Rybrevant by is a Prescription medication manufactured, distributed, or labeled by Janssen Biotech, Inc., Janssen Pharmaceutical Sciences Unlimited Company, Cilag AG. Drug facts, warnings, and ingredients follow.
RYBREVANT is a bispecific EGF receptor-directed and MET receptor-directed antibody indicated:
Body Weight (at Baseline) | Dosage | Recommended Dose |
---|---|---|
RYBREVANT in Combination with Carboplatin and Pemetrexed | ||
Less than 80 kg | Weeks 1–4 | 1400 mg |
Week 7 onwards | 1750 mg | |
Greater than or equal to 80 kgs | Weeks 1–4 | 1750 mg |
Week 7 onwards | 2100 mg | |
RYBREVANT as a Single Agent | ||
Less than 80 kg | Weeks 1–5
Week 7 onwards | 1050 mg |
Greater than or equal to 80 kg | Weeks 1–5
Week 7 onwards | 1400 mg |
Injection: 350 mg/7 mL (50 mg/mL) solution in a single-dose vial ( 3)
None. ( 4)
RYBREVANT in Combination with Carboplatin and Pemetrexed
RYBREVANT as a Single Agent
To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 3/2024
RYBREVANT is indicated in combination with carboplatin and pemetrexed for the first-line 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 an FDA-approved test [see Dosage and Administration (2.2)] .
RYBREVANT is indicated as a single agent for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test [see Dosage and Administration (2.2)] , whose disease has progressed on or after platinum-based chemotherapy.
Select patients for treatment with RYBREVANT based on the presence of EGFR exon 20 insertion mutations in tumor or plasma specimens [see Clinical Studies (14)]. If no mutation is detected in a plasma specimen, test tumor tissue. Information on FDA-approved tests is available at: http://www.fda.gov/CompanionDiagnostics.
The recommended dosages of RYBREVANT, administered in combination with carboplatin and pemetrexed, based on baseline body weight are provided in Table 1.
Body weight at Baseline * | Recommended Dose | Dosing Schedule |
---|---|---|
|
||
Less than 80 kg | 1400 mg | Weekly (total of 4 doses) from Weeks 1 to 4
|
1750 mg | Every 3 weeks starting at Week 7 onwards | |
Greater than or equal to 80 kg | 1750 mg | Weekly (total of 4 doses) for Weeks 1 to 4
|
2100 mg | Every 3 weeks starting at Week 7 onwards |
The recommended order of administration and regimen for RYBREVANT in combination with carboplatin and pemetrexed is provided in Table 2.
RYBREVANT in Combination with Carboplatin and Pemetrexed | ||
---|---|---|
Administer the regimen in the following order: pemetrexed first, carboplatin second and RYBREVANT last. | ||
Drug | Dose | Duration/Timing of Treatment |
Pemetrexed | Pemetrexed 500 mg/m
2intravenously
Refer to the pemetrexed Full Prescribing Information for complete information. | Every 3 weeks, continue until disease progression or unacceptable toxicity. |
Carboplatin | Carboplatin AUC 5 intravenously
Refer to the carboplatin Full Prescribing Information for complete information. | Every 3 weeks for up to 12 weeks. |
RYBREVANT | RYBREVANT intravenously
See Table 1. | Every 3 weeks, continue until disease progression or unacceptable toxicity. |
The recommended dosages of RYBREVANT as a single agent, based on baseline body weight, are provided in Table 3.
Body weight at Baseline * | Recommended Dose | Dosing Schedule |
---|---|---|
|
||
Less than 80 kg | 1050 mg | Weekly (total of 5 doses) from Weeks 1 to 5
|
Every 2 weeks starting at Week 7 onwards | ||
Greater than or equal to 80 kg | 1400 mg | Weekly (total of 5 doses) from Weeks 1 to 5
|
Every 2 weeks starting at Week 7 onwards |
Administer RYBREVANT until disease progression or unacceptable toxicity.
Prior to the initial infusion of RYBREVANT (Week 1, Day 1 and 2), administer premedication as described in Table 4 to reduce the risk of infusion-related reactions [see Warnings and Precautions (5.1)].
Glucocorticoid administration is required for Week 1, Day 1 and 2 dose only and upon re-initiation after prolonged dose interruptions, then as necessary for subsequent infusions (see Table 4). Administer both antihistamine and antipyretic prior to all infusions.
Medication | Dose | Route of Administration | Dosing Window Prior to RYBREVANT Administration |
---|---|---|---|
|
|||
Antihistamine * | Diphenhydramine (25 to 50 mg) or equivalent | Intravenous | 15 to 30 minutes |
Oral | 30 to 60 minutes | ||
Antipyretic * | Acetaminophen (650 to 1,000 mg) | Intravenous | 15 to 30 minutes |
Oral | 30 to 60 minutes | ||
Glucocorticoid † | Dexamethasone (20 mg) or equivalent | Intravenous | 45 to 60 minutes |
Glucocorticoid ‡ | Dexamethasone (10 mg) or equivalent | Intravenous | 45 to 60 minutes |
The recommended dose reductions for adverse reactions for RYBREVANT are listed in Table 5.
Dose * | 1 stDose Reduction | 2 ndDose Reduction | 3 rdDose Reduction |
---|---|---|---|
|
|||
1050 mg | 700 mg | 350 mg | Discontinue RYBREVANT |
1400 mg | 1050 mg | 700 mg | |
1750 mg | 1400 mg | 1050 mg | |
2100 mg | 1750 mg | 1400 mg |
The recommended dosage modifications and management for adverse reactions for RYBREVANT are provided in Table 6.
Adverse Reaction | Severity | Dosage Modifications |
---|---|---|
Infusion-related reactions (IRR) [see Warnings and Precautions (5.1)] | Grade 1 to 2 |
|
Grade 3 |
|
|
Grade 4 |
|
|
Interstitial Lung Disease (ILD)/pneumonitis [see Warnings and Precautions (5.2)] | Any Grade |
|
Dermatologic Adverse Reactions (including dermatitis acneiform, pruritus, dry skin) [see Warnings and Precautions (5.3)] | Grade 1 |
|
Grade 2 |
|
|
Grade 3 |
|
|
Grade 4 |
|
|
Severe bullous, blistering or exfoliating skin conditions (including toxic epidermal necrolysis (TEN) |
|
|
Other Adverse Reactions [see Adverse Reactions (6.1)] | Grade 3 |
|
Grade 4 |
|
Recommended Dosage Modifications for Adverse Reactions for RYBREVANT in Combination with Carboplatin and Pemetrexed
When administering RYBREVANT in combination with carboplatin and pemetrexed, modify the dosage of one or more drugs. Withhold or discontinue RYBREVANT as shown in Table 6. Refer to prescribing information for carboplatin and pemetrexed for additional dosage modification information.
Dilute and prepare RYBREVANT for intravenous infusion before administration.
RYBREVANT in Combination with Carboplatin and Pemetrexed
|
|||
Body Weight Less Than 80 kg | |||
Week | Dose
(per 250 mL bag) | Initial Infusion Rate
(mL/hr) | Subsequent Infusion Rate*
(mL/hr) |
Week 1 (split dose infusion) | |||
Week 1 Day 1 | 350 mg | 50 | 75 |
Week 1 Day 2 | 1050 mg | 33 | 50 |
Week 2 | 1400 mg | 65 | |
Week 3 | 1400 mg | 85 | |
Week 4 | 1400 mg | 125 | |
Weeks 5 and 6 | No dose | ||
Week 7 and every 3 weeks thereafter | 1750 mg | 125 | |
Body Weight Greater Than or Equal to 80 kg | |||
Week | Dose
(per 250 mL bag) | Initial Infusion Rate
(mL/hr) | Subsequent Infusion Rate
(mL/hr) |
Week 1 (split dose infusion) | |||
Week 1 Day 1 | 350 mg | 50 | 75 |
Week 1 Day 2 | 1400 mg | 25 | 50 |
Week 2 | 1750 mg | 65 | |
Week 3 | 1750 mg | 85 | |
Week 4 | 1750 mg | 125 | |
Week 5 and 6 | No dose | ||
Week 7 and every 3 weeks thereafter | 2100 mg | 125 |
RYBREVANT as a Single Agent
|
|||
Body Weight Less Than 80 kg | |||
Week | Dose
(per 250 mL bag) | Initial Infusion Rate
(mL/hr) | Subsequent Infusion Rate*
(mL/hr) |
Week 1 (split dose infusion) | |||
Week 1 Day 1 | 350 mg | 50 | 75 |
Week 1 Day 2 | 700 mg | 50 | 75 |
Week 2 | 1050 mg | 85 | |
Week 3 | 1050 mg | 125 | |
Week 4 | 1050 mg | 125 | |
Week 5 | 1050 mg | 125 | |
Week 6 | No dose | ||
Week 7 and every 2 weeks thereafter | 1050 mg | 125 | |
Body Weight Greater Than or Equal to 80 kg | |||
Week | Dose
(per 250 mL bag) | Initial Infusion Rate
(mL/hr) | Subsequent Infusion Rate
*
(mL/hr) |
Week 1 (split dose infusion) | |||
Week 1 Day 1 | 350 mg | 50 | 75 |
Week 1 Day 2 | 1050 mg | 35 | 50 |
Week 2 | 1400 mg | 65 | |
Week 3 | 1400 mg | 85 | |
Week 4 | 1400 mg | 125 | |
Week 5 | 1400 mg | 125 | |
Week 6 | No dose | ||
Week 7 and every 2 weeks thereafter | 1400 mg | 125 |
RYBREVANT can cause infusion-related reactions (IRR); signs and symptoms of IRR include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension and vomiting.
RYBREVANT with Carboplatin and Pemetrexed
RYBREVANT in combination with carboplatin and pemetrexed can cause infusion-related reactions. Based on the safety population [see Adverse Reactions (6.1)] , infusion-related reactions occurred in 42% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed, including Grade 3 (1.3%) adverse reactions. The incidence of infusion modifications due to IRR was 40%, and 0.7% of patients permanently discontinued RYBREVANT.
RYBREVANT as a Single Agent
Based on the safety population [see Adverse Reactions (6.1)], IRR occurred in 66% of patients treated with RYBREVANT as a single agent. 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 Dosage and Administration (2.4)] . Administer RYBREVANT via a peripheral line on Week 1 and Week 2 [see Dosage and Administration (2.7)] .
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 and Administration (2.5)].
RYBREVANT can cause interstitial lung disease (ILD)/pneumonitis.
RYBREVANT with Carboplatin and Pemetrexed
Based on the safety population [see Adverse Reactions (6.1)], Grade 3 ILD/pneumonitis occurred in 2.6% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed, all patients required permanent discontinuation.
RYBREVANT as a Single Agent
Based on the safety population [see Adverse Reactions (6.1)] , ILD/pneumonitis occurred in 3.3% of patients treated with RYBREVANT as a single agent, 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 and Administration (2.5)] .
RYBREVANT can cause rash (including dermatitis acneiform), pruritus and dry skin.
RYBREVANT with Carboplatin and Pemetrexed
RYBREVANT in combination with carboplatin and pemetrexed can cause dermatologic adverse reactions. Based on the safety population [see Adverse Reactions (6.1)] , rash occurred in 89% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed, including Grade 3 (19%) adverse reactions. Rash leading to dose reductions occurred in 19% of patients, and 2% permanently discontinued RYBREVANT and 1.3% discontinued pemetrexed.
RYBREVANT as a Single Agent
Based on the safety population [see Adverse Reactions (6.1)] , rash occurred in 74% of patients treated with RYBREVANT as a single agent, 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 Adverse Reactions (6.1)].
Toxic epidermal necrolysis (TEN) occurred in one patient (0.3%) treated with RYBREVANT as a single agent.
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 and Administration (2.6)] .
RYBREVANT can cause ocular toxicity including keratitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, and uveitis.
RYBREVANT with Carboplatin and Pemetrexed
Based on the safety population [see Adverse Reactions (6.1)] RYBREVANT in combination with carboplatin and pemetrexed can cause ocular toxicity including blepharitis, dry eye, conjunctival redness, blurred vision, and eye pruritus. All events were Grade 1–2.
RYBREVANT as a Single Agent
Based on the safety population [see Adverse Reactions (6.1)], 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 and Administration (2.6)] .
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 last dose of RYBREVANT. [see Use in Specific Populations (8.1, 8.3)] .
The following adverse reactions are discussed elsewhere in the labeling:
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 data described in the WARNINGS AND PRECAUTIONS reflect exposure to RYBREVANT in combination with carboplatin and pemetrexed in the PAPILLON study in 151 patients with locally advanced or metastatic NSCLC. Patients received RYBREVANT 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, in combination with carboplatin at area under the curve AUC 5 once every 3 weeks, for up to 12 weeks, and pemetrexed at 500 mg/m2 once every 3 weeks until disease progression or unacceptable toxicity. Among 151 patients who received RYBREVANT in combination with carboplatin and pemetrexed, 76% were exposed for 6 months or longer and 38% were exposed for greater than one year. In the safety population, the most common (≥ 20%) adverse reactions were rash, nail toxicity, stomatitis, infusion-related reaction, fatigue, edema, constipation, decreased appetite, nausea, COVID-19, diarrhea, and vomiting. The most common Grade 3 to 4 laboratory abnormalities (≥ 2%) were increased alanine aminotransferase decreased albumin, decreased potassium and decreased magnesium.
The data in the WARNINGS AND PRECAUTIONS also reflect exposure to RYBREVANT as a single agent in the CHRYSALIS study in 302 patients with locally advanced or metastatic NSCLC. 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. Among 302 patients who received RYBREVANT as a single agent, 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 increased gamma glutamyl transference, decreased sodium, decreased potassium and increased alkaline phosphatase.
First-line Treatment of Non-Small Cell Lung Cancer (NSCLC) with Exon 20 Insertion Mutations
The data described below reflect exposure to RYBREVANT in combination with carboplatin and pemetrexed at the recommended dosage in the PAPILLON trial [see Clinical Studies (14.1)] in 151 patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. Among patients who received RYBREVANT in combination with carboplatin and pemetrexed the median exposure was 9.7 months (range: 0.0 to 26.9 months). In patients that received carboplatin and pemetrexed alone, the median exposure was 6.7 months (range 0.0 to 25.3).
The median age was 61 years (range: 27 to 86 years); 56% were female; 64% were Asian, 32% were White, 1.3% were Black or African American, race was not reported in 1.3% of patients; 89% were not Hispanic or Latino; 86% had baseline body weight <80 kg.
Serious adverse reactions occurred in 37% of patients who received RYBREVANT in combination with carboplatin and pemetrexed. Serious adverse reactions in ≥ 2% of patients included rash, pneumonia, interstitial lung disease (ILD), pulmonary embolism, vomiting and COVID-19. Fatal adverse reactions occurred in 7 patients (4.6%) due to pneumonia, cerebrovascular accident, cardio-respiratory arrest, COVID-19, sepsis and death not otherwise specified.
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 rash and ILD.
Dose interruptions of RYBREVANT due to an adverse reaction occurred in 64% of patients. Infusion-related reactions (IRR) requiring infusion interruptions occurred in 38% of patients. Adverse reactions requiring dose interruption in ≥5% of patients included rash and nail toxicity.
Dose reductions of RYBREVANT due to an adverse reaction occurred in 36% of patients. Adverse reactions requiring dose reductions in ≥ 5% of patients included rash, and nail toxicity.
The most common adverse reactions (≥ 20%) were rash, nail toxicity, stomatitis, infusion-related reaction, fatigue, edema, constipation, decreased appetite, nausea, COVID-19, diarrhea, and vomiting. The most common Grade 3 to 4 laboratory abnormalities (≥ 2%) were decreased albumin, increased alanine aminotransferase, increased gamma-glutamyl transferase, decreased sodium, decreased potassium, decreased magnesium, and decreases in white blood cells, hemoglobin, neutrophils, platelets, and lymphocytes.
Table 9 summarizes the adverse reactions in PAPILLON.
Adverse Reaction * | RYBREVANT in Combination with Carboplatin and Pemetrexed
(n=151) | Carboplatin and Pemetrexed
(n=155) |
||
---|---|---|---|---|
All Grades
(%) | Grade 3 or 4
(%) | All Grades
(%) | Grade 3 or 4
(%) |
|
|
||||
Skin and subcutaneous tissue disorders | ||||
Rash † | 90 | 19 | 19 | 0 |
Nail toxicity † | 62 | 7 | 3 | 0 |
Dry skin † | 17 | 0 | 6 | 0 |
Gastrointestinal disorders | ||||
Stomatitis † | 43 | 4 | 11 | 0 |
Constipation | 40 | 0 | 30 | 0.7 |
Nausea | 36 | 0.7 | 42 | 0 |
Vomiting | 21 | 3.3 | 19 | 0.7 |
Diarrhea | 21 | 3 | 13 | 1.3 |
Hemorrhoids | 12 | 1 | 1.3 | 0 |
Abdominal pain † | 11 | 0.7 | 8 | 0 |
General disorders and administration site conditions | ||||
Infusion related reaction | 42 | 1.3 | 1.3 | 0 |
Fatigue † | 42 | 6 | 45 | 3.9 |
Edema † | 40 | 1.3 | 19 | 0 |
Pyrexia † | 17 | 0 | 6 | 0 |
Metabolism and nutrition disorders | ||||
Decreased appetite | 36 | 2.6 | 28 | 1.3 |
Infections and Infestations | ||||
COVID-19 | 24 | 2 | 14 | 0.6 |
Pneumonia † | 13 | 5 | 6 | 1.9 |
Vascular Disorders | ||||
Hemorrhage † | 18 | 0.7 | 11 | 1.9 |
Respiratory, thoracic and mediastinal disorders | ||||
Cough † | 17 | 0 | 16 | 0 |
Dyspnea † | 11 | 1.3 | 16 | 3.2 |
Investigations | ||||
Weight decreased | 14 | 0.7 | 8 | 0 |
Nervous System Disorders | ||||
Dizziness † | 11 | 0 | 12 | 0 |
Psychiatric Disorders | ||||
Insomnia | 11 | 0 | 13 | 0 |
Clinically relevant adverse reactions in <10% of patients who received RYBREVANT in combination with carboplatin and pemetrexed included pulmonary embolism, deep vein thrombosis, skin ulcer, conjunctivitis and interstitial lung disease (ILD)/pneumonitis.
Table 10 summarizes the laboratory abnormalities in PAPILLON.
Laboratory Abnormality * | RYBREVANT in Combination with Carboplatin and Pemetrexed † | Carboplatin in Combination with Pemetrexed ‡ | ||
---|---|---|---|---|
All Grades
(%) | Grade 3 or 4
(%) | All Grades
(%) | Grade 3 or 4
(%) |
|
|
||||
Hematology | ||||
Decreased white blood cells | 89 | 17 | 76 | 10 |
Decreased hemoglobin | 79 | 11 | 85 | 13 |
Decreased neutrophils | 76 | 36 | 61 | 23 |
Decreased platelets | 70 | 10 | 54 | 12 |
Decreased lymphocytes | 61 | 11 | 49 | 13 |
Chemistry | ||||
Decreased albumin | 87 | 7 | 34 | 1 |
Increased aspartate aminotransferase | 60 | 1 | 61 | 1 |
Increased alanine aminotransferase | 57 | 4 | 54 | 1 |
Decreased sodium | 55 | 7 | 39 | 4 |
Increased alkaline phosphatase | 51 | 1 | 28 | 0 |
Decreased potassium | 44 | 11 | 17 | 1 |
Decreased magnesium | 39 | 2 | 30 | 1 |
Increased gamma-glutamyl transferase | 38 | 4 | 43 | 4 |
Decreased calcium (corrected) | 27 | 1 | 18 | 1 |
Previously Treated NSCLC Exon 20 Insertion Mutations
The data described below reflect exposure to RYBREVANT at the recommended dosage in 129 patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations in the CHRYSALIS trial [see Clinical Studies (14.2)], 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 11 summarizes the adverse reactions in CHRYSALIS.
Adverse Reactions | RYBREVANT
*
(N=129) |
|
---|---|---|
All Grades (%) | Grades 3 or 4 (%) | |
|
||
Skin and subcutaneous tissue disorders | ||
Rash † | 84 | 3.9 |
Pruritus | 18 | 0 |
Dry skin | 14 | 0 |
General disorders and administration site conditions | ||
Infusion related reaction | 64 | 3.1 |
Fatigue † | 33 | 2.3 |
Edema † | 27 | 0.8 |
Pyrexia | 13 | 0 |
Infections and infestations | ||
Paronychia | 50 | 3.1 |
Pneumonia † | 10 | 0.8 |
Musculoskeletal and connective tissue disorders | ||
Musculoskeletal pain † | 47 | 0 |
Respiratory, thoracic and mediastinal disorders | ||
Dyspnea † | 37 | 2.3 |
Cough † | 25 | 0 |
Gastrointestinal disorders | ||
Nausea | 36 | 0 |
Stomatitis † | 26 | 0.8 |
Constipation | 23 | 0 |
Vomiting | 22 | 0 |
Diarrhea | 16 | 3.1 |
Abdominal Pain † | 11 | 0.8 |
Vascular disorders | ||
Hemorrhage † | 19 | 0 |
Metabolism and nutrition disorders | ||
Decreased appetite | 15 | 0 |
Nervous system disorders | ||
Peripheral neuropathy † | 13 | 0 |
Dizziness | 12 | 0.8 |
Headache † | 10 | 0.8 |
Clinically relevant adverse reactions in <10% of patients who received RYBREVANT included ocular toxicity, ILD/pneumonitis, and toxic epidermal necrolysis (TEN).
Table 12 summarizes the laboratory abnormalities in CHRYSALIS.
Laboratory Abnormality | RYBREVANT
*
(N=129) |
|
---|---|---|
All Grades
(%) | Grades 3 or 4
(%) |
|
|
||
Chemistry | ||
Decreased albumin | 79 | 8 |
Increased glucose | 56 | 4 |
Increased alkaline phosphatase | 53 | 4.8 |
Increased creatinine | 46 | 0 |
Increased alanine aminotransferase | 38 | 1.6 |
Decreased phosphate | 33 | 8 |
Increased aspartate aminotransferase | 33 | 0 |
Decreased magnesium | 27 | 0 |
Increased gamma-glutamyl transferase | 27 | 4 |
Decreased sodium | 27 | 4 |
Decreased potassium | 26 | 6 |
Hematology | ||
Decreased lymphocytes | 36 | 8 |
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) .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.
Risk Summary
There are no data on the presence of amivantamab-vmjw in human milk, the effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions from RYBREVANT in breast-fed children, advise women not to breast-feed during treatment with RYBREVANT and for 3 months after the last dose.
RYBREVANT can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
The safety and efficacy of RYBREVANT have not been established in pediatric patients.
Of the 151 patients with locally advanced or metastatic NSCLC treated with RYBREVANT in combination with carboplatin and pemetrexed in the PAPILLON study, 37% were ≥65 years of age and 8% were ≥75 years of age.
Of the 302 patients with locally advanced or metastatic NSCLC treated with RYBREVANT as a single agent in the CHRYSALIS study, 39% were ≥65 years of age and 11% were ≥75 years of age.
No clinically important differences in safety or efficacy were observed between patients who were ≥65 years of age and younger patients.
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.
Each RYBREVANT vial contains 350 mg (50 mg/mL) amivantamab-vmjw, 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.
Amivantamab-vmjw is a bispecific antibody that binds to the extracellular domains of EGFR and MET.
In in vitroand in vivostudies 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.
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.
Based on RYBREVANT single agent data, amivantamab-vmjw exposures increased proportionally over a dosage range from 350 to 1750 mg. Based on the population pharmacokinetics of RYBREVANT, steady-state concentrations of RYBREVANT were reached by week 13 for both the 3-week and 2-week dosing regimen and the systemic accumulation was 1.9-fold.
Elimination
The geometric mean (% CV) linear clearance (CL) and terminal half-life is 0.266 L/day (30.4%) and 13.7 days (31.9%), respectively.
Specific Populations
No clinically meaningful differences in the pharmacokinetics of amivantamab-vmjw were observed based on age (range: 27–87 years), sex, race, creatinine clearance (CLcr 29 to 301 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 dose.
The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies (ADA) in the studies described below with the incidence of anti-drug antibodies in other studies, including those of amivantamab-vmjw or amivantamab products.
In patients with NSCLC who received RYBREVANT as a single agent or as part of a combination therapy, 3 of the 663 (0.5%) 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. Given the low incidence of detectable antibody-drug antibodies, the effect of ADA on the efficacy of RYBREVANT remains unknown.
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.
The efficacy of RYBREVANT was evaluated in PAPILLON (NCT04538664), in a randomized, open-label, multicenter study. Eligible patients were required to have previously untreated locally advanced or metastatic NSCLC with EGFR Exon 20 insertion mutations measurable disease per RECIST v1.1, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤1, and adequate organ and bone marrow function. 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 interstitial lung disease or active ILD were excluded from the clinical study.
A total of 308 patients were randomized 1:1 to receive RYBREVANT in combination with carboplatin and pemetrexed (n=153) or carboplatin and pemetrexed (n=155). Patients received RYBREVANT 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/m 2on once every 3 weeks until disease progression or unacceptable toxicity. Patients were stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1) and prior brain metastases (yes or no).
The primary efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review (BICR). Additional efficacy outcome measures included overall response rate (ORR), duration of response (DOR) and overall survival (OS). Cross-over to single agent RYBREVANT was permitted for patients who had confirmed disease progression on carboplatin and pemetrexed.
The median age was 62 (range: 27 to 92) years, with 40% of the patients ≥ 65 years of age; 58% were female; 61% were Asian and 36% were White, 0.7% were Black or African American and race was not reported in 2.3% of patients; 93% were not Hispanic or Latino. Baseline ECOG performance status was 0 (35%) or 1 (65%); 58% were never smokers; 23% had history of brain metastasis and 84% had Stage IV cancer at initial diagnosis.
PAPILLON demonstrated a statistically significant improvement in progression free survival for patients randomized to RYBREVANT in combination with carboplatin and pemetrexed compared with carboplatin and pemetrexed.
Efficacy results are summarized in Table 13 and Figure 1.
RYBREVANT+ carboplatin+ pemetrexed
(N=153) | carboplatin+ pemetrexed
(N=155) |
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CI = confidence interval | ||
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Progression-Free Survival (PFS) | ||
Number of events (%) | 84 (55) | 132 (85) |
Median, months (95% CI) | 11.4 (9.8, 13.7) | 6.7 (5.6, 7.3) |
HR (95% CI) | 0.40 (0.30, 0.53) | |
p-value | p<0.0001 | |
Overall Response Rate (ORR)* | ||
ORR, % (95% CI) | 67 (59, 75) | 36 (29, 44) |
Complete response, % | 4 | 1 |
Partial response, % | 63 | 36 |
Duration of response (DOR)† | ||
Median (95% CI), months | 10.1 (8.5, 13.9) | 5.6 (4.4, 6.9) |
Figure 1: Kaplan-Meier Curve of PFS in Previously Untreated NSCLC Patients by BICR Assessment – Papillon Study
While OS results were immature at the current analysis, with 44% of pre-specified deaths for the final analysis reported, no trend towards a detriment was observed. Seventy-five (48%) of the treated patients crossed over from the carboplatin and pemetrexed arm after confirmation of disease progression to receive RYBREVANT as a single agent.
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 14.
Prior Platinum-based Chemotherapy Treated
(N=81) |
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Based on Kaplan-Meier estimates.
NE=Not Estimable, CI=confidence interval. |
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Overall Response Rate(95% CI) | 40% (29%, 51%) |
Complete response (CR) | 3.7% |
Partial response (PR) | 36% |
Duration of Response (DOR) | |
Median, months (95% CI), months | 11.1 (6.9, NE) |
Patients with DOR ≥6 months | 63% |
How Supplied
RYBREVANT ®(amivantamab-vmjw) injection is a sterile, preservative-free, colorless to pale yellow solution for intravenous infusion. Each single-dose vial contains 350 mg/7 mL (50 mg/mL) RYBREVANT. Each vial is individually packed in a single carton. (NDC: 57894-501-01).
Advise the patient to read the FDA-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 Warnings and Precautions (5.1)] .
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 Warnings and Precautions (5.2)] .
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 Warnings and Precautions (5.3)] . 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 Warnings and Precautions (5.4)] .
Paronychia/Nail Toxicity
Advise patients of the risk of paronychia. Advise patients to contact their healthcare provider for signs or symptoms of paronychia [see Adverse Reactions (6.1)].
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 last dose, and to inform their healthcare provider of a known or suspected pregnancy. [see Warnings and Precautions (5.5), Use in Specific Populations (8.1, 8.3)].
Lactation
Advise women not to breastfeed during treatment with RYBREVANT and for 3 months after the last dose [see Use in Specific Populations (8.2)] .
PATIENT INFORMATION
RYBREVANT ®(RYE–breh–vant) (amivantamab-vmjw) injection, for intravenous use |
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This Patient Information has been approved by the U.S. Food and Drug Administration. | Revised: March/2024 | ||
What is RYBREVANT?
RYBREVANT is a prescription medicine used to treat adults:
It is not known if RYBREVANT is safe and effective in children. |
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Before you receive RYBREVANT, tell your healthcare provider about all of your medical conditions, including if you:
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How will I receive RYBREVANT?
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RYBREVANT can cause skin reactions. You should limit your time in the sun during and for 2 months after your treatment with RYBREVANT. Wear protective clothing and use sunscreen during treatment with RYBREVANT. | |||
What are the possible side effects of RYBREVANT?
RYBREVANT may cause serious side effects, including:
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Your healthcare provider may send you to see an eye specialist (ophthalmologist) if you get eye problems during treatment with RYBREVANT. You should not use contact lenses until your eye symptoms are checked by a healthcare provider. | |||
The most common side effects of RYBREVANT in combination with carboplatin and pemetrexed include: | |||
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The most common side effects of RYBREVANT when given alone: | |||
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Your healthcare provider may temporarily stop, decrease your dose or completely stop your treatment with RYBREVANT if you have serious side effects.
These are not all of the possible side effects of RYBREVANT. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. |
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General information about safe and effective use of RYBREVANT
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your healthcare provider or pharmacist for information about RYBREVANT that is written for health professionals. |
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What are the ingredients of RYBREVANT?
Active ingredient: amivantamab-vmjw Inactive ingredients: EDTA disodium salt dihydrate, L-histidine, L-histidine hydrochloride monohydrate, L-methionine, polysorbate 80, sucrose, and water for injection. Product of Ireland Manufactured by: Janssen Biotech, Inc., Horsham, PA 19044, USA. U.S. License Number 1864 For patent information: www.janssenpatents.com © 2022 Janssen Pharmaceutical Companies For more information, call 1-800-526-7736 (1-800-JANSSEN) or go to www.RYBREVANT.com. |
NDC: 57894-501-01
Rybrevant
®
(amivantamab-vmjw)
Injection
350 mg/7 mL
(50 mg/mL)
For Intravenous Infusion Only
Dilute Before Use
Rx only
7 mL Vial
janssen
Single-dose vial.
Discard unused portion.
RYBREVANT
amivantamab injection |
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Labeler - Janssen Biotech, Inc. (099091753) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
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Janssen Pharmaceutical Sciences Unlimited Company | 985639841 | api manufacture(57894-501) , analysis(57894-501) |
Establishment | |||
Name | Address | ID/FEI | Business Operations |
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Cilag AG | 483237103 | label(57894-501) , manufacture(57894-501) , analysis(57894-501) |
Mark Image Registration | Serial | Company Trademark Application Date |
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RYBREVANT 87876593 not registered Live/Pending |
Johnson & Johnson 2018-04-13 |