Rybrevant

Amivantamab.

Each RYBREVANT vial contains 350 mg amivantamab (50 mg/mL).
Amivantamab-vmjw is a low-fucose human immunoglobulin G1-based bispecific antibody directed against the EGF and MET receptors, produced by mammalian cell line (Chinese Hamster Ovary [CHO]) using recombinant DNA technology that has a molecular weight of approximately 148 kDa. RYBREVANT (amivantamab-vmjw) injection for intravenous infusion is a sterile, preservative-free, colorless to pale yellow solution in single-dose vials. The pH is 5.7.
Excipients/Inactive Ingredients: EDTA disodium salt dihydrate (0.14 mg), L-histidine (2.3 mg), L-histidine hydrochloride monohydrate (8.6 mg), L-methionine (7 mg), polysorbate 80 (4.2 mg), sucrose (595 mg), and water for injection, USP.

Pharmacology: Mechanism of Action: Amivantamab-vmjw is a bispecific antibody that binds to the extracellular domains of EGFR and MET.
In in vitro and in vivo studies amivantamab-vmjw was able to disrupt EGFR and MET signaling functions through blocking ligand binding and, in exon 20 insertion mutation models, degradation of EGFR and MET. 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.
Pharmacodynamics: The exposure-response relationship and time-course of pharmacodynamic response of amivantamab-vmjw have not been fully characterized in patients with NSCLC with EGFR exon 20 insertion mutations.
Clinical Studies: The efficacy of RYBREVANT was evaluated in patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations in a multicenter, open-label, multi-cohort clinical trial (CHRYSALIS, NCT02609776). The study included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy, Patients with untreated brain metastases and patients with a history of ILD requiring treatment with prolonged steroids or other immunosuppressive agents within the last 2 years were not eligible for the study.
In the efficacy population, EGFR exon 20 insertion mutation status was determined by prospective local testing using tissue (94%) and/or plasma (6%) samples. Of the 81 patients with EGFR exon 20 insertion mutations identified by local testing, plasma samples from 78/81 (96%) patients were tested retrospectively using Guardant360 CDx, identifying 62/78 (79%) samples with an EGFR exon 20 insertion mutation; 16/78 (21%) samples did not have an EGFR exon 20 insertion mutation identified.
Patients received RYBREVANT at 1050 mg (for patient baseline body weight <80 kg) or 1400 mg (for patient baseline body weight ≥80 kg) once weekly for 4 weeks, then every 2 weeks thereafter until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by Blinded Independent Central Review (BICR). An additional efficacy outcome measure was duration of response (DOR) by BICR.
The efficacy population included 81 patients with NSCLC with EGFR exon 20 insertion mutation with measurable disease who were previously treated with platinum-based chemotherapy. The median age was 62 (range: 42 to 84) years, 59% were female; 49% were Asian, 37% were White, 2.5% were Black; 74% had baseline body weight <80 kg; 95% had adenocarcinoma; and 46% had received prior immunotherapy. The median number of prior therapies was 2 (range: 1 to 7). At baseline, 67% had Eastern Cooperative Oncology Group (ECOG) performance status of 1; 53% never smoked; all patients had metastatic disease; and 22% had previously treated brain metastases.
Efficacy results are summarized in Table 1. (See Table 1.)

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Pharmacokinetics: Amivantamab-vmjw exposures increased proportionally over a dosage range from 350 to 1750 mg (0.25 to 1.25 times the maximum approved recommended dosage). Steady state of amivantamab-vmjw concentrations was achieved by the 9^th infusion. The accumulation ratio at steady state was 2.4.
Distribution: The amivantamab-vmjw mean (±SD) volume of distribution is 5.13 (±1.78) L.
Elimination: The mean (±SD) clearance of amivantamab-vmjw is 360 (±144) mL/day and the terminal half-life is 11.3 (±4.53) days.
Specific Populations: No clinically meaningful differences in the pharmacokinetics of amivantamab-vmjw were observed based on age (range: 32-87 years), sex, race, creatinine clearance (CLcr 29 to 276 mL/min), or mild hepatic impairment [(total bilirubin ≤ULN and AST >ULN) or (ULN <total bilirubin ≤1.5 times ULN)]. The pharmacokinetics of amivantamab-vmjw have not been studied in patients with severe renal impairment (CLcr 15 to 29 mL/min) or patients with moderate (total bilirubin 1.5 to 3 times ULN) to severe (total bilirubin >3 times ULN) hepatic impairment.
Body Weight: Increases in body weight increased the volume of distribution and clearance of amivantamab-vmjw. Amivantamab-vmjw exposures are 30-40% lower in patients who weighed ≥80 kg compared to patients with body weight <80 kg at the same dose. Exposures of amivantamab-vmjw were comparable between patients who weighed <80 kg and received 1050 mg dose and patients who weighed ≥80 kg and received 1400 mg.
Toxicology: Preclinical Safety Data: Carcinogenesis, Mutagenesis, Impairment of Fertility: No studies have been performed to assess the potential of amivantamab-vmjw for carcinogenicity or genotoxicity. Fertility studies have not been performed to evaluate the potential effects of amivantamab-vmjw. In 6-week and 3-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs.

RYBREVANT (amivantamab) is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by a validated test, whose disease has progressed on or after platinum-based chemotherapy.
This indication is approved under accelerated approval based on overall response rate and duration of response [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Patient Selection: Select patients for treatment with RYBREVANT based on the presence of EGFR exon 20 insertion mutations in tumor or plasma specimens [see Pharmacology: Pharmacodynamics: Clinical Studies under Actions]. If no mutation is detected in a plasma specimen, test tumor tissue.
Recommended Dosage: The recommended doses of RYBREVANT, based on baseline body weight, are provided in Table 2, and the dosing schedule is provided in Table 3. (See Tables 2 and 3.)

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Administer premedications before each RYBREVANT infusion as recommended [see Recommended Premedications as follows]. Administer diluted RYBREVANT intravenously according to the infusion rates in Table 7, with the initial dose as a split infusion on Week 1 on Day 1 and Day 2 [see Preparation and Administration as follows]. Administer RYBREVANT until disease progression or unacceptable toxicity.
Recommended Premedications: Prior to initial infusion of RYBREVANT (Week 1, Days 1 and 2), administer premedication as described in Table 4 to reduce the risk of infusion-related reactions: [see Infusion-Related Reactions under Precautions]. (See Table 4.)

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Administer both antihistamine and antipyretic prior to all infusions. Glucocorticoid administration required for Week 1, Days 1 and 2 doses only and as necessary for subsequent infusions.
Dosage Modifications for Adverse Reactions: The recommended RYBREVANT dose reductions for adverse reactions (see Table 6) are listed in Table 5. (See Table 5.)

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The recommended RYBREVANT dosage modifications for adverse reactions are provided in Table 6. (See Table 6.)

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Preparation: Dilute and prepare RYBREVANT for intravenous infusion before administration.
Check that the RYBREVANT solution is colorless to pale yellow. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if discoloration or visible particles are present.
Determine the dose required (either 1050 mg or 1400 mg) and number of RYBREVANT vials needed based on patient's baseline weight [see Recommended Dosage as previously mentioned]. Each vial of RYBREVANT contains 350 mg of amivantamab-vmjw.
Withdraw and then discard a volume of either 5% dextrose 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). Only use infusion bags made of polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE), or polyolefin blend (PP+PE).
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. Discard any unused portion left in the vial.
Gently invert the bag to mix the solution. Do not shake.
Diluted solutions should be administered within 10 hours (including infusion time) at room temperature 59°F to 77°F (15°C to 25°C).
Administration: Administer the diluted solution [see Preparation as previously mentioned] 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) primed with diluent only. Administration sets must be made of either polyurethane (PU), polybutadiene (PBD), PVC, PP, or PE.
Do not infuse RYBREVANT concomitantly in the same intravenous line with other agents.
Administer RYBREVANT via a peripheral line on Week 1 and Week 2 given the high incidence of infusion-related reactions during initial treatment [see Infusion-Related Reactions under Precautions]. RYBREVANT may be administered via central line for subsequent weeks. For the initial infusion, prepare RYBREVANT as close to administration time as possible to allow for the possibility of extended infusion time in the event of an infusion-related reaction.
Administer RYBREVANT infusion intravenously according to the infusion rates in Table 7. (See Table 7.)

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Pediatric Use: The safety and efficacy of RYBREVANT have not been established in pediatric patients.
Geriatric Use: Of the 129 patients treated with RYBREVANT, 41% were 65 years of age or older, and 9% were 75 years of age or older. No clinically important differences in safety or efficacy were observed between patients who were ≥65 years of age and younger patients.

None.

Warning according to the announcement from Ministry of Public Health: This medicinal product may cause serious harm. It must be used only under physician's supervision.

Infusion-Related Reactions: RYBREVANT can cause infusion-related reactions (IRR); signs and symptoms of IRR include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting.
Based on the safety population [see Clinical Trials Experience under Adverse Reactions], IRR occurred in 66% of patients treated with RYBREVANT. Among patients receiving treatment on Week 1 Day 1, 65% experienced an IRR, while the incidence of IRR was 3.4% with the Day 2 infusion, 0.4% with the Week 2 infusion, and cumulatively 1.1% with subsequent infusions. Of the reported IRRs, 97% were Grade 1-2, 2.2% were Grade 3, and 0.4% were Grade 4. The median time to onset was 1 hour (range 0.1 to 18 hours) after start of infusion. The incidence of infusion modifications due to IRR was 62% and 1.3% of patients permanently discontinued RYBREVANT due to IRR.
Premedicate with antihistamines, antipyretics, and glucocorticoids and infuse RYBREVANT as recommended [see Recommended Premedications under Dosage & Administration]. Administer RYBREVANT via a peripheral line on Week 1 and Week 2 [see Administration under Dosage & Administration].
Monitor patients for any signs and symptoms of infusion reactions during RYBREVANT infusion in a setting where cardiopulmonary resuscitation medication and equipment are available. Interrupt infusion if IRR is suspected. Reduce the infusion rate or permanently discontinue RYBREVANT based on severity [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
Interstitial Lung Disease/Pneumonitis: RYBREVANT can cause interstitial lung disease (ILD)/pneumonitis. Based on the safety population [see Clinical Trials Experience under Adverse Reactions], ILD/pneumonitis occurred in 3.3% of patients treated with RYBREVANT, with 0.7% of patients experiencing Grade 3 ILD/pneumonitis. Three patients (1%) discontinued RYBREVANT due to ILD/pneumonitis.
Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold RYBREVANT in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
Dermatologic Adverse Reactions: RYBREVANT can cause rash (including dermatitis acneiform), pruritus and dry skin. Based on the safety population [see Clinical Trials Experience under Adverse Reactions], rash occurred in 74% of patients treated with RYBREVANT, including Grade 3 rash in 3.3% of patients. The median time to onset of rash was 14 days (range: 1 to 276 days). Rash leading to dose reduction occurred in 5% of patients, and RYBREVANT was permanently discontinued due to rash in 0.7% of patients [see Clinical Trials Experience under Adverse Reactions].
Toxic epidermal necrolysis (TEN) occurred in one patient (0.3%) treated with RYBREVANT.
Instruct patients to limit sun exposure during and for 2 months after treatment with RYBREVANT. Advise patients to wear protective clothing and use broad-spectrum UVA/UVB sunscreen. Alcohol-free emollient cream is recommended for dry skin.
If skin reactions develop, start topical corticosteroids and topical and/or oral antibiotics. For Grade 3 reactions, add oral steroids and consider dermatologic consultation. Promptly refer patients presenting with severe rash, atypical appearance or distribution, or lack of improvement within 2 weeks to a dermatologist. Withhold, dose reduce or permanently discontinue RYBREVANT based on severity [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
Ocular Toxicity: RYBREVANT can cause ocular toxicity including keratitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, and uveitis. Based on the safety population [see Clinical Trials Experience under Adverse Reactions], keratitis occurred in 0.7% and uveitis occurred in 0.3% of patients treated with RYBREVANT. All events were Grade 1-2. Promptly refer patients presenting with eye symptoms to an ophthalmologist. Withhold, dose reduce or permanently discontinue RYBREVANT based on severity [see Dosage Modifications for Adverse Reactions under Dosage & Administration].
Effect on ability to drive and use machine: 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.
Use in Pregnancy: Embryo-Fetal Toxicity: Based on its mechanism of action and findings from animal models, RYBREVANT can cause fetal harm when administered to a pregnant woman. Administration of other EGFR inhibitor molecules to pregnant animals has resulted in an increased incidence of impairment of embryo-fetal development, embryo lethality, and abortion. Advise females of reproductive potential of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment and for 3 months after the final dose of RYBREVANT [see Pregnancy and Females and Males of Reproductive Potential under Use in Pregnancy & Lactation].

Pregnancy: Risk Summary: Based on the mechanism of action and findings in animal models, RYBREVANT can cause fetal harm when administered to a pregnant woman. There are no available data on the use of RYBREVANT in pregnant women or animal data to assess the risk of RYBREVANT in pregnancy. Disruption or depletion of EGFR in animal models resulted in impairment of embryo-fetal development including effects on placental, lung, cardiac, skin, and neural development. The absence of EGFR or MET signaling has resulted in embryo lethality, malformations, and post-natal death in animals (see Data as follows). Advise pregnant women of the potential risk to a fetus.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data: Animal Data: No animal studies have been conducted to evaluate the effects of amivantamab-vmjw on reproduction and fetal development; however, based on its mechanism of action, RYBREVANT can cause fetal harm or developmental anomalies. In mice, EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryo-fetal/postnatal survival and development. Reduction or elimination of embryo-fetal or maternal EGFR signaling can prevent implantation, can cause embryo-fetal loss during various stages of gestation (through effects on placental development) and can cause developmental anomalies and early death in surviving fetuses. Adverse developmental outcomes were observed in multiple organs in embryos/neonates of mice with disrupted EGFR signaling. Similarly, knock out of MET or its ligand HGF was embryonic lethal due to severe defects in placental development, and fetuses displayed defects in muscle development in multiple organs. Human IgG1 is known to cross the placenta; therefore, amivantamab-vmjw has the potential to be transmitted from the mother to the developing fetus.
Lactation: Risk Summary: There are no data on the presence of amivantamab-vmjw in human milk on milk production, or its effects on the breastfed child. 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 after the final dose.
Females and Males of Reproductive Potential: RYBREVANT can cause fetal harm when administered to a pregnant woman [see Pregnancy as previously mentioned].
Pregnancy Testing: Verify pregnancy status of females of reproductive potential prior to initiating RYBREVANT.
Contraception: Females: Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the final dose of RYBREVANT.

The following adverse reactions are discussed elsewhere in the monograph: Infusion-Related Reactions [see Infusion-Related Reactions under Precautions]; Interstitial Lung Disease/Pneumonitis [see Interstitial Lung Disease/Pneumonitis under Precautions]; Dermatologic Adverse Reactions [see Dermatologic Adverse Reactions under Precautions]; Ocular Toxicity [see Ocular Toxicity under Precautions].
Clinical Trials Experience: 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 population described in Precautions reflect exposure to RYBREVANT as a single agent in the CHRYSALIS study in 302 patients with locally advanced or metastatic NSCLC who received a dose of 1050 mg (for patients <80 kg) or 1400 mg (for patients ≥80 kg) once weekly for 4 weeks, then every 2 weeks thereafter. Among 302 patients who received RYBREVANT, 36% were exposed for 6 months or longer and 12% were exposed for greater than one year. In the safety population, the most common (≥20%) adverse reactions were rash, infusion-related reaction, paronychia, musculoskeletal pain, dyspnea, nausea, edema, cough, fatigue, stomatitis, constipation, vomiting and pruritus. The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased lymphocytes, decreased phosphate, decreased albumin, increased glucose, increased gamma glutamyl transferase, decreased sodium, decreased potassium, and increased alkaline phosphatase.
The data described as follows reflect exposure to RYBREVANT at the recommended dosage in 129 patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy. Among patients who received RYBREVANT, 44% were exposed for 6 months or longer and 12% were exposed for greater than one year.
The median age was 62 years (range: 36 to 84 years); 61% were female; 55% were Asian, 35% were White, and 2.3% were Black; and 82% had baseline body weight <80 kg.
Serious adverse reactions occurred in 30% of patients who received RYBREVANT. Serious adverse reactions in ≥2% of patients included pulmonary embolism, pneumonitis/ILD, dyspnea, musculoskeletal pain, pneumonia, and muscular weakness. Fatal adverse reactions occurred in 2 patients (1.5%) due to pneumonia and 1 patient (0.8%) due to sudden death.
Permanent discontinuation of RYBREVANT due to an adverse reaction occurred in 11% of patients. Adverse reactions resulting in permanent discontinuation of RYBREVANT in ≥1% of patients were pneumonia, IRR, pneumonitis/ILD, dyspnea, pleural effusion, and rash.
Dose interruptions of RYBREVANT due to an adverse reaction occurred in 78% of patients. Infusion-related reactions (IRR) requiring infusion interruptions occurred in 59% of patients. Adverse reactions requiring dose interruption in ≥5% of patients included dyspnea, nausea, rash, vomiting, fatigue, and diarrhea.
Dose reductions of RYBREVANT due to an adverse reaction occurred in 15% of patients. Adverse reactions requiring dose reductions in ≥2% of patients included rash and paronychia.
The most common adverse reactions (≥20%) were rash, IRR, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting. The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased lymphocytes, decreased albumin, decreased phosphate, decreased potassium, increased glucose, increased alkaline phosphatase, increased gamma-glutamyl transferase, and decreased sodium.
Table 8 summarizes the adverse reactions in CHRYSALIS. (See Table 8.)

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Clinically relevant adverse reactions in <10% of patients who received RYBREVANT included ocular toxicity, ILD/pneumonitis, and toxic epidermal necrolysis (TEN).
Table 9 summarizes the laboratory abnormalities in CHRYSALIS. (See Table 9.)

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Immunogenicity: As with all therapeutic proteins, there is the potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described as follows with the incidence of antibodies in other studies or to other amivantamab products may be misleading.
In CHRYSALIS, 3 of the 286 (1%) patients who were treated with RYBREVANT and evaluable for the presence of anti-drug antibodies (ADA), tested positive for treatment-emergent anti-amivantamab-vmjw antibodies (one at 27 days, one at 59 days and one at 168 days after the first dose) with titers of 1:40 or less. There are insufficient data to evaluate the effect of ADA on the pharmacokinetics, safety, or efficacy of RYBREVANT.

No drug interaction studies have been performed.

Incompatibilities: None.

Store in a refrigerator at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze.

Advise the patient to read the approved patient labeling (Patient Information).
Infusion-Related Reactions: Advise patients that RYBREVANT can cause infusion-related reactions, the majority of which may occur with the first infusion. Advise patients to alert their healthcare provider immediately for any signs or symptoms of infusion-related reactions [see Infusion-Related Reactions under Precautions].
Interstitial Lung Disease/Pneumonitis: Advise patients of the risks of interstitial lung disease (ILD)/pneumonitis. Advise patients to immediately contact their healthcare provider for new or worsening respiratory symptoms [see Interstitial Lung Disease/Pneumonitis under Precautions].
Dermatologic Adverse Reactions: Advise patients of the risk of dermatologic adverse reactions. Advise patients to limit direct sun exposure, to use broad spectrum UVA/UVB sunscreen, and to wear protective clothing during treatment with RYBREVANT [see Dermatologic Adverse Reactions under Precautions]. Advise patients to apply alcohol free emollient cream to dry skin.
Ocular Toxicity: Advise patients of the risk of ocular toxicity. Advise patients to contact their ophthalmologist if they develop eye symptoms and advise discontinuation of contact lenses until symptoms are evaluated [see Ocular Toxicity under Precautions].
Paronychia: Advise patients of the risk of paronychia. Advise patients to contact their healthcare provider for signs or symptoms of paronychia [see Clinical Trials Experience under Adverse Reactions].
Embryo-Fetal Toxicity: Advise females of reproductive potential of the potential risk to a fetus, to use effective contraception during treatment with RYBREVANT and for 3 months after the final dose, and to inform their healthcare provider of a known or suspected pregnancy [see Use in Pregnancy: Embryo-Fetal Toxicity under Precautions, Pregnancy and Females and Males of Reproductive Potential under Use in Pregnancy & Lactation].
Lactation: Advise women not to breastfeed during treatment with RYBREVANT and for 3 months after the final dose [see Lactation under Use in Pregnancy & Lactation].

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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