Mobocertinib - A Brief Overview

What Is Mobocertinib?

Mobocertinib is used to treat adults with non-small cell lung cancer that has metastasized or spread to other body parts and cannot be treated with surgery. It is administered to individuals whose disease has gotten worse during or after platinum-based chemotherapy and whose cancer has an aberrant epidermal growth factor receptor (EGFR) gene.

Is Mobocertinib FDA Approved?

It was approved by the Food and Drug Administration (FDA) in September 2021 for people with locally advanced or metastatic non-small cell lung cancer (NSCLC) that had EGFR exon 20 insertion mutations and had progressed during or after platinum-based chemotherapy. However, the approval was taken away in 2024 because post-marketing study results did not show that the drug was clinically beneficial.

How Does Mobocertinib Work?

Mobocertinib belongs to a class of kinase inhibitors (drugs that inhibit the kinase enzyme, which promotes cell growth) and works by blocking the action of abnormal proteins that signal the multiplication of cancer cells, stopping or slowing the spread of cancerous cells, and shrinking tumors. It targets the EGRF exon 20 insertion mutations (a protein that helps cells grow and divide) found in cancer cells.

Indications:

• Mobocertinib is indicated for the treatment of non-small cell lung cancer in adults with locally advanced or metastatic disease (spread to other parts of the body) with epidermal growth factor receptor exon 20 insertion mutations.

• Mobocertinib is also used in patients whose disease has progressed on or after treatment with platinum-based chemotherapy.

Dosage and Administration:

• Patients with advanced or metastatic NSCLC are selected for treatment based on the presence of EGFR exon 20 insertion mutations.

• Mobocertinib is recommended at a dose of 160 mg orally, once daily, until the disease progresses or has unacceptable toxicity.

• Do not chew, open, or dissolve capsules; they must be consumed whole.

• The initial dose is reduced to 120 mg, followed by a subsequent reduction to 80 mg per day.

How Should Mobocertinib Be Taken?

Mobocertinib must be taken exactly as prescribed by the doctor, at the same time each day, with or without food. If a dose of Mobocertinib is missed by more than six hours, the dose is skipped, and the next dose must be taken the following day at the regularly scheduled time. If a dose of Mobocertinib is vomited, an additional dose must not be taken, and the next dose must be taken as prescribed the following day.

Warnings and Precautions:

• Interstitial Lung Disease (ILD) or Pneumonitis: Mobocertinib has the potential to induce severe or fatal ILD or pneumonitis. Monitor patients for the development of new or worsening pulmonary symptoms, including dyspnea, coughing, or chest pain. If there is suspicion, the medication should be withheld; if confirmed, it should be permanently discontinued.

• Cardiotoxicity: Mobocertinib can sometimes affect the heart. It may cause problems such as weakened heart muscle, heart failure, a lower ejection fraction, or changes in heart rhythm, such as QT prolongation. In rare cases, this can lead to serious rhythm problems such as Torsades de Pointes. Because of this risk, doctors usually check heart function and the QTc interval before and during treatment. If significant heart-related side effects occur, the medicine may be paused, the dose adjusted, or the treatment stopped.

• Diarrhea: Dehydration or electrolyte imbalance may result from severe diarrhea. Begin antidiarrheal treatment (e.g., Loperamide) at the first sign of diarrhea and ensure you are consuming adequate fluids and electrolytes. Treatment should be adjusted according to severity.

• Embryo-Fetal Toxicity: Fetal injury may result from mobocertinib. Effective non-hormonal contraception should be utilized by women of reproductive potential during treatment and for a period of one month following the final dose. Males with reproductive potential partners should use effective contraception both during therapy and for a week after the last dosage.

Adverse Reactions:

• Gastrointestinal Disorders Include:

  • Diarrhea.

  • Stomatitis (inflammation of the mouth).

  • Vomiting.

  • Decreased appetite.

  • Nausea.

  • Decreased weight.

  • Abdominal pain.

  • Gastroesophageal reflux disease.

  • Dyspepsia.

• Skin and Subcutaneous Disorders:

  • Rashes.

  • Dry skin.

  • Paronychia (nail infection).

  • Pruritus (itching).

  • Alopecia (hair loss).

• Musculoskeletal and Connective Tissue Disorders Include:

  • Musculoskeletal pain.

• General Disorders:

  • Fatigue.

• Respiratory Disorders Include:

  • Cough.

  • Upper respiratory tract infection.

  • Dyspnea (shortness of breath).

  • Rhinorrhea (runny nose).

• Eye Disorders Include:

  • Ocular toxicity.

• Cardiac Disorders Include:

  • QTc interval prolongation.

  • Hypertension.

• Nervous System Disorders Include:

  • Headache.

• Clinically Relevant Adverse Reactions Include:

  • Edema.

  • Acute kidney injury.

  • Peripheral neuropathy (nerve damage causing numbness).

  • Palmar plantar erythrodysesthesia (painful redness and swelling of palms and soles).

  • Pneumonitis(Inflammation of lung tissue).

  • Cardiac failure.

What Is the Most Important Information Regarding Mobocertinib?

Mobocertinib may cause changes in the electrical activity of the heart, including QTc prolongation and Torsades de Pointes. It can cause irregular heartbeats, be life-threatening, and may lead to death. The doctor will perform an ECG, and blood tests will be done to check electrolytes before and during treatment with Mobocertinib. The doctor should be contacted immediately if symptoms such as dizziness, lightheadedness, faintness, or an irregular heartbeat occur.

What Are Some of the Important Instructions to Patients?

• Patients are informed about the risk of QTc prolongation and the symptoms that may indicate significant QTc prolongation, including dizziness, lightheadedness, and syncope. Patients are advised to report to the doctor if they experience these symptoms or use any other cardiac medications.

• Patients are informed about the risks of severe or fatal interstitial lung disease (ILD) or pneumonitis, and in case of symptoms such as cough, shortness of breath, or chest pain, patients must contact the doctor.

• Patients are informed of the risk of heart failure and are advised to contact the doctor immediately if palpitations or shortness of breath are noticed.

• Mobocertinib may cause diarrhea, which may be severe in some cases and require prompt treatment. Hence, patients are advised to take antidiarrheal medicine (eg, Loperamide) to increase the intake of oral fluids and electrolytes and contact the doctor in case diarrhea occurs.

• Females of reproductive potential are advised of the potential risk to the fetus and to contact the doctor in case of suspected pregnancy. Use of effective non-hormonal contraception during Mobocertinib treatment and for one month after the last dose. Males of reproductive potential are also advised to use effective contraception during the treatment and for one week after the last dose of Mobocertinib.

• Women are advised not to breastfeed during the treatment with Mobocertinib and for one week after the last dose.

• Males and females of reproductive potential are advised that Mobocertinib may impair fertility.

• Patients are advised to inform the doctor of all concomitant medications, prescription medicines, over-the-counter drugs, vitamin supplements, or herbal products taken during the treatment.

• Grapefruit and grapefruit juice must be avoided during the treatment with Mobocertinib.

• If a dose of Mobocertinb is missed by six hours or vomiting occurs, the treatment must be resumed as prescribed the following day.

• Mobocertinib must not be used for conditions other than prescribed by the doctor and must not be given to others, even if they have the same symptoms, as it may harm them.

For Doctors:

Description:

• Mobocertinib is for oral administration. Each capsule contains 40 mg of Mobocertinib, which is equivalent to 48.06 mg of Mobocertinib succinate. The capsule shells are composed of gelatin and titanium dioxide, while the printing ink comprises shellac, isopropyl alcohol, dehydrated alcohol, propylene glycol, butyl alcohol, strong ammonia solution, black iron oxide, potassium hydroxide, and purified water.

Clinical Pharmacology:

• Mechanism of Action:

  • Mobocertinib is an irreversible EGFR inhibitor used to treat non-small cell lung cancer (NSCLC) with exon 20 insertion mutations. These EGFR mutations, usually found in exons 18–21, disturb the normal function of epithelial cells and contribute to cancer growth.

  • The first- and second-generation TKIs were often ineffective against mutations such as EGFR T790M or exon 20 insertions. Mobocertinib was developed to help overcome this type of drug resistance.

• Pharmacodynamics: The exposure-response relationship is not entirely elucidated; the maximal QTc increase observed was 23 msec at 160 mg daily.

• Pharmacokinetics: Dose-proportional C_max and AUC for over 5 to 180 mg per day.

• Mobocertinib has a bioavailability of about 37% and usually reaches its peak blood concentration about 4 hours after administration.

• It binds to proteins in the blood, and its active metabolites have similar strength.

• The drug is mainly metabolized by CYP3A. Most of it leaves the body through stool (about 76%), while a small amount is excreted in urine (about 4%).

• There are no substantial differences in age, race, sex, body weight, or mild-to-moderate renal/hepatic impairment. The consequences of severe impairment are undetermined.

Clinical Research:

• Phase I: The recommended dose was 160 mg, as determined by dose escalation; diarrhea and pneumonitis were dose-limiting toxicities.

• Phase II: 136 patients were assessed; 131 patients experienced TRAEs (diarrhea, nausea, rash, anemia, and stomatitis); the objective response rate was 44%, and the disease control rate was 86%.

• Phase III: Presently conducting a trial in comparison to platinum-based chemotherapy; anticipated outcomes are expected in 2026.

Toxicology That Is Not Clinical:

• Studies on embryo-fetal development, fertility, and carcinogenicity were not conducted.

• No mutagenicity was observed in vitro; lymphocytes did not exhibit any chromosomal aberrations; the in vivo micronucleus test was negative.

• Reversible reproductive organ changes in rats and canines at a clinical dose of ≥0.2.

• Ophthalmologic findings in canines at a clinical dose of ≥0.2–0.3; clinical relevance is unknown.

Drug Interactions:

• Mobocertinib plasma levels are elevated by CYP3A inhibitors, which can lead to an increase in adverse reactions. It is important to monitor the QTc.

• Mobocertinib levels are reduced by CYP3A inducers, so it is recommended to avoid them whenever possible.

• Mobocertinib may decrease the plasma concentrations of CYP3A substrates, such as hormonal contraceptives. It is recommended that the dosage be monitored or adjusted.

• If coadministration with pharmaceuticals that prolong QTc cannot be avoided, it is recommended to monitor ECGs frequently.

Application in Particular Populations:

• Pregnancy: Potential fetal injury; animal studies have demonstrated embryo lethality and maternal toxicity.

• Lactation: It is advised to refrain from lactating for 1 week after the final dose of treatment and throughout the course of treatment.

• Reproductive Potential: Confirm pregnancy status; employ effective non-hormonal contraceptives. Fertility may be impaired in both males and females.

• Pediatric: Safety and efficacy have not been established.

• Geriatric: There is no overall difference; however, the incidence of severe adverse events is higher in individuals aged 65 years or older.

• Renal Impairment: No adjustment is required for mild to moderate impairment; the dose for severe impairment has not been established.

• Hepatic Impairment: The dose for mild-moderate impairment has not been adjusted, and the dose for severe impairment has not been established.