RYBREVANT 350mg perfusive solution concentrate medication leaflet

Rybrevant 350 mg concentrate for solution for infusion.

One mL of concentrate for solution for infusion contains 50 mg amivantamab.

One 7 mL vial contains 350 mg of amivantamab.

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

One mL of solution contains 0.6 mg of polysorbate 80.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion.

The solution is colourless to pale yellow, with a pH of 5.7 and an osmolality of approximately310 mOsm/kg.

Rybrevant is indicated:

- in combination with lazertinib for the first-line treatment of adult patients with advancednon-small cell lung cancer (NSCLC) with EGFR Exon 19 deletions or Exon 21 L858Rsubstitution mutations.

- in combination with carboplatin and pemetrexed for the treatment of adult patients withadvanced NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations afterfailure of prior therapy including an EGFR tyrosine kinase inhibitor (TKI).

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

- as monotherapy for treatment of adult patients with advanced NSCLC with activating EGFR

Exon 20 insertion mutations, after failure of platinum-based therapy.

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

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

Before initiation of Rybrevant therapy, EGFR mutation status in tumour tissue or plasma specimensmust 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 forfalse negative results using a plasma-test. Testing may be performed at any time from initial diagnosisuntil the initiation of therapy; testing does not need to be repeated once EGFR mutation status hasbeen established (see section 5.1).

Premedications should be administered to reduce the risk of IRRs with Rybrevant (see below “Dosemodifications” and “Recommended concomitant medicinal products”).

Every 3 weeks

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

Table 1: Recommended dosage of Rybrevant every 3 weeks

Body weight at Rybrevant Schedule Number ofbaselinea dose vials

Less than 80 kg 1400 mg Weekly (total of 4 doses) from Weeks 1 to 4 4

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

- Weeks 2 to 4 - infusion on Day 11750 mg Every 3 weeks starting at Week 7 onwards 5

Greater than or 1750 mg Weekly (total of 4 doses) from Weeks 1 to 4 5equal to 80 kg - Week 1 - split infusion on Day 1 and Day 2

- Weeks 2 to 4 - infusion on Day 12100 mg Every 3 weeks starting at Week 7 onwards 6a Dose adjustments not required for subsequent body weight changes.

When used in combination with carboplatin and pemetrexed, Rybrevant should be administered aftercarboplatin and pemetrexed in the following order: pemetrexed, carboplatin and then Rybrevant. Seesection 5.1 and the manufacturer’s prescribing information for dosing instructions for carboplatin andpemetrexed.

Every 2 weeks

The recommended dosages of Rybrevant monotherapy or in combination with lazertinib is provided in

Table 2 (see below “Infusion rates” and Table 6).

Table 2: Recommended dosage of Rybrevant every 2 weeks

Body weight at Rybrevant Schedule Number ofbaselinea dose 350 mg/7 mL

Rybrevantvials

Less than 80 kg Weekly (total of 4 doses) from weeks 1 to 4

- Week 1 - split infusion on Day 1 and Day 21050 mg 3

- Weeks 2 to 4 - infusion on Day 1

Every 2 weeks starting at Week 5 onwards

Greater than or Weekly (total of 4 doses) from Weeks 1 to 4equal to 80 kg - Week 1 - split infusion on Day 1 and Day 21400 mg 4

- Weeks 2 to 4 - infusion on Day 1

Every 2 weeks starting at Week 5 onwardsa Dose adjustments not required for subsequent body weight changes.

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

Characteristics for recommended lazertinib dosing information.

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

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

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 interruptionis longer than 7 days, it is recommended restarting at a reduced dose as presented in Table 3. See alsospecific dose modifications for specific adverse reactions below Table 3.

If used in combination with lazertinib, refer to section 4.2 of the lazertinib Summary of Product

Characteristics for information about dose modifications.

Table 3: Recommended dose modifications for adverse reactions

Dose at which the Dose after 1st Dose after 2nd Dose after 3rdadverse reaction interruption for interruption for interruption foroccurred adverse reaction adverse reaction adverse reaction1050 mg 700 mg 350 mg1400 mg 1050 mg 700 mg

Discontinue Rybrevant1750 mg 1400 mg 1050 mg2100 mg 1750 mg 1400 mg

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

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

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

Venous thromboembolic (VTE) events with concomitant use with lazertinib

At the initiation of treatment, prophylactic anticoagulants should be administered to prevent VTEevents in patients receiving Rybrevant in combination with lazertinib. Consistent with clinicalguidelines, patients should receive prophylactic dosing of either a direct acting oral anticoagulant(DOAC) or a low-molecular weight heparin (LMWH). Use of Vitamin K antagonists is notrecommended.

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 productscan be resumed at the same dose. In the event of recurrence despite appropriate anticoagulation,discontinue Rybrevant. Treatment can continue with lazertinib at the same dose.

Skin and nail reactions

Patients should be instructed to limit sun exposure during and for 2 months after Rybrevant therapy.

Alcohol-free emollient cream is recommended for dry areas. For further information aboutprophylaxis for skin and nail reactions, see section 4.4. If the patient develops a Grade 1-2 skin or nailreaction, supportive care should be initiated; if there is no improvement after 2 weeks, dose reductionshould be considered for persistent Grade 2 rash (see Table 3). If the patient develops a Grade 3 skinor nail reaction, supportive care should be initiated, and interruption of Rybrevant should beconsidered until the adverse reaction improves. Upon recovery of the skin or nail reaction to≤ Grade 2, Rybrevant should be resumed at a reduced dose. If the patient develops Grade 4 skinreactions, permanently discontinue Rybrevant (see section 4.4).

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

Recommended concomitant medicinal products

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

Table 4: Dosing schedule of premedications

Recommendeddosing window

Route of prior to Rybrevant

Premedication Dose administration administration

* Diphenhydramine (25 to 50 mg) Intravenous 15 to 30 minutes

Antihistamineor equivalent Oral 30 to 60 minutes

* Paracetamol/Acetaminophen (650 Intravenous 15 to 30 minutes

Antipyreticto 1000 mg) Oral 30 to 60 minutes

Dexamethasone (20 mg) or

Glucocorticoid‡ Intravenous 60 to 120 minutesequivalent+ Dexamethasone (10 mg) or

Glucocorticoid Intravenous 45 to 60 minutesequivalent

* Required at all doses.

‡ Required at initial dose (Week 1, Day 1) or at the next subsequent dose in the event of an IRR.+ Required at second dose (Week 1, Day 2); optional for subsequent doses.

There is no relevant use of amivantamab in the paediatric population in the treatment of non-small celllung cancer.

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

No formal studies of amivantamab in patients with renal impairment have been conducted. Based onpopulation pharmacokinetic (PK) analyses, no dose adjustment is necessary for patients with mild ormoderate renal impairment. Caution is required in patients with severe renal impairment asamivantamab 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 recommendationsabove.

No formal studies of amivantamab in patients with hepatic impairment have been conducted. Based onpopulation 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 notbeen studied in this patient population (see section 5.2). If treatment is started, patients should bemonitored for adverse reactions with dose modifications per the recommendations above.

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

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

Infusion rates

Following dilution, the infusion should be administered intravenously at the infusion rates presented in

Table 5 or 6 below. Due to the frequency of IRRs at the first dose, amivantamab should be infused viaa peripheral vein at Week 1 and Week 2; infusion via a central line may be administered forsubsequent weeks when the risk of IRR is lower (see section 6.6). It is recommended for the first doseto be prepared as close to administration as possible to maximise the likelihood of completing theinfusion in the event of an IRR.

Table 5: Infusion rates for Rybrevant every 3 weeks

Body weight less than 80 kg

Week Dose Initial infusion Subsequent(per 250 mL bag) rate infusion rate†

Week 1 (split dose infusion)

Week 1 Day 1 350 mg 50 mL/hr 75 mL/hr

Week 1 Day 2 1050 mg 33 mL/hr 50 mL/hr

Week 2 1400 mg 65 mL/hr

Week 3 1400 mg 85 mL/hr

Week 4 1400 mg 125 mL/hr

Subsequent weeks* 1750 mg 125 mL/hr

Body weight greater than or equal to 80 kg

Week Dose Initial infusion Subsequent(per 250 mL bag) rate infusion rate†

Week 1 (split dose infusion)

Week 1 Day 1 350 mg 50 mL/hr 75 mL/hr

Week 1 Day 2 1400 mg 25 mL/hr 50 mL/hr

Week 2 1750 mg 65 mL/hr

Week 3 1750 mg 85 mL/hr

Week 4 1750 mg 125 mL/hr

Subsequent weeks* 2100 mg 125 mL/hr

* Starting at Week 7, patients are dosed every 3 weeks.† Increase the initial infusion rate to the subsequent infusion rate after 2 hours in the absence of infusion-relatedreactions.

Table 6: Infusion rates for Rybrevant every 2 weeks

Body weight less than 80 kg

Week Dose Initial infusion Subsequent(per 250 mL bag) rate infusion rate‡

Week 1 (split dose infusion)

Week 1 Day 1 350 mg 50 mL/hr 75 mL/hr

Week 1 Day 2 700 mg 50 mL/hr 75 mL/hr

Week 2 1050 mg 85 mL/hr

Subsequent weeks* 1050 mg 125 mL/hr

Body weight greater than or equal to 80 kg

Week Dose Initial infusion Subsequent(per 250 mL bag) rate infusion rate‡

Week 1 (split dose infusion)

Week 1 Day 1 350 mg 50 mL/hr 75 mL/hr

Week 1 Day 2 1050 mg 35 mL/hr 50 mL/hr

Week 2 1400 mg 65 mL/hr

Week 3 1400 mg 85 mL/hr

Subsequent weeks* 1400 mg 125 mL/hr

* After Week 5, patients are dosed every 2 weeks.‡ Increase the initial infusion rate to the subsequent infusion rate after 2 hours in the absence of IRRs.

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

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

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

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

Patients should be treated in a setting with appropriate medical support to treat IRRs. Infusions shouldbe interrupted at the first sign of IRRs of any severity and post-infusion medicinal products should beadministered as clinically indicated. Upon resolution of symptoms, the infusion should be resumed at50% of the previous rate. For recurrent Grade 3 or Grade 4 IRRs, Rybrevant should be permanentlydiscontinued (see section 4.2).

Interstitial lung disease (ILD) or ILD-like adverse reactions (e.g., pneumonitis) have been reported inpatients treated with amivantamab, including fatal events (see section 4.8). Patients should bemonitored for symptoms indicative of ILD/pneumonitis (e.g., dyspnoea, cough, fever). If symptomsdevelop, 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 beinitiated as necessary. Rybrevant should be permanently discontinued in patients with confirmed ILDor ILD-like adverse reactions (see section 4.2).

Venous thromboembolic (VTE) events with concomitant use with lazertinib

In patients receiving Rybrevant in combination with lazertinib, VTE events, including deep veinthrombosis (DVT) and pulmonary embolism (PE), including fatal events, were reported (seesection 4.8). Consistent with clinical guidelines, patients should receive prophylactic dosing of either adirect acting oral anticoagulant (DOAC) or 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 treatedwith anticoagulation as clinically indicated. For VTE events associated with clinical instabilitytreatment should be withheld until the patient is clinically stable. Thereafter, both drugs can beresumed at the same dose.

In the event of recurrence despite appropriate anticoagulation, Rybrevant should be discontinued.

Treatment can continue with lazertinib at the same dose (see section 4.2).

Skin and nail reactions

Rash (including dermatitis acneiform), pruritus and dry skin occurred in patients treated withamivantamab (see section 4.8). Patients should be instructed to limit sun exposure during and for2 months after Rybrevant therapy. Protective clothing and use of broad-spectrum UVA/UVBsunscreen are advisable. Alcohol-free emollient cream is recommended for dry areas. A prophylacticapproach to rash prevention should be considered. This includes prophylactic therapy with an oralantibiotic (e.g., doxycycline or minocycline, 100 mg twice daily) starting on Day 1 for the first12 weeks of treatment and after completion of oral antibiotic therapy, topical antibiotic lotion to thescalp (e.g., clindamycin 1%) for the next 9 months of treatment. Non-comedogenic skin moisturiser onthe face and whole body (except scalp) and chlorhexidine solution to wash hands and feet should beconsidered beginning on Day 1 and continued for the first 12 months of treatment.

Prescriptions for topical and/or oral antibiotics and topical corticosteroids are recommended to beavailable at the time of initial dosing to minimise any delay in reactive management should rashdevelop despite prophylactic treatment. If skin reactions develop, topical corticosteroids and topicaland/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 rashthat has an atypical appearance or distribution or lack improvement within 2 weeks should be referredpromptly to a dermatologist. Rybrevant should be dose reduced, interrupted, or permanentlydiscontinued based on severity (see section 4.2).

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

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 ophthalmologistand should discontinue use of contact lenses until symptoms are evaluated. For dose modifications for

Grade 3 or 4 eye disorders, see section 4.2.

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%) solutionfor infusion. This should be taken into consideration for patients on a controlled sodium diet (seesection 6.6).

Polysorbate content

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

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

Vaccines

No clinical data are available on the efficacy and safety of vaccinations in patients takingamivantamab. 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 aftercessation of amivantamab treatment.

There are no human data to assess the risk of amivantamab use during pregnancy. No animalreproductive 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 ofembryo-foetal development, embryo lethality, and abortion. Therefore, based on its mechanism ofaction and findings in animal models, amivantamab could cause foetal harm when administered to apregnant woman. Amivantamab should not be given during pregnancy unless the benefit of treatmentof the woman is considered to outweigh potential risks to the foetus. If the patient becomes pregnantwhile taking this medicinal product the patient should be informed of the potential risk to the foetus(see section 5.3).

It is unknown whether amivantamab is excreted in human milk. Human IgGs are known to be excretedin breast milk during the first few days after birth, which is decreasing to low concentrations soonafterwards. 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 notabsorbed. A decision must be made whether to discontinue breast-feeding or to discontinue/abstainfrom amivantamab therapy taking into account the benefit of breast-feeding for the child and thebenefit of therapy for the woman.

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

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

In the dataset of amivantamab as monotherapy (N=380), the most frequent adverse reactions in allgrades 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 ofpatients discontinued Rybrevant due to adverse reactions. The most frequent adverse reactions leadingto treatment discontinuation were IRR (1.1%), ILD (0.5%), and nail toxicity (0.5%).

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

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

Adverse reactions observed during clinical studies are listed below by frequency category. Frequencycategories 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 (frequencycannot be estimated from the available data).

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

Table 7: Adverse reactions in patients receiving amivantamab as monotherapy

System organ class Frequency Any Grade Grade 3-4

Adverse reaction category (%) (%)

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

Dizziness* Very common 13 0.3†

Visual impairment* Common 3 0

Growth of eyelashes* 1 0

Other eye disorders* 6 0

Keratitis Uncommon 0.5 0

Uveitis 0.3 0

Interstitial lung disease* Common 3 0.5†

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

Alanine aminotransferase increased Very common 15 2

Aspartate aminotransferase increased 13 1

Blood alkaline phosphatase increased 12 0.5†

Rash* Very common 76 3†

Nail toxicity* 47 2†

Dry skin* 19 0

Pruritus 18 0

Toxic epidermal necrolysis Uncommon 0.3 0.3†

Myalgia Very common 11 0.3†

Oedema* Very common 26 0.8†

Fatigue* 26 0.8†

Pyrexia 11 0

Infusion related reaction Very common 67 2

* Grouped terms† Grade 3 events only

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

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

The data reflects exposure to amivantamab in combination with carboplatin and pemetrexed in301 patients with locally advanced or metastatic non-small cell lung cancer. Patients receivedamivantamab 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 (forpatients ≥ 80 kg) every 3 weeks. The median exposure to amivantamab in combination withcarboplatin and pemetrexed was 7.7 months (range: 0.0 to 28.1 months).

Adverse reactions observed during clinical studies are listed below by frequency category. Frequencycategories 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 (frequencycannot be estimated from the available data).

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

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

System organ class Frequency Any Grade Grade 3-4

Adverse reaction category (%) (%)

Neutropenia Very common 57 39

Thrombocytopenia 40 12

Decreased appetite Very common 33 1.3

Hypoalbuminaemia* 32 3.7

Hypokalaemia 20 6.6

Hypomagnesaemia 13 1.3

Hypocalcaemia 12 1.0

Dizziness* Common 10 0.3

Venous thromboembolism* Very common 14 3.0

Other eye disorders* Common 7.3 0

Visual impairment* 3.0 0

Growth of eyelashes Uncommon 0.3 0

Keratitis 0.3 0

Uveitis 0.3 0

Interstitial lung disease* Common 2.3 1.7

Nausea Very common 43 1.0

Constipation 40 0.3

Stomatitis* 39 3.0

Vomiting 22 2.0

Diarrhoea 19 2.3

Abdominal pain* Common 11 0.3

Haemorrhoids 9.3 0.7

Alanine aminotransferase increased Very common 26 4.3

Aspartate aminotransferase increased 23 0.7

Blood alkaline phosphatase increased Common 10 0.3

Rash* Very common 83 14

Nail toxicity* 53 4.3

Dry skin* 16 0

Pruritus 10 0

Myalgia Common 5.0 0.7

Fatigue* Very common 43 4.7

Oedema* 40 1.3

Pyrexia 14 0

Infusion related reaction Very common 51 3.0

* Grouped terms

In the dataset of amivantamab in combination with lazertinib (N=421), the most frequent adversereactions in all grades were rash (89%), nail toxicity (71%), infusion-related reactions (63%),hypoalbuminaemia (48%), hepatotoxicity (47%), oedema (47%), stomatitis (43%), venousthromboembolism (37%), paraesthesia (lazertinib) (34%), fatigue (32%), diarrhoea (29%),constipation (29%), dry skin (26%), pruritis (24%), decreased appetite (24%), hypocalcaemia (21%),nausea (21%) and other eye disorders (21%). The most frequent serious adverse reactions includedvenous thromboembolism (11%), pneumonia (4.0%), rash (3.1%), ILD/pneumonitis (2.9%),hepatotoxicity (2.4%), COVID-19 (2.4%), and IRR and pleural effusion (2.1%). Twenty-three percentof patients discontinued Rybrevant due to adverse reactions. The most frequent adverse reactionsleading to Rybrevant discontinuation were rash (5.5%), infusion related reactions (4.5%), nail toxicity(3.6%), ILD (2.9%) and VTE (2.9%).

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

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

Adverse reactions observed during clinical studies are listed below by frequency category. Frequencycategories 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 (frequencycannot be estimated from the available data).

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

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

System organ class Frequency Any Grade Grade 3-4

Adverse reaction category (%) (%)

Hypoalbuminaemia* Very common 48 5

Decreased appetite 24 1.0

Hypocalcaemia 21 2.1

Hypokalaemia 14 3.1

Hypomagnesaemia Common 5.0 0

Paraesthesia*‡ Very common 34 1.7

Dizziness* 13 0

Venous thromboembolism* Very common 37 11

Other eye disorders* Very common 21 0.5

Visual impairment* Common 4.5 0

Keratitis 2.6 0.5

Growth of eyelashes* 1.9 0

Interstitial lung disease/Pneumonitis * Common 3.1 1.2

Stomatitis* Very common 43 2.4

Diarrhoea 29 2.1

Constipation 29 0

Nausea 21 1.2

Vomiting 12 0.5

Abdominal pain* 11 0

Haemorrhoids Common 10 0.2

Hepatotoxicity† Very common 47 9

Rash* Very common 89 27

Nail toxicity* 71 11

Dry skin* 26 1.0

Pruritus 24 0.5

Palmar-plantar erythrodysaesthesia Common 6 0.2syndrome

Urticaria 1.2 0

Muscle spasms Very common 17 0.5

Myalgia 13 0.7

Oedema* Very common 47 2.9

Fatigue* 32 3.8

Pyrexia 12 0

Infusion related reaction Very common 63 6

* Grouped terms‡ Assessed as ADR for lazertinib only.† The most common events included increased ALT (36%), increased AST (29%) and increase blood alkalinephosphatase (12%).

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

In patients treated with amivantamab in combination with carboplatin and pemetrexed,infusion-related reactions occurred in 50% of patients. Greater than 94% of IRRs were Grade 1-2. Amajority of IRRs occurred at the first infusion with a median time to onset of 60 minutes (range0-7 hours), and the majority occurring within 2 hours of infusion start. Occasionally an IRR can occurat re-initiation of amivantamab after prolonged dose interruptions of more than 6 weeks.

In patients treated with amivantamab in combination with lazertinib, infusion-related reactionsoccurred in 63% of patients. Ninety-four percent of IRRs were Grade 1-2. A majority of IRRsoccurred at the first infusion with a median time to onset of 1 hour, and the majority occurring within2 hours of infusion start. The most frequent signs and symptoms include chills, dyspnoea, nausea,flushing, chest discomfort, and vomiting (see section 4.4)

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

Interstitial lung disease or ILD-like adverse reactions have been reported with the use of amivantamabas well as with other EGFR inhibitors. Interstitial lung disease or pneumonitis was reported in 2.6% ofpatients treated with amivantamab monotherapy, 2.3 % of patients treated with amivantamab incombination with carboplatin and pemetrexed and 3.1% of patients treated with amivantamab incombination with lazertinib, including 1 (0.2%) fatal case. Patients with a medical history of ILD,drug-induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinicallyactive ILD were excluded from the clinical study (see section 4.4).

Venous thromboembolic (VTE) events with concomitant use with lazertinib

When Rybrevant is used in combination with lazertinib, VTE events, including deep venousthrombosis (DVT) and pulmonary embolism (PE), were reported in 37% of the 421 patients receiving

Rybrevant in combination with lazertinib. Most cases were Grade 1 or 2, with Grade 3-4 eventsoccurring in 11% of patients receiving Rybrevant in combination with lazertinib and deaths occurringin 0.5% of patients receiving Rybrevant in combination with lazertinib. For information onprophylactic anticoagulants and management of VTE events, see sections 4.2 and 4.4.

In patients receiving Rybrevant in combination with lazertinib, the median time to first onset of a VTEevent was 84 days. VTE events led to Rybrevant treatment discontinuation in 2.9% of patients.

Skin and nail reactions

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

Rash (including dermatitis acneiform), occurred in 83% of patients treated with amivantamab incombination with carboplatin and pemetrexed. Most cases were Grade 1 or 2, with Grade 3 rash eventsoccurring in 14% of patients. Rash leading to amivantamab discontinuation occurred in 2.3% ofpatients. Rash usually developed within the first 4 weeks of therapy, with a median time to onset of14 days. Nail toxicity occurred in patients treated with amivantamab in combination with carboplatinand pemetrexed. Most events were Grade 1 or 2, with Grade 3 nail toxicity occurring in 4.3% ofpatients (see section 4.4).

Rash (including dermatitis acneiform), occurred in 89% of patients treated with amivantamab incombination with lazertinib. Most cases were Grade 1 or 2, with Grade 3 rash events occurring in 27%of patients. Rash leading to amivantamab discontinuation occurred in 5.5% of patients. Rash usuallydeveloped within the first 4 weeks of therapy, with a median time to onset of 14 days. Nail toxicityoccurred in patients treated with amivantamab in combination with lazertinib. Most events were

Grade 1 or 2, with Grade 3 nail toxicity occurring in 11% of patients (see section 4.4).

Eye disorders, including keratitis (0.5%), occurred in 9% of patients treated with amivantamab alone.

Other reported adverse reactions included growth of eyelashes, visual impairment, and other eyedisorders. All events were Grade 1-2.

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

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

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.

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No maximum tolerated dose has been determined in a clinical study in which patients received up to2100 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 bemonitored for any signs or symptoms of adverse events and appropriate general supportive measuresshould be instituted immediately until clinical toxicity has diminished or resolved.

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

L01FX18.

Amivantamab is a low-fucose, fully-human IgG1-based EGFR-MET bispecific antibody with immunecell-directing activity that targets tumours with activating EGFR mutations such as Exon 19 deletions,

Exon 21 L858R substitution, and Exon 20 insertion mutations. Amivantamab binds to the extracellulardomains of EGFR and MET.

Amivantamab disrupts EGFR and MET signalling functions through blocking ligand binding andenhancing degradation of EGFR and MET, thereby preventing tumour growth and progression. Thepresence of EGFR and MET on the surface of tumour cells also allows for targeting of these cells fordestruction by immune effector cells, such as natural killer cells and macrophages, throughantibody-dependent cellular cytotoxicity (ADCC) and trogocytosis mechanisms, respectively.

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 theremainder of amivantamab treatment.

Previously-untreated NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations(MARIPOSA)

NSC3003 (MARIPOSA) is a randomised, open-label, active-controlled, multicenter phase 3 studyassessing the efficacy and safety of Rybrevant in combination with lazertinib as compared toosimertinib monotherapy as first-line treatment in patients with EGFR-mutated locally advanced ormetastatic NSCLC not amenable to curative therapy. Patient samples were required to have one of thetwo common EGFR mutations (Exon 19 deletion or Exon 21 L858R substitution mutation), asidentified by local testing. Tumour tissue (94%) and/or plasma (6%) samples for all patients weretested locally to determine EGFR Exon 19 deletion and/or Exon 21 L858R substitution mutation statususing polymerase chain reaction (PCR) in 65% and next generation sequencing (NGS) in 35% ofpatients.

A total of 1074 patients were randomised (2:2:1) to receive Rybrevant in combination with lazertinib,osimertinib monotherapy, or lazertinib monotherapy until disease progression or unacceptable toxicity.

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 thereafter starting at week 5. Lazertinib wasadministered at 240 mg orally once daily. Osimertinib was administered at a dose of 80 mg orally oncedaily. Randomisation was stratified by EGFR mutation type (Exon 19 deletion or Exon 21 L858R),race (Asian or non-Asian), and history of brain metastasis (yes or no).

Baseline demographics and disease characteristics were balanced across the treatment arms. Themedian age was 63 (range: 25-88) years with 45% of patients ≥ 65 years; 62% were female; and 59%were Asian, and 38% were White. Baseline Eastern Cooperative Oncology Group (ECOG)performance status was 0 (34%) or 1 (66%); 69% never smoked; 41% had prior brain metastases; and90% had Stage IV cancer at initial diagnosis. With regard to EGFR mutation status, 60% were

Exon 19 deletions and 40% were Exon 21 L858R substitution mutations.

Rybrevant in combination with lazertinib demonstrated a statistically significant improvement inprogression-free survival (PFS) by BICR assessment.

With a median follow up of approximately 31 months, the updated OS HR was 0.77; (95% CI: 0.61,0.96; p=0.0185). This was not statistically significant as compared to a 2-sided significance level of0.00001.

Table 10: Efficacy results in MARIPOSA

Rybrevant + lazertinib Osimertinib(N=429) (N=429)

Progression-free survival (PFS)a

Number of events 192 (45%) 252 (59%)

Median, months (95% CI) 23.7 (19.1, 27.7) 16.6 (14.8, 18.5)

Hazard Ratio (95% CI); p-value 0.70 (0.58, 0.85); p=0.0002

Overall survival (OS)

Number of events 142 (33%) 177 (41%)

Median, months (95% CI) NE (NE, NE) 37.3 (32.5, NE)

Hazard Ratio (95% CI); p-valueb 0.77 (0.61, 0.96); p=0.0185

Objective response rate (ORR)a,c

ORR % (95% CI) 80% (76%, 84%) 77% (72%, 81%)

Duration of response (DOR)a,c

Median (95% CI), months 25.8 (20.3, 33.9) 18.1 (14.8, 20.1)

BICR = blinded independent central review; CI = confidence interval; NE = not estimable

PFS results are from data cut-off 11 August 2023 with a median follow-up of 22.0 months. OS, DOR and ORR results arefrom data cut-off 13 May 2024 with a median follow-up of 31.3 months.a BICR by RECIST v1.1.b The p-value is compared to a 2-sided significance level of 0.00001. Thus the OS results are not statistically significantas of the latest interim analysis.c Based on confirmed responders.

Figure 1: Kaplan-Meier curve of PFS in previously untreated NSCLC patients by BICRassessment

Figure 2: Kaplan-Meier curve of OS in previously untreated NSCLC patients

Intracranial ORR and DOR by BICR were pre-specified endpoints in MARIPOSA. In the subset ofpatients with intracranial lesions at baseline, the combination of Rybrevant and lazertinib,demonstrated similar intracranial ORR to the control. Per protocol, all patients in MARIPOSA hadserial brain MRIs to assess intracranial response and duration. Results are summarised in Table 11.

Table 11: Intracranial ORR and DOR by BICR assessment in subjects with intracraniallesions at baseline - MARIPOSA

Rybrevant + lazertinib Osimertinib(N=180) (N=186)

Intracranial Tumour Response Assessment

Intracranial ORR (CR+PR), % 77% 77%(95% CI) (70%, 83%) (70%, 82%)

Complete response 63% 59%

Intracranial DOR

Number of responders 139 144

Median, months (95% CI) NE (21.4, NE) 24.4 (22.1, 31.2)

CI = confidence interval

NE = not estimable

Intracranial ORR and DOR results are from data cut-off 13 May 2024 with a median follow-up of 31.3 months.

Previously treated NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations(MARIPOSA-2)

MARIPOSA-2 is a randomised (2:2:1) open-label, multicentre Phase 3 study in patients with locallyadvanced or metastatic NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitutionmutations (mutation testing could have been performed at or after the time of locally advanced ormetastatic disease diagnosis. Testing did not need to be repeated at the time of study entry once EGFRmutation status was previously established) after failure of prior therapy including a third-generation

EGFR tyrosine kinase inhibitor (TKI). A total of 657 patients were randomised in the study, of which263 received carboplatin and pemetrexed (CP); and 131 which received Rybrevant in combinationwith carboplatin and pemetrexed (Rybrevant-CP). Additionally, 263 patients were randomised toreceive Rybrevant in combination with lazertinib, carboplatin, and pemetrexed in a separate arm of thestudy. Rybrevant was administered intravenously at 1400 mg (for patients < 80 kg) or 1750 mg (forpatients ≥ 80 kg) once weekly through 4 weeks, then every 3 weeks with a dose of 1750 mg (forpatients < 80 kg) or 2100 mg (for patients ≥ 80 kg) starting at Week 7 until disease progression orunacceptable toxicity. Carboplatin was administered intravenously at area under theconcentration-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 diseaseprogression or unacceptable toxicity.

Patients were stratified by osimertinib line of therapy (first-line or second-line), prior brain metastases(yes or no), and Asian race (yes or no).

Of the 394 patients randomised to the Rybrevant-CP arm or CP arm, the median age was 62 (range:31-85) years, with 38% of the patients ≥ 65 years of age; 60% were female; and 48% were Asian and46% were White. Baseline Eastern Cooperative Oncology Group (ECOG) performance status was 0(40%) or 1 (60%); 66% never smoked; 45% had history of brain metastasis, and 92% had Stage IVcancer at initial diagnosis.

Rybrevant in combination with carboplatin and pemetrexed demonstrated a statistically significantimprovement in progression-free survival (PFS) compared to carboplatin and pemetrexed, with a HRof 0.48 (95% CI: 0.36, 0.64; p<0.0001). At the time of the second interim analysis for OS, with amedian follow-up of approximately 18.6 months for Rybrevant-CP and approximately 17.8 months for

CP, the OS HR was 0.73 (95%CI: 0.54, 0.99; p=0.0386). This was not statistically significant (testedat a prespecified significance level of 0.0142).

Efficacy results are summarised in Table 12.

Table 12: Efficacy results in MARIPOSA-2

Rybrevant+carboplatin+ carboplatin+pemetrexed pemetrexed(N=131) (N=263)

Progression-free survival (PFS)a

Number of events (%) 74 (57) 171 (65)

Median, months (95% CI) 6.3 (5.6, 8.4) 4.2 (4.0, pct. 4.4)

HR (95% CI); p-value 0.48 (0.36, 0.64); p<0.0001

Overall survival (OS)

Number of events (%) 65 (50) 143 (54)

Median, months (95% CI) 17.7 (16.0, 22.4) 15.3 (13.7, 16.8)

HR (95% CI); p-valueb 0.73 (0.54, 0.99); p=0.0386

Objective response ratea

ORR, % (95% CI) 64% (55%, 72%) 36% (30%, 42%)

Odds Ratio (95% CI); p-value 3.10 (2.00, pct. 4.80); p<0.0001

Duration of response (DOR) a

Median (95% CI), months 6.90 (5.52, NE) 5.55 (4.17, 9.56)

Patients with DOR ≥ 6 months 31.9% 20.0%

CI = Confidence Interval

NE = not estimable

PFS, DOR and ORR results are from data cut-off 10 July-2023 when hypothesis testing and final analysis for theseendpoints was performed. OS results are from data cut-off 26 April 2024 from the second interim OS analysis.a BICR-assessedb The p-value is compared to a 2-sided significance level of 0.0142. Thus the OS results are not significant as of thesecond interim analysis.

Figure 3: Kaplan-Meier curve of PFS in previously treated NSCLC patients by BICRassessment

The PFS benefit of Rybrevant-CP compared to CP was consistent across all the predefined subgroupsanalysed, including ethnicity, age, gender, smoking history, and CNS metastases status at study entry.

Figure 4: Kaplan-Meier curve of OS in previously treated NSCLC patients

Intracranial metastases efficacy data

Patients with asymptomatic or previously treated and stable intracranial metastases were eligible to berandomised in MARIPOSA-2. Treatment with Rybrevant-CP was associated with a numeric increasein intracranial ORR (23.3% for Rybrevant-CP versus 16.7% for CP, odds ratio of 1.52; 95% CI (0.51,4.50), and intracranial DOR (13.3 months; 95% CI (1.4, NE) in the Rybrevant-CP arm compared with2.2 months; 95% CI (1.4, NE) in the CP arm). The median follow-up for Rybrevant-CP wasapproximately 18.6 months.

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 andpemetrexed) in patients with treatment-naïve, locally advanced or metastatic NSCLC with activating

EGFR Exon 20 insertion mutations. Tumour tissue (92.2%) and/or plasma (7.8%) samples for all308 patients were tested locally to determine EGFR Exon 20 insertion mutation status using nextgeneration 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 definitivelytreated, clinically stable, asymptomatic, and off corticosteroid treatment for at least 2 weeks prior torandomisation.

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 orunacceptable 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 wasadministered intravenously at 500 mg/m2 on once every 3 weeks until disease progression orunacceptable toxicity. Randomisation was stratified by ECOG performance status (0 or 1), and priorbrain metastases (yes or no). Patients randomised to the carboplatin and pemetrexed arm who hadconfirmed 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 andpemetrexed (N=153) or carboplatin and pemetrexed (N=155). The median age was 62 (range: 27 to92) years, with 39% of the subjects ≥ 65 years of age; 58% were female; and 61% were Asian and36% 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 IVcancer at initial diagnosis.

The primary endpoint for PAPILLON was PFS, as assessed by BICR. The median follow-up was14.9months (range: 0.3 to 27.0).

Efficacy results are summarised in Table 13.

Table 13: Efficacy results in PAPILLON

Rybrevant +carboplatin+ carboplatin+pemetrexed pemetrexed(N=153) (N=155)

Progression-free survival (PFS) a

Number of events 84 (55%) 132 (85%)

Median, months (95% CI) 11.4 (9.8, 13.7) 6.7 (5.6, 7.3)

HR (95% CI); p-value 0.395 (0.29, 0.52); p<0.0001

Objective response ratea, b

ORR, % (95% CI) 73% (65%, 80%) 47% (39%, 56%)

Odds ratio (95% CI); p-value 3.0 (1.8, pct. 4.8); p<0.0001

Complete response 3.9% 0.7%

Partial response 69% 47%

Overall survival (OS)c

Number of events 40 52

Median OS, months (95% CI) NE (28.3, NE) 28.6 (24.4, NE)

HR (95% CI); p-value 0.756 (0.50, 1.14); p=0.1825

CI = confidence interval

NE = not estimablea Blinded Independent Central Review by RECIST v1.1b Based on Kaplan-Meier estimate.c Based on the results of an updated OS with median follow-up of 20.9 months. The OS analysis was not adjusted forthe potentially confounding effects of crossover (78 [50.3%] patients on the carboplatin + pemetrexed arm whoreceived subsequent Rybrevant monotherapy treatment).

Figure 5: Kaplan-Meier curve of PFS in previously untreated NSCLC patients by BICRassessment

The PFS benefit of Rybrevant in combination with carboplatin and pemetrexed compared tocarboplatin and pemetrexed was consistent across all the predefined subgroups of brain metastases atstudy 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 6: Kaplan-Meier curve of OS in previously untreated NSCLC patients by BICRassessment

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 andefficacy of Rybrevant in patients with locally advanced or metastatic NSCLC. Efficacy was evaluatedin 114 patients with locally advanced or metastatic NSCLC who had EGFR Exon 20 insertionmutations, whose disease had progressed on or after platinum-based chemotherapy, and who had amedian follow-up of 12.5 months. Tumour tissue (93%) and/or plasma (10%) samples for all patientswere tested locally to determine EGFR Exon 20 insertion mutation status using next generationsequencing (NGS) in 46% of patients and/or polymerase chain reaction (PCR) in 41% of patients; for4% of patients, the testing methods were not specified. Patients with untreated brain metastases or ahistory of ILD requiring treatment with prolonged steroids or other immunosuppressive agents withinthe last 2 years were not eligible for the study. Rybrevant was administered intravenously at 1050 mgfor patients < 80 kg or 1400 mg for patients ≥ 80 kg once weekly for 4 weeks, then every 2 weeksstarting at Week 5 until loss of clinical benefit or unacceptable toxicity. The primary efficacy endpointwas 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 ablinded independent central review (BICR). Secondary efficacy endpoints included duration ofresponse (DOR).

The median age was 62 (range: 36-84) years, with 41% of the patients ≥ 65 years of age; 61% werefemale; 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 wereobserved at 8 different residues; the most common residues were A767 (22%), S768 (16%), D770(12%), and N771 (11%).

Efficacy results are summarised in Table 14.

Table 14: Efficacy results in CHRYSALIS

Investigator assessment(N=114)

Overall response ratea, b (95% CI) 37% (28%, 46%)

Complete response 0%

Partial response 37%

Duration of response

Medianc (95% CI), months 12.5 (6.5, 16.1)

Patients with DOR ≥ 6 months 64%

CI = Confidence Intervala Confirmed responseb 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 was10.8 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.

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

The European Medicines Agency 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 forinformation on paediatric use).

Based on Rybrevant monotherapy data, amivantamab area under the concentration-time curve(AUC1 week) increases proportionally over a dose range from 350 to 1750 mg.

Based on simulations from the population pharmacokinetic model, AUC1 week was approximately2.8-fold higher after the fifth dose for the 2-week dosing regimen and 2.6-fold higher after the fourthdose 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.

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

Based on the individual amivantamab PK parameter estimates in population PK analysis, thegeometric mean (CV%) linear clearance (CL) and terminal half-life associated with linear clearance is0.266 (30.4%) L/day and 13.7 (31.9%) days respectively.

No clinically meaningful differences in the pharmacokinetics of amivantamab were observed based onage (21-88 years).

No clinically meaningful effect on the pharmacokinetics of amivantamab was observed in patientswith mild (60 ≤ creatinine clearance [CrCl] < 90 mL/min), moderate (29 ≤ CrCl < 60 mL/min) orsevere (15 ≤ CrCl < 29 mL/min) renal impairment. Data in patients with severe renal impairment arelimited (n=1), but there is no evidence to suggest that dose adjustment is required in these patients.

The effect of end-stage renal disease (CrCl < 15 mL/min) on amivantamab pharmacokinetics isunknown.

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[(total bilirubin ≤ ULN and AST > ULN) or (ULN < total bilirubin ≤ 1.5 x ULN)] or moderate(1.5×ULN < total bilirubin ≤ 3×ULN and any AST) hepatic impairment. Data in patients withmoderate hepatic impairment are limited (n=1), but there is no evidence to suggest that doseadjustment is required in these patients. The effect of severe (total bilirubin > 3 times ULN) hepaticimpairment on amivantamab pharmacokinetics is unknown.

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 dosetoxicity.

No animal studies have been performed to establish the carcinogenic potential of amivantamab.

Routine genotoxicity and carcinogenicity studies are generally not applicable to biologicpharmaceuticals as large proteins cannot diffuse into cells and cannot interact with DNA orchromosomal material.

No animal studies have been conducted to evaluate the effects on reproduction and foetaldevelopment; however, based on its mechanism of action, amivantamab can cause foetal harm ordevelopmental anomalies. As reported in the literature, reduction, elimination, or disruption of embryofoetal or maternal EGFR signaling can prevent implantation, cause embryo foetal loss during variousstages of gestation (through effects on placental development), cause developmental anomalies inmultiple organs or early death in surviving foetuses. Similarly, knock out of MET or its ligandhepatocyte 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 tocross the placenta; therefore, amivantamab has the potential to be transmitted from the mother to thedeveloping foetus.

Ethylenediaminetetraacetic acid (EDTA) disodium salt dihydrate

L-Histidine

L-Histidine hydrochloride monohydrate

L-Methionine

Polysorbate 80 (E433)

Sucrose

Water for injections

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

Unopened vial3 years

Chemical and physical in-use stability has been demonstrated for 10 hours at 15°C to 25°C in roomlight. From a microbiological point of view, unless the method of dilution precludes the risk ofmicrobial contamination, the product should be used immediately. If not used immediately, in-usestorage 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-offcap containing 350 mg amivantamab. Pack size of 1 vial.

Prepare the solution for intravenous infusion using aseptic technique as follows:

- Determine the dose required and the number of Rybrevant vials needed based on patient’sbaseline weight (see section 4.2). Each vial contains 350 mg of amivantamab.

- For every 2-week dosing, patients < 80 kg receive 1050 mg and for patients ≥ 80 kg, 1400 mgonce 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 weeklyfor 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 orvisible 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 volumeof 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 vialcontains a 0.5 mL overfill to ensure sufficient extractable volume. The final volume in theinfusion 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 ifdiscolouration or visible particles are observed.

- Administer the diluted solution by intravenous infusion using an infusion set fitted with a flowregulator 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 eitherpolyurethane (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 roomtemperature (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 peripheralvein at Week 1 and Week 2; infusion via a central line may be administered for subsequentweeks when the risk of IRR is lower. See infusion rates in section 4.2.

This medicinal product is for single use only and any unused medicinal product that is notadministered within 10 hours should be disposed of in accordance with local requirements.

Janssen-Cilag International NV

Turnhoutseweg 30

B-2340 Beerse

Belgium

EU/1/21/1594/001

Date of first authorisation: 09 December 2021

Date of latest renewal: 11 September 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.