4.1. Therapeutic indications

Rybrevant is indicated:

• in combination with lazertinib for the first‑line treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) Exon 19 deletions or Exon 21 L858R substitution mutations.

• in combination with carboplatin and pemetrexed for the treatment of adult patients with advanced NSCLC with 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 for the first‑line treatment of adult patients with advanced NSCLC with activating EGFR Exon 20 insertion mutations.

• as monotherapy for treatment of adult patients with advanced NSCLC with activating EGFR Exon 20 insertion mutations, after failure of platinum‑based therapy.

4.2. Posology and method of administration

Treatment with Rybrevant should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.

Rybrevant should be administered by a healthcare professional with access to appropriate medical support to manage infusion‑related reactions (IRRs) if they occur.

Before initiation of Rybrevant therapy, EGFR mutation status in tumour tissue or plasma specimens must be established using a validated test method. If no mutation is detected in a plasma specimen, tumour tissue should be tested if available in sufficient amount and quality due to the potential for false negative results using a plasma‑test. Testing may be performed at any time from initial diagnosis until the initiation of therapy; testing does not need to be repeated once EGFR mutation status has been established (see section 5.1).

Posology

Premedications should be administered to reduce the risk of IRRs with Rybrevant (see below “Dose modifications” and “Recommended concomitant medicinal products”). In patients receiving Rybrevant in combination with lazertinib, prophylactic anticoagulants are recommended to be used for the first four months of treatment. Consistent with clinical guidelines, patients should receive prophylactic dosing of appropriate anticoagulants, e.g. low-molecular weight heparin (LMWH). Use of Vitamin K antagonists is not recommended. Patients should be instructed to limit sun exposure during and for 2 months after Rybrevant therapy. For further information about prophylaxis for VTE and skin and nail reactions, see section 4.4.

Every 3 weeks

The recommended dosages of Rybrevant, when used in combination with carboplatin and pemetrexed, is provided in Table 1 (see below “Infusion rates” and Table 5).

Table 1: Recommended dosage of Rybrevant every 3 weeks

Body weight at baselinea

Rybrevant dose

Schedule

Number of vials

Less than 80 kg

1400 mg

Weekly (total of 4 doses) from Weeks 1 to 4

• Week 1 - split infusion on Day 1 and Day 2

• Weeks 2 to 4 - infusion on Day 1

4

1750 mg

Every 3 weeks starting at Week 7 onwards

5

Greater than or equal to 80 kg

1750 mg

Weekly (total of 4 doses) from Weeks 1 to 4

• Week 1 - split infusion on Day 1 and Day 2

• Weeks 2 to 4 - infusion on Day 1

5

2100 mg

Every 3 weeks starting at Week 7 onwards

6

a Dose adjustments not required for subsequent body weight changes.

When used in combination with carboplatin and pemetrexed, Rybrevant should be administered after carboplatin and pemetrexed in the following order: pemetrexed, carboplatin and then Rybrevant. See section 5.1 and the manufacturer's prescribing information for dosing instructions for carboplatin and pemetrexed.

Every 2 weeks

The recommended dosages of Rybrevant as monotherapy or in combination with lazertinib is provided in Table 2 (see below “Infusion rates” and Table 6).

Table 2: Recommended dosage of Rybrevant every 2 weeks

Body weight at baselinea

Rybrevant dose

Schedule

Number of vials

Less than 80 kg

1050 mg

Weekly (total of 4 doses) from Weeks 1 to 4

• Week 1 - split infusion on Day 1 and Day 2

• Weeks 2 to 4 - infusion on Day 1

3

Every 2 weeks starting at Week 5 onwards

Greater than or equal to 80 kg

1400 mg

Weekly (total of 4 doses) from Weeks 1 to 4

• Week 1 - split infusion on Day 1 and Day 2

• Weeks 2 to 4 - infusion on Day 1

4

Every 2 weeks starting at Week 5 onwards

a Dose adjustments not required for subsequent body weight changes.

When given in combination with lazertinib, it is recommended to administer Rybrevant any time after lazertinib when given on the same day. Refer to section 4.2 of the lazertinib Summary of Product Characteristics for recommended lazertinib dosing information.

Duration of treatment

It is recommended that patients are treated with Rybrevant until disease progression or unacceptable toxicity.

Missed dose

If a planned dose is missed, the dose should be administered as soon as possible and the dosing schedule should be adjusted accordingly, maintaining the treatment interval.

Dose modifications

Dosing should be interrupted for Grade 3 or 4 adverse reactions until the adverse reaction resolves to ≤ Grade 1 or baseline. If an interruption is 7 days or less, restart at the current dose. If an interruption is longer than 7 days, it is recommended restarting at a reduced dose as presented in Table 3. See also specific dose modifications for specific adverse reactions below Table 3. If used in combination with lazertinib, refer to section 4.2 of the lazertinib Summary of Product Characteristics for information about dose modifications.

Table 3: Recommended dose modifications for adverse reactions

Dose at which the adverse reaction occurred

Dose after 1st interruption for adverse reaction

Dose after 2nd interruption for adverse reaction

Dose after 3rd interruption for adverse reaction

1050 mg

700 mg

350 mg

Discontinue Rybrevant

1400 mg

1050 mg

700 mg

1750 mg

1400 mg

1050 mg

2100 mg

1750 mg

1400 mg

Infusion‑related reactions

Infusion should be interrupted at the first sign of IRRs. Additional supportive medicinal products (e.g., additional glucocorticoids, antihistamine, antipyretics and antiemetics) should be administered as clinically indicated (see section 4.4).

• Grade 1‑3 (mild‑severe): Upon recovery of symptoms, resume infusion at 50% of the previous rate. If there are no additional symptoms, the rate may be increased per the recommended infusion rate (see Tables 5 and 6). Concomitant medicinal products should be administered at the next dose (including dexamethasone (20 mg) or equivalent (see Table 4).

• Recurrent Grade 3 or Grade 4 (life‑threatening): Permanently discontinue Rybrevant.

Venous thromboembolic (VTE) events with concomitant use with lazertinib

For VTE events associated with clinical instability (e.g., respiratory failure or cardiac dysfunction), both medicinal products should be held until the patient is clinically stable. Thereafter, both medicinal products can be resumed at the same dose, at the discretion of the treating physician. In the event of recurrence despite therapeutic level anticoagulation, the combination of Rybrevant and lazertinib should be permanently discontinued. Treatment can continue with either Rybrevant or lazertinib, but not both at the discretion of the treating physician.

Skin and nail reactions

Prophylactic therapy with oral and topical antibiotics is recommended to reduce the risk and severity of skin and nail reactions in patients receiving Rybrevant. Non‑comedogenic skin moisturiser (ceramide‑based or other formulations that provide long lasting skin hydration and exclude drying agents are preferred) on the face and whole body (except scalp) and chlorhexidine solution to wash hands and feet is also recommended.

Patients should be instructed to limit sun exposure during and for 2 months after Rybrevant therapy. For further information about prophylaxis for skin and nail reactions, see section 4.4. If the patient develops a Grade 1-2 skin or nail reaction, supportive care should be initiated as clinically indicated; if there is no improvement after 2 weeks, dose reduction should be considered for persistent Grade 2 rash (see Table 3). If the patient develops a Grade 3 skin or nail reaction, supportive care should be initiated as clinically indicated, and interruption of Rybrevant should be considered until the adverse reaction improves. Upon recovery of the skin or nail reaction to ≤ Grade 2, Rybrevant should be resumed at a reduced dose. If the patient develops Grade 4 skin reactions, permanently discontinue Rybrevant (see section 4.4).

Interstitial lung disease

Rybrevant should be withheld if interstitial lung disease (ILD) or ILD-like adverse reactions (pneumonitis) is suspected. If the patient is confirmed to have ILD or ILD‑like adverse reactions (e.g., pneumonitis), permanently discontinue Rybrevant (see section 4.4).

Recommended concomitant medicinal products

Two days before the first infusion:

During the two days prior to the initial Rybrevant infusion, patients should receive 8 mg dexamethasone orally, twice daily.

Day of infusion:

On the day of the initial infusion (Week 1, Day 1), patients should receive 8 mg dexamethasone orally, one hour prior to infusion in addition to intravenous dexamethasone to further reduce the risk of IRRs.

Prior to infusion (Week 1, Days 1 and 2), antihistamines, antipyretics, and glucocorticoids should be administered to reduce the risk of IRRs (see Table 4). For subsequent doses, antihistamines and antipyretics are required to be administered. Glucocorticoids should also be re‑initiated after prolonged dose interruptions. Antiemetics should be administered as needed.

Table 4: Dosing schedule of premedications

Premedication

Dose

Route of administration

Recommended dosing window prior to Rybrevant administration

Antihistamine*

Chlorphenamine (10 mg) or equivalent

Intravenous

15 to 30 minutes

Antipyretic*

Paracetamol (650 to 1000 mg)

Intravenous

15 to 30 minutes

Oral

30 to 60 minutes

Glucocorticoid‡

Dexamethasone (8 mg)

Oral

60 minutes

Glucocorticoid‡

Dexamethasone (20 mg) or equivalent

Intravenous

60 to 120 minutes

Glucocorticoid+

Dexamethasone (10 mg) or equivalent

Intravenous

45 to 60 minutes

* Required at all doses.

‡ Required at initial dose (Week 1, Day 1); or at the next subsequent dose in the event of an IRR.

+ Required at second dose (Week 1, Day 2); optional for subsequent doses.

Special populations

Paediatric population

There is no relevant use of amivantamab in the paediatric population in the treatment of non‑small cell lung cancer.

Elderly

No dose adjustments are necessary (see section 4.8, section 5.1, and section 5.2).

Renal impairment

No formal studies of amivantamab in patients with renal impairment have been conducted. Based on population pharmacokinetic (PK) analyses, no dose adjustment is necessary for patients with mild or moderate renal impairment.

Caution is required in patients with severe renal impairment as amivantamab has not been studied in this patient population (see section 5.2). If treatment is started, patients should be monitored for adverse reactions with dose modifications per the recommendations above.

Hepatic impairment

No formal studies of amivantamab in patients with hepatic impairment have been conducted. Based on population PK analyses, no dose adjustment is necessary for patients with mild hepatic impairment.

Caution is required in patients with moderate or severe hepatic impairment as amivantamab has not been studied in this patient population (see section 5.2). If treatment is started, patients should be monitored for adverse reactions with dose modifications per the recommendations above.

Method of administration

Rybrevant is for intravenous use. It is administered as an intravenous infusion following dilution with sterile 5% glucose solution or sodium chloride 9 mg/mL (0.9%) solution for injection. Rybrevant must be administered with in‑line filtration.

For instructions on dilution of the medicinal product before administration, see section 6.6.

Infusion rates

Following dilution, the infusion should be administered intravenously at the infusion rates presented in Table 5 or 6 below.

Due to the frequency of IRRs at the first dose, amivantamab should be infused via a peripheral vein at Week 1 and Week 2; infusion via a central line may be administered for subsequent weeks when the risk of IRR is lower (see section 6.6). It is recommended for the first dose to be prepared as close to administration as possible to maximise the likelihood of completing the infusion in the event of an IRR.

Table 5: Infusion rates for Rybrevant every 3 weeks

Body weight less than 80 kg

Week

Dose

(per 250 mL bag)

Initial infusion rate

Subsequent infusion rate†

Week 1 (split dose infusion)

Week 1 Day 1

350 mg

50 mL/hr

75 mL/hr

Week 1 Day 2

1050 mg

33 mL/hr

50 mL/hr

Week 2

1400 mg

65 mL/hr

Week 3

1400 mg

85 mL/hr

Week 4

1400 mg

125 mL/hr

Subsequent weeks*

1750 mg

125 mL/hr

Body weight greater than or equal to 80 kg

Week

Dose

(per 250 mL bag)

Initial infusion rate

Subsequent infusion rate†

Week 1 (split dose infusion)

Week 1 Day 1

350 mg

50 mL/hr

75 mL/hr

Week 1 Day 2

1400 mg

25 mL/hr

50 mL/hr

Week 2

1750 mg

65 mL/hr

Week 3

1750 mg

85 mL/hr

Week 4

1750 mg

125 mL/hr

Subsequent weeks*

2100 mg

125 mL/hr

* Starting at Week 7, patients are dosed every 3 weeks.

† Increase the initial infusion rate to the subsequent infusion rate after 2 hours in the absence of infusion-related reactions.

Table 6: Infusion rates for Rybrevant every 2 weeks

Body weight less than 80 kg

Week

Dose

(per 250 mL bag)

Initial infusion rate

Subsequent infusion rate‡

Week 1 (split dose infusion)

Week 1 Day 1

350 mg

50 mL/hr

75 mL/hr

Week 1 Day 2

700 mg

50 mL/hr

75 mL/hr

Week 2

1050 mg

85 mL/hr

Subsequent weeks*

1050 mg

125 mL/hr

Body weight greater than or equal to 80 kg

Week

Dose

(per 250 mL bag)

Initial infusion rate

Subsequent infusion rate‡

Week 1 (split dose infusion)

Week 1 Day 1

350 mg

50 mL/hr

75 mL/hr

Week 1 Day 2

1050 mg

35 mL/hr

50 mL/hr

Week 2

1400 mg

65 mL/hr

Week 3

1400 mg

85 mL/hr

Subsequent weeks*

1400 mg

125 mL/hr

* After Week 5, patients are dosed every 2 weeks.

‡ Increase the initial infusion rate to the subsequent infusion rate after 2 hours in the absence of IRRs.

4.3. Contraindications

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Infusion‑related reactions

Infusion‑related reactions commonly occurred in patients treated with amivantamab (see section 4.8).

Prior to initial infusion (Week 1), antihistamines, antipyretics, and glucocorticoids should be administered to reduce the risk of IRRs. For subsequent doses, antihistamines and antipyretics should be administered. The initial infusion should be administered in split doses on Week 1, Day 1 and 2.

Patients should be treated in a setting with appropriate medical support to treat IRRs. Infusions should be interrupted at the first sign of IRRs of any severity and post‑infusion medicinal products should be administered as clinically indicated. Upon resolution of symptoms, the infusion should be resumed at 50% of the previous rate. For recurrent Grade 3 or Grade 4 IRRs, Rybrevant should be permanently discontinued (see section 4.2).

Interstitial lung disease

Interstitial lung disease (ILD) or ILD‑like adverse reactions (e.g., pneumonitis) have been reported in patients treated with amivantamab, including fatal events (see section 4.8). Patients should be monitored for symptoms indicative of ILD/pneumonitis (e.g., dyspnoea, cough, fever). If symptoms develop, treatment with Rybrevant should be interrupted pending investigation of these symptoms. Suspected ILD or ILD‑like adverse reactions should be evaluated and appropriate treatment should be initiated as necessary. Rybrevant should be permanently discontinued in patients with confirmed ILD or ILD-like adverse reactions (see section 4.2).

Venous thromboembolic (VTE) events with concomitant use with lazertinib

In patients receiving Rybrevant in combination with lazertinib, VTE events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), including fatal events, were reported (see section 4.8). VTE events occurred predominantly in the first four months of therapy. Prophylactic anticoagulants are recommended to be used for the first four months of treatment (see section 4.2 and 4.8). Consistent with clinical guidelines, patients should receive prophylactic dosing of appropriate anticoagulant, e.g. a low-molecular weight heparin (LMWH). Use of Vitamin K antagonists is not recommended.

Monitor for signs and symptoms of VTE events. Treat patients with VTE events with anticoagulation as clinically indicated. For VTE events associated with clinical instability treatment should be held until the patient is clinically stable. Thereafter, both drugs can be resumed at the same dose at the discretion of the treating physician.

In the event of recurrence despite appropriate anticoagulation, discontinue Rybrevant or lazertinib. Treatment can continue with Rybrevant or lazertinib, but not both, at the discretion of the treating physician (see section 4.2).

Skin and nail reactions

Rash (including dermatitis acneiform), pruritus, dry skin, and skin ulcer occurred in patients treated with amivantamab (see section 4.8). Patients should be instructed to limit sun exposure during and for 2 months after Rybrevant therapy. Protective clothing and use of broad‑spectrum UVA/UVB sunscreen are advisable. A prophylactic approach to rash prevention is recommended. This includes prophylactic therapy, at treatment initiation with an oral antibiotic starting on Day 1 for the first 12 weeks of treatment and after completion of oral antibiotic therapy, topical antibiotic lotion to the scalp for the next 9 months of treatment. Non-comedogenic skin moisturiser (ceramide‑based or other formulations that provide long‑lasting skin hydration and exclude drying agents are preferred) on the face and whole body (except scalp) and chlorhexidine solution to wash hands and feet is recommended beginning on Day 1 and continued for the duration of treatment.

Prescriptions for topical and/or oral antibiotics and topical corticosteroids are recommended to be available at the time of initial dosing to minimise any delay in reactive management should rash develop despite prophylactic treatment. If skin reactions develop, supportive care, topical corticosteroids and topical and/or oral antibiotics should be administered. For Grade 3 or poorly‑tolerated Grade 2 events, systemic antibiotics and oral steroids should also be administered. Patients presenting with severe rash that has an atypical appearance or distribution or lack improvement within 2 weeks should be referred promptly to a dermatologist. Rybrevant should be dose reduced, interrupted, or permanently discontinued based on severity (see section 4.2).

Toxic epidermal necrolysis (TEN) has been reported. Treatment with this medicinal product should be discontinued if TEN is confirmed.

Eye disorders

Eye disorders, including keratitis, occurred in patients treated with amivantamab (see section 4.8). Patients presenting with worsening eye symptoms should promptly be referred to an ophthalmologist and should discontinue use of contact lenses until symptoms are evaluated. For dose modifications for Grade 3 or 4 eye disorders, see section 4.2.

Sodium content

This medicinal product contains less than 1 mmol (23 mg) sodium per dose, that is to say essentially “sodium‑free”. This medicinal product may be diluted in sodium chloride 9 mg/mL (0.9%) solution for infusion. This should be taken into consideration for patients on a controlled sodium diet (see section 6.6).

Polysorbate content

This medicinal product contains 0.6 mg of polysorbate 80 in each mL, which is equivalent to 4.2 mg per 7 mL vial. Polysorbates may cause hypersensitivity reactions.

4.5. Interaction with other medicinal products and other forms of interaction

No drug interaction studies have been performed. As an IgG1 monoclonal antibody, renal excretion and hepatic enzyme‑mediated metabolism of intact amivantamab are unlikely to be major elimination routes. As such, variations in drug‑metabolising enzymes are not expected to affect the elimination of amivantamab. Due to the high affinity to a unique epitope on EGFR and MET, amivantamab is not anticipated to alter drug‑metabolising enzymes.

Vaccines

No clinical data are available on the efficacy and safety of vaccinations in patients taking amivantamab. Avoid the use of live or live‑attenuated vaccines while patients are taking amivantamab.

4.6. Fertility, pregnancy and lactation

Women of child‑bearing potential/Contraception

Women of child‑bearing potential should use effective contraception during and for 3 months after cessation of amivantamab treatment.

Pregnancy

There are no human data to assess the risk of amivantamab use during pregnancy. No animal reproductive studies were conducted to inform a drug‑associated risk. Administration of EGFR and MET inhibitor molecules in pregnant animals resulted in an increased incidence of impairment of embryo‑foetal development, embryo lethality, and abortion. Therefore, based on its mechanism of action and findings in animal models, amivantamab could cause foetal harm when administered to a pregnant woman. Amivantamab should not be given during pregnancy unless the benefit of treatment of the woman is considered to outweigh potential risks to the foetus. If the patient becomes pregnant while taking this medicinal product, the patient should be informed of the potential risk to the foetus (see section 5.3).

Breast‑feeding

It is unknown whether amivantamab is excreted in human milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which is decreasing to low concentrations soon afterwards. A risk to the breast-fed child cannot be excluded during this short period just after birth, although IgGs are likely to be degraded in the gastrointestinal tract of the breast‑fed child and not absorbed. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from amivantamab therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are no data on the effect of amivantamab on human fertility. Effects on male and female fertility have not been evaluated in animal studies.

4.7. Effects on ability to drive and use machines

Rybrevant may have moderate influence on the ability to drive and use machines. Please see section 4.8 (e.g., dizziness, fatigue, visual impairment). If patients experience treatment‑related symptoms, including vision‑related adverse reactions, affecting their ability to concentrate and react, it is recommended that they do not drive or use machines until the effect subsides.

4.8. Undesirable effects

Summary of the safety profile

In the dataset of amivantamab as monotherapy (N=380), the most frequent adverse reactions in all grades were rash (76%), infusion‑related reactions (67%), nail toxicity (47%), hypoalbuminaemia (31%), oedema (26%), fatigue (26%), stomatitis (24%), nausea (23%), and constipation (23%). Serious adverse reactions included ILD (1.3%), IRR (1.1%), and rash (1.1%). Three percent of patients discontinued Rybrevant due to adverse reactions. The most frequent adverse reactions leading to treatment discontinuation were IRR (1.1%), ILD (0.5%), and nail toxicity (0.5%).

Tabulated list of adverse reactions

Table 7 summarises the adverse drug reactions that occurred in patients receiving amivantamab as monotherapy.

The data reflects exposure to amivantamab in 380 patients with locally advanced or metastatic non‑small cell lung cancer after failure of platinum‑based chemotherapy. Patients received amivantamab 1050 mg (for patients < 80 kg) or 1400 mg (for patients ≥ 80 kg). The median exposure to amivantamab was 4.1 months (range: 0.0 to 39.7 months).

Adverse reactions observed during clinical studies are listed below by frequency category. Frequency categories are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); and not known (frequency cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 7: Adverse reactions in patients receiving amivantamab as monotherapy

System organ class

Adverse reaction

Frequency category

Any Grade (%)

Grade 3-4 (%)

Metabolism and nutrition disorders

Hypoalbuminaemia* (see section 5.1)

Very common

31

2†

Decreased appetite

16

0.5†

Hypocalcaemia

10

0.3†

Hypokalaemia

Common

9

2

Hypomagnesaemia

8

0

Nervous system disorders

Dizziness*

Very common

13

0.3†

Eye disorders

Visual impairment*

Common

3

0

Growth of eyelashes*

1

0

Other eye disorders*

6

0

Keratitis

Uncommon

0.5

0

Uveitis

0.3

0

Respiratory, thoracic and mediastinal disorders

Interstitial lung disease*

Common

3

0.5†

Gastrointestinal disorders

Diarrhoea

Very common

11

2†

Stomatitis*

24

0.5†

Nausea

23

0.5†

Constipation

23

0

Vomiting

12

0.5†

Abdominal pain*

Common

9

0.8†

Haemorrhoids

3.7

0

Hepatobiliary disorders

Alanine aminotransferase increased

Very common

15

2

Aspartate aminotransferase increased

13

1

Blood alkaline phosphatase increased

12

0.5†

Skin and subcutaneous tissue disorders

Rash*

Very common

76

3†

Nail toxicity*

47

2†

Dry skin*

19

0

Pruritus

18

0

Skin ulcer

Uncommon

0.8

0

Toxic epidermal necrolysis

0.3

0.3†

Musculoskeletal and connective tissue disorders

Myalgia

Very common

11

0.3†

General disorders and administration site conditions

Oedema*

Very common

26

0.8†

Fatigue*

26

0.8†

Pyrexia

11

0

Injury, poisoning and procedural complications

Infusion related reaction

Very common

67

2

* Grouped terms

† Grade 3 events only

Summary of the safety profile

In the dataset of amivantamab in combination with carboplatin and pemetrexed (N=301), the most frequent adverse reactions in all grades were rash (83%), neutropenia (57%), nail toxicity (53%), infusion related reactions (51%), fatigue (43%), stomatitis (39%), nausea (43%), thrombocytopenia (40%), constipation (40%), oedema (40%), decreased appetite (33%), hypoalbuminaemia (32%), alanine aminotransferase increased (26%), aspartate aminotransferase increased (23%), vomiting (22%), and hypokalaemia (20%). Serious adverse reactions included rash (2.7%), venous thromboembolism (2.3%), thrombocytopenia (2.3%) and ILD (2.0%). Eight percent of patients discontinued Rybrevant due to adverse reactions. The most frequent adverse reactions leading to treatment discontinuation were IRR (2.7%), rash (2.3%), ILD (2.3%), and nail toxicity (1.0%).

Table 8 summarises the adverse drug reactions that occurred in patients receiving amivantamab in combination with chemotherapy.

The data reflects exposure to amivantamab in combination with carboplatin and pemetrexed in 301 patients with locally advanced or metastatic non‑small cell lung cancer. Patients received amivantamab 1400 mg (for patients < 80 kg) or 1750 mg (for patients ≥ 80 kg) weekly for 4 weeks. Starting at Week 7, patients received amivantamab 1750 mg (for patients < 80 kg) or 2100 mg (for patients ≥ 80 kg) every 3 weeks. The median exposure to amivantamab in combination with carboplatin and pemetrexed was 7.7 months (range: 0.0 to 28.1 months).

Adverse reactions observed during clinical studies are listed below by frequency category. Frequency categories are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); and not known (frequency cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 8: Adverse reactions in patients receiving amivantamab in combination with carboplatin and pemetrexed

System organ class

Adverse reaction

Frequency category

Any Grade (%)

Grade 3-4 (%)

Blood and lymphatic system disorders

Neutropenia

Very common

57

39

Thrombocytopenia

40

12

Metabolism and nutrition disorders

Decreased appetite

Very common

33

1.3

Hypoalbuminaemia*

32

3.7

Hypokalaemia

20

6.6

Hypomagnesaemia

13

1.3

Hypocalcaemia

12

1.0

Nervous system disorders

Dizziness*

Common

10

0.3

Vascular disorders

Venous thromboembolism*

Very common

14

3.0

Eye disorders

Other eye disorders*

Common

7.3

0

Visual impairment*

3.0

0

Growth of eyelashes

Uncommon

0.3

0

Keratitis

0.3

0

Uveitis

0.3

0

Respiratory, thoracic and mediastinal disorders

Interstitial lung disease*

Common

2.3

1.7

Gastrointestinal disorders

Nausea

Very common

43

1.0

Constipation

40

0.3

Stomatitis*

39

3.0

Vomiting

22

2.0

Diarrhoea

19

2.3

Abdominal pain*

Common

11

0.3

Haemorrhoids

9.3

0.7

Hepatobiliary disorders

Alanine aminotransferase increased

Very common

26

4.3

Aspartate aminotransferase increased

23

0.7

Blood alkaline phosphatase increased

Common

10

0.3

Skin and subcutaneous tissue disorders

Rash*

Very common

83

14

Nail toxicity*

53

4.3

Dry skin*

16

0

Pruritus

10

0

Skin ulcer

Common

3.7

0.7

Musculoskeletal and connective tissue disorders

Myalgia

Common

5.0

0.7

General disorders and administration site conditions

Fatigue*

Very common

43

4.7

Oedema*

40

1.3

Pyrexia

14

0

Injury, poisoning and procedural complications

Infusion related reaction

Very common

51

3.0

* Grouped terms

Summary of the safety profile

In the dataset of amivantamab in combination with lazertinib (N=421), the most frequent adverse reactions in all grades were rash (89%), nail toxicity (71%), infusion‑related reactions (63%), hypoalbuminaemia (48%), oedema (47%), stomatitis (43%), venous thromboembolism (36%), alanine aminotransferase increased (36%), fatigue (32%), aspartate aminotransferase increased (29%), diarrhoea (29%), constipation (29%), dry skin (26%), pruritus (24%), decreased appetite (24%), hypocalcaemia (21%), nausea (21%) and other eye disorders (21%). The most frequent serious adverse reactions included venous thromboembolism (11%), ILD (2.9%), rash (2.4%), and IRR (2.1%). Twenty-two percent of patients discontinued Rybrevant due to adverse reactions. The most frequent adverse reactions leading to treatment discontinuation were rash (5.5%), infusion related reactions (4.5%), nail toxicity (3.6%), ILD (2.9%) and VTE (2.9%).

Table 9 summarises the adverse drug reactions that occurred in patients receiving amivantamab in combination with lazertinib.

The data reflects exposure to amivantamab in combination with lazertinib in 421 patients with locally advanced or metastatic non‑small cell lung cancer. Patients received amivantamab 1050 mg (for patients <80 kg) or 1400 mg (for patients ≥80 kg) once weekly for 4 weeks, then every 2 weeks thereafter. The median exposure to study treatment in the amivantamab and lazertinib combination group was 18.5 months (range: 0.2 to 31.4 months).

Adverse reactions observed during clinical studies are listed below by frequency category. Frequency categories are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); and not known (frequency cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Table 9: Amivantamab adverse reactions in patients receiving amivantamab in combination with lazertinib

System organ class

Adverse reaction

Frequency category

Any Grade (%)

Grade 3-4 (%)

Metabolism and nutrition disorders

Hypoalbuminaemia*

Very common

48

5.2

Decreased appetite

24

1.0

Hypocalcaemia

21

2.1

Hypokalaemia

14

3.1

Hypomagnesaemia

Common

5.0

0

Nervous system disorders

Dizziness*

Very common

13

0

Vascular disorders

Venous thromboembolism*‡

Very common

36

11

Eye disorders

Other eye disorders*

Very common

21

0.5

Visual impairment*

Common

4.5

0

Keratitis

2.6

0.5

Growth of eyelashes*

1.9

0

Respiratory, thoracic and mediastinal disorders

Interstitial lung disease*

Common

3.1

1.2

Gastrointestinal disorders

Stomatitis*

Very common

43

2.4

Constipation

29

0

Diarrhoea

29

2.1

Nausea

21

1.2

Vomiting

12

0.5

Abdominal pain*

11

0

Haemorrhoids

Common

9.7

0.2

Hepatobiliary disorders

Alanine aminotransferase increased

Very common

36

5.0

Aspartate aminotransferase increased

29

3.3

Blood alkaline phosphatase increased

12

1.2

Skin and subcutaneous tissue disorders

Rash*

Very common

89

27

Nail toxicity*

71

11

Dry skin*

26

1.0

Pruritus

24

0.5

Skin ulcer

Common

5

0.7

Musculoskeletal and connective tissue disorders

Myalgia

Very common

13

0.7

General disorders and administration site conditions

Oedema*

Very common

47

2.9

Fatigue*

32

3.8

Pyrexia

12

0

Injury, poisoning and procedural complications

Infusion related reaction

Very common

63

6.4

* Grouped terms

‡ Assessed as ADR for Rybrveant in combination with lazertinib only.

Refer to section 4.8 of the lazertinib Summary of Product Characteristics for a list of adverse reactions associated with lazertinib use.

Description of selected adverse reactions

Infusion‑related reactions

In patients treated with amivantamab monotherapy, infusion‑related reactions occurred in 67% of patients. Ninety‑eight percent of IRRs were Grade 1‑2. Ninety‑nine percent of IRRs occurred at the first infusion with a median time to onset of 60 minutes, and the majority occurring within 2 hours of infusion start. The most frequent signs and symptoms include chills, dyspnoea, nausea, flushing, chest discomfort, and vomiting (see section 4.4).

In patients treated with amivantamab in combination with carboplatin and pemetrexed, infusion‑related reactions occurred in 50% of patients. Greater than 94% of IRRs were Grade 1‑2. A majority of IRRs occurred at the first infusion with a median time to onset of 60 minutes (range 0‑7 hours), and the majority occurring within 2 hours of infusion start.

In patients treated with amivantamab in combination with lazertinib, infusion related reactions occurred in 62.9% of patients. Ninety-four percent of IRRs were Grade 1-2. A majority of IRRs occurred at the first infusion with a median time to onset of 1 hour, and the majority occurring within 2 hours of infusion start. The most frequent signs and symptoms include chills, dyspnoea, nausea, flushing, chest discomfort, and vomiting (see section 4.4).

Occasionally an IRR can occur at re-initiation of amivantamab after prolonged dose interruptions of more than 6 weeks.

In a Phase 2, open-label, multicenter study in patients with NSCLC, patients were administered 8 mg dexamethasone orally, twice daily on both of the two days prior to the first Rybrevant infusion and 8 mg orally, 60 minutes prior to infusion on the day of the first infusion (5 doses total) in addition to intravenous dexamethasone. With the addition of oral dexamethasone, a 22.5% incidence of IRRs and no grade ≥3 IRRs were reported on the day of the initial infusion (see section 4.2).

Interstitial lung disease

Interstitial lung disease or ILD‑like adverse reactions have been reported with the use of amivantamab as well as with other EGFR inhibitors. Interstitial lung disease or pneumonitis was reported in 2.6% of patients treated with amivantamab monotherapy, 2.3% of patients treated with amivantamab in combination with carboplatin and pemetrexed and 3.1% of patients treated with amivantamab in combination with lazertinib. Patients with a medical history of ILD, drug‑induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD were excluded from the clinical study (see section 4.4).

Venous thromboembolic (VTE) events with concomitant use with lazertinib

When Rybrevant is used in combination with lazertinib, VTE events, including deep venous thrombosis (DVT) and pulmonary embolism (PE), were reported in 35.6% of the 421 patients treated. Most cases were Grade 1 or 2, with Grade 3‑4 events occurring in 11% of patients, and Grade 5 events occurring in 0.5% of patients. In patients receiving Rybrevant is combination with lazertinib, the median time to first onset of a VTE event was 84 days.

The use of prophylactic anticoagulants was evaluated in the PALOMA-3 study. PALOMA-3 is a randomised, open-label, Phase 3 study assessing subcutaneous versus intravenous amivantamab, both in combination with lazertinib, in patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations whose disease has progressed on or after treatment with osimertinib and platinum-based chemotherapy. For patients treated with Rybrevant IV in combination with lazertinib in PALOMA-3 that received prophylactic anticoagulants, the overall incidence of VTE events was 11%, with Grade 3 VTE events reported in 1.2% and serious VTE events reported in 1.8%. For information on prophylactic anticoagulants and management of VTE events, see sections 4.2 and 4.4.

Skin and nail reactions

Rash (including dermatitis acneiform), pruritus, and dry skin occurred in 76% of patients treated with amivantamab alone. Most cases were Grade 1 or 2, with Grade 3 rash events occurring in 3% of patients. Rash leading to amivantamab discontinuation occurred in 0.3% of patients. Rash usually developed within the first 4 weeks of therapy, with a median time to onset of 14 days. Nail toxicity occurred in patients treated with amivantamab. Most events were Grade 1 or 2, with Grade 3 nail toxicity occurring in 1.8% of patients.

Rash (including dermatitis acneiform), occurred in 83% of patients treated with amivantamab in combination with carboplatin and pemetrexed. Most cases were Grade 1 or 2, with Grade 3 rash events occurring in 14% of patients. Rash leading to amivantamab discontinuation occurred in 2.3% of patients. Rash usually developed within the first 4 weeks of therapy, with a median time to onset of 14 days. Nail toxicity occurred in patients treated with amivantamab in combination with carboplatin and pemetrexed. Most events were Grade 1 or 2, with Grade 3 nail toxicity occurring in 4.3% of patients (see section 4.4).

Rash (including dermatitis acneiform), occurred in 89% of patients treated with amivantamab in combination with lazertinib. Most cases were Grade 1 or 2, with Grade 3 rash events occurring in 26.8% of patients. Rash leading to amivantamab discontinuation occurred in 5.5% of patients. Rash usually developed within the first 4 weeks of therapy, with a median time to onset of 14 days. Nail toxicity occurred in patients treated with amivantamab in combination with lazertinib. Most events were Grade 1 or 2, with Grade 3 nail toxicity occurring in 11.4% of patients (see section 4.4).

A Phase 2 study in patients treated with Rybrevant in combination with lazertinib was conducted to assess the use of prophylactic therapy with an oral antibiotic, a topical antibiotic on the scalp, a moisturiser on the face and whole body (except scalp), and an antiseptic on hands and feet (see sections 4.2 and 4.4). A reduction in the incidence of ≥ Grade 2 dermatologic adverse events during the first 12 weeks of treatment was demonstrated, compared with the standard dermatologic management used in clinical practice (38.6% vs. 76.5%, p<0.0001). In addition, there was a reduction in ≥ Grade 2 adverse events involving the scalp in the first 12 weeks of treatment (8.6% vs. 29.4%) along with lower incidence of dose reductions (7.1% vs. 19.1%), interruptions (15.7% vs. 33.8%), and treatment discontinuations (1.4% vs. 4.4%) due to dermatological adverse events.

Eye disorders

Eye disorders, including keratitis (0.5%), occurred in 9% of patients treated with amivantamab alone. Other reported adverse reactions included growth of eyelashes, visual impairment, and other eye disorders. All events were Grade 1‑2.

Eye disorders, including keratitis (0.3%), occurred in 11% of patients treated with amivantamab in combination with carboplatin and pemetrexed. Other reported adverse reactions included growth of eyelashes, visual impairment, uveitis, and other eye disorders. All events were Grade 1‑2 (see section 4.4).

Eye disorders, including keratitis (2.6%), occurred in 26.4% of patients treated with amivantamab in combination with lazertinib. Other reported adverse reactions included growth of eyelashes, visual impairment, and other eye disorders. Most events were Grade 1‑2 (see section 4.4).

Other special populations

Elderly

There are limited clinical data with amivantamab in patients 75 years of age or over (see section 5.1).

For patients treated with amivantamab alone or in combination with carboplatin and pemetrexed, no overall differences in safety were observed between patients ≥ 65 years of age and patients < 65 years of age.

For patients treated with the combination of amivantamab with Lazertinib, the rates of drug interruptions and dose reductions were similar, however there was a higher incidence of Grade 3 or higher adverse events, and adverse events leading to discontinuation of treatment in patients ≥ 65 years of age compared to patients <65 years of age.

Immunogenicity

As with all therapeutic proteins, there is the potential for immunogenicity. In clinical studies of patients with locally advanced or metastatic NSCLC treated with amivantamab, 4 of the 1862 (0.2%) participants who were treated with Rybrevant and evaluable for the presence of anti‑drug antibodies (ADA), tested positive for treatment‑emergent anti‑amivantamab antibodies. There was no evidence of an altered pharmacokinetic, efficacy, or safety profile due to anti‑amivantamab antibodies.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: https://yellowcard.mhra.gov.uk/ or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

No maximum tolerated dose has been determined in a clinical study in which patients received up to 2100 mg administered intravenously. There is no known specific antidote for amivantamab overdose. In the event of an overdose, treatment with Rybrevant should be stopped, the patient should be monitored for any signs or symptoms of adverse events and appropriate general supportive measures should be instituted immediately until clinical toxicity has diminished or resolved.