeted therapies. FINDINGS: Cardiovascular disease risk factors, advanced age, and previous anthracycline treatment predispose to trastuzumab-induced cardiotoxicity (TIC), with anthracycline exposure being the most significant risk factor. Cardiac biomarkers such as troponins and pro-BNP and imaging assessments such as echocardiogram before and during trastuzumab therapy may help in early identification of TIC. Initiation of beta-adrenergic antagonists and angiotensin converting enzyme inhibitors may prevent TIC. Cardiotoxicity rates of other HER2-targeted treatments, such as pertuzumab, T-DM1, lapatinib, neratinib, tucatinib, trastuzumab deruxtecan, and margetuximab, appear to be significantly lower as reported in the pivotal trials which led to their approval. CONCLUSIONS: Risk assessment for TIC should include cardiac imaging assessment and should incorporate prior anthracycline use, the strongest risk factor for TIC. Screening and prediction of cardiotoxicity, referral to a cardio-oncology specialist, and initiation of effective prophylactic therapy may all improve prognosis in patients receiving HER2-directed therapy. Beta blockers and ACE inhibitors appear to mitigate risk of TIC. Anthracycline-free regimens have been proven to be efficacious in early HER2-positive breast cancer and should now be considered the standard of care for early HER2-positive breast cancer. Newer HER2-directed therapies appear to have significantly lower cardiotoxicity compared to trastuzumab, but trials are needed in patients who have experienced TIC and patients with pre-existing cardiac dysfunction.

Margetuximab for the treatment of HER2-positive metastatic breast cancer.

INTRODUCTION: No specific standard treatment is currently recommended for HER2-positive advanced breast cancer (BC) patients progressing to dual HER2 blockade and to trastuzumab emtansine (TDM-1). However, several novel anti-HER2 agents are emerging and rapidly revolutionizing this setting. Among these, the FC-engineered monoclonal antibody margetuximab has recently demonstrated to slightly improve progression-free survival (PFS) compared with trastuzumab, when combined with chemotherapy for pretreated HER2-positive advanced BC. AREAS COVERED: The present review article recapitulates the clinical development of margetuximab, critically discussing its implications in the current landscape of BC treatment algorithms. EXPERT OPINION: The clinical role of Margetuximab can only be interpreted in view of the rapidly evolving treatment landscape for pretreated HER2-positive advanced BC. Indeed, the recently approved anti-HER2 agents tucatinib and trastuzumab deruxtecan currently represent appealing options for the post-TDM1 setting, while margetuximab may have a role after progression to the abovementioned agents, in case of a future approval. Regardless of its clinical uptake, it should be noted that the development of margetuximab has relevantly improved our biological understanding of HER2-positive BC, highlighting the implication of patient's genotype in determining treatment outcomes, as well as the relevance of antibody-dependent cellular cytotoxicity (ADCC) in the context of HER2-blockade.

Treatment Landscape for Patients with HER2-Positive Metastatic Breast Cancer: A Review on Emerging Treatment Options.

The prognosis of HER2-positive metastatic breast cancer (MBC) has radically changed in recent years and continues to improve due to the broad application of effective therapies like monoclonal antibodies and small molecules targeting HER2. Persistent dependency of tumor cells on the oncogene HER2, on one hand, as well as low expression levels in healthy tissue, on the other hand, make this protein an ideal target for anti-cancer therapy. New HER2 targeting strategies including targeted delivery of cytotoxic drugs via HER2 receptor have been developed. Recently, the US Food and Drug Administration (FDA) approved three new drugs for the treatment of HER2-positive MBC: the antibody-drug conjugate trastuzumab deruxtecan and the two tyrosine kinase inhibitors neratinib and tucatinib. Here, we summarize recent publications and developments of novel anti-HER2 therapies like monoclonal antibodies with improved properties compared to trastuzumab and bispecific antibodies, which bind two different HER-epitopes or bring T cells closer to tumor cells. Furthermore, novel antibody-drug conjugates and small molecules against HER2 are discussed. These developments coupled with new combination strategies (eg, with CDK4/6 inhibitors or immunotherapy) will change the treatment landscape for patients with HER2-positive MBC very soon and will hopefully further improve clinical outcomes.