4.1. Therapeutic indications

Rybrevant subcutaneous formulation 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.

• 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 subcutaneous formulation should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.

Before initiation of Rybrevant subcutaneous formulation, 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. Once EGFR mutation status has been established, testing does not need to be repeated (see section 5.1).

Rybrevant subcutaneous formulation should be administered by a healthcare professional with access to appropriate medical support to manage administration-related reactions if they occur.

Posology

Premedications should be administered to reduce the risk of administration-related reactions with Rybrevant subcutaneous formulation (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.

The recommended dosages of Rybrevant subcutaneous formulation in combination with lazertinib or as monotherapy based on baseline body weight, are provided in Table 1.

Table 1: Recommended dosage of Rybrevant subcutaneous formulation

Body weight at baseline*

Recommended dose

Dosing schedule

Less than 80 kg

1600 mga

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

• Every 2 weeks starting at Week 5 onwards

Greater than or equal to 80 kg

2240 mg

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

• Every 2 weeks starting at Week 5 onwards

* Dose adjustments not required for subsequent body weight changes.

a See SmPC for Rybrevant 1600 mg solution for injection.

When given in combination with lazertinib, it is recommended to administer Rybrevant subcutaneous formulation 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 subcutaneous formulation until disease progression or unacceptable toxicity.

Missed dose

If a dose of Rybrevant subcutaneous formulation is missed between Weeks 1 to 4, it should be administered within 24 hours. If a dose of Rybrevant subcutaneous formulation is missed from Week 5 onward, it should be administered within 7 days. Otherwise, the missed dose should not be administered and the next dose should be administered per the usual dosing schedule.

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 2. See also specific dose modifications for specific adverse reactions below Table 2.

If used in combination with lazertinib, refer to section 4.2 of the lazertinib Summary of Product Characteristics for information about dose modifications.

Table 2: Recommended dose modifications for adverse reactions

Dose*

Dose after 1st interruption for adverse reaction

Dose after 2nd interruption for adverse reaction

Dose after 3rd interruption for adverse reaction

1600 mga

1050 mg

700 mg

Discontinue Rybrevant subcutaneous formulation

2240 mg

1600 mg

1050 mg

* Dose at which the adverse reaction occurred

a See SmPC for Rybrevant 1600 mg solution for injection.

Administration‑related reactions

Premedications should be administered to reduce the risk of administration‑related reactions with Rybrevant subcutaneous formulation (see “Recommended concomitant medicinal products”). Injections should be interrupted at the first sign of administration‑related reactions. 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 Rybrevant subcutaneous formulation injections. Concomitant medicinal products should be administered at the next dose, including dexamethasone (20 mg) or equivalent (see Table 3).

• 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 drugs should be withheld 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 (see section 4.4).

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 2). If the patient develops a Grade 3 skin or nail reaction, supportive care should be initiated as clinically indicated, and interruption of Rybrevant subcutaneous formulation should be considered until the adverse reaction improves. Upon recovery of the skin or nail reaction to ≤ Grade 2, Rybrevant subcutaneous formulation 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 subcutaneous formulation 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

Prior to the initial dose (Week 1, Day 1), antihistamines, antipyretics, and glucocorticoids should be administered to reduce the risk of administration-related reactions (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 3: Dosing schedule of premedications

Premedication

Dose

Route of administration

Recommended dosing window prior to Rybrevant subcutaneous formulation administration

Antihistamine*

Chlorphenamine (10 mg) or equivalent

Intravenous

15 to 30 minutes

Oral

30 to 60 minutes

Antipyretic*

Paracetamol (650 to 1000 mg) or equivalent

Intravenous

15 to 30 minutes

Oral

30 to 60 minutes

Glucocorticoid†

Dexamethasone (20 mg) or equivalent

Intravenous

45 to 60 minutes

Oral

At least 60 minutes

Glucocorticoid‡

Dexamethasone (10 mg) or equivalent

Intravenous

45 to 60 minutes

Oral

60 to 90 minutes

* Required at all doses.

† Required at initial dose (Week 1, Day 1) or at the next subsequent dose in the event of an administration-related reaction.

‡ Optional for subsequent doses.

Special populations

Paediatric population

There is no relevant use of amivantamab in the paediatric population in the treatment of NSCLC.

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 solution for injection is for subcutaneous use only.

Rybrevant subcutaneous formulation is not intended for intravenous administration and should be given by subcutaneous injection only, using the doses specified. See section 6.6 for instructions on handling of the medicinal product before administration.

Inject the required volume of Rybrevant subcutaneous formulation into the subcutaneous tissue of the abdomen over approximately 5 minutes. Do not administer at other sites of the body as no data are available.

Pause or slow delivery rate if the patient experiences pain. In the event pain is not alleviated by pausing or slowing down delivery rate, a second injection site may be chosen on the opposite side of the abdomen to deliver the remainder of the dose.

If administering with a subcutaneous infusion set, ensure that the full dose is delivered through the infusion set. Sodium chloride 9 mg/mL (0.9%) solution may be utilised to flush remaining medicinal product through the line.

Do not inject into tattoos or scars or areas where the skin is red, bruised, tender, hard, not intact or within 5 cm around the periumbilical area.

Injection sites should be rotated for successive injections.

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.

Administration-related reactions

Administration-related reactions occurred in patients treated with Rybrevant subcutaneous formulation (see section 4.8).

Prior to the initial injection (Week 1 Day 1), antihistamines, antipyretics, and glucocorticoids should be administered to reduce the risk of administration-related reactions. For subsequent doses, antihistamines and antipyretics should be administered.

Patients should be treated in a setting with appropriate medical support to treat administration-related reactions. At the first sign of administration-related reactions of any severity, injections should be interrupted, if ongoing, and post-injection medicinal products should be administered as clinically indicated. Upon resolution of symptoms, the injection should be resumed. For Grade 4 or recurrent Grade 3 administration-related reactions, 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 amivantamab in combination with lazertinib, VTE events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), were reported (see section 4.8). Fatal events were observed with amivantamab intravenous formulation. 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.

Signs and symptoms of VTE events should be monitored. Patients with VTE events should be treated with anticoagulation as clinically indicated. For VTE events associated with clinical instability, treatment should be withheld 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” (see section 6.6).

Polysorbate content

This medicinal product contains 0.6 mg of polysorbate 80 in each mL, which is equivalent to 6 mg per 10 mL vial, or 8.4 mg per 14 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

Rybrevant as monotherapy

In the dataset of Rybrevant intravenous formulation 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 4 summarises the adverse drug reactions that occurred in patients receiving Rybrevant as monotherapy.

The data reflects exposure to Rybrevant intravenous formulation 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 4: Adverse reactions in patients receiving Rybrevant as monotherapy (N=380)

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

Rybrevant in combination with lazertinib

Overall, the safety profile of Rybrevant subcutaneous formulation was consistent with the established safety profile of Rybrevant intravenous formulation, with a lower incidence of administration-related reactions and VTEs observed with the subcutaneous formulation compared to the intravenous formulation.

In the dataset of Rybrevant (either intravenous or subcutaneous formulations) in combination with lazertinib (N=752), the most frequent adverse reactions of any grade (≥ 20% patients) 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%).

Clinically relevant differences between the intravenous and subcutaneous formulations, when given in combination with lazertinib, were observed for administration‑related reactions (63% for intravenous vs. 14% for subcutaneous) and VTE (37% for intravenous vs. 11% for subcutaneous).

Serious adverse reactions were reported in 14% of patients who received Rybrevant subcutaneous formulation in combination with lazertinib, including ILD (4.2%), VTE (2.7%), hepatotoxicity (2.1%), and fatigue (1.5%). Seven percent of patients discontinued Rybrevant subcutaneous formulation due to adverse reactions. In patients treated with Rybrevant subcutaneous formulation in combination with lazertinib, the most frequent adverse reactions of any grade (≥ 1% patients) leading to discontinuation of Rybrevant subcutaneous formulation were ILD (3.6%) and rash (1.5%).

Tabulated list of adverse reactions

The adverse reactions for Rybrevant (either intravenous or subcutaneous formulation) when received in combination with lazertinib are summarised in Table 5.

The safety data below reflect exposure to Rybrevant (either intravenous or subcutaneous formulation) in combination with lazertinib in 752 patients with locally advanced or metastatic NSCLC, including 421 patients in MARIPOSA, 125 patients in PALOMA-2 cohorts 1 and 6, and 206 patients in PALOMA-3 subcutaneous arm. Patients received Rybrevant (either intravenous or subcutaneous formulation) until disease progression or unacceptable toxicity. The median duration of treatment with amivantamab overall for both intravenous and subcutaneous formulations was 9.9 months (range: 0.1 to 31.4 months). Median duration on treatment for the subcutaneous formulation was 5.7 months (range: 0.1 to 13.2 months) while median duration on treatment for the intravenous formulation 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).

Table 5: Adverse reactions for Rybrevant (either intravenous or subcutaneous formulation) when received in combination with lazertinib (N=752)

System Organ Class

Adverse Reaction

Frequency category

Any grade

(%)

Grade 3‑4

(%)

Metabolism and nutrition disorders

Hypoalbuminaemia*

Very common

48

4.5

Decreased appetite

24

0.8

Hypocalcaemia

19

1.2

Hypokalaemia

13

2.7

Hypomagnesaemia

Common

6

0

Nervous system disorders

Paraesthesia*, a

Very common

29

1.3

Dizziness*

12

0

Eye disorders

Other eye disorders*

Very common

19

0.5

Visual impairment*

Common

3.6

0

Keratitis

1.7

0.3

Growth of eyelashes*

1.7

0

Vascular disorders

Venous thromboembolism

Amivantamab intravenous*, b

Very common

37

11

Amivantamab subcutaneous*, c

Very common

11

0.9

Respiratory, thoracic, and mediastinal disorders

Interstitial lung disease*

Common

3.6

1.7

Gastrointestinal disorders

Stomatitis*

Very common

43

2.0

Constipation

26

0

Diarrhoea

26

1.7

Nausea

24

0.8

Vomiting

15

0.5

Abdominal pain*

10

0.1

Haemorrhoids

Common

8

0.1

Hepatobiliary disorders

Hepatotoxicity*

Very common

43

7

Skin and subcutaneous tissue disorders

Rash*

Very common

87

23

Nail toxicity*

67

8

Dry skin*

25

0.7

Pruritus

23

0.3

Skin ulcer

Common

3.9

0.5

Palmar‑plantar erythrodysaesthesia syndrome

3.9

0.1

Urticaria

1.6

0

Musculoskeletal and connective tissue disorders

Myalgia

Very common

15

0.5

Muscle spasms

13

0.4

General disorders and administration site conditions

Oedema*

Very common

42

2.7

Fatigue*

35

3.5

Pyrexia

11

0

Injection site reactions*, c, d

Common

8

0

Injury, poisoning, and procedural complications

Infusion‑/Administration‑related reactions

Amivantamab intravenousb, e

Very common

63

6

Amivantamab subcutaneousc, f

Very common

14

0.3

* Grouped terms.

a Applicable only to lazertinib.

b Frequency based on amivantamab intravenous study only (MARIPOSA [N=421]).

c Frequency based on amivantamab subcutaneous studies only (PALOMA‑2 cohorts 1 and 6 [N=125] and PALOMA‑3 subcutaneous arm [N=206]).

d Injection site reactions are local signs and symptoms associated with subcutaneous mode of administration.

e Infusion‑related reactions are systemic signs and symptoms associated with infusion of amivantamab intravenous.

f Administration‑related reactions are systemic signs and symptoms associated with administration of amivantamab subcutaneous.

Description of selected adverse reactions

Administration-related reactions

Overall, administration-related reactions occurred in 14% of patients treated with Rybrevant subcutaneous formulation in combination with lazertinib. In PALOMA-3, administration-related reactions were reported in 13% of patients treated with Rybrevant subcutaneous formulation in combination with lazertinib compared to 66% when treated with Rybrevant intravenous formulation in combination with lazertinib. The most frequent signs and symptoms of administration-related reactions include dyspnoea, flushing, fever, chills, nausea, and chest discomfort. Median time to onset of first administration-related reactions was 2.1 hours (range: 0.0 to 176.5 hours). Most administration-related reactions (98%) were Grades 1 or 2 in severity.

Injection site reactions

Overall, injection site reactions occurred in 8% of patients treated with Rybrevant subcutaneous formulation in combination with lazertinib. All injection site reactions were Grade 1 or 2 in severity. The most frequent symptom of injection site reactions was erythema.

Interstitial lung disease

Interstitial lung disease (ILD) or ILD-like adverse reactions have been reported with the use of amivantamab as well as with other EGFR inhibitors. ILD was reported in 3.6% of patients treated with Rybrevant (either intravenous or subcutaneous formulation) in combination with lazertinib, including 2 (0.3%) patients with a fatal reaction. Patients with a medical history of ILD, including drug-induced ILD or radiation pneumonitis, were excluded from PALOMA-2 and PALOMA-3.

Venous thromboembolic (VTE) events with concomitant use with lazertinib

VTE events, including deep venous thrombosis (DVT) and pulmonary embolism (PE), were reported in 11% of patients receiving Rybrevant subcutaneous formulation in combination with lazertinib in PALOMA-2 and PALOMA-3. Most cases were Grade 1 or 2, with Grade 3 events occurring in 3 (0.9%) patients. Additionally, 269 (81%) of these 331 patients receiving Rybrevant subcutaneous formulation took prophylactic anticoagulants with a direct oral anticoagulant or low molecular weight heparin within the first four months of study treatment. In PALOMA-3, the incidence of VTE reactions was 9% for patients treated with Rybrevant subcutaneous formulation in combination with lazertinib, compared to 13% when treated with Rybrevant intravenous formulation in combination with lazertinib, with similar rates of prophylactic anticoagulant use in both treatment arms (80% in the subcutaneous arm vs. 81% in the intravenous arm). For patients who did not receive prophylactic anticoagulants, the overall incidence of VTE was 17% for patients treated with Rybrevant subcutaneous formulation in combination with lazertinib with all VTE reactions reported as Grade 1-2 and serious VTE reactions reported in 4.8% of these patients, compared to an overall incidence of 23% for patients treated with Rybrevant intravenous formulation in combination with lazertinib with Grade 3 VTE reactions reported in 10% and serious VTE reactions reported in 8% of these patients.

Skin and nail reactions

Rash (including dermatitis acneiform), pruritus, and dry skin have occurred in patients treated with Rybrevant (either intravenous or subcutaneous formulation) in combination with lazertinib. Rash occurred in 87% of patients, leading to discontinuation of Rybrevant in 0.7% of patients. Most cases were Grade 1 or 2, with Grade 3 and Grade 4 reactions occurring in 23% and 0.1% of patients, respectively.

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 (1.7%), occurred in patients treated with Rybrevant (either intravenous or subcutaneous formulation). Other reported adverse reactions included growth of eyelashes, visual impairment, and other eye disorders.

Special populations

Elderly

There are limited clinical data with amivantamab in patients 75 years of age or over (see section 5.1). No overall differences in safety were observed between patients ≥ 65 years of age and patients < 65 years of age.

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: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is no information on overdose with Rybrevant subcutaneous formulation and no known specific antidote for 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.