Amivantamab-vmjw - Indications, Dosages, Precautions, and Its Pharmacological Aspects

What Is Amivantamab-vmjw?

Amivantamab-vmjw is a medicine used to treat non-small cell lung cancer. It is given as an injection. Individuals with this cancer undergo a mutation in a gene. These changes occur in the epidermal growth factor receptor (EGFR) gene. The specific change that occurs is known as an exon 20 insertion (Exon 20 Ins) mutation. Because of this, cancer may not respond to other targeted medicines, such as tyrosine kinase inhibitors. In a few individuals, this change may make chemotherapy less effective.

Amivantamab-vmjw targets two proteins in the cancer cells. These are the EGFR receptor and the mesenchymal-epithelial transition (MET) receptor. This medicine is used for those whose cancer has spread to nearby areas and other parts of the body. It is also useful for those in whom the disease continues to grow during or after treatment with platinum-based chemotherapy. The Food and Drug Administration (FDA) approved this medicine on May 21, 2021. Research is being done for its use for other cancers as well. This again depends on the favorable clinical outcomes from these trials.

What Are the Indications of Amivantamab-vmjw?

Amivantamab-vmjw is a bispecific EGFR - MET (epidermal growth factor receptor, mesenchymal-epithelial transition) receptor-directed antibody. This is indicated for treating progressive types of lung cancer.

Some of its indications are as follows:

• In a person with locally advanced non-small cell lung cancer (NSCLC), there are EGFR and MET mutations that are commonly seen on or after platinum chemotherapy.
• In a person with metastatic non-small cell lung cancer, but that person cannot undergo surgery.
• Among those with recurrent locally invasive non-small cell lung cancers that are progressing even after chemotherapy, there are genetic mutations.

Contraindication:

There are no known contraindications reported for the use of Amivantamab-vmjw. Some of the conditions where its use is avoided are as follows:

• Known case of developing hypersensitivity to Amivantamab-vmjw.
• During pregnancy, it has harmful effects on the fetus.
• The safety and efficacy of Amivantamab-vmjw have not been established in pediatric patients.

What Are the Available Dosage Forms and Strengths of Amivantamab-vmjw?

• Amivantamab-vmjw is available as a solution (colorless to pale yellow) in single-dose vials for injection.
• Each vial contains 350 mg of Amivantamab-vmjw in 7 mL, corresponding to 50 mg/mL.

Dosage and Administration

The recommended doses of Amivantamab-vmjw are dependent on the baseline body weight of the individual and calculated according to it.

• Route of Administration: Amivantamab-vmjw is diluted before administering as an intravenous (IV) infusion.
• Recommended Dose: For a body weight of less than 80 kg, 1050 mg of Amivantamab-vmjw is given (three vials needed).
• For body weight, more than or equal to 80 kg, 1400 mg of Amivantamab-vmjw is given (four vials needed).
• Amivantamab-vmjw is administered once weekly for four weeks.
• The initial dose is given as a split infusion on days one and two of the first week.
• The following doses are administered every two weeks until evidence of progressive cancer or occurrence of intolerable toxicity.
• Premedications should be given before initiating Amivantamab-vmjw therapy.

Recommended Premedication

Premedications are given to reduce the potential risk of inducing infusion-related reactions (IRR). Antihistamines and antipyretics are given before starting each infusion. Glucocorticoids are administered only during the first week, on the first and second infusion days, and are given only if needed.

Preparation of Amivantamab-vmjw for IV Infusion

Amivantamab-vmjw is diluted and prepared before being administered intravenously as an infusion.

• The color of the vial solution is checked for turbidity or impurities. The solution should be clear, colorless to pale yellow, and free of particulate matter.
• The number of vials is calculated according to the patient’s baseline weight.
• Since each vial contains 350 mg of Amivantamab-vmjw in 7 mL of the solution, an equivalent amount of solution is discarded from the infusion bag before injecting the vial into it.
• Only polyvinyl chloride (PVC) and polypropylene (PP) infusion bags are used.
• 7 mL of Amivantamab-vmjw is withdrawn from each vial and added to the infusion bag, ensuring a final volume of 250 mL.
• The infusion bag is gently inverted to mix the solution and must not be shaken.
• Diluted Amivantamab-vmjw solutions are administered within ten hours of preparation.

Warnings and Precautions

The use of Amivantamab-vmjw could cause some infusion-associated side effects. Hence, certain precautions should be followed during its therapy. Some of the related warnings are as follows -

• Infusion-Related Reactions (IRR):

If infusion reactions such as flushing, chills, or fever develop, the infusion should be interrupted and the rate reduced or discontinued based on the severity of the reactions.

• Respiratory Problems:

Interstitial lung disease (ILD) or pneumonitis could be induced.

• Skin Reactions:

Dermatologic adverse reactions could occur, causing acneiform dermatitis or toxic epidermal necrolysis.

• Eye Problems:

Ocular toxicity could occur.

• Pregnancy:

Use of Amivantamab-vmjw is associated with embryo or fetal toxicity leading to fetal harm. Hence, women with reproductive potential are at risk of pregnancy.

For Patients

What Is Meant By Non-Small Cell Lung Cancer?

Non-small cell lung cancer (NSCLC) is one of the predominant types of lung cancer and is commonly seen in both smokers and non-smokers. It refers to a group of lung cancers that are further classified depending on the cells involved. Adenocarcinoma (the most common type), large cell carcinoma, and squamous cell carcinoma are the three important types of NSCLC. Their clinical symptoms include a persistent cough, breathing difficulty, unexplained weight loss, and a blood-tinged cough. Non-small cell lung cancers are treated by standard therapeutic interventions such as surgery, radiation, and chemotherapy.

Sometimes, these NSCLC cancers undergo mutations (EGFR gene mutations) on or after chemotherapeutic treatment with platinum. These mutated cancers spread aggressively and do not respond to chemotherapy or other anti-cancer agents such as tyrosine kinase inhibitors. Recent clinical studies suggest that immunomodulating agents, such as monoclonal antibodies, are effective in treating progressive non-small cell lung cancer.

How Is Amivantamab-vmjw Effective in Treating Non-small Cell Lung Cancer?

Amivantamab-vmjw is a recombinant monoclonal antibody, a class of therapeutic proteins. It is designed to target two specific proteins, the epidermal growth factor receptor (EGFR) and the mesenchymal-epithelial transition (MET) receptor, which are present on the surface of tumor cells in non-small cell lung cancer. Amivantamab-vmjw therapy is effective in treating these cancer forms in the following ways:

• EGFR and MET receptors are the primary proteins in tumor cells that cause abnormal genetic changes (exon 20 insertions) in non-small cell lung cancers. These genetic changes are commonly caused by platinum chemotherapy.
• The occurrence of these mutations makes non-small cell lung cancers unresponsive to ongoing chemotherapy or any other anticancer drugs.
• Also, these genetically mutated tumors become aggressive in spreading and malignant.
• When given as an IV infusion, Amivantamab-vmjw binds to EGFR and MET receptors, making them more easily detected by the body’s immune cells, such as natural killer cells and macrophages (immunomodulatory activity).
• This destroys tumor cells and prevents their progression.
• Amivantamab-vmjw also blocks these receptors and reduces the chance of genetic mutations.
• Thus, Amivantamab-vmjw is a potent immunomodulating agent and effective against non-small cell lung cancers that are genetically mutated and invasive.

What Are the Adverse Reactions Associated With Amivantamab-vmjw Therapy?

The majority of the adverse reactions are caused by overdosing on Amivantamab-vmjw. Some of them are as follows:

• Rash.
• IRR (infusion-related reactions).
• Paronychia (inflammatory changes in the fingernails).
• Musculoskeletal pain (pain in joints and muscles).
• Dyspnea.
• Nausea.
• Fatigue.
• Edema.
• Stomatitis.
• Cough.
• Constipation.
• Vomiting.
• Decreased lymphocytes (a type of white blood cell).
• Reduced albumin levels and phosphate levels.
• Potassium and sodium levels are also decreased.
• Elevated liver enzymes, such as alkaline phosphatase.
• Increased glucose levels are associated with increased gamma-glutamyl transferase enzymes.
• Hemorrhage (bleeding tendency).
• Peripheral neuropathy.
• Dizziness.
• Headache.

What Are the Precautions to Be Taken During Amivantamab-vmjw Therapy?

Some of the common precautions to be followed during Amivantamab-vmjw therapy are as follows:

• Patient counseling is provided before therapy initiation regarding its clinical effects and potential adverse reactions.
• Any known allergy or hypersensitivity history should be disclosed to the physician.
• Before infusion and preparation, the vials should be thoroughly inspected for the presence of particulate matter or discoloration.
• If discoloration or visible particles are detected in the vials, they should be discarded immediately.
• Women of reproductive age must be informed about their pregnancy status before the treatment since fetal harm is one of the toxicities of Amivantamab-vmjw.
• Contraception recommendations are given to them to avoid pregnancy during the therapy phases.
• Immunizations with live or attenuated vaccines should be avoided during or immediately after the Amivantamab-vmjw therapeutic regimen.

For Doctors

Clinical Pharmacology of Amivantamab-vmjw

Pharmacodynamics

Amivantamab-vmjw is a human immunoglobulin (IgG1-based) bispecific antibody that is target-specific and binds to the EGF and MET receptor binding sites. It is synthesized by recombinant DNA technology using mammalian cell lines (Chinese Hamster Ovary). The molecular weight of Amivantamab-vmjw is nearly 148 kDa. It exerts immunomodulatory effects on target proteins.

What Is the Mechanism of Action of Amivantamab-vmjw?

• Amivantamab-vmjw is a monoclonal antibody that binds specifically to two target sites, namely, the extracellular domains of EGFR and MET receptors on the surface of cancer cells.
• This binding disrupts the activation of EGFR and MET signaling, which eventually leads to the degradation of exon 20 insertion mutations.
• Since EGFR and MET receptors are present on the tumor cells’ surface, binding with Amivantamab-vmjw makes them easy targets for natural killer cells and macrophages.
• These immune effector cells destroy Amivantamab-vmjw-bound tumor cells through mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) and trogocytosis.

Pharmacokinetics

Amivantamab-vmjw is a therapeutic monoclonal antibody that gets readily absorbed, distributed, and metabolized in the body.

• When administered intravenously, Amivantamab-vmjw exposure increases proportionally with doses ranging from 350 mg to 1750 mg.
• Complete saturation of the target receptors, EGFR and MET, is achieved at 700 mg and above throughout the dosing duration.
• Half-Life - Its terminal half-life is found to be approximately 11.3 days.
• Steady-state concentrations of amivantamab-vmjw are attained on the 9th infusion. The accumulation ratio of the steady-state concentration is found to be 2.4.
• Distribution - The mean volume distribution of Amivantamab-vmjw is approximately 5.13 L.
• Elimination - The mean clearance of Amivantamab-vmjw is approximately 360 mL/day.
• Immunogenicity - Amivantamab-vmjw is well tolerated and has a minimal incidence of anti-Amivantamab-vmjw antibodies. No evidence of elevated antibody titers or their effect on the pharmacokinetic parameters, clinical efficacy, or safety of Amivantamab-vmjw is documented.

Toxicities

The toxicities that are associated with the use of Amivantamab-vmjw are often due to drug overdose, which commonly occurs when the doses are not calculated according to body weight. Some of its associated toxicities are as follows-

• Infusion-related reactions (IRR) cause nausea, vomiting, dyspnea, chest discomfort, fever, chills, flushing, and hypotension.
• Ocular toxicity can lead to keratitis, dry eyes, conjunctival redness, blurred vision, ocular itching, visual impairment, and uveitis.
• Fetal toxicity results in impairment of embryo-fetal development, lethality to the embryo, and abortion.
• Dermatological reactions such as dermatitis, acne, eczema, dermatitis acneiform, eczema asteatotic, palmar-plantar erythrodysesthesia syndrome, perineal rashes, rash erythematous, maculopapular rash, skin exfoliation, and toxic epidermal necrolysis.
• Asthenia and fatigue.
• Eyelid edema, facial edema, and generalized edema involving lips and periorbital regions.
• Interstitial lung disease and pneumonia symptoms, such as atypical pneumonia, lower respiratory tract infection, aspiration pneumonia, and pulmonary sepsis.
• Musculoskeletal pain, including arthralgia, back pain, arthritis, bone pain, and musculoskeletal discomfort.
• Myalgia, neck pain, and extremity pain.
• Stomatitis such as aphthous ulcer, cheilitis, mouth ulceration, glossitis, mucosal inflammation, and pharyngeal inflammation.
• Abdominal disturbances such as abdominal discomfort, abdominal pain, and epigastric discomfort.
• Hemorrhage complications such as epistaxis, gingival bleeding, hemoptysis, hematuria, and mucosal hemorrhage.
• Neurological reactions such as peripheral sensory neuropathy, hypoesthesia, neuralgia, and paresthesia.
• Headache and migraine.

What Are the Drug Interactions and Warnings of Amivantamab-vmjw?

Amivantamab-vmjw is an immunomodulator and is usually well-tolerated with other drugs. In some cases, drug interactions occur, affecting the efficacy of the therapy. Some of the reported drug interactions are as follows:

• The risk of adverse side effects increased when used concomitantly with other immunomodulators such as Burosumab and Canakinumab.
• The therapeutic efficacy of live or attenuated vaccines (Ebola vaccine, Zaire vaccine) is reduced when Amivantamab-vmjw is concomitantly administered.
• Hormone substitutes such as estradiol increase the thrombogenic potential of Amivantamab-vmjw.
• Toxicities have been reported in hypoalbuminemia conditions. Hence, its dose should be titrated according to the protein levels.

Use in Specific Populations

• Pregnancy:

Adequate evidence is required to evaluate the use of Amivantamab-vmjw in pregnant women. Available reports suggest the potential risk of fetal toxicity in Amivantamab-vmjw therapy, such as birth defects and early termination of pregnancy.

• Lactation:

No scientific data suggest the detection of Amivantamab-vmjw levels in human milk. However, due to its potential risk of inducing serious adverse side effects, breastfeeding is not recommended in lactating mothers receiving Amivantamab-vmjw.

• Pediatric and Geriatric Use:

The safety and efficacy of Amivantamab-vmjw in the pediatric population are not yet documented, and its use in geriatric patients has not shown significant changes.