RYBREVANT is indicated:

• in combination with carboplatin and pemetrexed for the first-line treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (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.

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 Exon 20 insertion mutation-positive 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 (see section 5.1).

Posology

Pre-infusion medications should be administered to reduce the risk of IRRs with RYBREVANT (see Table 4 and 5).

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 6).

Table 1: Recommended dosage of RYBREVANT every 3 weeks

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 monotherapy is provided in Table 2 (see below “ Infusion rates” and Table 7).

Table 2: Recommended dosage of RYBREVANT every 2 weeks

Duration of treatment

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

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 are provided in Table 3.

Table 3: RYBREVANT dose reductions for adverse reactions

The recommended RYBREVANT dosage modifications for adverse reactions are provided in Table 4.

Table 4: RYBREVANT dosage modifications for adverse reactions

Pre infusion medications

Prior to infusion (Week 1, Days 1 and 2), antihistamines, antipyretics, and glucocorticoids should be administered to reduce the risk of IRRs (see Table 5). 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 5: Dosing schedule of pre-medications

Special populations

Paediatric population

There is no relevant use of RYBREVANT 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 RYBREVANT 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 RYBREVANT 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 RYBREVANT 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 RYBREVANT 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 RYBREVANT infusion should be administered intravenously at the infusion rates presented in Table 6 or 7 below.

Due to the frequency of IRRs at the first dose, RYBREVANT should be infused via a peripheral line at Week 1 and Week 2 to minimise drug exposure in the event of an IRR. 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 6: Infusion rates for RYBREVANT every 3 weeks

Table 7: Infusion rates for RYBREVANT every 2 weeks

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

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 RYBREVANT (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 of RYBREVANT should be administered in split doses on Week 1, Day 1 and 2.

Patients should be treated with RYBREVANT in a setting with appropriate medical support to treat IRRs. RYBREVANT 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 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) have been reported in patients treated with RYBREVANT (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).

Skin and nail reactions

Rash (including dermatitis acneiform), pruritus 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 broad-spectrum UVA/UVB sunscreen are advisable. Alcohol-free emollient cream is recommended for dry areas of 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. 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 with RYBREVANT treatment. Treatment with this medicinal product should be discontinued if TEN is confirmed.

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. 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).

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.

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

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.

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 8 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 8: Adverse reactions in patients receiving amivantamab as monotherapy

Summary of the safety profile

In the dataset of amivantamab in combination with carboplatin and pemetrexed (N=151), the most frequent adverse reactions in all grades were rash (90%), nail toxicity (62%), stomatitis (43%), infusion related reactions (42%), hypoalbuminaemia (41%), oedema (40%), constipation (40%), nausea (36%), decreased appetite (36%), fatigue (34%), alanine aminotransferase increased (33%), aspartate aminotransferase increased (31%), diarrhoea (21%), vomiting (21%), and hypokalaemia (21%). Serious adverse reactions included rash (4.6%), ILD (2.6%), hypokalaemia (2.0%) and vomiting (2.0%). Five percent of patients discontinued RYBREVANT due to adverse reactions. The most frequent adverse reactions leading to treatment discontinuation were ILD (2.6%), rash (2.0%), nail toxicity (2.0%) and IRR (0.7%).

Table 9 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 151 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 9.7 months (range: 0.0 to 26.9 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: Adverse reactions in patients receiving amivantamab in combination with carboplatin and pemetrexed

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 42% of patients. Greater than 98% 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.

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

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 and 2.6% of patients treated with amivantamab in combination with carboplatin and pemetrexed. 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).

Skin and nail reactions

Rash (including dermatitis acneiform), pruritus, and dry skin occurred in 86% of patients treated with amivantamab alone or in combination with carboplatin and pemetrexed. Most cases were Grade 1 or 2, with Grade 3 rash events occurring in 8% of patients. Rash leading to amivantamab discontinuation occurred in 0.9% 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 3.2% of patients (see section 4.4).

Eye disorders

Eye disorders, including keratitis (0.4%), occurred in 9% of patients treated with amivantamab alone or in combination with carboplatin and pemetrexed. Other reported adverse reactions included growth of eyelashes, visual impairment, and other eye disorders. All 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). No overall differences in safety were observed between patients ≥ 65 years of age and 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, 3 of the 663 (0.5%) 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: www.yellowcard.mhra.gov.uk or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.

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 EGFR Exon 20 insertion mutations. Amivantamab binds to the extracellular domains of EGFR and MET.

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 (see section 4.8); thereafter, albumin concentration stabilised for the remainder of amivantamab treatment.

Clinical efficacy and safety

Previously-untreated non-small cell lung cancer (NSCLC) with Exon 20 insertion mutations (PAPILLON)

PAPILLON is a randomised, open-label, multicentre Phase 3 study comparing treatment with RYBREVANT in combination with carboplatin and pemetrexed to chemotherapy alone (carboplatin and pemetrexed) in patients with treatment-naï ve, locally advanced or metastatic NSCLC with activating EGFR Exon 20 insertion mutations. Tumour tissue (92.2%) and/or plasma (7.8%) samples for all 308 patients were tested locally to determine EGFR Exon 20 insertion mutation status using next generation sequencing (NGS) in 55.5% of patients and/or polymerase chain reaction (PCR) in 44.5% of patients. Central testing was also performed using the AmoyDx® LC10 tissue test, Thermo Fisher Oncomine Dx Target Test, and the Guardant 360® CDx plasma test.

Patients with brain metastases at screening were eligible for participation once they were definitively treated, clinically stable, asymptomatic, and off corticosteroid treatment for at least 2 weeks prior to randomisation.

RYBREVANT was administered intravenously at 1400 mg (for patients < 80 kg) or 1750 mg (for patients ≥ 80 kg) once weekly through 4 weeks, then every 3 weeks with a dose of 1750 mg (for patients < 80 kg) or 2100 mg (for patients ≥ 80 kg) starting at Week 7 until disease progression or unacceptable toxicity. Carboplatin was administered intravenously at area under the concentration-time curve 5 mg/mL per minute (AUC 5) once every 3 weeks, for up to 12 weeks. Pemetrexed was administered intravenously at 500 mg/m² on once every 3 weeks until disease progression or unacceptable toxicity. Randomisation was stratified by ECOG performance status (0 or 1), and prior brain metastases (yes or no). Patients randomised to the carboplatin and pemetrexed arm who had confirmed disease progression were permitted to cross over to receive RYBREVANT monotherapy.

A total of 308 subjects were randomised (1:1) to RYBREVANT in combination with carboplatin and pemetrexed (N=153) or carboplatin and pemetrexed (N=155). The median age was 62 (range: 27 to 92) years, with 39% of the subjects ≥ 65 years of age; 58% were female; and 61% were Asian and 36% were White. Baseline Eastern Cooperative Oncology Group (ECOG) performance status was 0 (35%) or 1 (64%); 58% never smoked; 23% had history of brain metastasis and 84% had Stage IV cancer at initial diagnosis.

The primary endpoint for PAPILLON was PFS, as assessed by BICR. The median follow-up was 14.9 months (range: 0.3 to 27.0).

Efficacy results are summarised in Table 10.

Table 10: Efficacy results in PAPILLON

Figure 1: Kaplan-Meier curve of PFS in previously untreated patients with NSCLC by BICR assessment

The PFS benefit of RYBREVANT in combination with carboplatin and pemetrexed compared to carboplatin and pemetrexed was consistent across all the predefined subgroups of brain metastases at study entry (yes or no), age (< 65 or ≥ 65), sex (male or female), race (Asian or non-Asian), weight (< 80 kg or ≥ 80 kg), ECOG performance status (0 or 1), and smoking history (yes or no).

Figure 2: Kaplan-Meier curve of OS in previously untreated patients with NSCLC by BICR assessment

Previously-treated non-small cell lung cancer (NSCLC) with Exon 20 insertion mutations (CHRYSALIS)

CHRYSALIS is a multicentre, open-label, multi-cohort study conducted to assess the safety and efficacy of RYBREVANT in patients with locally advanced or metastatic NSCLC. Efficacy was evaluated in 114 patients with locally advanced or metastatic NSCLC who had EGFR Exon 20 insertion mutations, whose disease had progressed on or after platinum-based chemotherapy, and who had a median follow-up of 12.5 months. Tumour tissue (93%) and/or plasma (10%) samples for all patients were tested locally to determine EGFR Exon 20 insertion mutation status using next generation sequencing (NGS) in 46% of patients and/or polymerase chain reaction (PCR) in 41% of patients; for 4% of patients, the testing methods were not specified. Patients with untreated brain metastases or a history of ILD requiring treatment with prolonged steroids or other immunosuppressive agents within the last 2 years were not eligible for the study. RYBREVANT was administered intravenously at 1050 mg for patients < 80 kg or 1400 mg for patients ≥ 80 kg once weekly for 4 weeks, then every 2 weeks starting at Week 5 until loss of clinical benefit or unacceptable toxicity. The primary efficacy endpoint was investigator-assessed overall response rate (ORR), defined as confirmed complete response (CR) or partial response (PR) based on RECIST v1.1. In addition, the primary endpoint was assessed by a blinded independent central review (BICR). Secondary efficacy endpoints included duration of response (DOR).

The median age was 62 (range: 36– 84) years, with 41% of the patients ≥ 65 years of age; 61% were female; and 52% were Asian and 37% were White. The median number of prior therapies was 2 (range: 1 to 7 therapies). At baseline, 29% had Eastern Cooperative Oncology Group (ECOG) performance status of 0 and 70% had ECOG performance status of 1; 57% never smoked; 100% had Stage IV cancer; and 25% had previous treatment for brain metastases. Insertions in Exon 20 were observed at 8 different residues; the most common residues were A767 (22%), S768 (16%), D770 (12%), and N771 (11%).

Efficacy results are summarised in Table 11.

Table 11: Efficacy Results in CHRYSALIS

CI = Confidence Interval

^a Confirmed response

^b ORR and DOR results by investigator assessment were consistent with those reported by BICR assessment; ORR by BICR assessment was 43% (34%, 53%), with a 3% CR rate and a 40% PR rate, median DOR by BICR assessment was 10.8 months (95% CI: 6.9, 15.0), and patients with DOR ≥ 6 months by BICR assessment was 55%.

^c Based on Kaplan-Meier estimate.

Anti-tumour activity was observed across studied mutation subtypes.

Elderly

No overall differences in effectiveness were observed between patients ≥ 65 years of age and patients < 65 years of age.

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).

Based on RYBREVANT monotherapy data, amivantamab area under the concentration-time curve (AUC_{1 week}) increases proportionally over a dose range from 350 to 1750 mg.

Based on simulations from the population pharmacokinetic model, AUC_{1 week} was approximately 2.8-fold higher after the fifth dose for the 2-week dosing regimen and 2.6-fold higher after the fourth dose for the 3-week dosing regimen. Steady-state concentrations of amivantamab were reached by Week 13 for both the 3-week and 2-week dosing regimen and the systemic accumulation was 1.9-fold.

Distribution

Based on the individual amivantamab PK parameter estimates in population PK analysis, the geometric mean (CV%) total volume of distribution, is 5.12 (27.8%) L, following administration of the recommended dose of RYBREVANT.

Elimination

Based on the individual amivantamab PK parameter estimates in population PK analysis, the geometric mean (CV%) linear clearance (CL) and terminal half-life associated with linear clearance is 0.266 (30.4%) L/day and 13.7 (31.9%) days respectively.

Special populations

Elderly

No clinically meaningful differences in the pharmacokinetics of amivantamab were observed based on age (27-87 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 metabolised 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.

Paediatric population

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

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity.

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 conducted to evaluate the effects on reproduction and foetal development; however, based on its mechanism of action, amivantamab can cause foetal harm or developmental anomalies. As reported in the literature, reduction, elimination, or disruption of embryo foetal or maternal EGFR signaling can prevent implantation, cause embryo foetal loss during various stages of gestation (through effects on placental development), cause developmental anomalies in multiple organs or early death in surviving foetuses. Similarly, knock out of MET or its ligand hepatocyte growth factor (HGF) was embryonic lethal due to severe defects in placental development, and foetuses displayed defects in muscle development in multiple organs. Human IgG1 is known to cross the placenta; therefore, amivantamab has the potential to be transmitted from the mother to the developing foetus.

Ethylenediaminetetraacetic acid (EDTA) disodium salt dihydrate

L-Histidine

L-Histidine hydrochloride monohydrate

L-Methionine

Polysorbate 80

Sucrose

Water for injections

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

Unopened vial

3 years

After dilution

Chemical and physical in-use stability has been demonstrated for 10 hours at 15° C to 25° C in room light. From a microbiological point of view, unless the method of dilution precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions are the responsibility of the user.

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.

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.

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

Preparation

• Determine the dose required 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.

• For every 2-week dosing, patients < 80 kg receive 1050 mg and for patients ≥ 80 kg, 1400 mg once weekly for a total of 4 doses, then every 2 weeks starting at Week 5.

• For every 3-week dosing, patients < 80 kg receive 1400 mg once weekly for a total of 4 doses, then 1750 mg every 3 weeks starting at Week 7, and for patients ≥ 80 kg, 1750 mg once weekly for a total of 4 doses, then 2100 mg every 3 weeks starting at Week 7.

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

• Withdraw and then discard a volume of either 5% glucose solution or sodium chloride 9 mg/mL (0.9%) solution for injection 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).

• 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 for particulate matter and discolouration prior to administration. Do not use if discolouration or visible particles are observed.

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.

• The administration set with filter must be primed with either 5% glucose solution or 0.9% sodium chloride solution prior to the initiation of each RYBREVANT infusion.

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

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

• 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 infusion rates in section 4.2.

Disposal

• This medicinal product is for single use only and any unused medicinal product that is not administered within 10 hours should be disposed of in accordance with local requirements.