CHMP recommends Janssen's RYBREVANT, LAZCLUZE combination for first-line treatment of EGFR-mutated advanced non-small cell lung cancer; treatment reduced risk of disease progression or death by 30 percent compared to osimertinib in Phase 3 MARIPOSA study

BEERSE, BELGIUM (15 November 2024) – Janssen-Cilag International NV, a Johnson & Johnson company, today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended the Marketing Authorisation (MA)for LAZCLUZE^®▼ (lazertinib), in combination with RYBREVANT^®▼ (amivantamab), for the first-line treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions (ex19del) or exon 21 L858R (L858R) substitution mutations.² The CHMP has simultaneously recommended approval of a Type II extension of indication for amivantamab in the same combination regimen.²

“Lung cancer remains the leading cause of cancer-related deaths globally, and patients with EGFR-mutated advanced non-small-cell lung cancer are in need of new targeted treatment options,” said Henar Hevia, Ph.D., Senior Director, EMEA Therapeutic Area Lead, Oncology, Johnson & Johnson Innovative Medicine. “Pending European Commission approval, the combination of amivantamab with lazertinib could establish a new first-line standard of care, with the potential to significantly delay disease progression and improve outcomes early in the treatment pathway while reserving chemotherapy regimens for later stages of treatment when resistance becomes more complex.”

The CHMP positive opinions for the MA and Type II extension of indication are supported by data from the Phase 3 MARIPOSA (NCT04487080) study, evaluating amivantamab in combination with lazertinib compared to osimertinib as first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR ex19del or exon 21 L858R substitution mutations.¹ The study met its primary endpoint, and at median follow-up of 22 months, reduced the risk of disease progression or death by 30 percent compared to osimertinib (median progression-free survival [PFS]: 23.7 months compared to 16.6 months for osimertinib; hazard ratio [HR]=0.70; 95 percent confidence Interval [CI], 0.58–0.85; P<0.001) as assessed by blinded independent central review (BICR).¹ The median duration of response (DOR) was significantly longer for patients receiving amivantamab plus lazertinib compared to osimertinib, with a nine-month improvement in median DOR (25.8 vs. 16.8 months).¹

Results from the MARIPOSA study were featured during a Presidential Symposium session at the 2023 European Society of Medical Oncology (ESMO) Congress, with longer-term follow-up data presented at the International Association for the Study of Lung Cancer (IASLC) 2024 World Conference on Lung Cancer (WCLC).^1,3

The MARIPOSA study required all patients to have serial brain imaging with magnetic resonance imaging (MRI) in order to detect or monitor brain metastases, a measure not implemented in most prior studies for EGFR-mutated NSCLC.¹ The primary endpoint of PFS in MARIPOSA included these central nervous system (CNS) events detected by serial brain MRIs.¹ The median PFS when censoring CNS-only first progressions was 27.5 months for the combination of amivantamab and lazertinib, compared to 18.4 months for osimertinib (HR=0.68; 95 percent CI, 0.55–0.83; P<0.001**).^1,4

Longer-term follow-up data shows a strong favourable overall survival trend for amivantamab plus lazertinib versus osimertinib.³ At three years (median follow-up of 31.1 months), 61 percent of patients receiving amivantamab plus lazertinib were alive compared to 53 percent of those treated with osimertinib based on an analysis performed at the request of health authorities*** (Median OS not estimable [NE] vs 37.3 months; HR=0.77; 95 percent CI, 0.61-0.96; nominal P=0.019).³

The safety profile of the combination of amivantamab and lazertinib was consistent with previous reports from Phase 1-2 studies, with mostly Grade 1 or 2 adverse events (AEs).¹ Toxicity was largely manageable with dose interruptions and reductions, along with supportive care measures commonly used in the treatment of patients with NSCLC.¹ The most common treatment emergent adverse events (TEAEs) of any grade were paronychia (68 percent), infusion-related reactions (63 percent), and rash (62 percent).¹ Amivantamab plus lazertinib had higher rates of EGFR- and MET-related AEs and venous thromboembolism compared to osimertinib, except diarrhoea, for which rates were higher for osimertinib.¹ The commonest grade 3 or higher TEAEs were rash (15 percent), paronychia (11 percent) and dermatitis acneiform (8 percent).¹ The rate of discontinuation of all study treatments due to treatment-related AEs for the amivantamab combination was 10 percent.¹ The rate of interstitial lung disease (including pneumonitis) was less than three percent in both arms.¹

“These CHMP positive opinions mark a pivotal step in our mission to deliver transformative first-line therapies for people living with EGFR-mutated NSCLC,” said Kiran Patel, M.D., Vice President, Clinical Development, Solid Tumours, Johnson & Johnson Innovative Medicine. “Based on the growing body of promising results we’ve seen to date and our ongoing clinical development programme, we believe amivantamab has the potential to become a foundational therapy for EGFR- and MET-driven NSCLC.”

About the MARIPOSA Study
MARIPOSA (NCT04487080), which enrolled 1,074 patients, is a randomised, Phase 3 study evaluating amivantamab in combination with lazertinib versus osimertinib and versus lazertinib alone in first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR ex19del or exon 21 L858R substitution mutations.¹ The primary endpoint of the study is PFS (using RECIST v1.1 guidelines^‡) as assessed by BICR.¹ Secondary endpoints include overall survival (OS), overall response rate (ORR), duration of response (DOR), second progression free survival (PFS2) and intracranial PFS.¹

The MARIPOSA study required all patients to have serial brain imaging with MRIs in order to detect or monitor brain metastases, a measure not implemented in most prior studies for EGFR-mutated NSCLC.¹ The primary endpoint of PFS in MARIPOSA included these central nervous system (CNS) events detected by serial brain MRIs.¹ Extracranial PFS, which may more closely approximate what would be seen in other trials, was also explored in MARIPOSA.¹

About Amivantamab
Amivantamab is a fully-human EGFR-MET bispecific antibody that acts by targeting tumours with activating and resistance EGFR mutations and MET mutations and amplifications, and by harnessing the immune system.^5,6,7,8

The European Commission (EC) has granted marketing authorisation of amivantamab in the following indications:⁹
· In combination in with carboplatin and pemetrexed, for the treatment of adult patients with advanced NSCLC with EGFR exon 19 deletions or 21 L858R substitution mutations, after failure of prior therapy including an EGFR TKI
· As monotherapy, for treatment of adult patients with advanced NSCLC with activating EGFR exon 20 insertion mutations, after failure of platinum-based therapy
· In combination with carboplatin and pemetrexed, for the first-line treatment of adult patients with advanced NSCLC with activating EGFR exon 20 insertion mutations

In February 2024, a Type II extension of indication application was submitted to the EMA based on the MARIPOSA study, for amivantamab in combination with lazertinib for the first-line treatment of adult patients with advanced NSCLC withEGFR ex19del or L858R substitution mutations.¹⁰ In May 2024, an application for the extension of the amivantamab marketing authorisation was submitted seeking approval for the use of a subcutaneous (SC) formulation of amivantamab in combination with lazertinib for the first-line treatment of adult patients with advanced NSCLC with EGFR ex19del or L858R mutations, and for the use of SC amivantamab monotherapy in adult patients with advanced NSCLC with activating EGFR exon 20 insertion mutations after failure of platinum-based therapy.¹¹

For a full list of adverse events and information on dosage and administration, contraindications and other precautions when using amivantamab, please refer to the Summary of Product CharacteristicsANNEX I SUMMARY OF PRODUCT CHARACTERISTICS 1 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 1. NAME OF THE MEDICINAL PRODUCT Rybrevant 350 mg concentrate for solution for infusion. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION 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 against the epidermal growth factor (EGF) and mesenchymal-epidermal transition (MET) receptors, produced by a mammalian cell line (Chinese Hamster Ovary [CHO]) using recombinant DNA technology. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Concentrate for solution for infusion. The solution is colourless to pale yellow, with a pH of 5.7 and an osmolality of approximately 310 mOsm/kg. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Rybrevant is indicated:  in combination with carboplatin and pemetrexed for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations after failure of prior therapy including an EGFR tyrosine kinase inhibitor (TKI).  in combination with carboplatin and pemetrexed for the first-line treatment of adult patients with advanced NSCLC with activating EGFR Exon 20 insertion mutations.  as monotherapy for treatment of adult patients with advanced NSCLC with activating EGFR Exon 20 insertion mutations, after failure of platinum-based therapy. 4.2 Posology and method of administration Treatment with Rybrevant should be initiated and supervised by a physician experienced in the use of anticancer medicinal products. Rybrevant should be administered by a healthcare professional with access to appropriate medical support to manage infusion-related reactions (IRRs) if they occur. Before initiation of Rybrevant therapy, EGFR mutation status in tumour tissue or plasma specimens must be established using a validated test method. If no mutation is detected in a plasma specimen, tumour tissue should be tested if available in sufficient amount and quality due to the potential for false negative results using a plasma-test. Testing may be performed at any time from initial diagnosis 2 until the initiation of therapy; testing does not need to be repeated once EGFR mutation status has been established (see section 5.1). Posology Premedications should be administered to reduce the risk of IRRs with Rybrevant (see below “Dose modifications” and “Recommended concomitant medicinal products”). 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 of baselinea 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 1 1750 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 5 equal to 80 kg  Week 1 - split infusion on Day 1 and Day 2  Weeks 2 to 4 - infusion on Day 1 2100 mg Every 3 weeks starting at Week 7 onwards 6 a Dose adjustments not required for subsequent body weight changes. When used in combination with carboplatin and pemetrexed, Rybrevant should be administered after carboplatin and pemetrexed in the following order: pemetrexed, carboplatin and then Rybrevant. See section 5.1 and the manufacturer’s prescribing information for dosing instructions for carboplatin and pemetrexed. Every 2 weeks The recommended dosages of Rybrevant monotherapy 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 of baselinea dose vials Less than 80 kg Weekly (total of 4 doses) from weeks 1 to 4  Week 1 - split infusion on Day 1 and Day 2 1050 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 4 equal to 80 kg  Week 1 - split infusion on Day 1 and Day 2 1400 mg 4  Weeks 2 to 4 - infusion on Day 1 Every 2 weeks starting at Week 5 onwards a Dose adjustments not required for subsequent body weight changes. Duration of treatment It is recommended that patients are treated with Rybrevant until disease progression or unacceptable toxicity. Missed dose If a planned dose is missed, the dose should be administered as soon as possible and the dosing schedule should be adjusted accordingly, maintaining the treatment interval. 3 Dose modifications Dosing should be interrupted for Grade 3 or 4 adverse reactions until the adverse reaction resolves to ≤ Grade 1 or baseline. If an interruption is 7 days or less, restart at the current dose. If an interruption is longer than 7 days, it is recommended restarting at a reduced dose as presented in Table 3. See also specific dose modifications for specific adverse reactions below Table 3. Table 3: Recommended dose modifications for adverse reactions Dose at which the Dose after 1st Dose after 2nd Dose after 3rd adverse reaction interruption for interruption for interruption for occurred adverse reaction adverse reaction adverse reaction 1050 mg 700 mg 350 mg 1400 mg 1050 mg 700 mg Discontinue Rybrevant 1750 mg 1400 mg 1050 mg 2100 mg 1750 mg 1400 mg Infusion-related reactions Infusion should be interrupted at the first sign of IRRs. Additional supportive medicinal products (e.g., additional glucocorticoids, antihistamine, antipyretics and antiemetics) should be administered as clinically indicated (see section 4.4).  Grade 1-3 (mild-severe): Upon recovery of symptoms, resume infusion at 50% of the previous rate. If there are no additional symptoms, the rate may be increased per the recommended infusion rate (see Tables 5 and 6). Concomitant medicinal products should be administered at the next dose (including dexamethasone (20 mg) or equivalent (see Table 4).  Recurrent Grade 3 or Grade 4 (life-threatening): Permanently discontinue Rybrevant. Skin and nail reactions If the patient develops a Grade 1-2 skin or nail reaction, supportive care should be initiated; if there is no improvement after 2 weeks, dose reduction should be considered for persistent Grade 2 rash (see Table 3). If the patient develops a Grade 3 skin or nail reaction, supportive care should be initiated, and interruption of Rybrevant should be considered until the adverse reaction improves. Upon recovery of the skin or nail reaction to ≤ Grade 2, Rybrevant should be resumed at a reduced dose. If the patient develops Grade 4 skin reactions, permanently discontinue Rybrevant (see section 4.4). Interstitial lung disease Rybrevant should be withheld if interstitial lung disease (ILD) or ILD-like adverse reactions (pneumonitis) is suspected. If the patient is confirmed to have ILD or ILD-like adverse reactions (e.g., pneumonitis), permanently discontinue Rybrevant (see section 4.4). Recommended concomitant medicinal products Prior to infusion (Week 1, Days 1 and 2), antihistamines, antipyretics, and glucocorticoids should be administered to reduce the risk of IRRs (see Table 4). For subsequent doses, antihistamines and antipyretics are required to be administered. Glucocorticoids should also be re-initiated after prolonged dose interruptions. Antiemetics should be administered as needed. Table 4: Dosing schedule of premedications Recommended dosing window Route of prior to Rybrevant Premedication Dose administration administration Antihistamine* Diphenhydramine (25 to 50 mg) Intravenous 15 to 30 minutes or equivalent Oral 30 to 60 minutes Antipyretic* Paracetamol/Acetaminophen (650 Intravenous 15 to 30 minutes to 1000 mg) Oral 30 to 60 minutes Glucocorticoid‡ Dexamethasone (20 mg) or Intravenous 60 to 120 minutes equivalent 4 Dexamethasone (10 mg) or Glucocorticoid+ Intravenous 45 to 60 minutes equivalent * Required at all doses. ‡ Required at initial dose (Week 1, Day 1) or at the next subsequent dose in the event of an IRR. + Required at second dose (Week 1, Day 2); optional for subsequent doses. Special populations Paediatric population There is no relevant use of amivantamab in the paediatric population in the treatment of non-small cell lung cancer. Elderly No dose adjustments are necessary (see section 4.8, section 5.1, and section 5.2). Renal impairment No formal studies of amivantamab in patients with renal impairment have been conducted. Based on population pharmacokinetic (PK) analyses, no dose adjustment is necessary for patients with mild or moderate renal impairment. Caution is required in patients with severe renal impairment as amivantamab has not been studied in this patient population (see section 5.2). If treatment is started, patients should be monitored for adverse reactions with dose modifications per the recommendations above. Hepatic impairment No formal studies of amivantamab in patients with hepatic impairment have been conducted. Based on population PK analyses, no dose adjustment is necessary for patients with mild hepatic impairment. Caution is required in patients with moderate or severe hepatic impairment as amivantamab has not been studied in this patient population (see section 5.2). If treatment is started, patients should be monitored for adverse reactions with dose modifications per the recommendations above. Method of administration Rybrevant is for intravenous use. It is administered as an intravenous infusion following dilution with sterile 5% glucose solution or sodium chloride 9 mg/mL (0.9%) solution for injection. Rybrevant must be administered with in-line filtration. For instructions on dilution of the medicinal product before administration, see section 6.6. Infusion rates Following dilution, the infusion should be administered intravenously at the infusion rates presented in Table 5 or 6 below. Due to the frequency of IRRs at the first dose, amivantamab should be infused via a peripheral vein at Week 1 and Week 2; infusion via a central line may be administered for subsequent weeks when the risk of IRR is lower (see section 6.6). It is recommended for the first dose to be prepared as close to administration as possible to maximise the likelihood of completing the infusion in the event of an IRR. Table 5: Infusion rates for Rybrevant every 3 weeks Body weight less than 80 kg Week Dose 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 5 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-related reactions. 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. 4.3 Contraindications Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Infusion-related reactions Infusion-related reactions commonly occurred in patients treated with amivantamab (see section 4.8). Prior to initial infusion (Week 1), antihistamines, antipyretics, and glucocorticoids should be administered to reduce the risk of IRRs. For subsequent doses, antihistamines and antipyretics should be administered. The initial infusion should be administered in split doses on Week 1, Day 1 and 2. Patients should be treated in a setting with appropriate medical support to treat IRRs. Infusions should be interrupted at the first sign of IRRs of any severity and post-infusion medicinal products should be administered as clinically indicated. Upon resolution of symptoms, the infusion should be resumed at 50% of the previous rate. For recurrent Grade 3 or Grade 4 IRRs, Rybrevant should be permanently discontinued (see section 4.2). 6 Interstitial lung disease Interstitial lung disease (ILD) or ILD-like adverse reactions (e.g., pneumonitis) have been reported in patients treated with amivantamab (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 amivantamab (see section 4.8). Patients should be instructed to limit sun exposure during and for 2 months after Rybrevant therapy. Protective clothing and use of broad-spectrum UVA/UVB sunscreen are advisable. Alcohol-free emollient cream is recommended for dry areas. A prophylactic approach to rash prevention should be considered. 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. Treatment with this medicinal product should be discontinued if TEN is confirmed. Eye disorders Eye disorders, including keratitis, occurred in patients treated with amivantamab (see section 4.8). Patients presenting with worsening eye symptoms should promptly be referred to an ophthalmologist and should discontinue use of contact lenses until symptoms are evaluated. For dose modifications for Grade 3 or 4 eye disorders, see section 4.2. Sodium content This medicinal product contains less than 1 mmol (23 mg) sodium per dose, that is to say essentially “sodium-free”. This medicinal product may be diluted in sodium chloride 9 mg/mL (0.9%) solution for infusion. This should be taken into consideration for patients on a controlled sodium diet (see section 6.6). 4.5 Interaction with other medicinal products and other forms of interaction No drug interaction studies have been performed. As an IgG1 monoclonal antibody, renal excretion and hepatic enzyme-mediated metabolism of intact amivantamab are unlikely to be major elimination routes. As such, variations in drug-metabolising enzymes are not expected to affect the elimination of amivantamab. Due to the high affinity to a unique epitope on EGFR and MET, amivantamab is not anticipated to alter drug-metabolising enzymes. Vaccines No clinical data are available on the efficacy and safety of vaccinations in patients taking amivantamab. Avoid the use of live or live-attenuated vaccines while patients are taking amivantamab. 4.6 Fertility, pregnancy and lactation Women of child-bearing potential/Contraception Women of child-bearing potential should use effective contraception during and for 3 months after cessation of amivantamab treatment. 7 Pregnancy There are no human data to assess the risk of amivantamab use during pregnancy. No animal reproductive studies were conducted to inform a drug-associated risk. Administration of EGFR and MET inhibitor molecules in pregnant animals resulted in an increased incidence of impairment of embryo-foetal development, embryo lethality, and abortion. Therefore, based on its mechanism of action and findings in animal models, amivantamab could cause foetal harm when administered to a pregnant woman. Amivantamab should not be given during pregnancy unless the benefit of treatment of the woman is considered to outweigh potential risks to the foetus. If the patient becomes pregnant while taking this medicinal product the patient should be informed of the potential risk to the foetus (see section 5.3). Breast-feeding It is unknown whether amivantamab is excreted in human milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which is decreasing to low concentrations soon afterwards. A risk to the breast-fed child cannot be excluded during this short period just after birth, although IgGs are likely to be degraded in the gastrointestinal tract of the breast-fed child and not absorbed. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from amivantamab therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility There are no data on the effect of amivantamab on human fertility. Effects on male and female fertility have not been evaluated in animal studies. 4.7 Effects on ability to drive and use machines Rybrevant may have moderate influence on the ability to drive and use machines. Please see section 4.8 (e.g., dizziness, fatigue, visual impairment). If patients experience treatment-related symptoms, including vision-related adverse reactions, affecting their ability to concentrate and react, it is recommended that they do not drive or use machines until the effect subsides. 4.8 Undesirable effects Summary of the safety profile In the dataset of amivantamab as monotherapy (N=380), the most frequent adverse reactions in all grades were rash (76%), infusion-related reactions (67%), nail toxicity (47%), hypoalbuminaemia (31%), oedema (26%), fatigue (26%), stomatitis (24%), nausea (23%), and constipation (23%). Serious adverse reactions included ILD (1.3%), IRR (1.1%), and rash (1.1%). Three percent of patients discontinued Rybrevant due to adverse reactions. The most frequent adverse reactions leading to treatment discontinuation were IRR (1.1%), ILD (0.5%), and nail toxicity (0.5%). Tabulated list of adverse reactions Table 7 summarises the adverse drug reactions that occurred in patients receiving amivantamab as monotherapy. The data reflects exposure to amivantamab in 380 patients with locally advanced or metastatic non-small cell lung cancer after failure of platinum-based chemotherapy. Patients received amivantamab 1050 mg (for patients < 80 kg) or 1400 mg (for patients ≥ 80 kg). The median exposure to amivantamab was 4.1 months (range: 0.0 to 39.7 months). Adverse reactions observed during clinical studies are listed below by frequency category. Frequency categories are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); and not known (frequency cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. 8 Table 7: Adverse reactions in patients receiving amivantamab as monotherapy System organ class Frequency Any Grade Grade 3-4 Adverse reaction category (%) (%) Metabolism and nutrition disorders Hypoalbuminaemia* (see section 5.1) Very common 31 2† Decreased appetite 16 0.5† Hypocalcaemia 10 0.3† Hypokalaemia Common 9 2 Hypomagnesaemia 8 0 Nervous system disorders Dizziness* Very common 13 0.3† Eye disorders Visual impairment* Common 3 0 Growth of eyelashes* 1 0 Other eye disorders* 6 0 Keratitis Uncommon 0.5 0 Uveitis 0.3 0 Respiratory, thoracic and mediastinal disorders Interstitial lung disease* Common 3 0.5† Gastrointestinal disorders Diarrhoea Very common 11 2† Stomatitis* 24 0.5† Nausea 23 0.5† Constipation 23 0 Vomiting 12 0.5† Abdominal pain* Common 9 0.8† Haemorrhoids 3.7 0 Hepatobiliary disorders Alanine aminotransferase increased Very common 15 2 Aspartate aminotransferase increased 13 1 Blood alkaline phosphatase increased 12 0.5† Skin and subcutaneous tissue disorders Rash* Very common 76 3† Nail toxicity* 47 2† Dry skin* 19 0 Pruritus 18 0 Toxic epidermal necrolysis Uncommon 0.3 0.3† Musculoskeletal and connective tissue disorders Myalgia Very common 11 0.3† General disorders and administration site conditions Oedema* Very common 26 0.8† Fatigue* 26 0.8† Pyrexia 11 0 Injury, poisoning and procedural complications Infusion related reaction Very common 67 2 * Grouped terms † Grade 3 events only Summary of the safety profile In the dataset of amivantamab in combination with carboplatin and pemetrexed (N=301), the most frequent adverse reactions in all grades were rash (83%), neutropenia (57%), nail toxicity (53%), infusion related reactions (51%), fatigue (43%), stomatitis (39%), nausea (43%), thrombocytopenia (40%), constipation (40%), oedema (40%), decreased appetite (33%), hypoalbuminaemia (32%), alanine aminotransferase increased (26%), aspartate aminotransferase increased (23%), vomiting (22%), and hypokalaemia (20%). Serious adverse reactions included rash (2.7%), venous thromboembolism (2.3%), thrombocytopenia (2.3%) and ILD (2.0%). Eight percent of patients 9 discontinued Rybrevant due to adverse reactions. The most frequent adverse reactions leading to treatment discontinuation were IRR (2.7%), rash (2.3%), ILD (2.3%), and nail toxicity (1.0%). Table 8 summarises the adverse drug reactions that occurred in patients receiving amivantamab in combination with chemotherapy. The data reflects exposure to amivantamab in combination with carboplatin and pemetrexed in 301 patients with locally advanced or metastatic non-small cell lung cancer. Patients received amivantamab 1400 mg (for patients < 80 kg) or 1750 mg (for patients ≥ 80 kg) weekly for 4 weeks. Starting at Week 7, patients received amivantamab 1750 mg (for patients < 80 kg) or 2100 mg (for patients ≥ 80 kg) every 3 weeks. The median exposure to amivantamab in combination with carboplatin and pemetrexed was 7.7 months (range: 0.0 to 28.1 months). Adverse reactions observed during clinical studies are listed below by frequency category. Frequency categories are defined as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); and not known (frequency cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Table 8: Adverse reactions in patients receiving amivantamab in combination with carboplatin and pemetrexed System organ class Frequency Any Grade Grade 3-4 Adverse reaction category (%) (%) Blood and lymphatic system disorders Neutropenia Very common 57 39 Thrombocytopenia 40 12 Metabolism and nutrition disorders Decreased appetite Very common 33 1.3 Hypoalbuminaemia* 32 3.7 Hypokalaemia 20 6.6 Hypomagnesaemia 13 1.3 Hypocalcaemia 12 1.0 Nervous system disorders Dizziness* Common 10 0.3 Vascular disorders Venous thromboembolism* Very common 14 3.0 Eye disorders Other eye disorders* Common 7.3 0 Visual impairment* 3.0 0 Growth of eyelashes Uncommon 0.3 0 Keratitis 0.3 0 Uveitis 0.3 0 Respiratory, thoracic and mediastinal disorders Interstitial lung disease* Common 2.3 1.7 Gastrointestinal disorders Nausea Very common 43 1.0 Constipation 40 0.3 Stomatitis* 39 3.0 Vomiting 22 2.0 Diarrhoea 19 2.3 Abdominal pain* Common 11 0.3 Haemorrhoids 9.3 0.7 Hepatobiliary disorders Alanine aminotransferase increased Very common 26 4.3 10 Aspartate aminotransferase increased 23 0.7 Blood alkaline phosphatase increased Common 10 0.3 Skin and subcutaneous tissue disorders Rash* Very common 83 14 Nail toxicity* 53 4.3 Dry skin* 16 0 Pruritus 10 0 Musculoskeletal and connective tissue disorders Myalgia Common 5.0 0.7 General disorders and administration site conditions Fatigue* Very common 43 4.7 Oedema* 40 1.3 Pyrexia 14 0 Injury, poisoning and procedural complications Infusion related reaction Very common 50 3.0 * Grouped terms Description of selected adverse reactions Infusion-related reactions In patients treated with amivantamab monotherapy, infusion-related reactions occurred in 67% of patients. Ninety-eight percent of IRRs were Grade 1-2. Ninety-nine percent of IRRs occurred at the first infusion with a median time to onset of 60 minutes, and the majority occurring within 2 hours of infusion start. The most frequent signs and symptoms include chills, dyspnoea, nausea, flushing, chest discomfort, and vomiting (see section 4.4). In patients treated with amivantamab in combination with carboplatin and pemetrexed, infusion-related reactions occurred in 50% of patients. Greater than 94% of IRRs were Grade 1-2. A majority of IRRs occurred at the first infusion with a median time to onset of 60 minutes (range 0-7 hours), and the majority occurring within 2 hours of infusion start. 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 2.3 % 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. Most cases were Grade 1 or 2, with Grade 3 rash events occurring in 3% of patients. Rash leading to amivantamab discontinuation occurred in 0.3% of patients. Rash usually developed within the first 4 weeks of therapy, with a median time to onset of 14 days. Nail toxicity occurred in patients treated with amivantamab. Most events were Grade 1 or 2, with Grade 3 nail toxicity occurring in 1.8% of patients. Rash (including dermatitis acneiform), occurred in 83% of patients treated with amivantamab in combination with carboplatin and pemetrexed. Most cases were Grade 1 or 2, with Grade 3 rash events occurring in 14% of patients. Rash leading to amivantamab discontinuation occurred in 2.3% of patients. Rash usually developed within the first 4 weeks of therapy, with a median time to onset of 14 days. Nail toxicity occurred in patients treated with amivantamab in combination with carboplatin and pemetrexed. Most events were Grade 1 or 2, with Grade 3 nail toxicity occurring in 4.3% of patients (see section 4.4). 11 Eye disorders Eye disorders, including keratitis (0.5%), occurred in 9% of patients treated with amivantamab alone. Other reported adverse reactions included growth of eyelashes, visual impairment, and other eye disorders. All events were Grade 1-2. Eye disorders, including keratitis (0.3%), occurred in 11% of patients treated with amivantamab in combination with carboplatin and pemetrexed. Other reported adverse reactions included growth of eyelashes, visual impairment, uveitis, and other eye disorders. All events were Grade 1-2 (see section 4.4). 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, 4 of the 865 (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 national reporting system listed in Appendix V. 4.9 Overdose No maximum tolerated dose has been determined in a clinical study in which patients received up to 2100 mg administered intravenously. There is no known specific antidote for amivantamab overdose. In the event of an overdose, treatment with Rybrevant should be stopped, the patient should be monitored for any signs or symptoms of adverse events and appropriate general supportive measures should be instituted immediately until clinical toxicity has diminished or resolved. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Monoclonal antibodies and antibody drug conjugates, ATC code: L01FX18. Mechanism of action Amivantamab is a low-fucose, fully-human IgG1-based EGFR-MET bispecific antibody with immune cell-directing activity that targets tumours with activating EGFR mutations such as Exon 19 deletions, L858R substitution, and 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. 12 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 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 locally advanced or metastatic NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations (mutation testing could have been performed at or after the time of locally advanced or metastatic disease diagnosis. Testing did not need to be repeated at the time of study entry once EGFR mutation 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 which 263 received carboplatin and pemetrexed (CP); and 131 which received Rybrevant in combination with carboplatin and pemetrexed (Rybrevant-CP). Additionally, 236 patients were randomised to receive Rybrevant in combination with lazertinib, carboplatin, and pemetrexed in a separate arm of the study. 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. 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 and 46% 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 IV cancer at initial diagnosis. Rybrevant in combination with carboplatin and pemetrexed demonstrated a statistically significant improvement in progression-free survival (PFS) compared to carboplatin and pemetrexed, with a HR of 0.48 (95% CI: 0.36, 0.64; p<0.0001). At the time of the second interim analysis for OS, with a median 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 (tested at a prespecified significance level of 0.0142). Efficacy results are summarised in Table 9. Table 9: 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, 4.4) HR (95% CI); p-value 0.48 (0.36, 0.64); p<0.0001 13 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, 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 PFS and ORR results are from data cut-off 10 July-2023 when hypothesis testing and final analysis for these endpoints was performed. OS results are from data cut-off 26 April 2024 from the second interim OS analysis. a BICR-assessed b The p-value is compared to a 2-sided significance level of 0.0142. Thus the OS results are not significant as of the second interim analysis. Figure 1: Kaplan-Meier curve of PFS in previously treated NSCLC patients by BICR assessment The PFS benefit of Rybrevant-CP compared to CP was consistent across all the predefined subgroups analysed, including ethnicity, age, gender, smoking history, and CNS metastases status at study entry. 14 Figure 2: 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 be randomised in MARIPOSA-2. Treatment with Rybrevant-CP was associated with a numeric increase in 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 with 2.2 months; 95% CI (1.4, NE) in the CP arm). The median follow-up for Rybrevant-CP was approximately 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 and pemetrexed) 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 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. 15 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 was14.9 months (range: 0.3 to 27.0). Efficacy results are summarised in Table 10. Table 10: 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, 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 estimable a Blinded Independent Central Review by RECIST v1.1 b 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 for the potentially confounding effects of crossover (78 [50.3%] patients on the carboplatin + pemetrexed arm who received subsequent Rybrevant monotherapy treatment). 16 Figure 3: Kaplan-Meier curve of PFS in previously untreated NSCLC patients 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 4: Kaplan-Meier curve of OS in previously untreated NSCLC patients 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 17 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 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 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 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 for information on paediatric use). 5.2 Pharmacokinetic properties 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 approximately 2.8-fold higher after the fifth dose for the 2-week dosing regimen and 2.6-fold higher after the fourth 18 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. 5.3 Preclinical safety data 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 19 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. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Ethylenediaminetetraacetic acid (EDTA) disodium salt dihydrate L-Histidine L-Histidine hydrochloride monohydrate L-Methionine Polysorbate 80 (E433) Sucrose Water for injections 6.2 Incompatibilities This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6. 6.3 Shelf life Unopened 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. 6.4 Special precautions for storage Store in a refrigerator (2°C to 8°C). Do not freeze. Store in the original package in order to protect from light. For storage conditions after dilution of the medicinal product, see section 6.3. 6.5 Nature and contents of container 7 mL concentrate in a Type 1 glass vial with an elastomeric closure and aluminium seal with a flip-off cap containing 350 mg amivantamab. Pack size of 1 vial. 6.6 Special precautions for disposal and other handling 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 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. 20  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. 7. MARKETING AUTHORISATION HOLDER Janssen-Cilag International NV Turnhoutseweg 30 B-2340 Beerse Belgium 8. MARKETING AUTHORISATION NUMBER(S) EU/1/21/1594/001 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Date of first authorisation: 09 December 2021 Date of latest renewal: 11 September 2023 21 10. DATE OF REVISION OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency https://www.ema.europa.eu. 22 ANNEX II A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT 23 A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE Name and address of the manufacturer of the biological active substance Janssen Sciences Ireland UC Barnahely Ringaskiddy, Co. Cork Ireland Name and address of the manufacturer responsible for batch release Janssen Biologics B.V. Einsteinweg 101 2333 CB Leiden The Netherlands B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product Characteristics, section 4.2). C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION  Periodic safety update reports (PSURs) The requirements for submission of PSURs for this medicinal product are set out in Article 9 of Regulation (EC) No 507/2006 and, accordingly, the marketing authorisation holder (MAH) shall submit PSURs every 6 months. The requirements for submission of PSURs for this medicinal product are set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any subsequent updates published on the European medicines web-portal. The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 6 months following authorisation. D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT  Risk management plan (RMP) The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation and any agreed subsequent updates of the RMP. An updated RMP should be submitted:  At the request of the European Medicines Agency;  Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. 24 ANNEX III LABELLING AND PACKAGE LEAFLET 25 A. LABELLING 26 PARTICULARS TO APPEAR ON THE OUTER PACKAGING OUTER CARTON 1. NAME OF THE MEDICINAL PRODUCT Rybrevant 350 mg concentrate for solution for infusion amivantamab 2. STATEMENT OF ACTIVE SUBSTANCE(S) One vial of 7 mL contains 350 mg of amivantamab (50 mg/mL). 3. LIST OF EXCIPIENTS Excipients: ethylenediaminetetraacetic acid (EDTA), L-histidine, L-histidine hydrochloride monohydrate, L-methionine, polysorbate 80, sucrose, and water for injections. 4. PHARMACEUTICAL FORM AND CONTENTS Concentrate for solution for infusion 1 vial 5. METHOD AND ROUTE(S) OF ADMINISTRATION For intravenous use after dilution. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE SIGHT AND REACH OF CHILDREN Keep out of the sight and reach of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY Do not shake. 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS Store in a refrigerator. Do not freeze. Store in the original package in order to protect from light. 27 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER Janssen-Cilag International NV Turnhoutseweg 30 B-2340 Beerse Belgium 12. MARKETING AUTHORISATION NUMBER(S) EU/1/21/1594/001 13. BATCH NUMBER Lot 14. GENERAL CLASSIFICATION FOR SUPPLY 15. INSTRUCTIONS ON USE 16. INFORMATION IN BRAILLE Justification for not including Braille accepted. 17. UNIQUE IDENTIFIER – 2D BARCODE 2D barcode carrying the unique identifier included. 18. UNIQUE IDENTIFIER - HUMAN READABLE DATA PC SN NN 28 MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS VIAL 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE OF ADMINISTRATION Rybrevant 350 mg sterile concentrate amivantamab IV 2. METHOD OF ADMINISTRATION 3. EXPIRY DATE EXP 4. BATCH NUMBER Lot 5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 7 mL 6. OTHER 29 B. PACKAGE LEAFLET 30 Package leaflet: Information for the patient Rybrevant 350 mg concentrate for solution for infusion amivantamab This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. See the end of section 4 for how to report side effects. Read all of this leaflet carefully before you are given this medicine because it contains important information for you.  Keep this leaflet. You may need to read it again.  If you have any further questions, ask your doctor or nurse.  If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. See section 4. What is in this leaflet 1. What Rybrevant is and what it is used for 2. What you need to know before you are given Rybrevant 3. How Rybrevant is given 4. Possible side effects 5. How to store Rybrevant 6. Contents of the pack and other information 1. What Rybrevant is and what it is used for What Rybrevant is Rybrevant is a cancer medicine. It contains the active substance ‘amivantamab’, which is an antibody (type of protein) designed to recognise and attach to specific targets in the body. What Rybrevant is used for Rybrevant is used in adults with a type of lung cancer called ‘non-small cell lung cancer’. It is used when the cancer has spread to other parts of your body and has gone through certain changes in a gene called ‘EGFR’. Rybrevant can be prescribed for you:  in combination with chemotherapy after failure of prior therapy including an EGFR tyrosine kinase inhibitor (TKI).  as the first medicine you receive for your cancer in combination with chemotherapy, or  when chemotherapy is no longer working against your cancer. How Rybrevant works The active substance in Rybrevant, amivantamab, targets two proteins found on cancer cells:  epidermal growth factor receptor (EGFR), and  mesenchymal-epithelial transition factor (MET). This medicine works by attaching to these proteins. This may help to slow or stop your lung cancer from growing. It may also help to reduce the size of the tumour. Rybrevant may be given in combination with other anti-cancer medicines. It is important that you also read the package leaflets for these other medicines. If you have any questions about these medicines, ask your doctor. 31 2. What you need to know before you are given Rybrevant Do not use Rybrevant if  you are allergic to amivantamab or any of the other ingredients of this medicine (listed in section 6). Do not use this medicine if the above applies to you. If you are not sure, talk to your doctor or nurse before you are given this medicine. Warnings and precautions Tell your doctor or nurse before you are given Rybrevant if:  you have suffered from inflammation of your lungs (a condition called ‘interstitial lung disease’ or ‘pneumonitis’). Tell your doctor or nurse straight away while taking this medicine if you get any of the following side effects (see section 4 for more information):  Any side effect while the medicine is being given into your vein.  Sudden difficulty in breathing, cough, or fever that may suggest inflammation of the lungs.  Skin problems. To reduce the risk of skin problems, keep out of the sun, wear protective clothing, apply sunscreen, and use moisturisers regularly on your skin and nails while taking this medicine. You will need to continue doing this for 2 months after you stop treatment.  Eye problems. If you have vision problems or eye pain contact your doctor or nurse straight away. If you use contact lenses and have any new eye symptoms, stop using contact lenses and tell your doctor straight away. Children and adolescents Do not give this medicine to children or young people below 18 years of age. This is because it is not known whether the medicine is safe and effective in this age group. Other medicines and Rybrevant Tell your doctor or nurse if you are taking, have recently taken or might take any other medicines. Contraception  If you could become pregnant, you must use effective contraception during Rybrevant treatment and for 3 months after stopping treatment. Pregnancy  Tell your doctor or nurse before you are given this medicine if you are pregnant, think you might be pregnant, or are planning to have a baby.  It is possible that this medicine may harm an unborn baby. If you become pregnant while being treated with this medicine, tell your doctor or nurse straight away. You and your doctor will decide if the benefit of having the medicine is greater than the risk to your unborn baby. Breast-feeding It is not known if Rybrevant passes into breast milk. Ask your doctor for advice before being given this medicine. You and your doctor will decide if the benefit of breast-feeding is greater than the risk to your baby. Driving and using machines If you feel tired, feel dizzy, or if your eyes are irritated or vision is affected after taking Rybrevant, do not drive or use machinery. Rybrevant contains sodium This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’. However, before Rybrevant is given to you, it may be mixed with a solution that contains sodium. Talk to your doctor if you are on a low salt diet. 32 Rybrevant contains polysorbate This medicine contains 0.6 mg of polysorbate 80 in each mL, which is equivalent to 4.2 mg per 7 mL vial. Polysorbates may cause allergic reactions. Tell your doctor if you have any known allergies. 3. How Rybrevant is given How much is given Your doctor will work out the correct dose of Rybrevant for you. The dose of this medicine will depend on your body weight at the start of your therapy. You will be treated with Rybrevant once every 2 or 3 weeks according to the treatment your doctor decides for you. The recommended dose of Rybrevant every 2 weeks is:  1050 mg if you weigh less than 80 kg.  1400 mg if you weigh more than or equal to 80 kg. The recommended dose of Rybrevant every 3 weeks is:  1400 mg for the first 4 doses and 1750 mg for subsequent doses if you weigh less than 80 kg.  1750 mg for the first 4 doses and 2100 mg for subsequent doses if you weigh more than or equal to 80 kg. How the medicine is given This medicine will be given to you by a doctor or nurse. It is given as a drip into a vein (‘intravenous infusion’) over several hours. Rybrevant is given as follows:  once a week for the first 4 weeks  then once every 2 weeks starting at week 5 or once every 3 weeks starting at week 7, for as long as you keep getting benefit from the treatment. In the first week, your doctor will give you the Rybrevant dose split over two days. Medicines given during treatment with Rybrevant Before each infusion of Rybrevant, you will be given medicines which help lower the chance of infusion-related reactions. These may include:  medicines for an allergic reaction (antihistamines)  medicines for inflammation (corticosteroids)  medicines for fever (such as paracetamol). You may also be given additional medicines based on any symptoms you may experience. If you are given more Rybrevant than you should This medicine will be given by your doctor or nurse. In the unlikely event that you are given too much (an overdose), your doctor will check you for side effects. If you forget your appointment to have Rybrevant It is very important to go to all your appointments. If you miss an appointment, make another one as soon as possible. If you have any further questions on the use of this medicine, ask your doctor or nurse. 4. Possible side effects Like all medicines, this medicine can cause side effects, although not everybody gets them. 33 Serious side effects Tell your doctor or nurse straight away if you notice the following serious side effects: Very common (may affect more than 1 in 10 people):  Signs of a reaction to the infusion - such as chills, feeling short of breath, feeling sick (nausea), flushing, chest discomfort, and vomiting while the medicine is being given. This can happen especially with the first dose. Your doctor may give you other medicines, or the infusion may need to be slowed down or stopped.  Skin problems - such as rash (including acne), infected skin around the nails, dry skin, itching, pain, and redness. Tell your doctor if your skin or nail problems get worse. Common (may affect up to 1 in 10 people):  Eye problems - such as dry eye, swollen eyelid, itchy eyes, problems with vision, growth of eyelashes.  Signs of an inflammation in the lungs - such as sudden difficulty in breathing, cough, or fever. This could lead to permanent damage (‘interstitial lung disease’). Your doctor may wish to stop Rybrevant if you get this side effect. Uncommon (may affect up to 1 in 100 people):  inflamed cornea (front part of the eye)  inflammation inside the eye that may affect vision  life-threatening rash with blisters and peeling skin over much of the body (toxic epidermal necrolysis). The following side effects have been reported in clinical studies with Rybrevant when given alone: Other side effects Tell your doctor if you notice any of the following side effects: Very common (may affect more than 1 in 10 people):  low level of the protein ‘albumin’ in the blood  swelling caused by fluid build up in the body  feeling very tired  sores in the mouth  constipation or diarrhoea  decreased appetite  increased level of the liver enzyme ‘alanine aminotransferase’ in the blood, a possible sign of liver problems  increased level of the enzyme ‘aspartate aminotransferase’ in the blood, a possible sign of liver problems  feeling dizzy  increased level of the enzyme ‘alkaline phosphatase’ in the blood  muscle aches  fever  low level of calcium in the blood Common (may affect up to 1 in 10 people)  stomach pain  low level of potassium in the blood  low level of magnesium in the blood  haemorrhoids The following side effects have been reported in clinical studies with Rybrevant in combination with chemotherapy: 34 Other side effects Tell your doctor if you notice any of the following side effects: Very common (may affect more than 1 in 10 people):  low number of a type of white blood cell (neutropenia)  low number of ‘platelets’(cells that help blood to clot)  blood clot in the veins  feeling very tired  nausea  sores in the mouth  constipation  swelling caused by fluid build up in the body  decreased appetite  low level of the protein ‘albumin’ in the blood  increased level of the liver enzyme ‘alanine aminotransferase’ in the blood, a possible sign of liver problems  increased level of the enzyme ‘aspartate aminotransferase’ in the blood, a possible sign of liver problems  vomiting  low level of potassium in the blood  diarrhoea  fever  low level of magnesium in the blood  low level of calcium in the blood Common (may affect up to 1 in 10 people)  increased level of the enzyme ‘alkaline phosphatase’ in the blood  stomach pain  feeling dizzy  haemorrhoids  muscle aches Reporting of side effects If you get any side effects, talk to your doctor or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine. 5. How to store Rybrevant Rybrevant will be stored at the hospital or clinic. Keep this medicine out of the sight and reach of children. Do not use this medicine after the expiry date which is stated on the carton and the vial label after “EXP”. The expiry date refers to the last day of that month. 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. 35 Medicines should not be disposed of via wastewater or household waste. Your healthcare professional will throw away any medicines that are no longer being used. These measures will help protect the environment. 6. Contents of the pack and other information What Rybrevant contains  The active substance is amivantamab. One mL of concentrate for solution for infusion contains 50 mg of amivantamab. One vial of 7 mL concentrate contains 350 mg of amivantamab.  The other ingredients are ethylenediaminetetraacetic acid (EDTA), L-histidine, L-histidine hydrochloride monohydrate, L-methionine, polysorbate 80, sucrose, and water for injections (see section 2). What Rybrevant looks like and contents of the pack Rybrevant is a concentrate for solution for infusion and is a colourless to pale yellow liquid. This medicine is available in a carton pack containing 1 glass vial of 7 mL of concentrate. Marketing Authorisation Holder Janssen-Cilag International NV Turnhoutseweg 30 B-2340 Beerse Belgium Manufacturer Janssen Biologics B.V. Einsteinweg 101 2333 CB Leiden The Netherlands For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: België/Belgique/Belgien Lietuva Janssen-Cilag NV UAB “JOHNSON & JOHNSON” Tel/Tél: +32 14 64 94 11 Tel: +370 5 278 68 88 janssen@jacbe.jnj.com lt@its.jnj.com България Luxembourg/Luxemburg „Джонсън & Джонсън България” ЕООД Janssen-Cilag NV Тел.: +359 2 489 94 00 Tél/Tel: +32 14 64 94 11 jjsafety@its.jnj.com janssen@jacbe.jnj.com Česká republika Magyarország Janssen-Cilag s.r.o. Janssen-Cilag Kft. Tel: +420 227 012 227 Tel.: +36 1 884 2858 janssenhu@its.jnj.com Danmark Malta Janssen-Cilag A/S AM MANGION LTD Tlf.: +45 4594 8282 Tel: +356 2397 6000 jacdk@its.jnj.com 36 Deutschland Nederland Janssen-Cilag GmbH Janssen-Cilag B.V. Tel: +49 2137 955 955 Tel: +31 76 711 1111 jancil@its.jnj.com janssen@jacnl.jnj.com Eesti Norge UAB "JOHNSON & JOHNSON" Eesti filiaal Janssen-Cilag AS Tel: +372 617 7410 Tlf: +47 24 12 65 00 ee@its.jnj.com jacno@its.jnj.com Ελλάδα Österreich Janssen-Cilag Φαρμακευτική Μονοπρόσωπη Janssen-Cilag Pharma GmbH Α.Ε.Β.Ε. Tel: +43 1 610 300 Tηλ: +30 210 80 90 000 España Polska Janssen-Cilag, S.A. Janssen-Cilag Polska Sp. z o.o. Tel: +34 91 722 81 00 Tel.: +48 22 237 60 00 contacto@its.jnj.com France Portugal Janssen-Cilag Janssen-Cilag Farmacêutica, Lda. Tél: 0 800 25 50 75 / +33 1 55 00 40 03 Tel: +351 214 368 600 medisource@its.jnj.com Hrvatska România Johnson & Johnson S.E. d.o.o. Johnson & Johnson România SRL Tel: +385 1 6610 700 Tel: +40 21 207 1800 jjsafety@JNJCR.JNJ.com Ireland Slovenija Janssen Sciences Ireland UC Johnson & Johnson d.o.o. Tel: 1 800 709 122 Tel: +386 1 401 18 00 medinfo@its.jnj.com Janssen_safety_slo@its.jnj.com Ísland Slovenská republika Janssen-Cilag AB Johnson & Johnson, s.r.o. c/o Vistor hf. Tel: +421 232 408 400 Sími: +354 535 7000 janssen@vistor.is Italia Suomi/Finland Janssen-Cilag SpA Janssen-Cilag Oy Tel: 800.688.777 / +39 02 2510 1 Puh/Tel: +358 207 531 300 janssenita@its.jnj.com jacfi@its.jnj.com Κύπρος Sverige Βαρνάβας Χατζηπαναγής Λτδ Janssen-Cilag AB Τηλ: +357 22 207 700 Tfn: +46 8 626 50 00 jacse@its.jnj.com Latvija United Kingdom (Northern Ireland) UAB "JOHNSON & JOHNSON" filiāle Latvijā Janssen Sciences Ireland UC Tel: +371 678 93561 Tel: +44 1 494 567 444 lv@its.jnj.com medinfo@its.jnj.com 37 This leaflet was last revised in. Other sources of information Detailed information on this medicine is available on the European Medicines Agency web site https://www.ema.europa.eu. 38 The following information is intended for healthcare professionals only: This medicinal product must not be mixed with other medicinal products except those mentioned below. 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. 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. 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. 39.⁹
▼ In line with EMA regulations for new medicines, amivantamab is subject to additional monitoring.

About Lazertinib
In 2018, Janssen Biotech, Inc., entered into a license and collaboration agreement with Yuhan Corporation for the development of lazertinib. Lazertinib is an oral, third-generation, brain-penetrant EGFR TKI that targets both the T790M mutation and activating EGFR mutations while sparing wild-type EGFR.¹² An analysis of the efficacy and safety of lazertinib from the Phase 3 study LASER301 was published in The Journal of Clinical Oncology in 2023.¹²

▼ In line with EMA regulations for new medicines, lazertinib is subject to additional monitoring.

About Non-Small Cell Lung Cancer
In Europe, it is estimated that 484,306 people were diagnosed with lung cancer in 2022.¹³ NSCLC accounts for 85 percent of all lung cancer cases.¹⁴ Lung cancer is Europe’s biggest cancer killer, with more deaths than breast cancer and prostate cancer combined.¹³

The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma and large cell carcinoma.¹³ Among the most common driver mutations in NSCLC are alterations in EGFR, which is a receptor tyrosine kinase controlling cell growth and division.^14,15 EGFR mutations are present in 10 to 15 percent of Western patients with NSCLC with adenocarcinoma histology and occur in 40 to 50 percent of Asian patients.^16,17,18,19 EGFR ex19del or EGFR exon 21 L858R mutations are the most common EGFR mutations.²⁰ The five-year survival rate for patients with advanced NSCLC and EGFR mutations treated with EGFR TKIs is less than 20 percent and between 25-32 percent of patients receiving the current first-line standard of care, osimertinib, do not survive long enough to reach second-line treatment.^21,22,23

About Johnson & Johnson
At Johnson & Johnson, we believe health is everything. Our strength in healthcare innovation empowers us to build a world where complex diseases are prevented, treated, and cured, where treatments are smarter and less invasive, and solutions are personal. Through our expertise in Innovative Medicine and MedTech, we are uniquely positioned to innovate across the full spectrum of healthcare solutions today to deliver the breakthroughs of tomorrow, and profoundly impact health for humanity.

Learn more at https://innovativemedicine.jnj.com/emea/. Follow us at http://www.linkedin.com/company/jnj-innovative-medicine-emea. Janssen-Cilag International NV, Janssen Research & Development, LLC, Janssen Biotech, Inc. and Janssen-Cilag, S.A. are Johnson & Johnson companies.

Cautions Concerning Forward-Looking Statements
This press release contains “forward-looking statements” as defined in the Private Securities Litigation Reform Act of 1995 regarding product development and the potential benefits and treatment impact of amivantamab or lazertinib. The reader is cautioned not to rely on these forward-looking statements. These statements are based on current expectations of future events. If underlying assumptions prove inaccurate or known or unknown risks or uncertainties materialise, actual results could vary materially from the expectations and projections of Janssen-Cilag International NV, Janssen Research & Development, LLC, Janssen Biotech, Inc., Janssen-Cilag, S.A., and/or Johnson & Johnson. Risks and uncertainties include, but are not limited to: challenges and uncertainties inherent in product research and development, including the uncertainty of clinical success and of obtaining regulatory approvals; uncertainty of commercial success; manufacturing difficulties and delays; competition, including technological advances, new products and patents attained by competitors; challenges to patents; product efficacy or safety concerns resulting in product recalls or regulatory action; changes in behaviour and spending patterns of purchasers of health care products and services; changes to applicable laws and regulations, including global health care reforms; and trends toward health care cost containment. A further list and descriptions of these risks, uncertainties and other factors can be found in Johnson & Johnson’s Annual Report on Form 10-K for the fiscal year ended December 31, 2023, including in the sections captioned “Cautionary Note Regarding Forward-Looking Statements” and “Item 1A. Risk Factors,” and in Johnson & Johnson’s subsequent Quarterly Reports on Form 10-Q and other filings with the Securities and Exchange Commission. Copies of these filings are available online at http://www.sec.gov/, http://www.jnj.com/ or on request from Johnson & Johnson. None of Janssen-Cilag International NV, Janssen Research & Development, LLC, Janssen Biotech, Inc., Janssen-Cilag, S.A., nor Johnson & Johnson undertakes to update any forward-looking statement as a result of new information or future events or developments.  

© Janssen-Cilag International NV, Inc. 2024. All rights reserved.

* Prof Felip has served as a consultant to Janssen-Cilag International NV; they have not been paid for any media work.

** Nominal P-value; endpoint was exploratory and not part of hierarchical hypothesis testing.

***This analysis was requested by health authorities and had nominal alpha spend. A P-value of ≤0.00001 was required for statistical significance.

^‡RECIST (version 1.1) refers to Response Evaluation Criteria in Solid Tumors, which is a standard way to measure how well solid tumours respond to treatment and is based on whether tumours shrink, stay the same or get bigger.

Footnotes
¹Cho BC, et al. Amivantamab Plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC. The New England Journal of Medicine 2024. doi:10.1056/NEJMoa2403614. Available at: https://www.nejm.org/doi/full/10.1056/NEJMoa2403614. Accessed November2024.

²European Medicines Agency. Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 11-14 November 2024. Available at: https://www.ema.europa.eu/en/news/meeting-highlights-committee-medicinal-products-human-use-chmp-11-14-november-2024. Accessed November2024.

³ Gadgeel SM, et al. Amivantamab Plus Lazertinib vs Osimertinib in First-line EGFR-mutant Advanced NSCLC: Longer Follow-up of the MARIPOSA Study. IASLC WCLC 2024. September 8, 2024.

⁴ Cho BC P, et al. Amivantamab Plus Lazertinib vs Osimertinib as First-line Treatment in Patients With EGFR-mutated, Advanced Non-small Cell Lung Cancer (NSCLC): Primary Results From MARIPOSA, a Phase 3, Global, Randomized, Controlled Trial. 2023 European Society for Medical Oncology. October 23, 2023

⁵ Grugan KD, et al. Fc-mediated activity of EGFR x c-Met bispecific antibody JNJ-61186372 enhanced killing of lung cancer cells. MAbs 2017;9(1):114-126.

⁶ Moores SL, et al. A Novel Bispecific Antibody Targeting EGFR and cMet Is Effective against EGFR Inhibitor-Resistant Lung Tumors. Cancer Res 2016;76(13)(suppl 27216193):3942-3953.

⁷ Yun J, et al. Antitumor Activity of Amivantamab (JNJ-61186372), an EGFR–MET Bispecific Antibody, in Diverse Models of EGFR Exon 20 Insertion–Driven NSCLC. Cancer Discov 2020;10(8):1194-1209.

⁸ Vijayaraghavan S, et al. Amivantamab (JNJ-61186372), an Fc Enhanced EGFR/cMet Bispecific Antibody, Induces Receptor Downmodulation and Antitumor Activity by Monocyte/Macrophage Trogocytosis. Mol Cancer Ther 2020;19(10):2044-2056.

⁹ European Medicines Agency. Amivantamab Summary of Product Characteristics. August 2024. Available at https://www.ema.europa.eu/en/documents/product-information/rybrevant-epar-product-information_en.pdf. Accessed November2024.

¹⁰ Janssen.com/EMEA. Janssen Submits Type II Extension of Indication Application to the European Medicines Agency Seeking Approval of RYBREVANT®▼ (amivantamab), in combination with Lazertinib, for the First-Line Treatment of Patients with EGFR Mutated Non-Small Cell Lung Cancer. Available at: https://innovativemedicine.jnj.com/emea/newsroom/immunology/janssen-submits-type-ii-extension-of-indication-application-to-the-european-medicines-agency-seeking-approval-of-rybrevant-amivantamab-in-combination-with-lazertinib-for-the-first-line-treatment-of-patients-with-egfr-mutated-non-small-cell-lung-cancer. Accessed November2024.

¹¹ Janssen.com/EMEA. Johnson & Johnson submits application to the European Medicines Agency seeking approval of subcutaneous formulation of RYBREVANT®▼ (amivantamab) for the treatment of patients with EGFR-mutated non-small cell lung cancer. Available at: https://innovativemedicine.jnj.com/emea/newsroom/oncology/johnson-johnson-submits-application-to-the-european-medicines-agency-seeking-approval-of-subcutaneous-formulation-of-rybrevant-amivantamab-for-the-treatment-of-patients-with-egfr-mutated-non-small-cell-lung-cancer. Accessed November2024.

¹² Cho, BC, et al. Lazertinib versus gefitinib as first-line treatment in patients with EGFR-mutated advanced non-small-cell lung cancer: Results From LASER301. J Clin Oncol. 2023;41(26):4208-4217.

¹³ Global Cancer Observatory. Cancer Today. Available at: https://gco.iarc.who.int/media/globocan/factsheets/populations/908-europe-fact-sheet.pdf. Accessed November2024.

¹⁴ Zappa C, et al. Non-small cell lung cancer: current treatment and future advances. Transl Lung Cancer Res 2016;5(3):288–300.

¹⁵ Wee P & Wang Z. Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways. Cancers 2017;9(12):52.

¹⁶ Pennell NA, et al. A phase II trial of adjuvant erlotinib in patients with resected epidermal growth factor receptor-mutant non-small cell lung cancer. J Clin Oncol 2019;37(2):97-104.

¹⁷ Burnett H, et al. Epidemiological and clinical burden of EGFR exon 20 insertion in advanced non-small cell lung cancer: a systematic literature review. Abstract presented at: World Conference on Lung Cancer Annual Meeting (Singapore); January 29, 2021.

¹⁸ Zhang YL, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget. 2016;7(48):78985- 78993.

¹⁹ Midha A, et al. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity. Am J Cancer Res 2015;5(9):2892-2911.

²⁰ American Lung Association. EGFR and Lung Cancer. Available at: https://www.lung.org/lung-health-diseases/lung-disease-lookup/lung-cancer/symptomsdiagnosis/biomarker-testing/egfr. Accessed November2024.

²¹ Lin JJ, et al. Five-Year Survival in EGFR-Mutant Metastatic Lung Adenocarcinoma Treated with EGFR-TKIs. J Thorac Oncol 2016;11(4):556-65.

²² Nieva J, et al. A real-world (rw) observational study of long-term survival (LTS) and treatment patterns after first-line (1L) osimertinib in patients (pts) with epidermal growth factor receptor (EGFR) mutation-positive (m) advanced non-small cell lung cancer (NSCLC). Ann Oncol 2023;34, S774.

²³ Girard N, et al. Mortality among EGFR-mutated advanced NSCLC patients after frontline osimertinib treatment: A real-world, US attrition analysis. J Thorac Oncol 2023;18(4), S51-52.