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FDA News: Issue 1, January 2021

Author: [AUTHOR] Published on 1/8/2021 3:00:00 PM


FDA Approves MARGENZA (Margetuximab-cmkb) in Adult Patients with Metastatic HER2-Positive Breast Cancer Who Have Received Two or More Prior Anti-HER2 Regimens MARGENZA

On December 16, 2020, the US Food and Drug Administration (FDA) approved MARGENZA (margetuximab-cmkb), in combination with chemotherapy, for the 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. The approved recommended dosage of MARGENZA is 15 mg/kg, administered as an intravenous infusion every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity. Administer MARGENZA as an intravenous infusion at 15 mg/kg over 120 minutes for the initial dose, then over a minimum of 30 minutes every 3 weeks for all subsequent doses. On days when both MARGENZA and chemotherapy are to be administered, MARGENZA may be administered immediately after chemotherapy completion. 

WARNING:
  • Left Ventricular Dysfunction: MARGENZA may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate cardiac function prior to and during treatment. Discontinue MARGENZA treatment for a confirmed clinically significant decrease in left ventricular function.  
  • Embryo-Fetal Toxicity: Exposure to MARGENZA during pregnancy can cause embryo-fetal harm. Advise patients of the risk and need for effective contraception. 

Additional information regarding dosage and administration as well as warnings and precautions about left ventricular dysfunction, embryo-fetal toxicity, and infusion-related reactions can be found in the full prescribing information linked below. 

Mechanism of Action (MOA) and Pharmacokinetics (PK)
  • MOA: Margetuximab-cmkb is a HER2/neu receptor antagonist. 
  • General PK: The steady-state geometric mean (%CV) Cmax of margetuximab-cmkb is 466 (20%) µg/mL and AUC0-21d is 4120 (21%) µg.day/mL in patients with HER2-positive relapsed or refractory advanced breast cancer. Margetuximab undergoes both linear and nonlinear elimination. Margetuximab-cmkb Cmax and AUC0-21d increase in an approximately dose proportional manner from 10 to 18 mg/kg (0.67 to 1.2 times the approved recommended dose). Accumulation ratio was 1.65 based on AUC0-21d
  • Distribution: Margetuximab-cmkb geometric mean (%CV) steady-state volume of distribution is 5.47 L (22%). 
  • Elimination: The geometric mean (%CV) terminal half-life of margetuximab-cmkb is 19.2 days (28%) and clearance is 0.22 L/day (24%). Four months after margetuximab-cmkb discontinuation, concentrations decrease to approximately 3% of the steady-state trough serum concentration. 
  • Metabolism: Margetuximab-cmkb is expected to be metabolized into small peptides by catabolic pathways. 
    Immunogenicity: Due to the limited number of patients who developed anti-margetuximab antibodies during treatment with MARGENZA, the impact of anti-margetuximab antibodies on the PK, safety and efficacy of MARGENZA is unknown. 

Drug Interactions
Anthracyclines: Patients who receive anthracyclines less than 4 months after stopping MARGENZA may be at increased risk of cardiac dysfunction. While this interaction has not been studied with MARGENZA, clinical data from other HER2-directed antibodies warrants consideration. Avoid anthracycline-based therapy for up to 4 months after stopping MARGENZA. If concomitant use is unavoidable, closely monitor patient’s cardiac function. 

Use in Specific Populations
No clinically significant differences in margetuximab-cmkb PK were observed based on age (29 to 83 years), sex, race (Caucasian, Black, Asian), mild to moderate (CLcr 30 to 89 mL/min estimated using the Cockcroft-Gault equation) renal impairment, mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1 to 1.5 ULN and any AST), HER2 expression level (0 to 3 by IHC), tumor burden (2 – 317 mm), ECOG score (0 to 2), albumin (24 to 50 g/L), FCGR3A (CD16A), FCGR2A (CD32A) and FCGR2B (CD32B) genotype, number of metastatic sites (≤ 2 or > 2), number of prior therapy lines (≤ 2 or > 2) or concurrent chemotherapies (capecitabine, gemcitabine, eribulin, and vinorelbine).

The effect of severe renal impairment (CLcr 15 to 29 mL/min), end-stage renal disease with or without hemodialysis, and moderate (total bilirubin > 1.5 to ≤ 3 ULN and any AST) or severe hepatic impairment (total bilirubin >3 ULN and any AST) on margetuximab-cmkb PK is unknown. 

Efficacy and Safety
Efficacy of MARGENZA plus chemotherapy was demonstrated in a randomized, multicenter, open-label trial of 536 patients with IHC 3+ or ISH-amplified HER2+ metastatic breast cancer who had received prior treatment with other anti-HER2 therapies. Major efficacy outcome measures were progression-free survival (PFS) by blinded independent central (BICR) review and overall survival (OS) of MARGENZA plus chemotherapy, compared with trastuzumab plus chemotherapy. Additional information regarding the efficacy trial can be found in the full prescribing information linked below.

The most common adverse drug reactions (> 10%) with MARGENZA in combination with chemotherapy are fatigue/asthenia, nausea, diarrhea, vomiting, constipation, headache, pyrexia, alopecia, abdominal pain, peripheral neuropathy, arthralgia/myalgia, cough, decreased appetite, dyspnea, infusion-related reactions, palmar-plantar erythodysasthesia, and extremity pain. 

Full prescribing infrmation is available at https://go.usa.gov/xANpz.

Visit Drugs@FDA at http://go.usa.gov/cMsjT for prescribing and patient information, approval letters, reviews and other information for FDA-approved drug products, which are often available shortly following approval. 

A non-comprehensive list of examples of clinical substrates, inhibitors and inducers for metabolic and transporter system related interactions may be found at https://go.usa.gov/xXY9C.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA's MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), or by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


The Office of Clinical Pharmacology (OCP) is pleased to offer the e-mail subscription service Clinical Pharmacology Corner. This is a free service from FDA to provide occasional updates from OCP regarding newly approved therapies, new regulatory and scholarly publications, upcoming events and other items of interest. Subscribe today at http://go.fda.gov/subscriptionmanagement (note: this link does not work with Internet Explorer) and select Clinical Pharmacology Corner under Drugs.

We always welcome your thoughts regarding the format, content, and utility of this communication. Comments may be sent via email to ocp@fda.hhs.gov.

This communication was prepared by Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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