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Mobocertinib is a Kinase Inhibitor. The mechanism of action of mobocertinib is as a HER1 Antagonist and Cytochrome P450 3A Inducer. Mobocertinib is an inhibitor of EGFR that irreversibly binds to and inhibits EGFR exon 20 insertion mutations at lower concentrations than wild-type EGFR proteins, exerting a pharmacologic effect on mutant variants at concentrations 1.5- to 10-fold lower than on wild-type proteins.
Mobocertinib is an orally available inhibitor of human epidermal growth factor receptor (EGFR) exon 20 insertion mutations, with antineoplastic activity. Upon oral administration, mobocertinib, and its active metabolites, specifically and irreversibly bind to and inhibits exon 20 insertion mutations of EGFR. This prevents EGFR-mediated signaling and leads to cell death in tumor cells expressing exon 20 insertion mutations. In addition, mobocertinib may inhibit the activity of other EGFR family members, such as human epidermal growth factor receptor 2 (HER2; ERBB2) and HER4. EGFR, HER-2, and -4 are receptor tyrosine kinases often mutated in numerous tumor cell types. They play key roles in tumor cell proliferation and tumor vascularization.
Mobocertinib is a kinase inhibitor targeted against the human epidermal growth factor receptor (EGFR). It is used specifically in the treatment of non-small cell lung cancer (NSCLC) caused by exon 20 insertion mutations in the EGFR gene, which are typically associated with a poorer prognosis (as compared to “classical” EGFR mutants causing NSCLC) and are associated with resistance to standard targeted EGFR inhibitors. Mobocertinib appears to be an effective means of treating this otherwise treatment-resistant NSCLC, exerting an inhibitory effect on EGFR exon 20 insertion mutant variants at concentrations 1.5- to 10-fold lower than those required to inhibit wild-type EGFR. Mobocertinib, under the brand name Exkivity (Takeda Pharmaceuticals Inc.), was granted accelerated approval by the FDA in September 2021 for the treatment of locally advanced or metastatic NSCLC in patients with EGFR exon 20 insertion mutations who have failed previous therapies.
Mobocertinib Succinate is the succinate salt form of mobocertinib, an orally available inhibitor of human epidermal growth factor receptor (EGFR) exon 20 insertion mutations, with antineoplastic activity. Upon oral administration, mobocertinib, and its active metabolites, specifically and irreversibly bind to and inhibit exon 20 insertion mutations of EGFR. This prevents EGFR-mediated signaling and leads to cell death in tumor cells expressing exon 20 insertion mutations. In addition, mobocertinib may inhibit the activity of other EGFR family members, such as human epidermal growth factor receptor 2 (HER2; ERBB2) and HER4. EGFR, HER-2, and -4 are receptor tyrosine kinases often mutated in numerous tumor cell types. They play key roles in tumor cell proliferation and tumor vascularization.
Mechanism of Action
The epidermal growth factor receptor (EGFR) is a transmembrane receptor that regulates signaling pathways in the control of cellular proliferation. Mutations in these proteins have been associated with certain types of lung cancer, including non-small cell lung cancer (NSCLC). While the majority of _EGFR_ mutations associated with NSCLC involve the _EGFR_ L858R point mutation or exon 19 deletions (referred to as “classical” _EGFR_ mutations), less common _EGFR_ exon 20 insertion mutations carry a particularly poor prognosis and are associated with resistance to standard targeted EGFR inhibitors. Mobocertinib is an inhibitor of EGFR that irreversibly binds to and inhibits EGFR exon 20 insertion mutations at lower concentrations than wild-type EGFR proteins, exerting a pharmacologic effect on mutant variants at concentrations 1.5- to 10-fold lower than on wild-type proteins.
Mobocertinib is an inhibitor of EGFR that preferentially targets exon 20 insertion mutant variants. It is available as an oral capsule taken with or without food once daily. Mobocertinib can cause a concentration-dependent increase in QTc interval which may lead to life-threatening complications such as Torsades de Pointes. Patients with baseline risk factors for QTc prolongation should consider alternative medications or be monitored carefully throughout therapy. The use of concomitant QTc-prolonging medications should be avoided, as should concomitant inhibitors of CYP3A, as these may increase the concentration of mobocertinib and thus the risk of QTc-prolongation.
Indications
Mobocertinib is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy.
Use in Cancer
Mobocertinib succinate is approved to treat:
- Non-small cell lung cancer (NSCLC) that is locally advanced or metastatic and got worse during or after platinum chemotherapy. It is used in adults whose cancer has certain EGFR gene mutations.
Mobocertinib succinate is approved under FDA’s Accelerated Approval Program. As a condition of approval, confirmatory trial(s) must show that it provides a clinical benefit in these patients.
Mobocertinib succinate is also being studied in the treatment of other conditions.
