Amivantamab

The dosage of amivantamab is determined by the patient's body weight. This weight-based approach ensures that the concentration of the antibody in the blood remains within the therapeutic window. The standard dosing categories are as follows:

• Patients weighing less than 80 kg: The recommended dose is 1050 mg.
• Patients weighing 80 kg or more: The recommended dose is 1400 mg.

Infusion Schedule:

• Week 1: The initial dose is split into two separate infusions given on Day 1 and Day 2. This 'split-dose' strategy is critical to reducing the risk and severity of infusion-related reactions (IRR).
• Weeks 2 through 4: The drug is administered once weekly.
• Week 5 and beyond: The drug is administered once every two weeks until disease progression or unacceptable toxicity occurs.

The safety and effectiveness of amivantamab in pediatric patients (under the age of 18) have not been established. Clinical trials for amivantamab have focused almost exclusively on adult populations with lung cancer, a disease that is extremely rare in children. Therefore, amivantamab is not approved for pediatric use.

Renal Impairment

Based on population pharmacokinetic analyses, no dosage adjustment is required for patients with mild or moderate renal impairment. There is insufficient data to provide a recommendation for patients with severe renal impairment (CrCl < 30 mL/min).

Hepatic Impairment

No dosage adjustment is necessary for patients with mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin 1 to 1.5 times ULN). Amivantamab has not been studied in patients with moderate or severe hepatic impairment.

Elderly Patients

Clinical studies did not identify significant differences in safety or efficacy between patients aged 65 and over and younger patients. No specific dose adjustments are required based solely on age, though close monitoring is advised due to the higher prevalence of comorbidities in the elderly.

Amivantamab is administered exclusively by a healthcare professional in a clinical setting (such as an infusion center or hospital). It is given as an intravenous infusion through a peripheral or central line.

• Pre-medication: Because infusion-related reactions are very common, patients must receive pre-medication before the first few doses. This typically includes an antihistamine (like diphenhydramine), an antipyretic (like acetaminophen), and a glucocorticoid (like dexamethasone).
• Infusion Time: The first infusion is given slowly over several hours. Subsequent infusions may be given faster if the patient tolerates the initial doses well.
• Storage: The vials must be stored in a refrigerator at 2°C to 8°C (36°F to 46°F) and protected from light. Once diluted, the solution should be used immediately or within specified timeframes if refrigerated.

If a scheduled appointment for an amivantamab infusion is missed, it should be rescheduled as soon as possible. The healthcare provider will then adjust the subsequent dosing schedule to maintain the appropriate interval between doses. It is vital not to skip doses, as consistent levels of the drug are necessary to keep the cancer under control.

There is no specific antidote for an amivantamab overdose. Because the drug is administered by professionals, the risk of a massive overdose is low. In the event of an accidental overdose, the infusion should be stopped immediately, and the patient should be monitored for adverse reactions. Treatment is supportive, focusing on managing symptoms such as infusion reactions or skin toxicity.

> Important: Follow your healthcare provider's dosing instructions. Do not adjust your dose or skip appointments without medical guidance. If you experience any new symptoms between infusions, contact your oncology team immediately.

Amivantamab is associated with several side effects, many of which are related to its inhibition of EGFR and MET in healthy tissues like the skin and digestive tract.

• Infusion-Related Reactions (IRR): Occurring in approximately 66% of patients, usually during the first infusion. Symptoms include chills, flushing, fever, chest discomfort, and nausea.
• Rash: Acneiform dermatitis (a rash that looks like acne) is very common. It usually appears on the face, chest, and back. It can feel itchy, painful, or dry.
• Paronychia: This is an infection or inflammation of the skin around the fingernails or toenails. It can cause swelling, redness, and pain, sometimes requiring antibiotic treatment.
• Musculoskeletal Pain: General aches in the joints, back, or muscles.
• Fatigue: A persistent feeling of tiredness or exhaustion that is not relieved by rest.
• Stomatitis: Inflammation of the mouth and lips, which can lead to mouth sores or a metallic taste.
• Edema: Swelling, particularly in the hands, ankles, or feet, often related to MET inhibition.

• Dry Skin and Pruritus: Excessive skin dryness and intense itching.
• Nausea and Constipation: Digestive upsets are common but usually manageable with supportive care.
• Hypoalbuminemia: A decrease in the level of albumin in the blood, which can contribute to swelling.
• Increased Alanine Aminotransferase (ALT): A sign of potential liver stress.
• Electrolyte Imbalances: Specifically low levels of magnesium, potassium, or sodium.

• Ocular Toxicity: Severe inflammation of the eye (keratitis) or changes in vision.
• Severe Dermatologic Toxicity: Toxic epidermal necrolysis or Stevens-Johnson syndrome (extremely rare).
• Severe Venous Thromboembolism: Deep vein thrombosis or pulmonary embolism.

> Warning: Stop taking Amivantamab and call your doctor immediately if you experience any of these.

• Interstitial Lung Disease (ILD) / Pneumonitis: This is a serious inflammation of the lungs. Symptoms include new or worsening shortness of breath, cough, or fever. It can be life-threatening.
• Severe Infusion Reactions: If you experience difficulty breathing, swelling of the face or throat, or a rapid drop in blood pressure during or after your infusion.
• Vision Changes: Eye pain, severe redness, or sudden blurring of vision. This may indicate keratitis (inflammation of the cornea).
• Severe Skin Reactions: Blistering or peeling skin, which could indicate a severe dermatological emergency.

With prolonged use, the most significant long-term concerns involve the skin and nails. Chronic paronychia can lead to nail loss or secondary fungal infections. Chronic dry skin can lead to fissures (cracks in the skin) that are painful and prone to infection. Patients may also experience long-term fatigue or persistent mild edema. Because amivantamab is a relatively new drug, long-term data spanning several decades is still being collected.

As of the most recent FDA updates in 2024, there are no Black Box Warnings for amivantamab. However, the drug carries significant warnings for Infusion-Related Reactions, Interstitial Lung Disease, and Embryo-Fetal Toxicity. The absence of a black box warning does not imply the drug is without risk; rather, it means the risks are currently managed through standard warnings and precautions in the prescribing information.

Report any unusual symptoms to your healthcare provider. Many side effects of amivantamab can be managed with dose interruptions, dose reductions, or supportive medications (like topical steroids for rash) if caught early.

Amivantamab is a potent targeted therapy that requires careful monitoring. Patients must be aware that while it targets cancer cells, it also affects the EGFR and MET pathways in normal cells, particularly in the skin and lungs. Prior to starting treatment, patients should disclose all pre-existing lung conditions, as these may increase the risk of serious pulmonary complications.

No FDA black box warnings for Amivantamab. While it is a high-risk medication, the FDA has determined that the standard warnings and precautions are sufficient for its safe use under the supervision of an oncologist.

• Infusion-Related Reactions (IRR): This is the most significant immediate risk. Most IRRs occur during the first dose. Healthcare facilities must have emergency equipment and medications (oxygen, epinephrine, corticosteroids) available to treat severe reactions. If a reaction occurs, the infusion is slowed or stopped, and symptoms are treated. Most patients can continue therapy after a reaction, provided it was not life-threatening.
• Interstitial Lung Disease (ILD) / Pneumonitis: Amivantamab can cause severe, life-threatening inflammation of the lung tissue. Patients with a history of ILD or radiation pneumonitis may be at higher risk. Any new respiratory symptoms must be investigated immediately with imaging (like a CT scan).
• Dermatologic Toxicity: Skin reactions are expected. Patients are advised to limit sun exposure, use alcohol-free moisturizing creams, and apply broad-spectrum sunscreen. Photosensitivity is a known risk; the drug makes the skin more sensitive to UV light.
• Ocular Toxicity: Keratitis (inflammation of the cornea) has been reported. Patients who develop sudden eye pain or vision changes should be referred to an ophthalmologist immediately. Use of contact lenses during treatment should be discussed with a doctor.
• Embryo-Fetal Toxicity: Based on its mechanism of action, amivantamab can cause harm to a developing fetus. It is not recommended for use during pregnancy.

Patients undergoing treatment with amivantamab require regular monitoring to ensure safety:

• Liver Function Tests (LFTs): Blood tests to check ALT, AST, and bilirubin should be performed periodically, as the drug can cause liver enzyme elevations.
• Electrolytes: Monitoring for low magnesium, potassium, and calcium is necessary, as EGFR inhibitors are known to cause 'wasting' of these minerals through the kidneys.
• Physical Exams: Regular assessment of the skin and nails to catch paronychia or severe rash early.
• Respiratory Assessment: Continuous monitoring for cough or shortness of breath at every clinical visit.

Amivantamab is unlikely to affect the ability to drive or operate machinery directly. However, some patients may experience fatigue or dizziness following an infusion. It is recommended that patients see how the drug affects them before attempting to drive, especially after the first few doses.

There is no direct contraindication between amivantamab and alcohol. However, alcohol can dehydrate the skin and body, potentially worsening the skin dryness and fatigue associated with the drug. Patients should discuss their alcohol consumption with their oncologist.

Amivantamab does not cause a physical withdrawal syndrome and does not typically require a tapering schedule. However, stopping the drug can lead to a 'flare' or rapid progression of the cancer. Treatment should only be discontinued under the direction of an oncologist, usually due to disease progression or severe toxicity.

> Important: Discuss all your medical conditions, especially lung or skin problems, with your healthcare provider before starting Amivantamab.

There are no specific drugs that are strictly contraindicated (never to be used) with amivantamab based on metabolic pathways, as it is a monoclonal antibody. However, live vaccines should generally be avoided in patients receiving systemic cancer therapies like amivantamab due to the potential for an inadequate immune response or unintended infection.

• Other EGFR Inhibitors: Combining amivantamab with other EGFR TKIs (like osimertinib) outside of a controlled clinical trial can significantly increase the risk of skin and gastrointestinal toxicities. While some combinations are now FDA-approved (e.g., with lazertinib), they require specific monitoring protocols.
• Hepatotoxic Drugs: Since amivantamab can cause elevations in liver enzymes, using it alongside other medications known to stress the liver (such as high-dose methotrexate or certain anti-fungals) requires frequent LFT monitoring.
• Nephrotoxic Agents: While amivantamab is not primarily cleared by the kidneys, electrolyte imbalances are common. Drugs that affect renal electrolyte handling (like diuretics or amphotericin B) can exacerbate low magnesium or potassium levels.

• Corticosteroids: While used as pre-medication, long-term high-dose steroids can mask the early signs of infection or interstitial lung disease, requiring clinicians to be more vigilant.
• Anticoagulants: Patients on warfarin or DOACs (like apixaban) should be monitored closely, as cancer and its treatments can alter the risk of both bleeding and clotting (venous thromboembolism is a known risk with amivantamab).

• Grapefruit and Starfruit: Unlike many oral cancer pills, amivantamab is not processed by the CYP3A4 enzyme in the gut or liver. Therefore, grapefruit juice does not significantly affect the levels of amivantamab in the blood.
• General Nutrition: No specific food restrictions exist, but maintaining high protein intake is often recommended to manage the hypoalbuminemia (low protein in the blood) that can occur during treatment.

• St. John’s Wort: This herbal supplement is a potent inducer of many metabolic pathways. While it may not affect amivantamab levels directly, it can interfere with many other medications used in cancer care. Its use is generally discouraged.
• Antioxidant Supplements: Some oncologists advise against high-dose antioxidant supplements (like Vitamin E or C) during active treatment, as they could theoretically interfere with the oxidative stress mechanisms used by some cancer therapies to kill tumor cells.

• Serum Albumin: Amivantamab can cause a decrease in measured serum albumin. This is not an interference with the test itself, but a physiological effect of the drug.
• Imaging: Amivantamab can cause changes on CT scans (pneumonitis) that may be difficult to distinguish from cancer progression or infection. Radiologists should be informed that the patient is receiving an EGFR/MET bispecific antibody.

For each major interaction, the management strategy involves:

• Mechanism: Usually pharmacodynamic (additive toxicities) rather than pharmacokinetic (changing drug levels).
• Clinical Consequence: Increased risk of skin, lung, or liver toxicity.
• Management Strategy: Frequent lab monitoring, dose delays, or use of supportive medications.

> Important: Tell your doctor about ALL medications, supplements, and herbal products you are taking, including over-the-counter skin creams.

Amivantamab has very few absolute contraindications, but they are critical for patient safety:

• Severe Hypersensitivity: Amivantamab must NEVER be used in patients with a known history of severe, life-threatening hypersensitivity (anaphylaxis) to the drug or any of its excipients (such as histidine, sucrose, or polysorbate 80). The mechanism is an immediate, IgE-mediated or cytokine-mediated immune response that can lead to airway closure and cardiovascular collapse.
• Active, Uncontrolled Interstitial Lung Disease (ILD): Because amivantamab can cause ILD, giving it to a patient who is currently experiencing an acute exacerbation of lung inflammation is contraindicated, as it can be fatal.

These conditions require a careful risk-benefit analysis by the oncology team:

• Pre-existing Pulmonary Fibrosis: Patients with significant baseline lung scarring are at much higher risk for fatal pneumonitis. Treatment may only proceed if the potential benefit of cancer control outweighs the high risk of respiratory failure.
• Severe Hepatic Impairment: Due to a lack of data, amivantamab is generally avoided in patients with Child-Pugh Class C liver disease unless no other options exist.
• Pregnancy: Amivantamab is relatively contraindicated during pregnancy. While not an absolute contraindication in a life-or-death maternal situation, the risk of fetal loss or malformation is high enough that it is strongly discouraged.

There is a theoretical risk of cross-sensitivity with other monoclonal antibodies, particularly those that are also IgG1-based or target the EGFR pathway (like cetuximab or panitumumab). If a patient has had a severe reaction to another EGFR-targeting antibody, amivantamab should be administered with extreme caution and enhanced pre-medication.

> Important: Your healthcare provider will evaluate your complete medical history, including any previous reactions to antibody treatments, before prescribing Amivantamab.

Amivantamab is not recommended for use during pregnancy. There are no adequate and well-controlled studies in pregnant women. However, based on its mechanism of action and animal models, EGFR and MET signaling are essential for normal fetal development. Inhibiting these receptors can lead to embryotoxicity, fetotoxicity, and even fetal death.

• Contraception: Females of reproductive potential should use effective contraception during treatment and for at least 3 months after the final dose.
• Pregnancy Testing: Healthcare providers should verify the pregnancy status of females of reproductive potential prior to initiating amivantamab.

It is not known whether amivantamab is excreted in human milk. Because many drugs, including antibodies, are excreted in human milk and because of the potential for serious adverse reactions in a nursing infant, women are advised not to breastfeed during treatment and for 3 months after the last dose. This allows enough time for the drug to be cleared from the mother's system.

Amivantamab is not approved for use in children. The safety and efficacy in patients under 18 years of age have not been established. Clinical trials are currently restricted to adult populations as the specific mutations targeted by amivantamab (EGFR exon 20 insertions) are virtually non-existent in pediatric malignancies.

In clinical trials, approximately 40% of patients were 65 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients. However, elderly patients may be more susceptible to certain side effects like dehydration from diarrhea or complications from skin infections. Close monitoring of fluid status and skin integrity is essential in this population.

• Mild to Moderate (CrCl 30-89 mL/min): No dose adjustment is required. The drug's clearance is not significantly affected by these levels of renal dysfunction.
• Severe (CrCl < 30 mL/min): Amivantamab has not been studied in this population. It should be used with caution, and patients should be monitored closely for any signs of increased toxicity.

• Mild: No dose adjustment is required for patients with mild hepatic impairment.
• Moderate to Severe: There is no data available for these populations. Because monoclonal antibodies are not primarily cleared by the liver, significant changes in pharmacokinetics are not expected, but the risk of hepatotoxicity may be higher.

> Important: Special populations require individualized medical assessment. Always inform your doctor if you are planning a pregnancy or have underlying organ dysfunction.

Amivantamab is a bispecific, IgG1-based antibody that binds to the extracellular domains of both the Epidermal Growth Factor Receptor (EGFR) and the Mesenchymal-Epithelial Transition (MET) receptor. Its anti-tumor activity is derived from three distinct mechanisms:

1. 1Ligand Blocking: By binding to the receptors, it prevents EGF and HGF (Hepatocyte Growth Factor) from binding, thereby inhibiting the activation of the MAPK, PI3K/Akt, and STAT pathways.
2. 2Receptor Downregulation: Binding induces the internalization and subsequent lysosomal degradation of the EGFR and MET receptors from the cell surface.
3. 3Immune Effector Function: The Fc region of the antibody interacts with FcyRIIIa receptors on immune cells (like Natural Killer cells), triggering antibody-dependent cellular cytotoxicity (ADCC) and trogocytosis, where immune cells 'nibble' away parts of the cancer cell membrane.

The pharmacodynamics of amivantamab are characterized by a dose-dependent saturation of the EGFR and MET receptors. In clinical studies, the weight-based dosing (1050 mg or 1400 mg) was shown to maintain serum concentrations above the levels required for target saturation throughout the dosing interval. There is no evidence of tolerance development; the drug remains active as long as the receptors are expressed and the signaling pathways are relevant to tumor survival.

| Parameter | Value |

|---|---|

| Bioavailability | 100% (Intravenous) |

| Protein Binding | Not applicable (Monoclonal Antibody) |

| Half-life | 11 - 15 days |

| Tmax | End of infusion |

| Metabolism | Proteolysis (not CYP-mediated) |

| Excretion | Reticuloendothelial system |

Amivantamab is a large, complex protein with a molecular weight of approximately 148 kDa. It is produced using recombinant DNA technology in a mammalian cell line (Chinese Hamster Ovary cells). The molecular formula is typical of a human IgG1 antibody, consisting of two heavy chains and two light chains. It is highly soluble in aqueous buffers used for infusion but sensitive to heat and mechanical agitation (shaking).

Amivantamab is classified as an Endoglycosidase [EPC] in some regulatory frameworks, but therapeutically it is a bispecific monoclonal antibody. It belongs to the broader class of antineoplastic agents and targeted therapies. It is unique in its ability to target two distinct drivers of oncogenesis simultaneously, distinguishing it from monospecific antibodies like cetuximab.