Amivantamab

Amivantamab is a low-fucose, fully human bispecific antibody of the IgG1 class, produced in Chinese hamster ovary cells by recombinant DNA technology. It is directed against the epidermal growth factor receptor (EGFR) and the MET receptor and targets tumours with activating EGFR mutations: exon 19 deletions, the exon 21 L858R substitution and exon 20 insertions. It acts on the extracellular domains of the two receptors rather than inside the cell.

Mechanism of Action

• Dual receptor binding: amivantamab binds the extracellular domains of EGFR and MET and blocks the binding of their ligands, interrupting the signalling that drives tumour growth and survival. Binding to MET prevents hepatocyte growth factor from engaging the receptor.
• Receptor degradation: it also enhances the degradation of EGFR and MET, so fewer of these receptors remain on the tumour cell surface.
• Immune-cell engagement: because EGFR and MET are present on the surface of tumour cells, the bound antibody marks them for destruction by immune effector cells: natural killer cells through antibody-dependent cellular cytotoxicity, and macrophages through trogocytosis. Its Fc region carries about 90% less fucose than a normal antibody, which strengthens binding to the Fc receptor on these cells.
• Effect on circulating receptors: after the first full subcutaneous dose, mean serum EGFR and MET concentrations fell substantially and stayed suppressed for the whole of treatment at every dose studied.
• Serum albumin: albumin concentration falls, a pharmacodynamic effect of MET inhibition, typically during the first 8 weeks, and then stabilises for the rest of treatment.
• Hyaluronidase in the injection: the subcutaneous formulation contains recombinant human hyaluronidase (rHuPH20), which acts locally and only transiently to break down hyaluronan in the tissue under the skin.

Pharmacokinetics

• Absorption (subcutaneous): mean bioavailability is about 67%, with a median time to peak concentration of 3 days. Steady state is reached by about Week 13. On the every-2-week schedule the highest trough concentration (after the fourth weekly dose) was 335 µg/mL, compared with 293 µg/mL after intravenous dosing, and the steady-state trough was 206 µg/mL; this comparison supported switching from intravenous to subcutaneous dosing. On the every-3-week schedule the corresponding troughs were 438 µg/mL (after the third weekly dose) and 208 µg/mL (steady state); on the every-4-week schedule they were 350 µg/mL (after the fourth weekly dose) and 131 µg/mL.
• Distribution: the volume of distribution is about 5 L (mean 5.13 L), as expected for a large antibody that stays mainly in the circulation.
• Metabolism: like other antibodies, amivantamab is expected to be broken down into small peptides and amino acids. Renal excretion and hepatic enzyme metabolism of the intact antibody are unlikely to be major elimination routes.
• Elimination: clearance is about 360 mL/day and the terminal half-life about 11 days (values reported for intravenous dosing).
• Special populations: population analyses showed no need to adjust the dose in older patients, in mild or moderate renal impairment or in mild hepatic impairment. No formal studies were done in renal or hepatic impairment, and severe renal impairment and moderate or severe hepatic impairment have not been studied.

Rybrevant (both the intravenous and the subcutaneous formulation) is indicated in adults with advanced non-small cell lung cancer (NSCLC):

• First line, EGFR exon 19 deletions or exon 21 L858R substitution mutations: in combination with lazertinib.
• EGFR exon 19 deletions or exon 21 L858R substitution mutations after failure of prior therapy including an EGFR tyrosine kinase inhibitor (TKI): in combination with carboplatin and pemetrexed.
• First line, activating EGFR exon 20 insertion mutations: in combination with carboplatin and pemetrexed.
• Activating EGFR exon 20 insertion mutations after failure of platinum-based therapy: as monotherapy.

EGFR mutation status must be established with a validated test before treatment starts.

• Hypersensitivity to amivantamab or to any of the excipients.

Rash, nail toxicity and infusion-related reactions are the most frequent side effects. In 380 patients given intravenous amivantamab alone after platinum-based chemotherapy, the most frequent reactions were rash (76%), infusion-related reactions (67%), nail toxicity (47%), hypoalbuminaemia (31%), oedema (26%), fatigue (26%), stomatitis (24%), nausea (23%) and constipation (23%). Serious reactions included interstitial lung disease (1.3%), infusion-related reactions (1.1%) and rash (1.1%). Three percent of patients stopped treatment because of side effects, most often infusion-related reactions (1.1%), interstitial lung disease (0.5%) and nail toxicity (0.5%). The frequency groups below are those of this monotherapy data set.

Very common (≥1/10): hypoalbuminaemia, decreased appetite, hypocalcaemia, dizziness, diarrhoea, stomatitis, nausea, constipation, vomiting, increased alanine aminotransferase, increased aspartate aminotransferase, increased blood alkaline phosphatase, rash, nail toxicity, dry skin, pruritus, myalgia, oedema, fatigue, pyrexia, infusion-related reaction (any grade 67%; grade 3 or 4 in 2%).

Common (≥1/100 to <1/10): hypokalaemia, hypomagnesaemia, visual impairment, growth of eyelashes, other eye disorders, interstitial lung disease, abdominal pain, haemorrhoids.

Uncommon (≥1/1,000 to <1/100): keratitis, uveitis, toxic epidermal necrolysis.

With lazertinib (752 patients given the intravenous or subcutaneous formulation): the most frequent reactions (≥20%) were rash (87%), nail toxicity (67%), hypoalbuminaemia (48%), hepatotoxicity (43%), stomatitis (43%), oedema (42%), fatigue (35%), paraesthesia (29%), constipation (26%), diarrhoea (26%), dry skin (25%), decreased appetite (24%), nausea (24%) and pruritus (23%). Among patients given the subcutaneous formulation with lazertinib, 14% had serious reactions, including interstitial lung disease (4.2%), venous thromboembolism (2.7%), hepatotoxicity (2.1%) and fatigue (1.5%), and 7% stopped treatment, most often for interstitial lung disease (3.6%) and rash (1.5%). Administration-related reactions occurred in 14% of patients on the subcutaneous formulation against 63% on the intravenous one, and venous thromboembolic events in 11% against 37%.

With carboplatin and pemetrexed: the SmPC gives the safety data of these combinations in section 4.8; the side effects of the two chemotherapy medicines are listed in their own SmPCs.

Serious reactions to watch for are infusion-related or administration-related reactions, interstitial lung disease or pneumonitis (fatal cases reported), venous thromboembolism with lazertinib (fatal cases reported with the intravenous formulation), severe skin reactions including toxic epidermal necrolysis, and eye disorders such as keratitis and uveitis.

No drug interaction studies have been performed. As an IgG1 antibody, amivantamab is unlikely to be eliminated mainly by renal excretion or hepatic enzymes, so variations in drug-metabolising enzymes are not expected to affect its elimination. Because of its high affinity for a unique epitope on EGFR and MET, it is not expected to alter drug-metabolising enzymes.

• Vaccines: there are no clinical data on the efficacy and safety of vaccination during treatment. Live or live-attenuated vaccines should be avoided while a patient is taking amivantamab.
• Lazertinib: on days when both are given, amivantamab is given any time after lazertinib. Prophylactic anticoagulation is needed with this combination (see Special Instructions); vitamin K antagonists are not recommended for it.
• Carboplatin and pemetrexed: amivantamab is given after them, in the order pemetrexed, carboplatin, then amivantamab.
• Premedication: an antihistamine, an antipyretic and, at the first dose, a glucocorticoid are given to reduce infusion-related and administration-related reactions (see Administration and Dosage).

Treatment is started and supervised by a physician experienced in anticancer medicines. Before the first dose, EGFR mutation status must be established in tumour tissue or plasma with a validated test; if a plasma test finds no mutation, tumour tissue should be tested when enough is available, because plasma tests can give false negatives. Testing need not be repeated once the status is known. Rybrevant is given by a healthcare professional with access to appropriate medical support for infusion-related reactions (intravenous formulation) or administration-related reactions (subcutaneous formulation). The dose depends on the formulation, the schedule and the body weight at baseline (less than 80 kg, or 80 kg or more); it is not changed when the weight later changes. Treatment continues until disease progression or unacceptable toxicity.

Subcutaneous Formulation

Rybrevant solution for injection (160 mg/mL) is for subcutaneous use only and must not be given intravenously.

• With lazertinib or alone, every 4 weeks: less than 80 kg: 1,600 mg weekly for 4 doses (Weeks 1–4), then 3,520 mg every 4 weeks from Week 5. 80 kg or more: 2,240 mg weekly for 4 doses, then 4,640 mg every 4 weeks from Week 5.
• With lazertinib or alone, every 2 weeks: less than 80 kg: 1,600 mg weekly for 4 doses, then 1,600 mg every 2 weeks from Week 5. 80 kg or more: 2,240 mg weekly for 4 doses, then 2,240 mg every 2 weeks from Week 5.
• With carboplatin and pemetrexed, every 3 weeks: less than 80 kg: 1,600 mg at Week 1 Day 1, then 2,400 mg weekly for 3 doses (Weeks 2–4) and 2,400 mg every 3 weeks from Week 7. 80 kg or more: 2,240 mg at Week 1 Day 1, then 3,360 mg weekly for 3 doses (Weeks 2–4) and 3,360 mg every 3 weeks from Week 7.
• Order of administration: with lazertinib on the same day, amivantamab is given any time after lazertinib. With carboplatin and pemetrexed, the order is pemetrexed, carboplatin, then amivantamab.
• Switching: a patient on the intravenous formulation can change to the subcutaneous one from the next scheduled dose, and a patient on the every-2-week subcutaneous schedule can change to every 4 weeks from the next scheduled dose.
• Injection: the required volume is injected into the subcutaneous tissue of the abdomen over about 5 minutes; other body sites have not been studied. Delivery is paused or slowed if the patient feels pain, and if that does not relieve it, the rest of the dose can be given at a second site on the opposite side of the abdomen. Injection sites are rotated. Injections avoid tattoos, scars, skin that is red, bruised, tender, hard or not intact, and the area within 5 cm of the navel.

Intravenous Formulation

• With carboplatin and pemetrexed, every 3 weeks: less than 80 kg: 1,400 mg weekly for 4 doses (Weeks 1–4; 4 vials of 350 mg/7 mL), then 1,750 mg every 3 weeks from Week 7 (5 vials). 80 kg or more: 1,750 mg weekly for 4 doses (5 vials), then 2,100 mg every 3 weeks from Week 7 (6 vials).
• Alone or with lazertinib, every 2 weeks: less than 80 kg: 1,050 mg weekly for 4 doses (Weeks 1–4; 3 vials), then 1,050 mg every 2 weeks from Week 5. 80 kg or more: 1,400 mg weekly for 4 doses (4 vials), then 1,400 mg every 2 weeks from Week 5.
• Split first dose: in Week 1 the dose is divided, 350 mg on Day 1 and the remainder on Day 2. Weeks 2 to 4 are single infusions on Day 1.
• Preparation and infusion: the concentrate is diluted with 5% glucose solution or sodium chloride 9 mg/mL (0.9%) solution and given as an intravenous infusion through an in-line filter, each dose in a 250 mL bag. The first infusions start slowly (25–50 mL/hr in Week 1, raised after 2 hours if there is no reaction) and the rate is stepped up over the following weeks to a maximum of 125 mL/hr, following the infusion-rate tables in the SmPC. Because reactions are frequent at the first dose, the infusions in Weeks 1 and 2 are given through a peripheral vein; a central line can be used later. The first dose should be prepared as close to administration as possible, so that the infusion can still be completed if a reaction occurs.
• Order of administration: as for the subcutaneous formulation.

Premedication and Supportive Medicines

Premedication lowers the risk of infusion-related and administration-related reactions. Antiemetics are given as needed.

• Every dose: an antihistamine (diphenhydramine 25–50 mg or equivalent) and an antipyretic (paracetamol 650–1,000 mg or equivalent), each given intravenously 15–30 minutes or orally 30–60 minutes before amivantamab.
• First dose, subcutaneous formulation: also a glucocorticoid, dexamethasone 20 mg or equivalent, intravenously 45–60 minutes before or orally at least 60 minutes before. At later doses dexamethasone 10 mg or equivalent is optional (intravenously 45–60 minutes before, orally 60–90 minutes before).
• First infusions, intravenous formulation: dexamethasone 8 mg orally twice daily on each of the two days before the first infusion. On Week 1 Day 1, dexamethasone 8 mg orally one hour before the infusion, plus dexamethasone 20 mg or equivalent intravenously 60–120 minutes before. On Week 1 Day 2, dexamethasone 10 mg or equivalent intravenously 45–60 minutes before; this is optional at later doses.
• After a reaction or a long interruption: the glucocorticoid (dexamethasone 20 mg or equivalent) is given again at the next dose after any infusion-related or administration-related reaction, and is restarted after prolonged dose interruptions.

Dose Modifications

• General rule: dosing is interrupted for grade 3 or 4 side effects until they resolve to grade 1 or lower (or baseline). After an interruption of 7 days or less, treatment restarts at the current dose; after a longer interruption it restarts at a reduced dose. With lazertinib, the lazertinib SmPC governs its own dose changes.
• Reduction steps, subcutaneous (dose at which the reaction occurred, then the dose after the first and second interruption; treatment is discontinued after a third): 1,600 mg, 1,050 mg, 700 mg; 2,240 mg, 1,600 mg, 1,050 mg; 2,400 mg, 1,600 mg, 1,050 mg; 3,360 mg, 2,240 mg, 1,600 mg; 3,520 mg, 2,400 mg, 1,600 mg; 4,640 mg, 3,360 mg, 2,240 mg.
• Reduction steps, intravenous (same pattern): 1,050 mg, 700 mg, 350 mg; 1,400 mg, 1,050 mg, 700 mg; 1,750 mg, 1,400 mg, 1,050 mg; 2,100 mg, 1,750 mg, 1,400 mg.
• Infusion-related or administration-related reactions: interrupt at the first sign and give supportive medicines (additional glucocorticoid, antihistamine, antipyretic, antiemetic) as clinically indicated. For grade 1–3, resume once symptoms recover; an intravenous infusion restarts at 50% of the previous rate, which may be raised again if there are no further symptoms. For a recurrent grade 3 or a grade 4 (life-threatening) reaction, discontinue permanently.
• Venous thromboembolism with lazertinib: for an event with clinical instability (for example respiratory failure or cardiac dysfunction), withhold both medicines until the patient is stable, then resume both at the same dose. If an event recurs despite appropriate anticoagulation, discontinue amivantamab; lazertinib can continue at the same dose.
• Skin and nail reactions: for grade 1–2, give supportive care and consider a dose reduction for persistent grade 2 rash that has not improved after 2 weeks. For grade 3, give supportive care, consider interrupting treatment until improvement and resume at a reduced dose once the reaction is grade 2 or lower. For grade 4, discontinue permanently.
• Interstitial lung disease: withhold if suspected; discontinue permanently if confirmed.

Special Populations

• Elderly: no dose adjustment.
• Renal impairment: no adjustment in mild or moderate impairment. Severe impairment has not been studied, so use caution and monitor for side effects.
• Hepatic impairment: no adjustment in mild impairment. Moderate and severe impairment have not been studied, so use caution and monitor for side effects.
• Children and adolescents: there is no relevant use of amivantamab in the treatment of NSCLC in children.

Missed Dose

• Subcutaneous, every 4 or every 2 weeks: a dose missed in Weeks 1–4 is given within 24 hours; a dose missed from Week 5 onward is given within 7 days.
• Subcutaneous, every 3 weeks: a dose missed in Weeks 1–3 is given within 24 hours; a dose missed from Week 4 onward is given within 7 days.
• If a subcutaneous dose is not given within these limits it is skipped, and the next dose follows the usual schedule.
• Intravenous: a missed dose is given as soon as possible, and the schedule is adjusted to keep the treatment interval.

Traceability

To make biological medicines traceable, the name and the batch number of the product given must be recorded clearly.

Infusion-Related and Administration-Related Reactions

Reactions during or after the infusion (intravenous formulation) or the injection (subcutaneous formulation) are very common. Infusion-related reactions occurred in 67% of patients given intravenous amivantamab alone. With lazertinib, administration-related reactions occurred in 63% of patients on the intravenous formulation and 14% on the subcutaneous one. They are frequent at the first dose, which is why the first-week dose is split over two days and the early infusions go through a peripheral vein. An antihistamine, an antipyretic and, at the first dose, a glucocorticoid are given beforehand, and treatment is given only where appropriate medical support is available. At the first sign of a reaction of any severity the infusion or injection is stopped, supportive medicines are given, and it is resumed once symptoms have resolved. Amivantamab is permanently discontinued for a life-threatening (grade 4) reaction or a recurrent grade 3 reaction.

Interstitial Lung Disease

Interstitial lung disease (ILD) or ILD-like reactions such as pneumonitis have been reported, including fatal events. Patients are monitored for symptoms such as dyspnoea, cough and fever. If symptoms develop, treatment is interrupted while they are investigated, and it is stopped permanently if ILD is confirmed.

Venous Thromboembolism with Lazertinib

Venous thromboembolic events, including deep vein thrombosis and pulmonary embolism, occurred in patients given amivantamab with lazertinib; fatal events were seen with the intravenous formulation. Preventive (prophylactic) anticoagulation is given from the start of treatment, either a direct-acting oral anticoagulant or a low-molecular-weight heparin. Vitamin K antagonists are not recommended. Patients are watched for signs and symptoms of venous thromboembolism, and events are treated with anticoagulation as clinically indicated.

Skin and Nail Reactions

Rash (including acneiform dermatitis), pruritus, dry skin and skin ulcers occur. A preventive approach is recommended: oral and topical antibiotics, a non-comedogenic moisturiser on the face and body (except the scalp) and chlorhexidine solution to wash the hands and feet. Patients should limit sun exposure during treatment and for 2 months afterwards; protective clothing and a broad-spectrum UVA/UVB sunscreen are advisable. Toxic epidermal necrolysis is uncommon.

Eye Disorders

Keratitis, uveitis, visual impairment and other eye disorders are among the listed side effects. Patients should report new or worsening eye symptoms promptly.

Pregnancy, Breastfeeding and Fertility

• Contraception: women who could become pregnant should use effective contraception during treatment and for 3 months after the last dose.
• Pregnancy: there are no human data and no animal reproduction studies. Based on its mechanism and on findings with other EGFR and MET inhibitors in animals, amivantamab could cause foetal harm. It should not be given in pregnancy unless the benefit to the woman outweighs the risk to the foetus.
• Breastfeeding: it is unknown whether amivantamab passes into human milk. Human IgG is present in milk in the first days after birth, so a risk to the infant cannot be excluded in that short period. A decision is made whether to stop breastfeeding or to stop or avoid the treatment.
• Fertility: there are no data in humans, and effects on male and female fertility have not been evaluated in animals.

Excipients

Each mL contains 0.6 mg of polysorbate 80.

Effect on Driving

Rybrevant may have a moderate influence on the ability to drive and use machines, for example through dizziness, fatigue or visual impairment. Patients with treatment-related symptoms that affect concentration and reaction, including vision-related ones, should not drive or use machines until the effect subsides.

Store the vials in a refrigerator at 2–8 °C, in the original package to protect them from light. Do not freeze. Keep the cold chain unbroken during transport and storage up to the point of preparation. After the infusion solution is diluted, or the injection is drawn into a syringe, the in-use limits under Shelf Life apply.

• Unopened vials: 3 years (350 mg/7 mL concentrate for infusion); 2 years (solution for injection).
• After dilution (infusion): chemical and physical in-use stability has been shown for 10 hours at 15–25 °C in room light.
• Prepared syringe (injection): up to 24 hours at 2–8 °C, followed by up to 24 hours at 15–30 °C.
• From a microbiological point of view, the product should be used immediately unless the method of dilution or preparation rules out the risk of microbial contamination; otherwise the in-use storage times and conditions are the responsibility of the user.

Prescription only (Rx), under restricted medical prescription (Annex II B): treatment is started and supervised by a physician experienced in anticancer medicines. Rybrevant is given by a healthcare professional, as an intravenous infusion or a subcutaneous injection, with medical support at hand for reactions, so it is supplied to the hospital or clinic that administers it, under cold-chain conditions (2–8 °C, not frozen, protected from light).