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

Overview

Frequently, non-small cell lung cancers (NSCLC) undergo mutations at exon 20 insertion (Exon 20 Ins) gene sequences of the epidermal growth factor receptor (EGFR), exhibiting intrinsic resistance to already existing tyrosine kinase inhibitors and resulting in the failure of chemotherapy. Amivantamab-vmjw is a potent bispecific antibody targeted against the EGFR receptor and the mesenchymal-epithelial transition (MET) receptor, which is effective against non-small cell lung cancer that develops genetic mutations. The Food and Drug Administration granted accelerated approval to Amivantamab-vmjw on May 21, 2021, for treating adult patients with locally advanced as well as metastatic non-small cell lung cancer with mutations that developed during or following platinum-based chemotherapy. Confirmatory clinical trials are ongoing to prove and substantiate its use in treating various types of cancer, depending 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 indicated for treating progressive types of lung cancer. Some of its indications are as follows -

• In locally advanced non-small cell lung cancer (NSCLC) showing epidermal growth factor receptor (EGFR) exon 20 insertion mutations commonly seen on or after platinum chemotherapy.

• In metastatic non-small cell lung cancers where surgery is contraindicated.

• Recurrent locally invasive non-small cell lung cancers that are progressing even after chemotherapy due to genetic mutations.

Contraindications

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 due to its 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 in solution form (colorless to pale yellow) as a single-dose vial for injection.

• Each vial contains 350 mg of Amivantamab-vmjw in 7 mL in a proportion of 50 mg per mL of solution.

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 day one and day 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 days of infusions, and are further 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 the presence of turbidity or impurities. The solution should be clear, colorless to pale yellow without 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 in such a way that the final volume present in the infusion bag is 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) - In case of developing infusion reactions such as flushing, chills, or fever, the infusion should be interrupted and the rate of infusion should be reduced or discontinued depending 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 potential 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, abnormal weight loss, and the presence of blood while coughing. 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 the use of immunomodulating agents such as monoclonal antibodies is effective in treating progressive non-small cell lung cancers.

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

Amivantamab-vmjw is a recombinant monoclonal antibody that belongs to the class of therapeutic proteins. It is designed and targeted to attack two specific proteins, the epidermal growth factor receptor (EGFR) and the mesenchymal-epithelial transition (MET) receptor, that 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 the tumor cells that are responsible for causing abnormal genetic changes (exon 20 insertion gene mutations) 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.

• On giving Amivantamab-vmjw through IV infusion, it binds with the EGFR and MET receptors and makes them easily detected by the body’s own immune cells, such as natural killer cells and macrophages (immunomodulating activity).

• This causes the destruction of 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 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 given prior to the initiation of the therapy regarding its clinical effects and adverse reactions.

• Any known allergy or hypersensitivity history should be informed 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 inform about the chances of pregnancy status prior to 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 (Ig G1-based) bispecific antibody that is target specific and directed against the binding sites in EGF and MET receptors. 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 expresses immunomodulating acidity on the 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 receptor domains of EGFR and MET receptors that are present 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 cause the destruction of 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.

• On administering Amivantamab-vmjw intravenously, its exposure increases proportionally to 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 nearly 360 mL per day.

• Immunogenicity - Amivantamab-vmjw is well tolerated and has a minimal incidence of anti-Amivantamab-vmjw antibodies. No known evidence of elevated antibody titer levels or its effect on the pharmacokinetic parameters, clinical efficacy, and 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 the 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 leads to keratitis, dry eyes, redness of the conjunctiva, blurred vision, ocular itching, visual impairment, and uveitis.

• Fetal toxicity results in impairment of embryo-fetal development, lethality to the embryo, and also 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, pneumonia aspiration, and pulmonary sepsis.

• Musculoskeletal pain, including arthralgia, back pain, arthritis, bone pain, and musculoskeletal discomfort.

• Myalgia, neck pain, and pain in the extremities.

• 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 as well as efficacy of Amivantamab-vmjw in the pediatric population is still not documented, and its use in geriatric patients reports no significant changes.