Margetuximab-cmkb binds to the extracellular domain of the human epidermal growth factor receptor 2 protein (HER2). Upon binding to HER2-expressing tumor cells, margetuximab-cmkb inhibits tumor cell proliferation, reduces shedding of the HER2 extracellular domain and mediates antibody-dependent cellular cytotoxicity (ADCC).
In vitro, the modified Fc region of margetuximab-cmkb increases binding to activating Fc receptor FCGR3A (CD16A) and decreases binding to inhibitory Fc receptor FCGR2B (CD32B). These changes lead to greater in vitro ADCC and NK cell activation.
The exposure-response relationship and time course of pharmacodynamic response for the safety and effectiveness of margetuximab-cmkb have not been fully characterized.
Following the approved recommended dosage, 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-cmkb undergoes both linear and nonlinear elimination. After a single dose, 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). At the approved recommended dosage, time to steady-state was 2 months, and accumulation ratio was 1.65 based on AUC0-21d. No clinically significant differences in margetuximab-cmkb exposure were observed when infusion time was reduced from 120 minutes to 30 minutes.
Margetuximab-cmkb geometric mean (CV) steady-state volume of distribution is 5.47 L (22).
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.
Margetuximab-cmkb is expected to be metabolized into small peptides by catabolic pathways.
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.
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