This information is intended for use by health professionals

 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1. Name of the medicinal product

RYBREVANT 50 mg/mL concentrate for solution for infusion.

2. Qualitative and quantitative composition

Each 7 mL vial contains 350 mg of amivantamab (50 mg amivantamab per mL).

Amivantamab is a fully-human Immunoglobulin G1 (IgG1)-based bispecific antibody directed against the epidermal growth factor (EGF) and mesenchymal-epidermal transition (MET) receptors, produced by mammalian cell line (Chinese Hamster Ovary [CHO]) using recombinant DNA technology.

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Concentrate for solution for infusion.

The solution is colourless to pale yellow.

4. Clinical particulars
4.1 Therapeutic indications

RYBREVANT as monotherapy is indicated for treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) Exon 20 insertion mutations, whose disease has progressed on or after platinum-based chemotherapy.

4.2 Posology and method of administration

RYBREVANT should be administered by a healthcare professional with access to appropriate medical support to manage any infusion-related reactions (IRRs).

Pre-infusion medications should be administered to reduce the risk of IRRs with RYBREVANT (see Table 3).

Before starting treatment with RYBREVANT, EGFR Exon 20 insertion mutation status should be determined by an experienced laboratory using a validated test method (see section 4.4).

Posology

The recommended dose of RYBREVANT, based on baseline body weight, is provided in Table 1, and the dosing schedule is provided in Table 2. The initial dose is administered as a split infusion in Week 1 on Day 1 and Day 2.

Table 1: Recommended Dose of RYBREVANT based on Baseline Body Weight*

Body Weight

Recommended Dose

Number of 350 mg/7 mL RYBREVANT Vials

Less than 80 kg

1050 mg

3

Greater than or equal to 80 kg

1400 mg

4

* Dose adjustments not required for subsequent body weight changes.

Table 2: Dosing schedule for RYBREVANT

Weeks

Schedule

Weeks 1 to 4

Weekly (total of 4 doses)

Week 5 onwards

Every 2 weeks starting at Week 5

Duration of treatment

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

Pre infusion medications

Prior to the initial infusion of RYBREVANT on Week 1 (Days 1 and 2), antihistamines, antipyretics, and glucocorticoids should be administered to reduce the risk of IRRs (see Table 3). For all subsequent doses, antihistamines and antipyretics should be administered. Glucocorticoid administration is required for Week 1, Days 1 and 2 doses only and as necessary for subsequent infusions. Antiemetics should be administered as needed.

Table 3: Pre-medications

Medication

Dose

Route of Administration

Recommended Dosing Window Prior to RYBREVANT Administration

Antihistamine*

Chlorphenamine (10 mg) or equivalent

IV

15 to 30 minutes

Antipyretic*

Paracetamol (650 to 1000 mg)

IV

15 to 30 minutes

Oral

30 to 60 minutes

Glucocorticoid

Dexamethasone (10 mg) or Methylprednisolone (40 mg) or equivalent

IV

45 to 60 minutes

* Required at all doses.

Required at initial dose (Week 1, Days 1 and 2); optional for subsequent doses.

Infusion rates

Following dilution, the RYBREVANT infusion should be intravenously administered at the infusion rates presented in Table 4 below.

Due to the high frequency of IRRs at the first dose, RYBREVANT should be infused via a peripheral line for Week 1 and Week 2 to minimise drug exposure in the event of an IRR. Infusions may be administered via a central line for subsequent weeks (see section 6.6). It is recommended that Week 1 doses are diluted as close to the time of administration as possible to allow for an extended infusion time, if required, in the event of an IRR.

Table 4: Infusion Rates for RYBREVANT Administration

1050 mg Dose

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

1400 mg Dose

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

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

Missed dose

If a planned dose of RYBREVANT 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

The recommended RYBREVANT dose reductions for adverse reactions (see Table 6) are listed in Table 5.

Table 5: RYBREVANT Dose Reductions for Adverse Reactions

Body Weight

(at baseline)

Initial Dose

1st Dose Reduction

2nd Dose Reduction

3rd Dose Modification

<80 kg

1050 mg

700 mg

350 mg

Discontinue RYBREVANT

≥ 80 kg

1400 mg

1050 mg

700 mg

The recommended RYBREVANT dosage modifications for adverse reactions are provided in Table 6.

Table 6: RYBREVANT Dosage Modifications for Adverse Reactions

Adverse Reaction

Severity

Dose Modification

Infusion-Related Reactions (IRR)

(see section 4.4)

Grade 1 to 3

• Interrupt RYBREVANT infusion at the first sign of IRRs (see section 4.4).

• Additional supportive medications (e.g., additional glucocorticoids, antihistamine, antipyretics and antiemetics) should be administered as clinically indicated.

• Upon resolution 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 Table 4).

• Pre-medications should be administered prior to the next dose.

Recurrent Grade 3 or Grade 4:

• Permanently discontinue RYBREVANT

Interstitial Lung Disease / Pneumonitis

(see section 4.4)

Suspected ILD/ pneumonitis

• Withhold RYBREVANT

Confirmed ILD/ pneumonitis

• Permanently discontinue RYBREVANT

Skin and Nail Reactions

(see section 4.4)

Grade 2

• Supportive care should be initiated.

• If there is no improvement after 2 weeks, consider reducing the RYBREVANT dose (see Table 5).

Grade 3

• Supportive care should be initiated.

• Interrupt RYBREVANT until the adverse reaction improves. Upon recovery to ≤ Grade 2, resume RYBREVANT at a reduced dose (see Table 5).

• If no improvement within 2 weeks, permanently discontinue treatment.

Grade 4 (including bullous skin conditions, toxic epidermal necrolysis)

• Permanently discontinue RYBREVANT

Other Adverse Reactions

(see section 4.8)

Grade 3

• Withhold RYBREVANT until the adverse reaction improves to ≤ Grade 1 or returns to baseline.

• Resume at the same dose if recovery occurs within 7 days.

• Resume at reduced dose if recovery occurs after 7 days.

• Permanently discontinue if recovery does not occur within 4 weeks.

Grade 4

• Withhold RYBREVANT until the adverse reaction improves to ≤ Grade 1 or returns to baseline.

• Resume at the same dose if recovery occurs within 7 days.

• Consider permanently discontinuing with interruption longer than 7 days.

• Permanently discontinue RYBREVANT for recurrent Grade 4 reactions.

Special Populations

Paediatric population

The safety and efficacy of RYBREVANT have not been established in paediatric patients. No data are available.

Elderly

No dose adjustments are necessary.

Renal impairment

No formal studies of RYBREVANT in patients with renal impairment have been conducted. Based on population pharmacokinetic (PK) analyses, no dosage adjustment is necessary for patients with mild or moderate renal impairment. No data are available in patients with severe renal impairment (see section 5.2).

Hepatic impairment

No formal studies of RYBREVANT in patients with hepatic impairment have been conducted (see section 5.2). Based on population pharmacokinetic (PK) analyses, no dosage adjustment is necessary for patients with mild hepatic impairment. No data are available in patients with moderate or severe hepatic impairment (see section 5.2).

Method of administration

RYBREVANT is administered as an intravenous infusion following dilution with sterile 5% glucose solution or a sterile saline solution [0.9% NaCl]. RYBREVANT must be administered with in-line filtration.

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

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

Assessment of EGFR Exon 20 insertion mutation status

When considering using RYBREVANT, it is important that the EGFR Exon 20 insertion mutation status of a patient is determined. A validated test should be used to minimise false negative or false positive determinations.

Infusion-related reactions

Infusion-related reactions occurred very commonly in patients treated with RYBREVANT. The most frequent signs and symptoms of IRR include chills, nausea, dyspnoea, flushing, chest discomfort, hypotension, and vomiting (see section 4.8).

Prior to initial infusion (Week 1) of RYBREVANT, 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 of RYBREVANT should be administered in split doses on Week 1, Day 1 and 2. Administer RYBREVANT via a peripheral line on Week 1 and Week 2.

Patients should be treated with RYBREVANT in a setting with appropriate medical support to treat IRRs. RYBREVANT infusion should be interrupted at the first sign of IRRs of any severity and post-infusion medication should be administered as clinically indicated. Upon resolution of symptoms, the infusion of RYBREVANT 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) occurred in patients treated with RYBREVANT (see section 4.8). 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.

Patients should be monitored for symptoms indicative of ILD/pneumonitis (e.g., dyspnoea, cough, fever). If symptoms develop, treatment with RYBREVANT should be interrupted. Suspected ILD should be evaluated and appropriate treatment should be initiated as necessary. RYBREVANT should be discontinued permanently in patients with confirmed ILD (see section 4.2).

Skin and Nail reactions

Rash (including dermatitis acneiform), pruritis and dry skin occurred in patients treated with RYBREVANT (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 sunscreen are advisable. Alcohol-free emollient cream is recommended for dry skin.

If skin reactions develop, 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 and referral to a dermatologist should be considered. RYBREVANT should be interrupted based on severity (see section 4.2).

Toxic epidermal necrolysis (TEN) has been reported with RYBREVANT treatment. Interrupt RYBREVANT and promptly refer patients presenting with severe rash, atypical appearance, or distribution to a dermatologist. RYBREVANT should be discontinued permanently in patients with Grade 4 skin reactions, including TEN (see section 4.2).

Eye disorders

Eye disorders, including keratitis, occurred in patients treated with RYBREVANT (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 (see section 4.2).

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.

4.5 Interaction with other medicinal products and other forms of interaction

No drug interaction studies have been performed.

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 have been conducted. Administration of EGFR and MET inhibitors in pregnant animals resulted in an increased incidence of impairment of embryo-foetal development, embryo lethality, and abortion. Therefore, 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 the potential risks to the foetus. If the patient becomes pregnant while taking amivantamab, the patient should be informed of the potential risk to the foetus (see section 5.3).

Breast-feeding

It is not known whether amivantamab is excreted into human milk or affects milk production. Because of the potential for serious adverse reactions from amivantamab in breast-fed infants, women should not breast-feed during treatment with RYBREVANT and for 3 months following the last dose of RYBREVANT.

Fertility

No data are available to determine potential effects of amivantamab on fertility in males or females.

4.7 Effects on ability to drive and use machines

If patients experience treatment-related symptoms 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

The most frequent adverse reactions (≥ 20%) were IRR, paronychia, rash, dermatitis acneiform, hypoalbuminaemia, nausea, constipation, oedema peripheral, stomatitis, and alanine aminotransferase increased.

Serious adverse reactions occurred in 29% of patients. Serious adverse reactions in ≥2% of patients included pneumonia, dyspnoea, pulmonary embolism, pneumonitis, back pain and muscular weakness.

Twelve percent of patients discontinued RYBREVANT due to adverse reactions. The most frequent adverse reactions leading to treatment discontinuation were pneumonia, pleural effusion, pneumonitis and IRR.

Dose interruptions due to an adverse reaction other than IRR occurred in 36% of patients who received RYBREVANT. Adverse reactions requiring dose interruption in >2% of patients included rash, fatigue, paronychia, pneumonia, stomatitis, pyrexia and diarrhoea.

Dose reductions due to an adverse reaction occurred in 14% of patients. Adverse reactions requiring dose reductions in ≥ 2% of patients included dermatitis acneiform and paronychia.

Tabulated list of adverse reactions

Table 7 summarises the adverse drug reactions that occurred in patients receiving RYBREVANT.

The data reflects exposure to RYBREVANT in 153 patients with locally advanced or metastatic non-small cell lung cancer after failure of platinum-based chemotherapy. Patients received RYBREVANT 1050 mg (for patients < 80 kg) or 1400 mg (for patients ≥ 80 kg).

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 (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000) and not known (frequency cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing frequency.

Table 7: Adverse reactions in patients receiving RYBREVANT

Metabolism and nutrition disorders

Very common

hypoalbuminaemiaa, decreased appetite, hypokalaemia, hypomagnesaemia hypocalcaemia

Nervous system disorders

Very common

dizzinessb

Eye disorders

Common

visual impairmentc, growth of eyelashesd, keratitis, other eye disorderse

Uncommon

uveitis

Respiratory, thoracic and mediastinal disorders

Common

interstitial lung diseasef

Gastrointestinal disorders

Very common

stomatitisg, nausea, constipation, diarrhoea, vomiting

Common

abdominal painh

Skin and subcutaneous tissue disorders

Very common

rashi, nail toxicityj, pruritus, dry skink

Uncommon

toxic epidermal necrolysis

Musculoskeletal and connective tissue disorders

Very common

myalgia

General disorders and administration site conditions

Very common

fatiguel, oedemam

Investigations

Very common

alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased

Injury, poisoning and procedural complications

Very common

Infusion-related reaction

a Hypoalbuminaemia: blood albumin decreased, hypoalbuminaemia

b Dizziness: dizziness, dizziness exertional, vertigo

c Visual impairment: vision blurred, visual acuity reduced, visual impairment

d Growth of eyelashes: growth of eyelashes, trichomegaly

e Other eye disorders: blepharitis, conjunctival hyperaemia, corneal irritation, dry eye, episcleritis, eye disorder, eye pruritus, noninfective conjunctivitis, ocular hyperaemia

f Interstitial lung disease: interstitial lung disease, pneumonitis

g Stomatitis: aphthous ulcer, cheilitis, glossitis, lip ulceration, mouth ulceration, mucosal inflammation, stomatitis

h Abdominal pain: abdominal discomfort, abdominal pain, abdominal pain lower, abdominal pain upper, epigastric discomfort, gastrointestinal pain

i Rash: acne, dermatitis, dermatitis acneiform, erythema, erythema multiforme, folliculitis, impetigo, palmar-plantar erythrodysaesthesia syndrome, perineal rash, perioral dermatitis, pustule, rash, rash erythematous, rash macular, rash maculo-papular, rash papular, rash pruritic, rash pustular, rash vesicular, skin exfoliation, skin lesion

j Nail toxicity: ingrowing nail, nail bed infection, nail cuticle fissure, nail disorder, nail ridging, onychoclasis, onycholysis, paronychia

k Dry skin: dry skin, eczema, eczema asteatotic, skin fissures, xeroderma

l Fatigue: asthenia, fatigue

m Oedema: eye oedema, eyelid oedema, face oedema, generalised oedema, localised oedema, oedema, oedema peripheral, periorbital oedema, periorbital swelling, peripheral swelling, swelling face

Description of selected adverse reactions

The data reflects the safety profile of 489 patients with locally advanced or metastatic NSCLC who received any dose of RYBREVANT monotherapy.

Infusion-related reactions

Infusion-related reactions (IRRs) occurred in 67% of patients. Ninety-nine percent of IRRs occurred at the first infusion, with a median time to onset of 60 minutes (range: 0 to 1071 minutes), and the remaining 1% occurred at subsequent infusions. 2% of IRRs were Grade 3 and 0.2% were Grade 4. The incidence of infusion modifications due to IRR was 62% and 1.6% of patients permanently discontinued RYBREVANT due to IRR.

Interstitial lung disease

Interstitial lung disease or ILD-like adverse reactions have been reported with the use of RYBREVANT. Interstitial lung disease or pneumonitis was reported in 2.7% of patients with 0.6% of patients experiencing Grade 3 ILD/pneumonitis and 0.6% of patients discontinued RYBREVANT due to ILD/pneumonitis.

Skin and nail reactions

Rash occurred in 75% of patients treated with RYBREVANT, with Grade 3 rash events occurring in 3.7% of patients. Dermatitis acneiform leading to RYBREVANT discontinuation occurred in 0.2% of patients and in an additional 0.2% of patients with TEN. Rash usually developed within the first 4 weeks of therapy, with a median time to onset of 14 days. Rash leading to dose reduction occurred in 7% of patients.

Paronychia occurred in 43% of patients treated with RYBREVANT. Grade 3 paronychia occurred in 2% of patients, with a median time from onset of paronychia to complete resolution of 235 days (range: 26 to 443 days). Paronychia leading to RYBREVANT discontinuation occurred in 2% of patients.

Ocular toxicity

Eye disorders, including keratitis (0.4%) occurred in 12% of patients treated with RYBREVANT. Most events were Grade 1 or 2, with Grade 3 events occurring in 0.2% of patients. Keratitis led to RYBREVANT dose interruption in 0.2% of patients, and vision blurred led to discontinuation of RYBREVANT in 0.2% of patients.

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

In the event of an overdose, treatment with RYBREVANT should be stopped, the patient should be monitored for any signs or symptoms of adverse effects and appropriate general supportive measures should be instituted.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Monoclonal antibodies and antibody drug conjugates, ATC code: L01FX18.

Mechanism of action

Amivantamab is a low-fucose, fully-human IgG1-based EGFR-MET bispecific antibody with immune cell-directing activity that targets tumours with activating and resistance EGFR mutations and MET mutations and amplifications. Amivantamab binds to the extracellular domains of EGFR and MET.

Preclinical studies show amivantamab is active against tumours with primary EGFR activating mutations such as Exon 19 deletions, L858R substitution, and Exon 20 insertion mutations; secondary EGFR resistance mutations such as T790M and C797S; and resistance to EGFR inhibition due to activation of the MET pathway. Amivantamab disrupts EGFR and MET signalling functions through blocking ligand binding and enhancing degradation of EGFR and MET, thereby preventing tumour growth and progression. The presence of EGFR and MET on the surface of tumour cells also allows for targeting of these cells for destruction by immune effector cells, such as natural killer cells and macrophages, through antibody-dependent cellular cytotoxicity (ADCC) and trogocytosis mechanisms, respectively.

Pharmacodynamic effects

Albumin

Amivantamab decreased serum albumin concentration, a pharmacodynamic effect of MET inhibition, typically during the first 8 weeks; thereafter, albumin concentration stabilized for the remainder of amivantamab treatment.

Immunogenicity

As with all therapeutic proteins, there is the potential for immunogenicity. In a clinical trial of patients with locally advanced or metastatic NSCLC treated with RYBREVANT, 3 (1%) of the 286 evaluable patients tested positive for anti-amivantamab antibodies.

Clinical efficacy

The efficacy of RYBREVANT was evaluated in a Phase 1, first in human, single-arm, multicentre, open-label, multi-cohort study [EDI1001 (NCT02609776)]. Eligible patients (n=77) with locally advanced (unresectable and not amenable to curative treatment approaches) or metastatic NSCLC had EGFR Exon 20 insertion mutations, determined by local testing, and disease progression on or after platinum-based chemotherapy. Patients with untreated brain metastases were excluded.

RYBREVANT was administered intravenously at 1050 mg for patients with a baseline body weight < 80 kg or 1400 mg for subjects ≥ 80 kg once weekly for 4 weeks, then every 2 weeks until disease progression or unacceptable toxicity. The primary efficacy endpoint was overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumours (RECIST v1.1) by investigator assessment and confirmed by Blinded Independent Central Review (BICR). Additional efficacy outcomes were clinical benefit rate, duration of response, progression-free survival, and overall survival.

The median age was 62 (range: 42 to 84) years, 58% were female; 51% were Asian; 36% were White; 74% had baseline body weight <80 kg and 95% had adenocarcinoma. The median number of prior therapies was 2 (range: 1 to 7) and 47% had received prior immunotherapy. At baseline, most had Eastern Cooperative Oncology Group (ECOG) performance status of 0 (31%) or 1 (68%); 53% never smoked; and 22% had received previous treatment for brain metastases. Insertions in Exon 20 were observed at 8 different residues; the most common residues were A767 (25%), S768 (17%), D770 (10%), and N771 (12%). Median follow-up was 14.3 months.

Table 8: Efficacy Results in EDI1001 (N=77) – data cut-off 30 March 2021

Investigator assessment

BICR assessment

Overall Response Rate a (95% CI)

38% (27%, 49%)

43% (32%, 55%)

Complete response

0 (0%)

3 (3.9%)

Partial response

29 (38%)

30 (39%)

Clinical Benefit Rateb (95% CI)

73% (61%, 82%)

74% (63%, 83%)

Duration of Response (DOR)

Median, months c (95% CI)

12.45 (6.5, NE)

11.01 (6.90, NE)

Patients with DOR ≥ 6 months

20 (69.0%)

19 (58%)

Median Progression-Free Survivalc (95% CI), months

7.9 (5.4, 10.6)

6.8 (4.6, 9.6)

Median Overall Survival (95% CI), months

23.0 (17.4, NE)

a Confirmed response

b Defined as complete response + partial response +stable disease (duration of at least 11 weeks)

c Based on Kaplan-Meier estimate.

NE = Not Estimable

Of the patients who responded to RYBREVANT, 1 had a concomitant MET mutation and 4 had an additional EGFR mutation other than EGFR exon 20 insertion.

Paediatric population

The Licensing Authority has waived the obligation to submit the results of studies with RYBREVANT in all subsets of the paediatric population in non-small cell lung cancer (see section 4.2 for information on paediatric use).

This medicinal product has been authorised under a so-called 'conditional approval' scheme. This means that further evidence on this medicinal product is awaited. The MHRA will review new information on this medicinal product at least every year and this SmPC will be updated as necessary.

5.2 Pharmacokinetic properties

Amivantamab area under the concentration-time curve (AUC1 week) increases proportionally over a dose range from 350 to 1750 mg (0.33 to 1.67 times the recommended dose for subjects < 80 kg and 0.25 to 1.25 times the recommended dose for subjects ≥ 80 kg).

Following administration of RYBREVANT at the recommended dose and schedule, the mean ± SD serum maximal concentration (Cmax) was 836 ± 264 mcg/mL at 1050 mg for subjects < 80 kg and 655 ± 109 mcg/mL at 1400 mg for subjects ≥ 80 kg at the end of weekly dosing following the fifth dose. The mean ± SD AUC1 week following the fifth dose was 94,946 ± 35,440 mcg.h/mL at 1050 mg for subjects < 80 kg and 76,946 ± 14,557 mcg.h/mL at 1400 mg for subjects ≥80 kg. The mean serum AUC1 week was approximately 2.9-fold higher after the fifth dose following the weekly dosing compared to the first dose.

When RYBREVANT was administered, amivantamab steady state was achieved approximately 2 months into the every 2-week dosing period (by the ninth infusion) at 1050 mg, and amivantamab mean ± SD ratio of AUC1 week at steady state to AUC1 week after the first dose was 2.44 ± 0.54.

Distribution

Amavintamab mean ± SD volume of distribution estimated from population PK parameters was 5.13 ± 1.78 L following administration of the recommended dose of RYBREVANT.

Elimination

Amivantamab clearance decreased with increasing dose and with multiple dosing. The mean ± SD linear clearance was estimated to be 360 ± 144 mL/day and the mean ± SD estimated terminal half-life associated with linear clearance estimated from population PK parameter estimates was 11.3 ± 4.53 days following administration of the recommended dosage of RYBREVANT as monotherapy.

Special populations

Paediatrics population

The pharmacokinetics of RYBREVANT in paediatric patients have not been investigated.

Elderly

No clinically meaningful differences in the pharmacokinetics of amivantamab were observed based on age (32-87 years).

Renal impairment

No clinically meaningful effect on the pharmacokinetics of amivantamab was observed in patients with mild (60 ≤ creatinine clearance [CrCl] < 90 mL/min) and moderate (29 ≤ CrCl < 60 mL/min) renal impairment. The effect of severe renal impairment (15 ≤ CrCl < 29 mL/min) on amivantamab pharmacokinetics is unknown.

Hepatic impairment

Changes in hepatic function are unlikely to have any effect on the elimination of amivantamab since IgG1-based molecules such as amivantamab are not metabolized through hepatic pathways.

No clinically meaningful effect in the pharmacokinetics of amivantamab was observed based on mild hepatic impairment [(total bilirubin ≤ ULN and AST > ULN) or (ULN < total bilirubin ≤ 1.5 x ULN)]. The effect of moderate (total bilirubin 1.5 to 3 times ULN) and severe (total bilirubin > 3 times ULN) hepatic impairment on amivantamab pharmacokinetics is unknown.

5.3 Preclinical safety data

In repeat-dose toxicity studies in cynomolgus monkeys, amivantamab was well-tolerated at weekly doses up to 120 mg/kg intravenously for 3 months and up to 125 mg/kg subcutaneously for 2 weeks. There were no effects on cardiovascular, respiratory, and nervous system function. Clinical pathology demonstrated non-adverse elevations in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and globulins and non-adverse decreases in albumin when compared to the control group. All these values returned to normal ranges in recovery groups.

Carcinogenicity and mutagenicity

No animal studies have been performed to establish the carcinogenic potential of amivantamab. Routine genotoxicity and carcinogenicity studies are generally not applicable to biologic pharmaceuticals as large proteins cannot diffuse into cells and cannot interact with DNA or chromosomal material.

Reproductive toxicology

No animal studies have been performed to determine potential effects on fertility, embryo-foetal development, or prenatal and postnatal development.

6. Pharmaceutical particulars
6.1 List of excipients

Ethylenediaminetetraacetic acid (EDTA) disodium salt dihydrate

L-Histidine

L-Histidine hydrochloride monohydrate

L-Methionine

Polysorbate 80

Sucrose

Water for injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

Unopened vials:

24 months

After dilution:

Since amivantamab solutions do not contain a preservative, unless the method of opening/dilution precludes the risk of microbial contamination, the product should be used immediately. In-use storage times and conditions are the responsibility of the user. The diluted solutions should be administered within 10 hours (including infusion time) at room temperature (15°C to 25°C) and in room light.

6.4 Special precautions for storage

Store in a refrigerator (2°C to 8°C).

Do not freeze.

Store in the original package in order to protect from light.

For storage conditions after dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

7 mL concentrate in a Type 1 glass vial with an elastomeric closure and aluminium seal with a flip-off cap containing 350 mg (50 mg/mL) of sterile amivantamab solution. Pack size of 1 vial.

6.6 Special precautions for disposal and other handling

This medicinal product is for single-use only. Prepare the solution for intravenous infusion using aseptic technique as follows:

Preparation

• Determine the dose required (either 1050 mg or 1400 mg) and the number of RYBREVANT vials needed based on patient's baseline weight (see section 4.2). Each vial of RYBREVANT contains 350 mg of amivantamab.

• Check that the RYBREVANT solution is colourless to pale yellow. Do not use if discoloration or visible particles are present.

• Withdraw and then discard a volume of either 5% glucose solution or 0.9% sodium chloride solution from the 250 mL infusion bag that is equal to the required volume of RYBREVANT solution to be added (discard 7 mL diluent from the infusion bag for each vial). Infusion bags must be made of polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE), or polyolefin blend (PP+PE). Dilute under appropriate aseptic conditions. Discard any unused portion left in the vial.

• Withdraw 7 mL of RYBREVANT from each vial needed then add it to the infusion bag. Each vial contains a 0.5 mL overfill to ensure sufficient extractable volume. The final volume in the infusion bag should be 250 mL. Discard any unused portion left in the vial.

• Gently invert the bag to mix the solution. Do not shake.

• Visually inspect parenteral medicinal products for particulate matter and discoloration prior to administration. Do not use if discoloration or visible particles are observed.

• Diluted solutions should be administered within 10 hours (including infusion time) at room temperature (15°C to 25°C) and in room light.

Administration

• Administer the diluted solution by intravenous infusion using an infusion set fitted with a flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.22 or 0.2 micrometer). Administration sets must be made of either polyurethane (PU), polybutadiene (PBD), PVC, PP, or PE.

• Do not infuse RYBREVANT concomitantly in the same intravenous line with other agents.

• This medicinal product is for single use only and any unused medicinal product should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Janssen-Cilag Ltd

50-100 Holmers Farm Way

High Wycombe

Buckinghamshire

HP12 4EG

UK

8. Marketing authorisation number(s)

PLGB 00242/0740

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 15/11/2021

10. Date of revision of the text

15/11/2021