Rybrevant

The solution is colourless to pale yellow, with a pH of 5.7 and an osmolality of approximately 310 mOsm/kg.
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.
Excipient with known effect: One mL of solution contains 0.6 mg of polysorbate 80.
Excipients/Inactive Ingredients: Ethylenediaminetetraacetic acid (EDTA) disodium salt dihydrate, L-Histidine, L-Histidine hydrochloride monohydrate, L-Methionine, Polysorbate 80 (E433), Sucrose, Water for injections.

Pharmacotherapeutic group: Monoclonal antibodies and antibody drug conjugates. ATC code: L01FX18.
Pharmacology: Pharmacodynamics: 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.
Pharmacodynamic effects: Albumin: Amivantamab decreased serum albumin concentration, a pharmacodynamic effect of MET inhibition, typically during the first 8 weeks (see Adverse Reactions); 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 1. (See Table 1 and Figure 1.)

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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. (See Figure 2.)

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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.
Locally advanced or metastatic NSCLC with exon 20 insertion mutations: Previously-untreated NSCLC: NSC3001 (PAPILLON) is a randomized, open-label, multicenter phase 3 study comparing treatment with RYBREVANT in combination with carboplatin and pemetrexed to treatment as compared to chemotherapy alone (carboplatin and pemetrexed) in subjects with treatment-naïve, locally advanced or metastatic NSCLC with EGFR Exon 20 insertion mutations, as identified by local testing, plasma samples from 209/308 (67.9%) patients were tested retrospectively using Guardant360 CDx, identifying 155/209 (74.2%) samples with an EGFR exon 20 insertion mutation; 50/209 (23.9%) samples did not have an EGFR exon 20 insertion mutation identified. The remaining 4/209 (1.9%) samples generated an invalid test result.
Tumor 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.
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 randomization. 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.
RYBREVANT was administered intravenously at 1,400 mg (for subjects <80 kg) or 1,750 mg (for subjects ≥80 kg) once weekly through 4 weeks, then every 3 weeks with a dose of 1,750 mg (for patients <80 kg) or 2,100 mg (for subjects ≥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. Randomization was stratified by ECOG performance status, prior brain metastases, and prior EGFR TKI use. Subjects randomized to the carboplatin and pemetrexed arm who had confirmed disease progression were permitted to cross over to receive RYBREVANT monotherapy.
A total of 308 subjects were randomized (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 (65%); 58% never smoked; 23% had history of brain metastasis and 84% had Stage IV cancer at initial diagnosis.
RYBREVANT in combination with carboplatin and pemetrexed demonstrated a clinically meaningful and statistically significant improvement in progression-free survival (PFS) compared to carboplatin and pemetrexed, with a HR of 0.40 (95% CI: 0.30, 0.53; p<0.0001), demonstrating a 61% reduction in the risk of disease progression or death in the patients. At the time of primary analysis, overall survival showed a strong trend suggestive of a survival benefit in favor of the RYBREVANT-treated arm, where 65 subjects (42%) randomized to receive carboplatin and pemetrexed crossed over to receive RYBREVANT monotherapy (see Figure 5). A greater proportion of patients treated with RYBREVANT in combination with carboplatin and pemetrexed were alive at 12 months and 18 months (74% and 72%, respectively) compared to patients treated with carboplatin and pemetrexed (68% and 54%, respectively). Analyses of post-progression endpoints demonstrated that PFS benefit was preserved through subsequent lines of therapy, with a median follow-up of 14.9 (range: 0.3 to 27.0) months.
Efficacy results for Study 3001 are summarized in Table 2, Figure 3 and Figure 4. (See Table 2 and Figure 3.)

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The pre-planned sensitivity analysis evaluating PFS as assessed by the treating investigator showed a 62% reduction in the risk of disease progression or death (median 12.9 months) in participants randomized to the RYBREVANT in combination with carboplatin and pemetrexed arm (HR of 0.38 [95% CI: 0.29, 0.52, nominal p<0.001]), consistent with that observed in the BICR assessment of PFS.
Additionally, consistent with the assessment by BICR, results of the DOR and ORR analysis based on the treating investigator's assessment also showed a significant treatment benefit with RYBREVANT in combination with carboplatin and pemetrexed. The median DOR was 15.28 months (95% CI: 10.87, NE) and the ORR analysis showed significantly improved anti-tumor activity with an ORR of 66.0% (95% CI: 57.9, 73.5).
The PFS benefit of RYBREVANT in combination with carboplatin and pemetrexed compared to carboplatin and pemetrexed was consistent across 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). See Figure 4. (See Figures 4 and 5.)

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Patient Reported Outcomes: Patient-reported symptoms and health-related quality of life (HRQoL) were electronically collected using the EORTC QLQ-C30 and PROMIS-PF. These instruments were administered approximately once every 6 weeks until end of treatment. They were then administered 30 days after last dose of treatment, then once every 12 weeks for one year. Compliance was high at baseline (>97%) and during treatment (>80% through Cycle 31) in both arms. At baseline, patients in both treatment arms reported low symptom burden and high levels of functioning.
The PRO analyses demonstrated that the clinical benefits of receiving RYBREVANT with carboplatin and pemetrexed were achieved without compromising HRQoL. Across all PRO scales, patients’ baseline HRQoL was maintained while on treatment in both arms.
Time to deterioration analyses showed that median time to symptom worsening was delayed by 2 to 5 months for RYBREVANT with carboplatin and pemetrexed compared to carboplatin and pemetrexed alone for dyspnea (HR=0.75, 95% CI: 0.55, 1.01), pain (HR=0.74, 95% CI: 0.55, 1.00), insomnia (HR=0.75, 95% CI: 0.54, 1.04), diarrhea (HR=0.67, 95% CI: 0.47, 0.95), and nausea/vomiting (HR=0.74, 95% CI: 0.55, 0.98).
Previously-treated NSCLC: EDI1001 (CHRYSALIS) is a multicenter, open-label, multi-cohort study conducted to assess the safety and efficacy of RYBREVANT in subjects with locally advanced or metastatic NSCLC. Efficacy was evaluated in 81 subjects with locally advanced or metastatic NSCLC who had EGFR Exon 20 insertion mutations as determined by previous local standard of care testing, whose disease had progressed on or after platinum-based chemotherapy, and who had median follow-up of 9.7 months. RYBREVANT was administered intravenously at 1050 mg for subjects <80 kg or 1400 mg for subjects ≥80 kg once weekly for 4 weeks, then every 2 weeks starting at Week 5 until disease progression or unacceptable toxicity.
The median age was 62 (range: 42–84) years, with 9% of the subjects ≥75 years of age; 59% were female; and 49% were Asian and 37% were White. The median number of prior therapies was 2 (range: 1 to 7 therapies). At baseline, 99% had Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (99%); 53% never smoked; 75% had Stage IV cancer; and 22% had previous treatment for brain metastases. Insertions in Exon 20 were observed at 8 different residues; the most common residues were A767 (24%), S768 (16%), D770 (11%), and N771 (11%).
Efficacy results are summarized in Table 3. (See Table 3.)

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Anti-tumor activity was observed across all mutation variants.
Elderly: No overall differences in effectiveness were observed between patients ≥65 years of age and patients <65 years of age.
Pharmacokinetics: 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 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.
Toxicology: 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 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.

RYBREVANT is indicated: in combination with carboplatin and pemetrexed for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) Exon 19 deletions or Exon 21 L858R substitution mutations 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 locally advanced or metastatic NSCLC with activating EGFR Exon 20 insertion mutations.
As monotherapy for the treatment of adult patients with locally advanced or metastatic NSCLC with activating EGFR Exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy.

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 until the initiation of therapy; testing does not need to be repeated once EGFR mutation status has been established (see Pharmacology: Pharmacodynamics under Actions)
Posology: Premedications should be administered to reduce the risk of IRRs with RYBREVANT (see "Dose modifications" and "Recommended concomitant medicinal products" as follows).
Every 3 weeks: The recommended dosages of RYBREVANT, when used in combination with carboplatin and pemetrexed, is provided in Table 4 (see "Infusion rates" as follows and Table 8). (See Table 4.)

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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 Pharmacology: Pharmacodynamics under Actions 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 5 (see "Infusion rates" as follows and Table 9). (See Table 5.)

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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.
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 6. See also specific dose modifications for specific adverse reactions Table 6 as follows. (See Table 6.)

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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 Precautions).
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 8 and 9). Concomitant medicinal products should be administered at the next dose (including dexamethasone (20 mg) or equivalent (see Table 7).
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 6). 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 Precautions).
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 Precautions).
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 7). 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. (See Table 7.)

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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 Adverse Reactions, Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions).
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 Pharmacology: Pharmacokinetics under Actions). If treatment is started, patients should be monitored for adverse reactions with dose modifications per the recommendations as previously mentioned.
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 Phamacology: Pharmacokinetics under Actions). If treatment is started, patients should be monitored for adverse reactions with dose modifications per the recommendations as previously mentioned.
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 Special precautions for disposal and other handling under Cautions for Usage.
Infusion rates: Following dilution, the infusion should be administered intravenously at the infusion rates presented in Tables 8 or 9 as follows. 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 Special precautions for disposal and other handling under Cautions for Usage). 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. (See Tables 8 and 9.)

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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.

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

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 Adverse Reactions).
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 Dosage & Administration).
Interstitial lung disease: Interstitial lung disease (ILD) or ILD-like adverse reactions (e.g., pneumonitis) have been reported in patients treated with amivantamab (see Adverse Reactions). 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 Dosage & Administration).
Skin and nail reactions: Rash (including dermatitis acneiform), pruritus and dry skin occurred in patients treated with amivantamab (see Adverse Reactions). 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 Dosage & Administration).
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 Adverse Reactions). 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 Dosage & Administration.
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 Special precautions for disposal and other handling under Cautions for Usage).
Polysorbate content: This medicinal product contains 0.6 mg of polysorbate 80 in each mL, which is equivalent to 4.2 mg per 7 mL vial. Polysorbates may cause hypersensitivity reactions.
Effects on ability to drive and use machines: RYBREVANT may have moderate influence on the ability to drive and use machines. See Adverse Reactions (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.

Women of child-bearing potential/Contraception: Women of child-bearing potential should use effective contraception during and for 3 months after cessation of amivantamab treatment.
Pregnancy: There are no human data to assess the risk of amivantamab use during pregnancy. No animal reproductive studies were conducted to inform a drug-associated risk. Administration of EGFR and MET inhibitor molecules in pregnant animals resulted in an increased incidence of impairment of embryo-foetal development, embryo lethality, and abortion. Therefore, based on its mechanism of action and findings in animal models, amivantamab could cause foetal harm when administered to a pregnant woman. Amivantamab should not be given during pregnancy unless the benefit of treatment of the woman is considered to outweigh potential risks to the foetus. If the patient becomes pregnant while taking this medicinal product the patient should be informed of the potential risk to the foetus (see Pharmacology: Toxicology: Preclinical safety data under Actions).
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.

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 10 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 as follows 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. (See Table 10.)

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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 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 11 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 as follows 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. (See Table 11.)

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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 Precautions).
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 Precautions).
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 Precautions).
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 Precautions).
Other special populations: Elderly: There are limited clinical data with amivantamab in patients 75 years of age or over (see Pharmacology: Pharmacodynamics under Actions). 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.

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.

Incompatibilities: This medicinal product must not be mixed with other medicinal products except those mentioned in Special precautions for disposal and other handling as follows.
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 Dosage & Administration). 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.
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 Dosage & Administration.
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.

Store in a refrigerator (2°C to 8°C).
Do not freeze.
Store in the original package in order to protect from light.
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.

Targeted Cancer Therapy

L01FX18 - amivantamab ; Belongs to the class of other monoclonal antibodies and antibody drug conjugates. Used in the treatment of cancer.

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