Mobocertinib - A Brief Overview

Overview:

Mobocertinib is a kinase inhibitor used in adults to treat advanced or metastatic non-small cell lung cancer (NSCLC) associated with epidermal growth factor receptor (EGFR) exon 20 insertion mutations detected by FDA-approved tests and in patients whose disease has progressed on or after platinum-based chemotherapy.

Approval for Mobocertinib was granted by the United States Food and Drug Administration (USFDA) on September 15th, 2021. The indication of the drug was approved under accelerated approval based on the duration of response and overall response rate of the drug. This is the first approval of a drug targeted for oral therapy, and the approval was based on data from international, nonrandomized, multi-cohort clinical trials in which were included, patients with advanced NSCLC with EGFR exon 20 insertion mutations.

How Does Mobocertinib Work?

Mobocertinib belongs to a class of kinase inhibitors (a drug that inhibits kinase enzyme, which promotes cell growth) and works by blocking the action of abnormal proteins which signal the multiplication of cancer cells and stop or slow the spread of cancerous cells and shrinks the tumors. It works against the EGRF exon 20 insertion mutations (a protein that helps the cells grow and divide) found on cancer cells.

Indications-

• Mobocertinib is indicated for the treatment of non-small cell lung cancer in adults with locally advanced or metastatic progress (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 the treatment with platinum-based chemotherapy.

Supply and Storage of Mobocertinib:

Mobocertinib is supplied in 40 mg capsules and must be stored at 20 to 25 degrees.

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; it can be taken with or without food at the same time daily. The capsules must be swallowed whole without opening, chewing, or dissolving the contents.

• In case a dose is missed by more than six hours, it must be skipped, and the next dose must be taken the following day at the regularly scheduled time. In case a dose is vomited, an additional dose must not be taken, but the next dose must be taken as prescribed the following day.

Warnings and Precautions:

• QTc Prolongation and Torsades de Pointes: Mobocertinib can cause life-threatening heart rate corrected QT (QTc) prolongation, including Torsades de Pointes, which can be fatal. QTc interval and electrolytes at baseline must be assessed, and abnormalities in sodium, potassium, calcium, and magnesium must be corrected prior to initiating treatment with Mobocertininb. It must be periodically monitored during the treatment in patients with risk factors for QTc prolongation, such as congenital long QT syndrome, cardiac diseases, or electrolyte irregularities. Concomitant drugs that may prolong the QTc interval and strong or moderate CYP3A inhibitors must be avoided with Mobocertinib as they may further prolong the QTc. Mobocertinib must be withheld, the dose must be reduced, or it must be permanently discontinued based on the severity of the QTc prolongation.

• Interstitial Lung Disease or Pneumonitis: Mobocertinib can cause interstitial lung disease (ILD) or pneumonitis, which can be fatal. Patients must be monitored for new or worsening pulmonary symptoms which are indicative of ILD or pneumonitis. In the case of patients with suspected ILD or pneumonitis, Mobocertinib must be withheld and permanently discontinued if ILD or pneumonitis is confirmed.

• Cardiac Toxicity: Mobocertinib can cause cardiac toxicity, including decreased ejection fraction, cardiomyopathy, and congestive heart failure, and may be fatal. In a pooled Mobocertinib safety population, heart failure was seen in 2.7 percent of patients, including 1.2 percent of grade 3 reactions and one 0.4 percent fatal case of heart failure. Mobocertinib can cause QTc prolongation, resulting in Torsades de Pointes; the following conditions also occurred in patients receiving Mobocertinib: atrial fibrillation, ventricular tachycardia, first-degree atrioventricular block, second-degree atrioventricular block, left bundle branch block, supraventricular extrasystoles, and ventricular extrasystoles. The cardiac function must be monitored, including the assessment of left ventricular ejection fraction at baseline and during the treatment. Based on the severity, Mobocertinib can be withheld, reduced, or permanently discontinued.

• Diarrhea: Mobocertinib can cause severe diarrhea leading to dehydration or electrolyte imbalance, with or without renal impairment; hence diarrhea must be treated promptly. At the first sign of diarrhea or increased bowel movement frequency, antidiarrheal agents such as Loperamide are advised, along with the increased intake of fluid and electrolytes. Electrolyte levels are monitored and based on the severity, Mobocertinib can be withheld, reduced, or permanently discontinued.

• Embryo-Fetal Toxicity: Findings from animal studies and its mechanism of action show that Mobocertinib can harm the fetus when administered to a pregnant woman. Mobocertinib, administered orally to pregnant rats during organogenesis, caused embryo lethality at plasma exposures approximately 1.7 times exposure in humans. It is based on the area under the curve (AUC) at a clinical dose of 160 mg once daily. Pregnant women are advised of the potential risk caused to the fetus due to the treatment with Mobocertinib. Effective non-hormonal contraception is advised in females of reproductive potential during the treatment and also for one month after the last dose of Mobocertinib. Males of reproductive potential are also advised to use effective contraception during the treatment and for one week after the last dose of Mobocertinib.

Adverse Reactions:

Gastrointestinal Disorders Include:

• Diarrhea.

• Stomatitis.

• Vomiting.

• Decreased appetite.

• Nausea.

• Decreased weight.

• Abdominal pain.

• Gastroesophageal reflux disease.

• Dyspepsia.

Skin and Subcutaneous Disorders:

• Rashes.

• Dry skin.

• Paronychia.

• Pruritus.

• Alopecia.

Musculoskeletal and Connective Tissue Disorders Include:

• Musculoskeletal pain.

General Disorders:

• Fatigue.

Respiratory Disorders Include:

• Cough.

• Upper respiratory tract infection.

• Dyspnea.

• Rhinorrhea.

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.

• Palmar plantar erythrodysesthesia.

• Pneumonitis.

• Cardiac failure.

For Doctors:

Description:

Mobocertinib is a kinase inhibitor, and the capsule for oral administration contains Mobocertinib 40 mg of, equivalent to 48.06 mg of Mobocertinib succinate, with no active ingredients. The shells of the capsules consist of gelatin and titanium dioxide. The printing ink consists of shellac, isopropyl alcohol, dehydrated alcohol, propylene glycol, butyl alcohol, strong ammonia solution, black iron oxide, potassium hydroxide, and purified water.

Recommended Dosage:

• The recommended dose of Mobocertinib is 160 mg orally with or without food once daily, at the same time daily, until disease progression or unacceptable toxicity.

• Capsules must be swallowed whole, not opened or chewed, or the contents must not be dissolved.

• 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.

Mechanism of Action:

Epidermal growth factor receptors (EGFR), a receptor tyrosine kinase, play a vital role in physiology by regulating the development and homeostasis of epithelial cells. Mutation of EGFR in exons 18 to 21 causes dysregulation in the physiology of epithelial cells, leading to the development of NSCLC. The common mutations are seen in 90 percent of cases of EGFR mutations leading to NSCLC, including point mutations at exon 21, L858R, and deletion of exon 19. The first and second tyrosine kinase inhibitors (TKI) have been effectively used in such cases, but with the occurrence of EGFR T790M mutations, their effectiveness is lost, leading to the development of drug resistance. A third-generation TKI was developed to overcome this mutation due to the drug resistance of other TKIs. But none of the TKIs were effective against the third commonly seen resistance EGFR exon 20 insertions, seen in 4 to 9 percent cases of NSCLC. Mobocertinib is an irreversible inhibitor of EGFR, effective even for cases of NSCLC with exon insertions.

Clinical Pharmacology:

• Pharmacodynamics: The exposure-response relationship and the time course of the pharmacodynamic response of Mbocertinib are unknown. The largest mean increase in QTc was 23.0 msec, following the administration of Mobocertinib 160 mg daily. Pharmacokinetics:

• After single and multiple administration of doses, combined molar C (max) and area under the curve (AUC) of Mobocertinib, and its active metabolites, AP32960 and AP32914, were dose-proportional over the dose range of 5 to 180 mg once daily.

• The median time to peak concentration of Mobocertinib is four hours; the mean absolute bioavailability is 37 percent. No clinical differences were observed following a high-fat or low-fat meal compared to the administration of Mobocertinib after an overnight fast.

• Mobocertinib was a human plasma protein bound in a concentration-independent manner; the blood-to-plasma ratio was 0.76 for Mobocertinib,1.2 for AP32960, and 0.71 for AP32914.

• The mean apparent volume of distribution of Mobocertinib was 3,509 L at a steady state.

• Mobocertinib is metabolized by CYP3A, and the active metabolites are AP32960 and AP32914 and are equipotent to Mobocerinib.

• After the administration of Mobocertinib 160 mg oral dose, 76 percent of the dose was recovered in feces, 4 percent was recovered in urine, and the administered dose of about 12 percent was recovered in feces and one percent in urine for AP32960 and below the detection limit in urine and feces for AP 32914.

• No clinical differences were observed in the pharmacokinetics of Mobocertinib based on age, race, sex, body weight, mild to moderate renal impairment, or mild to moderate hepatic impairment. The effect of severe renal and hepatic impairment on Mobocertinib pharmacokinetics is unknown.

Clinical Studies:

• Phase I: A dose escalation study was conducted in a cohort of patients of NSCLC who were refractory to the available standard of care. Cohorts were administered a single dose of 5 mg,10 mg,20 mg,40 mg,80 mg, and 120mg sequentially and twice daily doses of 40 mg and 60 mg sequentially. After the 120 mg cohort, the dose was further escalated to 180mg in a cohort of four patients. Out of four, two developed dose-limiting toxicities in the form of grade 3 diarrhea and treatment-related adverse events (TRAE), leading to the missing of more than 25 percent of the doses. Due to this, 180 mg was reduced to 160 mg and selected as the recommended dose for phase II clinical studies. The other adverse effect was grade 3 pneumonitis in one patient of cohorts 80mg, and one patient of 160mg cohort developed grade 3 mucositis. The other data deduced included the mean effective half-life of 11 to 17 hours, maximum plasma concentration reached in four hours, and a dose-dependent increase in area under the concentration-time curve.

• Phase II: A total of 130 patients were enrolled, along with patients who were treated with 160 mg in phase I. They were grouped into a cohort of seven and administered Mobocertinib at 160 mg daily. A safety evaluation of 136 patients demonstrated TRAEs in 131 patients, including diarrhea, nausea, vomiting, rash, stomatitis, anemia, and a decrease in appetite. The objective response rate of 44 percent and disease control rate of 86 % was estimated in those receiving a daily dose of 160 mg.

• Phase III: A randomized phase III, multicentre clinical trial with groups assigned to receive either Mobocertinib or platinum-based chemotherapy for patients of NSCLC with exon 20 insertion mutation is undergoing, and the results are expected in 2026.

Non-clinical Toxicology:

• As the drug received accelerated approval, studies on carcinogenicity, fertility, early development of the embryo, and toxicology studies pre and post-natal have not been performed.

• An in vitro reverse mutation assay using Salmonella typhimurium demonstrated no mutagenicity with Mobocertinib.

• In vitro assay of chromosomal aberrations using lymphocytes did not demonstrate any chromosomal aberrations.

• Micronucleus test in vivo in the bone marrow of rats did not demonstrate any breaks in the chromosomes causing mutations upon administration of Mobocertinib.

• Reversible changes in the organs of reproduction were noticed in repeated dose toxicological studies conducted over 4 and 13 weeks in rats and dogs. These changes included; a decrease in the weight of multiple organs of reproduction, cervix or vagina demonstrated a decrease in thickness of epithelium or inflammation upon microscopic examination, there may be atrophy of mammary glands, prostrate or uterus when administered at a dose greater than 0.2 times that of a daily administered clinical dose of 160 mg to rats or dogs. These findings compel the label of embryo-fetal toxicity to Mobocertinib.

• A 4 and 13-week repeated dose toxicity studies at doses greater than 0.8 times the recommended clinical dose; were conducted, and in the 4-week dose study in dogs, Mobocertinib administration caused the partial or complete closure of the eye, discharge from the eye, sclera injection, and histological findings of corneal epithelial atrophy at doses greater than 0.3 times the daily administered dose. In the 13-week repeat dose study in dogs, Mobocertinib administration resulted in a discharge, congenital hyperemia, and corneal opacity correlating histological decrease in the thickness of the corneal epithelium at doses 0.2 times greater than the daily recommended dose at 160 mg, but the clinical relevance of these findings is unknown.

Recommended Dose Reductions:

The first dose reduction is made at the dose level of 120 mg once daily, and the second dose reduction at 80 mg once daily.

Drug Interactions:

• Coadministration of Mobocertinib with strong or moderate CYP3A inhibitors results in increased plasma concentrations of Mobocertinib, which leads to the risk of an increase in adverse reactions, including QTc interval prolongation. It can be prevented by the concomitant use of strong or moderate CYP3A inhibitors with Mobocertinib. If concomitant use cannot be avoided, the dose of Mobocertinib is reduced, and the QTc interval is monitored more frequently with ECGs.

• Coadministration of Mobocertinib with strong or moderate CYP3A inducers results in decreased plasma concentrations of Mobocertinib, which leads to a reduction in the anti-tumor activity of Mobocertinib. It can be prevented by avoiding the concomitant use of strong or moderate CYP3A inducers with Mobocertinib.

• Coadministration of Mobocertinib with CYP3A substrates may result in a decrease in plasma concentrations of CYP3A substrates, leading to a reduction in the efficacy of these substrates. It can be prevented by avoiding the concomitant use of Mobocertinib with hormonal contraceptives and other CYP2A substrates, where minimal concentration changes may cause serious therapeutic failures. If it cannot be avoided, an increase in the CYP3A substrate dosage may be done in accordance with the approved product prescribing information.

• Mobocertinib can cause QTc interval prolongation, and hence coadministration of drugs known to prolong the QTc interval with Mobocertinib may further increase the risk of QTc interval prolongation. It can be avoided by using other drugs known to prolong QTc interval with Mobocertinib, or if it cannot be avoided, QTc interval is frequently monitored with ECGs.

Use of Mobocertinib in Specific Populations:

• Pregnancy: Pregnant females must be advised on the potential risk to the fetus; although no data is available on the use of Mobocertinib on pregnant women, findings and mechanism of action from animal studies have shown that Mobocertinib can cause fetal harm when administered to pregnant females. Mobocertinib, administered orally to pregnant rats during organogenesis, caused embryo lethality (embryo or fetal death) and maternal toxicity at plasma exposures approximately 1.7 times the human exposure, based on the area under the curve (AUC), at a clinical dose of 160 mg once daily. Adverse effects on the development of the embryo or the fetus included post-implantation loss and decreased fetal weights, and no clear evidence was seen of fetal malformations at a high dose level of 10 mg/kg.

• Lactation: No data is present on the presence of Mobocertinib or its metabolites in human milk or the milk production in lactating mothers, or its effects on the breastfed infant, but due to the potential for serious adverse reactions, women are advised not to breastfeed during the treatment with Mobocertinib, and for one week after the last dose.

• Females and Males of Reproductive Potential: As Mobocertinib can cause fetal harm, pregnancy status must be verified in females of reproductive potential prior to initiating treatment with Mobocertinib. Females of reproductive potential are recommended to use effective non-hormonal contraception during Mobocertinib treatment and for one month after the last dose. Male patients with female partners of reproductive potential are also advised to use effective contraception during the treatment and for one week after the last dose of Mobocertinib. Evidence from animal studies shows Mobocertinib may impair fertility in males and females of reproductive potential.

• Pediatric Use: The safety and effectiveness of Mobocertinib in pediatric patients have not been established.

• Geriatric Use: Out of 114 patients, who received Mobocertinib in clinical studies, 37 percent were 65 years and above, 7 percent were 75 years and above, and no overall difference was observed between patients of 65 years and older and younger patients. Grade 3 and Grade 4 adverse reactions and serious adverse reactions are seen at higher incidence rates in patients 65 years and older as compared to younger patients, as suggested by an exploratory analysis.

• Renal Impairment: No adjustment is recommended in doses of Mobocertinib in patients with mild to moderate kidney impairment (estimated glomerular filtration rate [eGFR] 30 to 89mL/min/1.73sq.m, by modification diet in renal disease [MDRD] equation). A recommended dose of Mobocertinib for patients with severe renal impairment (eGFR less than 30 mL/min/1.73sq.m) has not been established.

• Hepatic Impairment: No adjustment is recommended in doses of Mobocertinib for patients with mild or moderate hepatic impairment. The recommended dose of Mobocertinib has not been established for patients with severe hepatic impairment.

For Patients:

What Is Mobocertinib?

Mobocertinib is a medicine used to treat adults with non-small cell lung cancer that has metastasized (spread) to other body parts and cannot be removed by surgery, has an abnormal epidermal growth factor receptor gene, and also in patients whose disease has worsened while on or after chemotherapy, that contains platinum.

How Should Mobocertinib Be Taken?

Mobocertinib must be taken exactly as prescribed by the doctor and at the same time daily, 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.

What Is the Most Important Information Regarding Mobocertinib?

Mobocertinib may cause changes in the electrical activity of the heart called the 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 are done to check the electrolytes before starting and during the treatment with Mobocertinib. The doctor should be immediately contacted of symptoms like dizziness, lightheadedness, and faint or irregular heartbeat.

How Should Mobocertinib Be Stored?

Mobocertinib must be stored at 20 to 25 degrees; excursions permitted from 15 to 30 degrees.

What Are Some of the Side Effects of Mobocertinib?

Some of the side effects of Mobocerrtinib include:

• Lung problems.

• Heart problems.

• Diarrhea.

• Rash.

• Nausea and vomiting.

• Mouth sores.

• Decreased appetite.

• Muscle or bone pain and tiredness.

• Dry skin.

• Infection around the nails.

• Fertility may be affected.

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 in case of these symptoms or about the use of 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 any of the symptoms, such as shortness of breath, chest pain, palpitations, and syncope, are experienced.

• Mobocertinib may cause diarrhea, may be severe in some cases, and require prompt treatment, and 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.