2020 New Antibody Drug: Margetuximab
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2020 New Antibody Drug: Margetuximab
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2020 New Antibody Drug: Margetuximab. Margetuximab is a monoclonal antibody drug targeting human epidermal growth factor receptor 2 (HER2).
Overview
On December 16, 2020, the U.S. Food and Drug Administration (FDA) approved Margetuximab (trade name MARGENZATM) for the first time in combination with chemotherapy for the treatment of two or more anti-HER2 regimens (at least one of them) Adult patients with metastatic HER2-positive breast cancer for metastatic disease.
Margetuximab is a monoclonal antibody drug targeting human epidermal growth factor receptor 2 (HER2), which has HER2 binding and anti-proliferative effects similar to trastuzumab.
In addition, Margetuximab has been engineered through MacroGenics’ Fc optimization technology to enhance the participation of its immune system and affect the lethality of cancer cells through antibody-dependent cell-mediated cytotoxicity (ADCC).
In June 2020, Margetuximab was approved by the FDA as an orphan drug for gastroesophageal cancer.
This approval is based on the positive results of the Phase III SOPHIA study (NCT02492711).
The recommended dose of Margetuximab is 15 mg/kg by intravenous infusion within 120 minutes for the first time, and then every 3 weeks for at least 30 minutes.
Margetuximab was developed by MacroGenics, a clinical-stage biopharmaceutical company focused on the discovery and development of innovative monoclonal antibody therapies for the treatment of cancer.
It is worth mentioning that at the end of November 2018, Zai Lab (ZLAB) and MacroGenics reached a strategic cooperation and obtained the exclusive authorization for the development and commercialization of 3 immuno-oncology products in Mainland China, Hong Kong, Macau and Taiwan. That includes Margetuximab.
Pharmacodynamics and pharmacokinetics
Human epidermal growth factor receptor 2 is a protein that exists on the surface of certain cancer cells.
It can promote tumor growth and is associated with aggressive diseases and poor prognosis. Approximately 15-20% of breast cancer cases are HER2 positive.
Monoclonal antibodies (mAbs) targeting HER2 have greatly improved the prognosis of patients with HER2-positive breast cancer and have become the standard treatment for early and advanced breast cancer.
However, there is currently no approved HER2 targeted therapy for patients with metastatic breast cancer who receive these drugs to treat their disease progression.
For relapsed or refractory patients, continuous HER2 blockade is recommended, but there are no approved treatments outside of third-line and beyond third-line treatments.
Trastuzumab, pertuzumab, and ado-trastuzumab are used There is no standard care established after memtansine (T-DM1) disease progresses.
Margetuximab is an Fc-optimized monoclonal antibody that can target to block HER2. It has HER2 binding and anti-proliferation effects similar to trastuzumab.
At the same time, its engineered Fc domain can enhance the participation of the immune system.
According to the approved recommended dose, in patients with HER2-positive relapsed or refractory advanced breast cancer, the steady-state geometric mean Cmax (CV%) of Margetuximab was 466 (20%) µg/mL, and AUC0-21d was 4120 (21%) µg.day/mL.
The geometric mean steady-state distribution volume of Margetuximab is 5.47L (22%).
The geometric mean terminal half-life of Margetuximab is 19.2 days (28%), and the clearance rate is 0.22 L/day (24%).
Clinical Trials
SOPHIA is a head-to-head, randomized, multi-center, open-label study that evaluates the efficacy and safety of margetuximab + chemotherapy versus trastuzumab + chemotherapy in the treatment of patients with HER2-positive metastatic breast cancer.
Patients enrolled in the study must have received at least two HER2-targeted therapies in the treatment of metastatic disease, or received Pertuzumab (new) adjuvant therapy and at least one HER2-targeted therapy for metastatic disease, metastatic disease There are no more than 3 therapies in the total treatment of the disease.
A total of 536 patients were enrolled in the study.
All of these patients had previously received Herceptin (trastuzumab) and Perjeta (Pertuzumab) treatment, and approximately 90% of patients had also received Kadcyla (ado-trastuzumabemtansine) treatment. .
In the study, these patients were randomly assigned to two treatment groups at a 1:1 ratio, and received an intravenous infusion of 15 mg/kg of margetuximab (n=266) every 3 weeks or an intravenous infusion of 6 mg/kg every 3 weeks (or 8mg/kg loading dose) trastuzumab (n=270), while receiving one of 4 chemotherapy drugs (capecitabine, eribulin, gemcitabine, vinorelbine, the dose is the standard dose) treatment.
The main efficacy indicators are the progression-free survival rate (PFS) evaluated by the blinded independent center (BICR) and the overall survival rate (OS) of MARGENZA plus chemotherapy, compared with trastuzumab plus chemotherapy.
Other efficacy indicators are objective response rate (ORR) and duration of response (DOR).
The results showed that the study reached the primary endpoint of PFS: compared with trastuzumab + chemotherapy group, the risk of disease progression or death in the margetuximab + chemotherapy group was reduced by 24% (median PFS: 5.8 months vs 4.9 months; HR=0.76; 95%CI: 0.59-0.98; p=0.033).
Approximately 85% of the patients enrolled in the study carried the CD16A (FcγRIIIa) 158F allele, which is associated with reduced clinical response to trastuzumab and other antibody therapies.
The secondary endpoint ORR was 22% (95% CI: 17.3-27.7%) in the margetuximab + chemotherapy group, and 16% (95% CI: 11.8-21.0%) in the trastuzumab + chemotherapy group.
In the study, the safety of margetuximab + chemotherapy was comparable to trastuzumab + chemotherapy and was consistent with previously reported data.
There were 145 patients (55%) in the margetuximab treatment group with ≥3 grade adverse events, and 140 patients (53%) in the trastuzumab group. Serious adverse reactions occurred in 45 patients (17%) in the margetuximab group and 50 (19%) in the trastuzumab group.
Infusion-related reactions were more common in the margetuximab group than in the trastuzumab group (13% vs 3%), mostly grade 1 or 2, and related to the first dose.
Adverse reactions
The most common adverse drug reactions (>10%) of MARGENZA combined with chemotherapy are fatigue/fatigue, nausea, diarrhea, vomiting, constipation, headache, fever, hair loss, abdominal pain, peripheral neuropathy, arthralgia/myalgia, cough, loss of appetite, Difficulty breathing, infusion-related reactions, palmar and plantar red paresthesia, and limb pain.
Immunogenicity
Like all therapeutic proteins, Margetuximab is immunogenic. In the SOPHIA clinical trial, all registered patients had received trastuzumab treatment, and 4 patients (1.7%) were observed to develop anti-antibodies after treatment. Among these 4 patients, 1 patient had anti-antibodies detected before the 7th cycle of administration, and 3 patients had anti-antibodies detected more than 2 months after the last administration.
The effect of anti-antibody on the PK, safety and efficacy of Margetuximab is unclear.
references:
1. FDA Label for BLA 761150
2. MacroGenics Announces Second Interim Overall Survival Data from Phase 3 SOPHIA Study of Margetuximab in Patients with HER2-Positive Metastatic Breast Cancer
3. clinicaltrials.gov
2020 New Antibody Drug: Margetuximab
(source:internet, reference only)
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