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Amivantamab – Uses, Dosage, Side Effects, Interactions

Dr. Harun Ar Rashid, MD - Arthritis, Bones, Joints Pain, Trauma, and Internal Medicine Specialist Dr. Harun Ar Rashid, MD - Arthritis, Bones, Joints Pain, Trauma, and Internal Medicine Specialist
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Drugs (A - Z)

Amivantamab, also known as JNJ-61186372, is an anti-EGFR-MET bispecific antibody, derived from Chinese hamster ovary cells, approved for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.[rx,rx] Patients with NSCLC often develop resistance to drugs that target EGFR and MET individually, so amivantamab was developed to attack both targets, reducing the chance of resistance developing.[rx,rx] Amivantamab was found to be more effective than the EGFR inhibitor erlotinib or the MET inhibitor crizotinib in vivo.[rx,rx] Patients with NSCLC with exon 20 insertion mutations in EGFR do not respond to tyrosine kinase inhibitors and were generally treated with platinum-based therapy.[rx]

Amivantamab was granted FDA approval on 21 May 2021,[rx] followed by the approval by the EMA on 9 December 2021 [rx] and Health Canada on 30 March 2022.[rx]

Mechanism of action

Mesenchymal-epithelial transition factor (MET) is a receptor with tyrosine kinase activity expressed on epithelial cells that, upon signaling, dimerizes and activates downstream pathways that signal cell division.[rx,rx] The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein with tyrosine kinase activity that can further activate downstream pathways that signal cell division, survival, and angiogenesis.[rx,rx] Patients with NSCLC with exon 20 insertion mutations in EGFR do not respond to tyrosine kinase inhibitors and are generally treated with platinum-based therapy.[rx] Exon 20 insertion mutations in EGFR also lead to conformational changes that activate EGFR.[rx]

Amivantamab targets both EGFR and MET, preventing ligands from binding to the receptors, blocking signalling, marking the cancerous cells for antibody-dependant cellular cytotoxicity by natural killer cells, and allowing macrophages to perform trogocytosis.[rx]

Amivantamab’s binding to the EGFR H epitope shares some of the same amino acids that cetuximab binds to.[rx]

Amivantamab’s binding to the alpha chain of MET stabilizes the Sema domain loop 1 to 2 in a position 6 Angstroms away from the position it would be in under normal binding, preventing its interaction with the hepatocyte growth factor’s (HGF) beta chain.1 Another smaller conformational change in the MET Sema domain loop 1 to 3 also contributes to preventing the interaction of the MET Sema domain with HGF’s beta chain.[rx] HGF is no longer able to bind to MET, preventing downstream signaling.[rx]

Amivantamab’s Fc portion contains 90% less fucose than normal antibodies, allowing for increased binding to the FcγRIIIa region.[rx] Binding of the Fc portion of Amivantamab signals the complement system and innate immune system to target the bound cells for complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and antibody-dependent cellular phagocytosis.[rx] Binding of amivantamab to the Fc receptor also leads to an increase in levels of IFNγ.[rx]

Amivantamab also significantly downregulates the expression of EGFR and MET on NSCLC cell surfaces, further reducing downstream signaling.[rx,rx] EGFR and MET on the cell surface are internalized, and possibly degrading by fusing endosomes with lysosomes.[rx] Alternatively, EGFR and MET are the subjects of monocyte-dependent trogocytosis.[rx] Trogocytosis allows monocytes to internalize and break down EGFR and MET from the NSCLC cells without cytotoxicity, downmodulating EGFR and MET receptors.[rx]

Indications

  • Amivantamab is indicated in the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, whose disease has progressed on or after platinum-based chemotherapy.[rx]
  • Locally Advanced Non-Small Cell Lung Cancer
  • Metastatic Non-Small Cell Lung Cancer

Use in Cancer

Amivantamab-view is approved to treat:

Amivantamab-vmjw is approved under FDA’s Accelerated Approval Program. As a condition of approval, confirmatory trial(s) must show that it provides a clinical benefit to these patients.

Amivantamab-vmjw is also being studied in the treatment of other types of cancer.

Contraindication

  • Patients should not take amivantamab if they are pregnant or breastfeeding.
  • Mesenchymal-epithelial transition factor (MET) is a receptor with tyrosine kinase activity expressed on epithelial cells that, upon signaling, dimerizes and activates downstream pathways that signal cell division.

Dosage

Strengths: vmjw 50 mg/mL

Non-Small Cell Lung Cancer

Body weight at baseline (NOTE: dose adjustments are not required for subsequent body weight changes after baseline measurement):

  • Less than 80 kg: 1050 mg IV once a week for 4 weeks (with the initial dose as a split infusion in Week 1 on Day 1 and Day 2) then every 2 weeks thereafter until disease progression or unacceptable toxicity
  • Greater than or equal to 80 kg: 1400 mg IV once a week for 4 weeks (with the initial dose as a split infusion in Week 1 on Day 1 and Day 2) then every 2 weeks thereafter until disease progression or unacceptable toxicity

INFUSION RATES FOR THE 1050 MG DOSE
WEEK 1 (split dose infusion)

  • Week 1 Day 1: 350 mg IV at 50 mL/hr initially; increase the initial rate to the subsequent rate of 75 mL/hr after 2 hours in the absence of infusion-related reactions
  • Week 1 Day 2: 700 mg IV at 50 mL/hr initially; increase the initial rate to the subsequent rate of 75 mL/hr after 2 hours in the absence of infusion-related reactions

WEEK 2: 1050 mg IV at 85 mL/hr both initially and subsequently
WEEK 3: 1050 mg IV at 125 mL/hr both initially and subsequently
WEEK 4: 1050 mg IV at 125 mL/hr both initially and subsequently
SUBSEQUENT WEEKS (after Week 4 patients are dosed every 2 weeks): 1050 mg IV at 125 mL/hr

INFUSION RATES FOR THE 1400 MG DOSE
WEEK 1 (split dose infusion)

  • Week 1 Day 1: 350 mg IV at 50 mL/hr initially; increase the initial rate to the subsequent rate of 75 mL/hr after 2 hours in the absence of infusion-related reactions
  • Week 1 Day 2: 1050 mg IV at 35 mL/hr initially; increase the initial rate to the subsequent rate of 50 mL/hr after 2 hours in the absence of infusion-related reactions

WEEK 2: 1400 mg IV at 65 mL/hr both initially and subsequently
WEEK 3: 1400 mg IV at 85 mL/hr both initially and subsequently
WEEK 4: 1400 mg IV at 125 mL/hr both initially and subsequently
SUBSEQUENT WEEKS (after Week 4 patients are dosed every 2 weeks): 1400 mg IV at 125 mL/hr

PREMEDICATION

Prior to initial infusion of this drug (Week 1, Days 1 and 2), administer premedication to reduce the risk of infusion-related reactions:
ANTIHISTAMINE (required at all doses):
Diphenhydramine (25 to 50 mg) or equivalent:

  • IV: Administer 15 to 30 minutes before administering this drug.
  • Oral: Administer 30 to 60 minutes before administering this drug.

ANTIPYRETIC (required at all doses):
Acetaminophen (650 to 1000 mg):

  • IV: Administer 15 to 30 minutes before administering this drug.
  • Oral: Administer 30 to 60 minutes before administering this drug.

GLUCOCORTICOID (required at initial dose [Week 1, Days 1 and 2]; optional for subsequent doses):
Dexamethasone (10 mg) or methylprednisolone (40 mg) or equivalent:

  • IV: Administer 45 to 60 minutes before administering this drug.

NOTE: Administer both antihistamine and antipyretic prior to all infusions. Glucocorticoid administration required for Week 1, Days 1 and 2 doses only and as necessary for subsequent infusions.

Use: For patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy

Dose Adjustments

DOSE ADJUSTMENTS FOR ADVERSE REACTIONS
Body weight less than 80 kg at baseline:

  • Initial dose: 1050 mg
  • First dose reduction: 700 mg
  • Second dose reduction: 350 mg
  • Third dose reduction: Discontinue therapy.

Body weight 80 kg or greater at baseline:

  • Initial dose: 1400 mg
  • First dose reduction: 1050 mg
  • Second dose reduction: 700 mg
  • Third dose reduction: Discontinue therapy.

INFUSION-RELATED REACTIONS (IRRs)

  • Grade 1 or 2: Interrupt the infusion if IRR is suspected until resolved; resume at 50% of the infusion rate at which the reaction occurred; if no additional symptoms after 30 minutes, the infusion rate may be escalated as described in the adult dosing section; include corticosteroid with premedications for subsequent dose as described in the adult dosing section.
  • Grade 3: Interrupt the infusion and administer supportive care medications; monitor until resolved; resume the infusion at 50% of the infusion rate at which the reaction occurred; if no additional symptoms after 30 minutes, the infusion rate may be escalated as described in the adult dosing section.

INTERSTITIAL LUNG DISEASE (ILD)/PNEUMONITIS

  • Any Grade: Withhold therapy if ILD/pneumonitis is suspected; permanently discontinue therapy if ILD/pneumonitis is confirmed.

DERMATOLOGIC ADVERSE REACTIONS (e.g., dermatitis acneiform, pruritus, dry skin)

  • Grade 2: Initiate supportive care; reassess after 2 weeks; if rash does not improve, consider dose reduction.
  • Grade 3 (e.g., severe bullous, blistering, or exfoliating skin conditions [i.e., toxic epidermal necrolysis]): Withhold therapy and initiate supportive care; upon recovery to Grade 2 or less, resume at reduced dose; if no improvement within 2 weeks, permanently discontinue therapy.
  • Grade 4: Permanently discontinue therapy.

OTHER ADVERSE REACTIONS:

  • Grade 3: Withhold therapy until recovery to Grade 1 or less or baseline; resume at the same dose if recovery occurs within 1 week; resume at reduced dose if recovery occurs after 1 week but within 4 weeks; permanently discontinue therapy if recovery does not occur within 4 weeks.
  • Grade 4: Withhold therapy until recovery to Grade 1 or less or baseline; resume at reduced dose if recovery occurs within 4 weeks; permanently discontinue therapy if recovery does not occur within 4 weeks or for recurrent Grade 4 reactions.

Administration advice:

  • Select patients for treatment with this drug based on the presence of EGFR exon 20 insertion mutations.
  • The diluted solution should be administered within 10 hours (including infusion time) at room temperature 59F to 77F (15C to 25C).
  • Administer by IV infusion using an infusion set fitted with a flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.2 micrometer) primed with diluent only.
  • Administration sets should be made of either polyurethane (PU), polybutadiene (PBD) PVC, PP, or PE.
  • Administer this drug via a peripheral line on Week 1 and Week 2 due to the high incidence of infusion-related reactions during initial treatment; it may be administered via central line for subsequent weeks.
  • Do not infuse this drug concomitantly in the same IV line with other agents.

Reconstitution/preparation techniques:

  • Dilute and prepare this drug for IV infusion before administration.
  • Verify that the solution is colorless to pale yellow.
  • Do not use if discoloration or visible particles are present.
  • For the initial infusion, prepare this drug as close to administration time as possible to allow for the possibility of extended infusion time in the event of an infusion-related reaction.
  • The manufacturer’s product information should be consulted.

IV compatibility:

  • This drug is compatible with 5% dextrose solution or 0.9% sodium chloride solution.

Side Effects

The Most Common

  • swelling, pain, or changes in the fingernails or toenails
  • unusual tiredness or weakness
  • swelling of the face, lips, or eyes
  • swelling of the hands, feet, ankles, or lower legs
  • bone, muscle, joint, arm, leg, neck, or back pain
  • muscle aches, cramps, or stiffness
  • pain in the arms or legs
  • pain in the joints
  • redness, swelling, or soreness of the tongue
  • scaling, redness, burning, pain, or other signs of inflammation of the lips
  • stomach pain
  • swelling or inflammation of the mouth
  • mouth sores
  • nausea
  • vomiting
  • diarrhea
  • constipation
  • stomach pain
  • decreased appetite
  • numbness, tingling, pain, or burning in arms or legs
  • headache
  • dizziness

More Common

  • new or worsening cough, shortness of breath, fever, or chest pain
  • burning, crawling, itching, numbness, painful, prickling, “pins and needles”, or tingling feelings
  • eye pain
  • dry, red, teary, itchy, or painful eyes
  • blurred vision
  • vision changes
  • sensitivity of eyes to light
  • easy bruising or bleeding
  • bleeding from gums or nose
  • blood in urine or stool
  • coughing up blood

Rare

  • bleeding gums
  • blistering, crusting, irritation, itching, or reddening of the skin
  • blood in the urine
  • bloody nose
  • chest pain or tightness
  • chills
  • cough
  • coughing or spitting up blood
  • cracked, dry, or scaly skin
  • dry, itching skin
  • fever
  • flushing
  • headache
  • loosening of the fingernails
  • muscle or bone pain
  • nausea and vomiting
  • nerve pain
  • rash with flat lesions or small raised lesions on the skin
  • redness or soreness around the fingernails
  • sneezing
  • swelling
  • trouble breathing
  • unsteadiness or awkwardness
  • weakness in the arms, hands, legs, or feet

Drug Interactions

 

Pregnancy and Lactation

US FDA pregnancy category: Not assigned.

Pregnancy

Based on the mechanism of action and findings in animal models, RYBREVANT can cause fetal harm when administered to a pregnant woman. There are no available data on the use of RYBREVANT in pregnant women or animal data to assess the risk of RYBREVANT in pregnancy. Disruption or depletion of EGFR in animal models resulted in impairment of embryo-fetal development including effects on placental, lung, cardiac, skin, and neural development. The absence of EGFR or MET signaling has resulted in embryolethality, malformations, and post-natal death in animals. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Lactation

There are no data on the presence of amivantamab in human milk on milk production or its effects on the breastfed child. Because of the potential for serious adverse reactions from RYBREVANT in breastfed infants, advise women not to breastfeed during treatment with RYBREVANT and for 3 months after the final dose.

RYBREVANT can cause fetal harm when administered to a pregnant woman. Verify the pregnancy status of females of reproductive potential prior to initiating RYBREVANT. Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the final dose of RYBREVANT.

What special precautions should I follow?

Before receiving amivantamab-vmjw injection,

  • tell your doctor and pharmacist if you are allergic to amivantamab-vmjw, any other medications, or any of the ingredients in amivantamab-vmjw injection. Ask your pharmacist for a list of the ingredients.
  • tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
  • tell your doctor if you have or have ever had a lung disease other than lung cancer, or breathing problems.
  • tell your doctor if you are pregnant or plan to become pregnant. You should not become pregnant while you are receiving amivantamab-vmjw injection. You will need to have a pregnancy test before you begin receiving this medication. Use effective birth control during your treatment with amivantamab-vmjw injection and for 3 months after your final dose. If you become pregnant while receiving amivantamab-vmjw injection, call your doctor. Amivantamab-vmjw injection may harm the fetus.
  • tell your doctor if you are breastfeeding. Your doctor will tell you not to breastfeed during your treatment with amivantamab-vmjw injection and for 3 months after your final dose.
  • you should know that amivantamab-vmjw may cause skin reactions, including some that may be severe. You should plan to avoid unnecessary or prolonged exposure to sunlight and to wear protective clothing, sunglasses, and sunscreen during your treatment with amivantamab-vmjw injection and for 2 months after your final dose. Your doctor may tell you to use an alcohol-free moisturizer if you develop dry or irritated skin. If you experience any of the following symptoms, call your doctor immediately: rash, itching, dry or cracking skin, or blistering, peeling, or shedding skin

References

 

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