mobocertinib

Action and Spectrum

Actions and spectrum: 

mobocertinib is a kinase inhibitor used to treat metastatic non-small cell lung cancer (NSCLC).

It is a small molecule that selectively and covalently inhibits the epidermal growth factor receptor (EGFR) with mutations in exon 20, which are associated with a poor response to first- and second-generation EGFR inhibitors. mobocertinib is considered a third-generation EGFR inhibitor.

It works by inhibiting the tyrosine kinase activity of the EGFR, which in turn inhibits the downstream signaling pathways involved in cancer cell growth, proliferation, and survival. 

Drug Interaction

Adverse Reaction

Frequency defined 

>10% 

All grades 

• Ocular toxicity (11%) 
• Dyspepsia (11%) 
• Rhinorrhea (13%) 
• Dyspnea (15%) 
• Gastroesophageal reflux disease (15%) 
• Upper respiratory tract infection (16%) 
• Abdominal pain (18%) 
• Alopecia (19%) 
• Decreased sodium (20%) 
• Decreased weight (21%) 
• Increased AST (21%) 
• Increased ALT (22%) 
• Decreased albumin (23%) 
• Decreased magnesium (23%) 
• Pruritus (24%) 
• Cough (24%) 
• Increased alkaline phosphatase (25%) 
• Decreased leukocytes (25%) 
• Decreased platelets (26%) 
• Decreased potassium (29%) 
• Fatigue (29%) 
• Dry skin (32%) 
• Musculoskeletal pain (34%) 
• Increased lipase (35%) 
• Nausea (37%) 
• Paronychia (39%) 
• Decreased appetite (39%) 
• Vomiting (40%) 
• Increased amylase (40%) 
• Stomatitis (46%) 
• Decreased lymphocytes (52%) 
• Increased creatinine (52%) 
• Decreased red blood cells (59%) 
• Rash (78%) 
• Diarrhoea (92%) 

Grade 3 or 4 

• Increased amylase (13%) 
• Decreased lymphocytes (15%) 
• Diarrhoea (22%) 

1-10% 

All grades 

• Headache (10%) 
• QTc prolongation (10%) 
• Hypertension (10%) 

Grade 3 or 4 

• Abdominal pain (1.8%) 
• Increased alkaline phosphatase (1.8%) 
• Increased AST (1.8%) 
• Rash (1.8%) 
• Decreased albumin (1.8%) 
• Musculoskeletal pain (2.6%) 
• Vomiting (2.6%) 
• Decreased magnesium (2.7%) 
• Increased creatinine (2.7%) 
• Increased ALT (2.7%) 
• QTc prolongation (3.5%) 
• Decreased red blood cells (3.5%) 
• Fatigue (3.5%) 
• Nausea (4.4%) 
• Hypertension (4.4%) 
• Stomatitis (4.4%) 
• Dyspnea (4.4%) 
• Decreased potassium (5.3%) 
• Increased lipase (10%) 

<1% 

Grade 3 or 4 

• Decreased sodium (0.9%) 
• Pruritus (0.9%) 
• Decreased appetite (0.9%) 
• Decreased platelets (0.9%) 
• Paronychia (0.9%) 

Black Box Warning

Contraindication / Caution

Contraindication/Caution: 

Contraindication: 

mobocertinib is contraindicated in individuals with a known severe hypersensitivity reaction to mobocertinib or any of its components. It is also contraindicated for use with medications that are strong CYP3A inducers, as they can significantly decrease mobocertinib concentrations, which may decrease its efficacy.  

Caution: 

• Interstitial Lung Disease (ILD): mobocertinib can cause ILD or pneumonitis, which can be fatal in severe cases. Patients who experience new or worsening respiratory symptoms should be evaluated for ILD or pneumonitis, and mobocertinib should be discontinued if either condition is confirmed. 
• Cardiomyopathy: mobocertinib can cause cardiomyopathy, which can lead to heart failure. Patients with a history of cardiac disease, hypertension, or decreased ejection fraction should be monitored for signs and symptoms of heart failure, including dyspnea, edema, and fatigue. 
• Hepatotoxicity: mobocertinib can cause hepatotoxicity, which can be severe and potentially fatal. Liver function tests should be monitored regularly, and mobocertinib should be discontinued if elevated liver function tests are detected. 
• Embryo-Fetal Toxicity: mobocertinib may cause fetal harm when given to a pregnant woman. Women of childbearing should be advised to use effective contraception during treatment with mobocertinib. 
• QTc Prolongation: mobocertinib can prolong the QT interval, which can lead to torsades de pointes or sudden death. Patients with a history of QTc prolongation, torsades de pointes, or other cardiac arrhythmias should be monitored closely while receiving mobocertinib. Electrolyte abnormalities and concomitant use of drugs that prolong the QT interval should also be considered. 
• Drug Interactions: mobocertinib is metabolized primarily by CYP3A4 and can interact with drugs that induce or inhibit CYP3A4. Concomitant use of strong CYP3A4 inhibitors or inducers should be avoided, or the dose of mobocertinib should be adjusted accordingly.

Comorbidities: 

• Hepatic Impairment: mobocertinib is metabolized in the liver and may cause adverse effects in patients with hepatic impairment. Dose adjustment may be necessary for patients with moderate to severe hepatic impairment. 
• Renal Impairment: the dosing adjustment is not necessary in patients with renal impairment, but the safety and efficacy of mobocertinib are not established in patients with severe renal impairment. 
• Cardiovascular Disease: mobocertinib may cause QTc prolongation and enhance the risk of arrhythmias in patients with cardiovascular disease or a history of QTc prolongation. 
• Interstitial Lung Disease (ILD) or Pneumonitis: mobocertinib may cause ILD or pneumonitis, which can be fatal. Patients should be monitored for symptoms of pneumonitis or ILD during treatment. 
• Gastrointestinal Disorders: mobocertinib may cause diarrhea, nausea, vomiting, and abdominal pain. Patients with a history of gastrointestinal disorders should be closely monitored during treatment. 
• Hyperlipidemia: mobocertinib may cause an increase in serum lipid levels. Patients with preexisting hyperlipidemia or who are receiving concomitant lipid-lowering medications should be monitored closely. 

Pregnancy / Lactation

Pregnancy consideration: pregnancy category D 

Lactation: safety and efficacy not established  

Pregnancy category: 

• Category A: Satisfactory and well-controlled studies show no risk to the fetus in the first or later trimester. 
• Category B: There is no evidence of risk to the fetus found in animal reproduction studies and there are not enough studies on pregnant women. 
• Category C: Adverse effects on the fetus found with evidence in animal reproduction studies and no adequate evidence for an effect in humans, care must be taken for potential risks in pregnant women. 
• Category D: There is adequate data available with sufficient evidence of human fetal risk from various platforms, but despite potential risks may be used only in emergency cases for potential benefits. 
• Category X: Drugs listed in this category outweigh risks over benefits These category drugs should be prohibited for pregnant women. 
• Category N: There is no data available for the drug under this category. 

Pharmacology

Pharmacology: 

mobocertinib is a small-molecule kinase inhibitor that acts on epidermal growth factor receptor (EGFR) kinase, which is involved in the growth and proliferation of cancer cells. Specifically, it selectively inhibits both the activating and the resistance T790M mutant forms of EGFR. 

In preclinical studies, mobocertinib demonstrated significant anti-tumor activity against a range of EGFR-mutated cancers, including non-small cell lung cancer (NSCLC).  

Pharmacodynamics: 

mobocertinib is a small molecule kinase inhibitor that acts on epidermal growth factor receptor (EGFR) with mutations at exon 20, including EGFR exon 20 insertion mutations.

EGFR is a transmembrane receptor that is often overexpressed or mutated in cancer cells, leading to the activation of intracellular signaling pathways that are involved in cell growth, differentiation, and survival. mobocertinib blocks the activity of EGFR, thereby inhibiting the downstream signaling pathways and leading to the inhibition of cancer cell growth and proliferation. 

Unlike other EGFR tyrosine kinase inhibitors, mobocertinib selectively targets exon 20 mutations, which are associated with resistance to other EGFR inhibitors.  

Pharmacokinetics: 

Absorption 

mobocertinib is orally administered and absorbed slowly, with a median time to maximum concentration (Tmax) of 4-6 hours. The absolute bioavailability is unknown. 

Distribution 

mobocertinib is highly bound to plasma proteins (≥99.5%) and has a large volume of distribution (>5000 L). 

Metabolism 

mobocertinib is primarily metabolized by cytochrome P450, (CYP) 3A4, CYP2C9, and CYP2C19 enzymes. The major metabolite is M12, which is formed by the oxidation and demethylation of mobocertinib. 

Elimination and excretion 

mobocertinib and its metabolites are primarily eliminated via feces (85%) and, to a lesser extent, via urine (9%). The terminal elimination half-life (t1/2) of mobocertinib is approximately 46 hours. 

Adminstartion

Administration: 

• mobocertinib is available as an oral tablet and is taken by mouth.
• The usual dose is 160 mg once daily, with or without food.
• The tablet should be swallowed whole with a glass of water and should not be crushed, chewed, or broken.
• The dose and duration of therapy may vary depending on the condition being treated, patient response, and other factors. 

Patient Information Leaflet

Patient information leaflet 

Generic Name: mobocertinib 

Pronounced: ( moe-boh-SER-ti-nib)  

Why do we use mobocertinib? 

mobocertinib is a medication used to treat metastatic or locally non-small cell lung cancer (NSCLC) with the epidermal growth factor receptor (EGFR) exon 20 insertion mutations. This medication is used in patients who have received prior treatment with at least one EGFR tyrosine kinase inhibitor (TKI).