Mogamulizumab

Mogamulizumab is a monoclonal antibody against chemokine receptor 4 (CCR4) that has been shown to be effective in various T-cell lymphomas. It has been approved by the US Food and Drug Administration (FDA) for the treatment of adult patients with relapsed or refractory mycosis fungoides (MF) or Sézary syndrome (SS) who have been treated with at least one prior line of therapy (Moore DC et al 2020). Mogamulizumab showed a significant improvement in progression-free survival compared to vorinostat in patients with relapsed or refractory MF or SS.

Mogamulizumab is a monoclonal antibody that selectively binds C-C chemokine receptor 4(CCR4), which is overexpressed on the surface of malignant T lymphocytes and supports the extravasation of T lymphocytes into the skin. CCR4 is a G-protein-coupled receptor for CC chemokines and is involved in cell trafficking from lymphocytes to various organs including the skin.

Preclinical studies have demonstrated in vitro and in vivo that binding of mogamulizumab to CCR4 on the surface of T lymphocytes induces antibody-dependent cellular cytotoxicity, thereby reducing the population of labeled T lymphocytes. Upon binding of mogamulizumab to CCR4 on the surface of the target cell, activation of natural killer cells then occurs, which subsequently mediate the destruction of the target cell.

Biotransformation: The metabolic pathway of mogamulizumab has not been described, but it is expected that mogamulizumab is degraded into small peptides and amino acids via catabolic pathways in the same manner as endogenous IgG. Elimination: According to a PK population analysis, the geometric mean (% coefficient of variation [CV%]) clearance (CL) is 12.0 ml/h (83.7%) and the geometric mean elimination half-life (t1/2) is 17 days (65.5%).

Mogamulizumab is a first-in-class CCR4 inhibitor and represents a new option for the treatment of relapsed or refractory cutaneous T-cell lymphoma. Mogamulizumab is used to treat adult patients with mycosis fungoides or Sézary syndrome who have received at least one prior systemic therapy. These are the two most common subtypes of cutaneous T-cell lymphoma (Tawa M et al (2019).

For precautionary reasons, mogamulizumab should not be used during pregnancy. It is known that IgG antibodies in humans pass into breast milk in the first few days after birth and drop to low concentrations soon afterwards. Therefore, a risk to the breastfed child cannot be excluded during this short period. Thereafter, mogamulizumab could be administered during breastfeeding if clinically necessary.

The recommended dose is 1 mg/kg mogamulizumab as an intravenous infusion over at least 60 minutes. Use is weekly on days 1, 8, 15, and 22 of the first 28-day cycle. Thereafter, infusions are given biweekly on days 1 and 15 of each subsequent 28-day cycle until disease progression or unacceptable toxicity.

The following adverse reactions occurred very frequently (≥1/10) during the use of mogamulizumab (Blackmon AL et al. 2020):

• Infusion-related reactions (32%)
• Drug exanthema (20 %)
• Diarrhea (23%)
• Fatigue (22%)

Furthermore:

• peripheral edema
• fever
• Infections

Serious adverse reactions in clinical trials were respiratory failure of severity 4 (1.1%), adverse reactions of severity 5 were polymyositis and sepsis (0.5% each).

Studies to detect interactions with mogamulizumab are not available.

In the open-label, international, randomized, controlled phase III study (MAVORIC study), patients with relapsed or refractory mycosis fungoides or Sézary syndrome were recruited at 61 medical centers. 372 eligible patients randomly received weekly 1.0 mg/kg mogamulizumab (n=186) intravenously for the first 28-day cycle, then on days 1 and 15 of subsequent cycles, or daily 400 mg vorinostat (n=186). Patients were over 18 years of age and had received at least one prior systemic therapy that did not improve progression or cause toxicity (Kim YH et al 2018).

Results: Mogamulizumab therapy resulted in superior progression-free survival compared with vorinostat therapy at 3.1 months [2,9-4). Mogamulizumab thus significantly prolonged progression-free survival compared to vorinostat Grade 3-4 adverse events of any cause were reported in 75 (41%) of 184 patients in the mogamulizumab group and 76 (41%) of 186 patients in the vorinostat group. The most common serious adverse events of any cause patients in the mogamulizumab group were fever in 8 (4%) patients and erysipelas in 5 (3%) patients. In the vorinostat group, erysipelas and pulmonary embolism each occurred in 6 (3%) patients and sepsis in 5 (3%) patients. Two (67%) of three deaths during treatment with mogamulizumab (due to sepsis and polymyositis) and three (33%) of nine deaths during treatment with vorinostat (two due to pulmonary embolism and one due to bronchopneumonia) were considered to be a result of treatment.

1. Blackmon AL et al. (2020) Spotlight on Mogamulizumab-Kpkc for Use in Adults with Relapsed or Refractory Mycosis Fungoides or Sézary Syndrome: Efficacy, Safety, and Patient Selection. Drug Des Devel Ther 14:3747-3754.
2. Ishida Tet al. (2006) CCR4 as a novel molecular target for immunotherapy of cancer. Cancer Sci 97:1139-1146.
3. Kim YH et al. (2018) Mogamulizumab versus vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC): an international, open-label, randomised, controlled phase 3 trial. Lancet Oncol19:1192-1204.
4. Moore DC et al (2020) Mogamulizumab: An anti-CC chemokine receptor 4 antibody for T-cell lymphomas. Ann Pharmacother 54:371-379.
5. Tawa M et al (2019) Cutaneous T-Cell Lymphoma: Optimizing Care in Patients Receiving Anti-CCR4 Monoclonal Antibody Mogamulizumab. Clin J Oncol Nurs 23:E73-E80.
6. Yoshie O et al (2015) CCR4 and its ligands: from bench to bedside. Int Immunol 27:11-20.