Rybrevant

Amivantamab.

Each single-use vial contains 350 mg of amivantamab per 7 mL vial (or 50 mg of amivantamab per mL).
RYBREVANT is available as a colorless to pale yellow preservative-free liquid concentrate for intravenous infusion after dilution.
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 (see Pharmacology: Pharmacodynamics: Mechanism of action under Actions).
Excipients/Inactive Ingredients: EDTA disodium salt dihydrate, L-Histidine, L-Histidine hydrochloride monohydrate, L-Methionine, Polysorbate 80, Sucrose, Water for Injection.

Pharmacotherapeutic group: EGFR and MET inhibitor. ATC code: not yet assigned.
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 tumors with activating and resistance EGFR mutations and MET mutations and amplifications. Amivantamab binds to the extracellular domains of EGFR and MET.
Preclinical studies show amivantamab is active against tumors with primary EGFR activating mutations such as Exon 19 deletions, L858R substitution, and Exon 20 insertion mutations; secondary EGFR resistance mutations such as T790M and C797S; and resistance to EGFR inhibition due to activation of the MET pathway. Amivantamab disrupts EGFR and MET signaling functions through blocking ligand binding and enhancing degradation of EGFR and MET, thereby preventing tumor growth and progression. The presence of EGFR and MET on the surface of tumor cells also allows for targeting of these cells for destruction by immune effector cells, such as natural killer cells and macrophages, through antibody-dependent cellular cytotoxicity (ADCC) and trogocytosis mechanisms, respectively.
Pharmacodynamic effects: Albumin: Amivantamab decreased serum albumin concentration, a pharmacodynamic effect of MET inhibition, typically during the first 8 weeks; thereafter, albumin concentration stabilized for the remainder of amivantamab treatment.
Immunogenicity: As with all therapeutic proteins, there is the potential for immunogenicity. In a clinical trial of patients with locally advanced or metastatic NSCLC treated with RYBREVANT, 3 (1%) of the 286 evaluable patients tested positive for anti-amivantamab antibodies.
Clinical studies: Locally advanced or metastatic NSCLC with exon 20 insertion mutations: 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 1. (See Table 1.)

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Anti-tumor activity was observed across all mutation variants.
Pharmacokinetics: Amivantamab area under the concentration-time curve (AUC_1week) increases proportionally over a dose range from 350 to 1750 mg (0.33 to 1.67 times the recommended dose for subjects <80 kg and 0.25 to 1.25 times the recommended dose for subjects ≥80 kg).
Following administration of RYBREVANT at the recommended dose and schedule, the mean ± SD serum maximal concentration (C_max) was 836 ± 264 mcg/mL at 1050 mg for subjects <80 kg and 655 ± 109 mcg/mL at 1400 mg for subjects ≥80 kg at the end of weekly dosing following the fifth dose. The mean ± SD AUC_1week following the fifth dose was 94,946 ± 35,440 mcg.h/mL at 1050 mg for subjects <80 kg and 76,946 ± 14,557 mcg.h/mL at 1400 mg for subjects ≥80 kg. The mean serum AUC_1week was approximately 2.9-fold higher after the fifth dose following the weekly dosing compared to the first dose.
When RYBREVANT was administered, amivantamab steady state was achieved approximately 2 months into the every 2-week dosing period (by the ninth infusion) at 1050 mg, and amivantamab mean ± SD ratio of AUC_1week at steady state to AUC_1week after the first dose was 2.44 ± 0.54.
Distribution: Amavintamab mean ± SD volume of distribution estimated from population PK parameters was 5.13 ± 1.78 L following administration of the recommended dose of RYBREVANT.
Elimination: Amivantamab clearance decreased with increasing dose and with multiple dosing. The mean ± SD linear clearance was estimated to be 360 ± 144 mL/day and the mean ± SD estimated terminal half-life associated with linear clearance estimated from population PK parameter estimates was 11.3 ± 4.53 days following administration of the recommended dose of RYBREVANT.
Special populations: Pediatrics (17 years of age and younger): The pharmacokinetics of RYBREVANT in pediatric patients have not been investigated.
Elderly (65 years of age and older): No clinically meaningful differences in the pharmacokinetics of amivantamab were observed based on age (32-87 years).
Renal impairment: No clinically meaningful effect on the pharmacokinetics of amivantamab was observed in patients with mild (60 ≤ creatinine clearance [CrCl] <90 mL/min) and moderate (29 ≤ CrCl <60 mL/min) renal impairment. The effect of severe renal impairment (15 ≤ CrCl <29 mL/min) on amivantamab pharmacokinetics is unknown.
Hepatic impairment: Changes in hepatic function are unlikely to have any effect on the elimination of amivantamab since IgG1-based molecules such as amivantamab are not metabolized through hepatic pathways.
No clinically meaningful effect in the pharmacokinetics of amivantamab was observed based on mild hepatic impairment [(total bilirubin ≤ ULN and AST > ULN) or (ULN < total bilirubin ≤1.5 x ULN)]. The effect of moderate (total bilirubin 1.5 to 3 times ULN) and severe (total bilirubin >3 times ULN) hepatic impairment on amivantamab pharmacokinetics is unknown.
Gender: The clearance of amivantamab was 24% higher in males than in females; however, no clinically meaningful differences in the pharmacokinetics of amivantamab were observed based on gender.
Weight: The central volume of distribution and clearance of amivantamab increased with increasing body weight. Similar amivantamab exposures were achieved at the recommended dose of RYBREVANT in patients with a body weight <80 kg who received 1050 mg and patients with a body weight ≥80 kg who received 1400 mg.
Toxicology: Non-clinical Information: In repeat-dose toxicity studies in cynomolgus monkeys, amivantamab was well-tolerated at weekly doses up to 120 mg/kg intravenously for 6 weeks or 3 months (~6-8x C_max and ~5-7x AUC human exposure for 1050 and 1400 mg intravenous doses). There were no effects on cardiovascular, respiratory, and nervous system function. Clinical pathology demonstrated non-adverse elevations in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and globulins, and non-adverse decreases in albumin when compared to the control group. All these values returned to normal ranges in recovery groups. A subcutaneous local tolerance study showed that amivantamab was well tolerated at injection sites in cynomolgus monkeys administered two 125 mg/kg weekly doses.
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 reproductive toxicology studies have been performed to evaluate the potential effects of amivantamab.

RYBREVANT is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating epidermal-growth factor receptor (EGFR) Exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy.
This indication is approved under conditional approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

RYBREVANT should be administered by a healthcare professional with appropriate medical support to manage infusion-related reactions (IRRs) if they occur (see Precautions).
Administer pre-infusion medications (see Pre-infusion medications as follows).
When considering the use of RYBREVANT, EGFR Exon 20 insertion mutation presence should be established using a validated test (see Pharmacology: Pharmacodynamics: Pharmacodynamic effects and Clinical studies under Actions).
Dosage - adults (≥18 years): The recommended dose of RYBREVANT is provided in Table 2, and the dosing schedule is provided in Table 3, (see Infusion Rates - Table 5). (See Tables 2 and 3.)

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It is recommended that patients are treated with RYBREVANT until unacceptable toxicity or lack of clinical benefit.
Pre-infusion medications: Prior to initial infusion of RYBREVANT (Week 1, Days 1 and 2), administer antihistamines, antipyretics, and glucocorticoids to reduce the risk of IRRs. For subsequent doses, administer antihistamines and antipyretics. Administer antiemetics as needed. (See Table 4.)

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Infusion Rates: Administer RYBREVANT infusion intravenously according to the infusion rates in Table 5. Due to the frequency of IRRs at the first dose, infusion via a peripheral vein at Week 1 and Week 2 should be considered to minimize drug exposure in the event of an IRR; infusion via central line may be administered for subsequent weeks. It is recommended for the first dose to be diluted as close to administration as possible to allow for maximal flexibility in IRR management. (See Table 5.)

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Missed dose(s): If a planned dose of RYBREVANT is missed, the dose should be administered as soon as possible and the dosing schedule should be adjusted accordingly, maintaining the treatment interval.
Dose modifications: The recommended dose reductions for adverse reactions (see Table 7) are listed in Table 6. (See Table 6.)

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The recommended dosage modifications for adverse reactions are provided in Table 7. (See Table 7.)

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Special populations: Pediatrics (17 years of age and younger): The safety and efficacy of RYBREVANT have not been established in pediatric patients.
Elderly (65 years of age and older): Of the 362 patients treated with RYBREVANT in EDI1001, 41% were 65 years of age or older, and 12% were 75 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients. No dosage adjustment is necessary (see Pharmacology: 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 dosage adjustment is necessary for patients with mild or moderate renal impairment. No data are available in patients with severe renal impairment (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: No formal studies of amivantamab in patients with hepatic impairment have been conducted. Based on population PK analyses, no dosage adjustment is necessary for patients with mild hepatic impairment. No data are available in patients with moderate or severe hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).

Symptoms and signs: There is no information on overdosage with RYBREVANT.
Treatment: There is no known specific antidote for RYBREVANT overdose. In the event of an overdose, stop RYBREVANT, undertake general supportive measures until clinical toxicity has diminished or resolved.

None.

The data described in Precautions reflects the safety profile of 380 patients with locally advanced or metastatic NSCLC who received 1050 mg (for patients <80 kg) or 1400 mg (for patients ≥80 kg) of RYBREVANT monotherapy in Study EDI1001.
Infusion-related reactions: Infusion-related reactions occurred in 67% of patients treated with RYBREVANT. 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. The most frequent signs and symptoms include chills, nausea, dyspnea, flushing, chest discomfort, and vomiting.
Prior to initial infusion (Week 1) of RYBREVANT, administer antihistamines, antipyretics, and glucocorticoids to reduce the risk of IRRs. For subsequent doses, administer antihistamines and antipyretics. Administer the initial infusion of RYBREVANT in split doses on Week 1, Days 1 and 2 (see Dosage & Administration).
Treat patients with RYBREVANT in a setting with appropriate medical support necessary to treat IRRs. Interrupt RYBREVANT infusion at the first sign of IRRs and institute post-infusion medication as clinically indicated. Upon resolution of symptoms, resume the infusion at 50% of the previous rate. For recurrent Grade 3 or 4 IRRs, permanently discontinue RYBREVANT (see Dosage & Administration).
Interstitial lung disease: Interstitial lung disease (ILD) or ILD-like adverse reactions (e.g. pneumonitis) occurred in 2.6% of patients treated with RYBREVANT. Patients with a medical history of ILD, drug-induced ILD, radiation pneumonitis that required steroid treatment, or any evidence of clinically active ILD have not been studied.
Monitor patients for symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). If symptoms develop, interrupt treatment with RYBREVANT pending investigation of these symptoms. Evaluate suspected ILD and initiate appropriate treatment as necessary. Discontinue RYBREVANT in patients with confirmed ILD (see Dosage & Administration).
Skin and nail reactions: Rash (including dermatitis acneiform), pruritus and dry skin occurred in patients treated with RYBREVANT. Most cases were Grade 1 or 2, with Grade 3 events occurring in 3% of patients. Rash leading to RYBREVANT 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 RYBREVANT. Most events were Grade 1 or 2, with Grade 3 nail toxicity occurring in 1.8% of patients.
Toxic epidermal necrolysis (TEN) has been reported. Permanently discontinue RYBREVANT if TEN is confirmed.
Instruct patients to limit sun exposure during and for 2 months after RYBREVANT therapy. Protective clothing and use of sunscreen is advisable. Alcohol-free emollient cream is recommended for dry areas with the use of RYBREVANT. If skin or nail reactions develop, start topical corticosteroids and topical and/or oral antibiotics. For Grade 3 or poorly-tolerated Grade 2 events, add systemic antibiotics and oral steroids and consider dermatologic consultation. Withhold, dose reduce, or permanently discontinue RYBREVANT based on severity (see Dosage & Administration).
Eye disorders: Eye disorders, including keratitis (0.5%), occurred in patients treated with RYBREVANT. Other reported adverse reactions included dry eye, blurred vision, eye pruritus, visual impairment, aberrant eyelash growth, ocular hyperemia, conjunctival hyperemia, blepharitis and uveitis. All events were Grade 1-2. Refer patients presenting with worsening eye symptoms promptly to an ophthalmologist and advise discontinuation of contact lenses until symptoms are evaluated.
Effects on Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed. If patients experience treatment-related symptoms affecting their ability to concentrate and react, it is recommended that they do not drive or use machines until the effect subsides.

Pregnancy: There are no human or animal data to assess the risk of RYBREVANT in pregnancy. Administration of other EGFR and MET inhibitor molecules to pregnant animals has resulted in an increased incidence of impairment of embryo-fetal development, embryolethality, and abortion. Therefore, based on its mechanism of action and findings in animal models, RYBREVANT could cause fetal harm when administered to a pregnant woman.
RYBREVANT should not be used during pregnancy unless the benefit of treatment to the woman is considered to outweigh potential risks to the fetus. If the patient becomes pregnant while taking this drug, the patient should be informed of the potential risk to the fetus.
Breast-feeding: It is not known whether RYBREVANT is excreted in human or animal milk or affects milk production. 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. Because of the potential for serious adverse reactions from RYBREVANT in breast-fed infants, advise women not to breast-feed during treatment with RYBREVANT and for 3 months following the last dose of RYBREVANT.
Contraception: Due to the risk that RYBREVANT can cause fetal harm when administered to pregnant women, advise female patients of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of RYBREVANT. Male patients must use effective contraception (e.g., condom) and not donate or store semen during treatment and for 3 months after the last dose of RYBREVANT.
Fertility: No data are available to determine potential effects of RYBREVANT on fertility in males or females.

Throughout this section, adverse reactions are presented. Adverse reactions are adverse events that were considered to be reasonably associated with the use of amivantamab based on the comprehensive assessment of the available adverse event information. A causal relationship with amivantamab cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of RYBREVANT was evaluated in Study EDI1001, which included 153 patients with locally advanced or metastatic NSCLC with EGFR Exon 20 mutations whose disease has progressed on or after platinum-based chemotherapy. Patients received RYBREVANT 1050 mg (for patients <80 kg) or 1400 mg (for patients ≥80 kg) by intravenous infusion once weekly for 4 weeks, then every 2 weeks starting at Week 5 until disease progression or unacceptable toxicity. The median treatment duration was 5.6 months (range: 0.0 to 23.9 months).
The most common adverse reactions ≥20% were rash, IRR, nail toxicity, hypoalbuminemia, fatigue, edema, stomatitis, nausea, constipation, dry skin, and alanine aminotransferase increased. Serious adverse reactions in >1% of patients included ILD, diarrhea, IRR, and rash. Five percent of patients discontinued RYBREVANT due to adverse reactions. The most frequent adverse reactions leading to treatment discontinuation were IRR and ILD. (See Table 8.)

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Adverse reactions occurring in <10% of RYBREVANT-treated patients with NSCLC Exon 20 insertion mutations in Study EDI1001 are summarized in Table 9. (See Table 9.)

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No drug interaction studies have been performed.

Preparation for administration: RYBREVANT solution must be diluted and prepared for intravenous infusion by a healthcare professional using aseptic technique.
1. Determine the dose required (either 1050 mg or 1400 mg) and number of RYBREVANT vials needed based on patient’s baseline weight (see Dosage under Dosage & Administration). Each vial of RYBREVANT contains 350 mg of amivantamab.
2. Check that the RYBREVANT solution is colorless to pale yellow. Do not use if discoloration or visible particles are present.
3. Withdraw and then discard a volume of either 5% dextrose [glucose] solution or 0.9% sodium chloride solution from the 250 mL infusion bag equal to the volume of RYBREVANT to be added (i.e., discard 7 mL diluent from the infusion bag for each RYBREVANT vial). Infusion bags must be made of polyvinyl chloride (PVC), polypropylene (PP), polyethylene (PE), or polyolefin blend (PP+PE).
4. Withdraw 7 mL of RYBREVANT from each vial and add it to the infusion bag. The final volume in the infusion bag should be 250 mL. Each vial contains a 0.5 mL overfill to ensure sufficient extractable volume. Discard any unused portion left in the vial.
5. Gently invert the bag to mix the solution. Do not shake.
6. Visually inspect the diluted solution before administration. Do not use if discoloration or visible particles are observed.
7. Diluted solutions should be administered within 10 hours (including infusion time) at room temperature (15°C to 25°C) and in room light.
Administration: 1. 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 0.2 micrometer). Administration sets must be made of either polyurethane (PU), polybutadiene (PBD), PVC, PP, or PE.
2. Do not infuse RYBREVANT concomitantly in the same intravenous line with other agents.
3. This medicinal product is for single use only. Any unused medicinal product should be disposed of in accordance with local requirements.
Incompatibilities: This medicinal product must not be mixed with other medicinal products except those mentioned in Dosage & Administration.
Instructions for Use and Handling and Disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Store in a refrigerator at 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 Shelf-Life as follows.
Shelf Life: 24 months.
After dilution: Since amivantamab solutions do not contain a preservative, unless the method of opening/dilution precludes the risk of microbial contamination, the product should be used immediately. Administer diluted solutions within 10 hours (including infusion time) at room temperature (15°C to 25°C) and in room light.

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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