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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.
RYBREVANT, in combination with lazertinib, is indicated 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 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test [see DOSAGE AND ADMINISTRATION].
RYBREVANT, in combination with carboplatin and pemetrexed, is indicated for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations, whose disease has progressed on or after treatment with an EFGR tyrosine kinase inhibitor [see DOSAGE AND ADMINISTRATION].
RYBREVANT, in combination with carboplatin and pemetrexed, is indicated for the first-line 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].
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], whose disease has progressed on or after platinum-based chemotherapy.
Select patients for treatment with RYBREVANT based on the presence of a mutation as detected by an FDA-approved test.
Table 1: Patient Selection
| Indication | Treatment Regimen | Source for Testing |
| First-Line Treatment of NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations [see INDICATIONS] | RYBREVANT in combination with lazertinib |
|
| Previously treated locally advanced or metastatic NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations (progressive disease on an EGFR tyrosine kinase inhibitor) [see INDICATIONS] | RYBREVANT in combination with carboplatin and pemetrexed | |
| First-Line Treatment of NSCLC with EGFR Exon 20 Insertion Mutations [see INDICATIONS] | RYBREVANT in combination with carboplatin and pemetrexed | |
| Previously Treated NSCLC with EGFR Exon 20 Insertion Mutations [see INDICATIONS] | RYBREVANT as a single agent |
Information on FDA approved tests is available at: https://www.fda.gov/CompanionDiagnostics.
The recommended dosage of RYBREVANT, administered in combination with carboplatin and pemetrexed is based on baseline body weight is provided in Table 2.
Table 2: Recommended Dosage for RYBREVANT in Combination with Carboplatin and Pemetrexed
| Body weight at Baselinea | 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) from Weeks 1 to 4
|
| 2100 mg | Every 3 weeks starting at Week 7 onwards | |
| a Dose adjustment is not required for subsequent body weight changes. | ||
The recommended order of administration and regimen for RYBREVANT in combination with carboplatin and pemetrexed are provided in Table 3.
Table 3: Order of Administration and Regimen for RYBREVANT in Combination with Carboplatin and Pemetrexed
| 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/m² intravenously 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 2. |
Every 3 weeks, continue until disease progression or unacceptable toxicity. |
The recommended dosage of RYBREVANT in combination with lazertinib or RYBREVANT as a single agent, based on baseline body weight, are provided in Table 4. Administer RYBREVANT until disease progression or unacceptable toxicity.
Table 4: Recommended Dosage Schedule for RYBREVANT in Combination with Lazertinib or RYBREVANT as a Single Agent
| Body weight at Baselinea | 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 | ||
| a Dose adjustment is not required for subsequent body weight changes. | ||
Order Of Administration
When given in combination with lazertinib, administer RYBREVANT any time after lazertinib when given on the same day. Refer to the lazertinib prescribing information for recommended lazertinib dosing information. Administer RYBREVANT in combination with lazertinib until disease progression or unacceptable toxicity.
Concomitant Medications
When initiating treatment with RYBREVANT in combination with lazertinib, administer anticoagulant prophylaxis to prevent venous thromboembolic (VTE) events for the first four months of treatment [see WARNINGS AND PRECAUTIONS]. If there are no signs or symptoms of VTE during the first four months of treatment, consider discontinuation of anticoagulant prophylaxis at the discretion of the healthcare provider. Refer to the lazertinib prescribing information for information about concomitant medications.
When initiating treatment with RYBREVANT in combination with lazertinib, administer alcohol-free (e.g., isopropanol-free, ethanol-free) emollient cream and encourage patients to limit sun exposure during and for 2 months after treatment, to wear protective clothing and use broad-spectrum UVA/UVB sunscreen to reduce the risk of dermatologic adverse reactions [see WARNINGS AND PRECAUTIONS]. Consider prophylactic measures (e.g., use of oral antibiotics) to reduce the risk of dermatologic adverse reactions. Refer to the lazertinib prescribing information for information about concomitant medications.
Prior to the initial infusion of RYBREVANT (Week 1, Day 1 and 2), administer premedications as described in Table 5 to reduce the risk of infusion-related reactions [see WARNINGS AND PRECAUTIONS].
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 5). Administer both antihistamine and antipyretic prior to all infusions.
Table 5: Premedications
| 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 1000 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 |
| * Required at all doses. ‡ Required at initial dose (Week 1 Day 1). + Required at second dose (Week 1 Day 2); optional for subsequent doses. |
|||
The recommended dose reductions for adverse reactions for RYBREVANT are listed in Table 6.
Table 6: Dose Reductions for Adverse Reactions for RYBREVANT
| Dose at which the adverse reaction occurred | 1st Dose Reduction | 2nd Dose Reduction | 3rd Dose 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 7.
Table 7: Recommended Dosage Modifications and Management for Adverse Reactions for RYBREVANT
| Adverse Reaction | Severity | Dosage Modifications |
| Grade 1 to 2 |
|
|
| Infusion-related reactions (IRR) [see WARNINGS AND PRECAUTIONS] | Grade 3 |
|
| Grade 4 |
|
|
| Interstitial Lung Disease (ILD)/pneumonitis [see WARNINGS AND PRECAUTIONS] | Any Grade |
|
| Venous Thromboembolic (VTE) Events [Applies to the combination with lazertinib, see WARNINGS AND PRECAUTIONS] | Grade 2 or 3 |
|
| Grade 4 or recurrent Grade 2 or 3 despite therapeutic level anticoagulation |
|
|
| Dermatologic Adverse Reactions (including dermatitis acneiform, pruritus, dry skin) [see WARNINGS AND PRECAUTIONS] | Grade 1 or Grade 2 |
|
| Grade 3 |
|
|
| Grade 4 |
|
|
| Severe bullous, blistering or exfoliating skin conditions (including toxic epidermal necrolysis (TEN) |
|
|
| Other Adverse Reactions [see ADVERSE REACTIONS] | Grade 3 |
|
| Grade 4 |
|
When administering RYBREVANT in combination with lazertinib, if there is an adverse reaction requiring dose reduction after withholding treatment and resolution, reduce the dose of RYBREVANT first.
Refer to the lazertinib prescribing information for information about dosage modifications for lazertinib.
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 7. Refer to prescribing information for carboplatin and pemetrexed for additional dosage modification information.
Dilute and prepare RYBREVANT for intravenous infusion before administration.
Table 8: Infusion Rates of RYBREVANT in Combination with Carboplatin and Pemetrexed for Treatment of NSCLC
| Body Weight Less Than 80 kg | |||
| Week | Dose (per 250 mL bag) | Initial Infusion Rate (mL/hr) | Subsequent Infusion Ratef (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 | |
| † In the absence of infusion-related reactions, increase the initial infusion rate to the subsequent infusion rate after 2 hours based on patient tolerance. Total infusion time is approximately 4-6 hours for day 1 and 6-8 hours for day 2. Subsequent infusion time is approximately 2 hours. | |||
Table 9: Infusion Rates of RYBREVANT in Combination with Lazertinib or RYBREVANT as Single Agent
| Body Weight Less Than 80 kg | |||
| Week | Dose (per 250 mL bag) | Initial Infusion Rate (mL/hr) | Subsequent Infusion Ratef (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 Ratef (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 | |
| † In the absence of infusion-related reactions, increase the initial infusion rate to the subsequent infusion rate after 2 hours based on patient tolerance. Total infusion time is approximately 4-6 hours for day 1 and 6-8 hours for day 2. Subsequent infusion time is approximately 2 hours. | |||
Injection: 350 mg/7 mL (50 mg/mL) colorless to pale yellow solution in a single-dose vial.
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).
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.
Manufactured by: Janssen Biotech, Inc. Horsham, PA 19044, USA. Revised: Sep 2024
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 lazertinib in the MARIPOSA study in 421 patients with previously untreated locally advanced or metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R substitution mutations [see Clinical Studies]. Patients received RYBREVANT intravenously at 1050 mg (for patients < 80 kg) or 1400 mg (for patients ≥ 80 kg) once weekly for 4 weeks, then every 2 weeks thereafter starting at week 5 in combination with lazertinib, 240 mg orally once daily, until disease progression or unacceptable toxicity. Among 421 patients who received RYBREVANT in combination with lazertinib, 73% were exposed for 6 months or longer and 59% were exposed for greater than one year. The most common adverse reactions (≥ 20%) were rash, nail toxicity, infusion-related reaction, edema, musculoskeletal pain, stomatitis, VTE, paresthesia, fatigue, diarrhea, constipation, COVID-19, dry skin, hemorrhage, decreased appetite, pruritus, nausea, and ocular toxicity. The most common Grade 3 or 4 laboratory abnormalities (≥ 2%) were decreased albumin, increased ALT, decreased sodium, decreased hemoglobin, increased AST, increased GGT and increased magnesium.
The pooled safety population described in the WARNINGS AND PRECAUTIONS also reflect exposure to RYBREVANT in combination with carboplatin and pemetrexed in 281 patients in two studies:
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 281 patients who received RYBREVANT in combination with carboplatin and pemetrexed, 65% were exposed for 6 months or longer and 24% were exposed for greater than one year. In the safety population, the most common (≥ 20%) adverse reactions were rash, nail toxicity, infusion-related reaction, fatigue, nausea, stomatitis, constipation, edema, decreased appetite, musculoskeletal pain, vomiting, and COVID-19. The most common Grade 3 to 4 laboratory abnormalities (≥ 2%) were decreased neutrophils, decreased leukocytes, decreased platelets, decreased hemoglobin, decreased potassium, decreased sodium, increased alanine aminotransferase, increased gamma-glutamyl transferase, and decreased albumin.
The data in the WARNINGS AND PRECAUTIONS also reflect exposure to RYBREVANT as a single agent in CHRYSALIS [see Clinical Studies] 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.
The safety data described below reflect exposure to RYBREVANT in combination with lazertinib in 421 previously untreated patients with locally advanced or metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R substitution mutation in the MARIPOSA [see Clinical Studies]. Patients received RYBREVANT intravenously at 1,050 mg (for patients < 80 kg) or 1,400 mg (for patients ≥ 80 kg) once weekly for 4 weeks, then every 2 weeks thereafter starting at week 5 in combination with lazertinib, 240 mg orally once daily. Among the 421 patients who received RYBREVANT in combination with lazertinib, 73% were exposed to RYBREVANT for ≥ 6 months and 59% were exposed to RYBREVANT for > 1 year.
The median age of patients who received RYBREVANT in combination with lazertinib was 64 years (range: 25 to 88); 64% were female; 59% were Asian, 38% were White, 1.7% were American Indian or Alaska Native, 0.7% were Black or African American, 1% were of unknown or other races; and 13% were Hispanic or Latino, 67% had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1, 33% had ECOG PS of 0, 60% had EGFR exon 19 deletions, and 40% had EGFR exon 21 L858R substitution mutations.
Serious adverse reactions occurred in 49% of patients who received RYBREVANT in combination with lazertinib. Serious adverse reactions occurring in ≥ 2% of patients included VTE (11%), pneumonia (4%), rash, and ILD/pneumonitis (2.9% each), COVID-19 (2.4%), pleural effusion and infusion-related reaction (2.1% each). Fatal adverse reactions occurred in 7% of patients who received RYBREVANT in combination with lazertinib due to death not otherwise specified (1.2%); sepsis and respiratory failure (1% each); pneumonia, myocardial infarction and sudden death (0.7% each); cerebral infarction, pulmonary embolism (PE), and COVID-19 infection (0.5% each); and ILD/pneumonitis, acute respiratory distress syndrome (ARDS), and cardiopulmonary arrest (0.2% each).
Permanent discontinuation of RYBREVANT due to an adverse reaction occurred in 34% of patients. Adverse reactions which resulted in permanent discontinuation in ≥ 1% of patients included rash, infusion-related reactions, nail toxicity, VTE, ILD/pneumonitis, pneumonia, edema, hypoalbuminemia, fatigue, paresthesia and dyspnea.
Dosage interruption of RYBREVANT due to an adverse reaction occurred in 88% of patients. Adverse reactions which required dosage interruption in ≥ 5% of patients were infusion-related reactions, rash, nail toxicity, COVID-19, VTE, increased ALT, edema, and hypoalbuminemia.
Dose reductions of RYBREVANT due to an adverse reaction occurred in 46% of patients. Adverse reactions requiring dose reductions in ≥ 5% of patients were rash and nail toxicity.
The most common adverse reactions (≥ 20%) were rash, nail toxicity, infusion-related reaction, musculoskeletal pain, stomatitis, edema, VTE, paresthesia, fatigue, diarrhea, constipation, COVID-19, hemorrhage, dry skin, decreased appetite, pruritus, and nausea. The most common Grade 3 or 4 laboratory abnormalities (≥ 2%) were decreased albumin, decreased sodium, increased ALT, decreased potassium, decreased hemoglobin, increased AST, increased GGT, and increased magnesium.
Table 10 summarizes the adverse reactions (≥ 10%) in MARIPOSA.
Table 10: Adverse Reactions (≥ 10%) in Patients with NSCLC with Exon 19 Deletion or Exon 21 L858R Substitution Mutations in MARIPOSA
| Adverse Reaction | RYREVANT in combination with lazertinib (N=421) |
Osimertinib (N=428) |
||
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) | |
| Skin and subcutaneous tissue disorders | ||||
| Rash* | 86 | 26 | 48 | 1.2 |
| Nail toxicity* | 71 | 11 | 34 | 0.7 |
| Dry skin* | 25 | 1 | 18 | 0.2 |
| Pruritus | 24 | 0.5 | 17 | 0.2 |
| Injury, poisoning and procedural complications | ||||
| Infusion-related reaction+ | 63 | 6 | 0 | 0 |
| Musculoskeletal and connective tissue disorders | ||||
| Musculoskeletal pain* | 47 | 2.1 | 39 | 1.9 |
| Gastrointestinal disorders | ||||
| Stomatitis* | 43 | 2.4 | 27 | 0.5 |
| Diarrhea* | 31 | 2.6 | 45 | 0.9 |
| Constipation | 29 | 0 | 13 | 0 |
| Nausea | 21 | 1.2 | 14 | 0.2 |
| Vomiting | 12 | 0.5 | 5 | 0 |
| Abdominal pain* | 11 | 0 | 10 | 0 |
| Hemorrhoids | 10 | 0.2 | 2.1 | 0.2 |
| General disorders and administration site conditions | ||||
| Edema* | 43 | 2.6 | 8 | 0 |
| Fatigue* | 32 | 3.8 | 20 | 1.9 |
| Pyrexia | 12 | 0 | 9 | 0 |
| Vascular disorders | ||||
| Venous thromboembolism* | 36 | 11 | 8 | 2.8 |
| Hemorrhage* | 25 | 1 | 13 | 1.2 |
| Nervous system disorders | ||||
| Paresthesia* | 35 | 1.7 | 10 | 0.2 |
| Dizziness* | 14 | 0 | 10 | 0 |
| Headache* | 13 | 0.2 | 13 | 0 |
| Infections and infestations | ||||
| COVID-19 | 26 | 1.7 | 24 | 1.4 |
| Conjunctivitis | 11 | 0.2 | 1.6 | 0 |
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 24 | 1 | 18 | 1.4 |
| Respiratory, thoracic, and mediastinal disorders | ||||
| Cough* | 19 | 0 | 23 | 0 |
| Dyspnea* | 14 | 1.7 | 17 | 3.5 |
| Eye disorders | ||||
| Ocular toxicity* | 16 | 0.7 | 7 | 0 |
| Psychiatric disorders | ||||
| Insomnia | 10 | 0 | 11 | 0 |
| * Grouped terms + Applicable for RYBREVANT only |
||||
Clinically relevant adverse reactions in < 10% of patients who received RYBREVANT in combination with lazertinib included ILD/pneumonitis (3.1%).
Table 11 summarizes the laboratory abnormalities in MARIPOSA.
Table 11: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with NSCLC with EGFR Exon 19 Deletion or Exon 21 L858R Substitution Mutations in MARIPOSA+
| Laboratory Abnormality | RYBREVANT in combination with lazertinib (N=421) |
Osimertinib (N=428) |
||
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) | |
| Chemistry | ||||
| Decreased albumin | 89 | 8 | 22 | 0.2 |
| Increased ALT | 65 | 7 | 29 | 2.6 |
| Increased AST | 52 | 3.8 | 36 | 1.9 |
| Increased alkaline phosphatase | 45 | 0.5 | 15 | 0.5 |
| Decreased calcium (corrected) | 41 | 1.4 | 27 | 0.7 |
| Increased GGT | 39 | 2.6 | 24 | 1.9 |
| Decreased sodium | 38 | 7 | 35 | 5 |
| Decreased potassium | 30 | 5 | 15 | 1.2 |
| Increased creatinine | 26 | 0.7 | 35 | 0.7 |
| Decreased magnesium | 25 | 0.7 | 10 | 0.2 |
| Increased magnesium | 12 | 2.6 | 20 | 4.8 |
| Hematology | ||||
| Decreased platelet count | 52 | 0.7 | 57 | 1.4 |
| Decreased hemoglobin | 47 | 3.8 | 56 | 1.9 |
| Decreased white blood cell | 38 | 1 | 66 | 0.7 |
| Decreased neutrophils | 15 | 1.4 | 33 | 1.4 |
| + The denominator used to calculate the rate is the number of patients with a baseline value and at least one post-treatment value for the specific lab test. | ||||
The safety data described below reflect exposure to RYBREVANT in combination with carboplatin and pemetrexed was evaluated in MARIPOSA-2 [see Clinical Studies]. Eligible patients had locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations with progressive disease on or after treatment with osimertinib. Patients with asymptomatic or previously treated and stable intracranial metastases were eligible. 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 patients who received RYBREVANT (n=130), 52% were exposed for 6 months or longer and 7% were exposed for greater than one year. The median treatment duration was 6.3 months (range: 0 to 14.7 months).
The median age was 62 years (range: 36 to 84 years); 62% were female; 48% were Asian, 46% were White, 2.3% Black or African American, 1.5% race not reported, 1.5% race unknown, 0.8% Alaska native; 7% were Hispanic or Latino; and 87% had baseline body weight < 80 kg.
Serious adverse reactions occurred in 32% of patients who received RYBREVANT in combination with carboplatin and pemetrexed. Serious adverse reactions in > 2% of patients included dyspnea (3.1%), thrombocytopenia (3.1%), sepsis (2.3%), and pulmonary embolism (2.3%). Fatal adverse reactions occurred in 2.3% of patients who received RYBREVANT in combination with carboplatin and pemetrexed; these included respiratory failure, sepsis, and ventricular fibrillation (0.8% each).
Permanent discontinuation of RYBREVANT due to adverse reactions occurred in 11% of patients. The most frequent adverse reactions leading to discontinuation of RYBREVANT in ≥ 5% of patients were infusion-related reactions.
Dose interruptions of RYBREVANT due to an adverse reaction occurred in 60% of patients. Infusion-related reactions (IRR) requiring infusion interruptions occurred in 52% of patients. Adverse reactions requiring dose interruption in ≥ 5% of patients included infusion-related reaction, rash and fatigue.
Dose reductions of RYBREVANT due to an adverse reaction occurred in 17% of patients. Adverse reactions requiring dose reductions in ≥ 2% of patients included rash.
The most common adverse reactions ≥ 20% were rash, infusion-related reactions, fatigue, nail toxicity, nausea, constipation, edema, stomatitis, decreased appetite, musculoskeletal pain, vomiting, and COVID-19.
Table 12 summarizes the adverse reactions in MARIPOSA-2.
Table 12: Adverse Reactions (≥ 10%) in Previously Treated Patients with NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations Treated with RYBREVANT in Combination with Carboplatin and Pemetrexed in MARIPOSA-2
| Adverse Reaction | RYBREVANT + Carboplatin + Pemetrexed (N=130) |
Carboplatin + Pemetrexed (N=243) |
||
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) | |
| Skin and subcutaneous tissue disorders | ||||
| Rash* | 72 | 11 | 12 | 0 |
| Nail toxicity* | 45 | 2.3 | 0.4 | 0 |
| Pruritus | 15 | 0 | 7 | 0 |
| Dry skin* | 15 | 0 | 2.5 | 0 |
| General disorders and administration site conditions | ||||
| Infusion-related reaction | 59 | 5.4 | 0.4 | 0 |
| Fatigue* | 51 | 3.8 | 35 | 3.7 |
| Edema* | 36 | 1.5 | 11 | 0.4 |
| Pyrexia | 12 | 0 | 10 | 0 |
| Gastrointestinal disorders | ||||
| Nausea | 45 | 0.8 | 37 | 0.8 |
| Constipation | 39 | 0.8 | 30 | 0 |
| Stomatitis* | 35 | 2.3 | 11 | 0 |
| Vomiting | 25 | 0.8 | 17 | 0.4 |
| Diarrhea* | 15 | 1.5 | 7 | 0.8 |
| Metabolism and nutrition disorders | ||||
| Decreased appetite | 31 | 0 | 21 | 1.2 |
| Musculoskeletal and connective tissue disorders | ||||
| Musculoskeletal pain* | 30 | 3.1 | 19 | 0.8 |
| Infections and infestations | ||||
| COVID-19 | 21 | 1.5 | 10 | 0 |
| Eye disorders | ||||
| Ocular toxicity* | 17 | 0 | 3.7 | 0 |
| Vascular disorders | ||||
| Hemorrhage* | 14 | 0.8 | 4.9 | 0 |
| Venous Thromboembolism* (VTE) | 10 | 2.3 | 4.5 | 2.9 |
| Respiratory, thoracic, and mediastinal disorders | ||||
| Cough* | 14 | 0 | 16 | 0.4 |
| Dyspnea* | 13 | 1.5 | 8 | 1.2 |
| * Grouped term | ||||
Clinically relevant adverse reactions in < 10% of patients who received RYBREVANT in combination with carboplatin and pemetrexed include: abdominal pain, hemorrhoids, dizziness, visual impairment, trichomegaly, keratitis, and interstitial lung disease.
Table 13 summarizes the laboratory abnormalities in MARIPOSA-2.
Table 13: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations Treated with RYBREVANT in Combination with Carboplatin and Pemetrexed in MARIPOSA-2
| Laboratory Abnormality | RYBREVANT + Carboplatin + Pemetrexed (N=130) |
Carboplatin + Pemetrexed (N=243) |
||
| All Grades (%) | Grade 3 or 4 (%) | All Grades (%) | Grade 3 or 4 (%) | |
| Hematology | ||||
| Decreased white blood cells | 91 | 42 | 85 | 19 |
| Decreased neutrophils | 74 | 49 | 64 | 25 |
| Decreased platelets | 74 | 17 | 58 | 9 |
| Decreased hemoglobin | 71 | 12 | 77 | 9 |
| Decreased lymphocytes | 69 | 28 | 58 | 18 |
| Chemistry | ||||
| Decreased albumin | 73 | 3.8 | 26 | 0.4 |
| Decreased sodium | 49 | 11 | 30 | 6 |
| Increased aspartate aminotransferase | 47 | 0.8 | 52 | 0.9 |
| Increased alkaline phosphatase | 42 | 0 | 29 | 0.4 |
| Increased alanine aminotransferase | 39 | 3.9 | 56 | 6 |
| Decreased magnesium | 38 | 0.8 | 17 | 0.4 |
| Decreased Potassium | 37 | 11 | 12 | 3.4 |
| Increased gamma-glutamyl transferase | 30 | 3.1 | 41 | 1.3 |
| Decreased calcium (corrected) | 25 | 0 | 11 | 0.9 |
The safety data described below reflect exposure to RYBREVANT in combination with carboplatin and pemetrexed at the recommended dosage in the PAPILLON trial [see Clinical Studies] 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 14 summarizes the adverse reactions in PAPILLON.
Table 14: Adverse Reactions (≥ 10%) in Patients with Metastatic NSCLC with Exon 20 Insertion Mutations Who Received RYBREVANT in Combination with Carboplatin and Pemetrexed in PAPILLON
| Adverse Reaction1 | 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 | ||||
| Rash2 | 90 | 19 | 19 | 0 |
| Nail toxicity2 | 62 | 7 | 3 | 0 |
| Dry skin2 | 17 | 0 | 6 | 0 |
| Gastrointestinal disorders | ||||
| Stomatitis2 | 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 pain2 | 11 | 0.7 | 8 | 0 |
| General disorders and administration site conditions | ||||
| Infusion-related reaction | 42 | 1.3 | 1.3 | 0 |
| Fatigue2 | 42 | 6 | 45 | 3.9 |
| Edema2 | 40 | 1.3 | 19 | 0 |
| Pyrexia2 | 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 |
| Pneumonia2 | 13 | 5 | 6 | 1.9 |
| Vascular disorders | ||||
| Hemorrhage2 | 18 | 0.7 | 11 | 1.9 |
| Respiratory, thoracic, and mediastinal disorders | ||||
| Cough2 | 17 | 0 | 16 | 0 |
| Dyspnea2 | 11 | 1.3 | 16 | 3.2 |
| Investigations | ||||
| Weight decreased | 14 | 0.7 | 8 | 0 |
| Nervous system disorders | ||||
| Dizziness2 | 11 | 0 | 12 | 0 |
| Psychiatric disorders | ||||
| Insomnia | 11 | 0 | 13 | 0 |
| 1 Adverse reactions were graded using CTCAE version 5.0 2 Grouped Term |
||||
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 15 summarizes the laboratory abnormalities in PAPILLON.
Table 15: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with Metastatic NSCLC with EGFR Exon 20 Insertion Mutations Who Received RYBREVANT in Combination with Carboplatin and Pemetrexed in PAPILLON
| Laboratory Abnormality1 | RYBREVANT in Combination with Carboplatin and Pemetrexed2 | Carboplatin in Combination with Pemetrexed3 | ||
| 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 |
| 1 Adverse reactions were graded using CTCAE version 5.0 2 The denominator used to calculate the rate varied from 113 to 150 based on the number of patients with a baseline value and at least one post-treatment value. 3 The denominator used to calculate the rate varied from 119 to 154 based on the number of patients with a baseline value and at least one post-treatment value. |
||||
The safety 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], 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 16 summarizes the adverse reactions in CHRYSALIS.
Table 16: Adverse Reactions (≥ 10%) in Patients with NSCLC with Exon 20 Insertion Mutations Whose Disease Has Progressed on or after Platinum-based Chemotherapy and Received RYBREVANT in CHRYSALIS
| Adverse Reactions | RYBREVANT1 (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 |
| * Grouped term 1 Adverse reactions were graded using CTCAE version 4.03 |
||
Clinically relevant adverse reactions in < 10% of patients who received RYBREVANT included ocular toxicity, ILD/pneumonitis, and toxic epidermal necrolysis (TEN).
Table 17 summarizes the laboratory abnormalities in CHRYSALIS.
Table 17: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients With Metastatic NSCLC with EGFR Exon 20 Insertion Mutations Whose Disease Has Progressed on or After Platinum-based Chemotherapy and Who Received RYBREVANT 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 |
| + The denominator used to calculate the rate was 126 based on the number of patients with a baseline value and at least one post-treatment value. | ||
No Information provided
Included as part of the PRECAUTIONS section.
RYBREVANT can cause infusion-related reactions (IRR); signs and symptoms of IRR include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension and vomiting. The median time to IRR onset is approximately 1 hour.
RYBREVANT in combination with lazertinib can cause infusion-related reactions. In MARIPOSA, [see ADVERSE REACTIONS], IRRs occurred in 63% of patients treated with RYBREVANT in combination with lazertinib, including Grade 3 in 5% and Grade 4 in 1% of patients. The incidence of infusion modifications due to IRR was 54%, and IRRs leading to dose reduction of RYBREVANT occurred in 0.7% of patients. Infusion-related reactions leading to permanent discontinuation of RYBREVANT occurred in 4.5% of patients receiving RYBREVANT in combination with lazertinib.
In PAPILLON, [see ADVERSE REACTIONS], 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.
In CHRYSALIS, [see ADVERSE REACTIONS], 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]. Administer RYBREVANT via a peripheral line on Week 1 and Week 2 to reduce the risk of infusion-related reactions [see DOSAGE AND ADMINISTRATION].
Monitor patients for 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].
RYBREVANT can cause severe and fatal interstitial lung disease (ILD)/pneumonitis.
In MARIPOSA, [see ADVERSE REACTIONS], ILD/pneumonitis occurred in 3.1% of patients treated with RYBREVANT in combination with lazertinib, including Grade 3 in 1.0% and Grade 4 in 0.2% of patients. There was one fatal case of ILD/pneumonitis and 2.9% of patients permanently discontinued RYBREVANT and lazertinib due to ILD/pneumonitis [see ADVERSE REACTIONS].
In PAPILLON, [see ADVERSE REACTIONS], Grade 3 ILD/pneumonitis occurred in 2.6% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed, all patients required permanent discontinuation.
In CHRYSALIS [see ADVERSE REACTIONS], 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].
RYBREVANT in combination with lazertinib can cause serious and fatal venous thromboembolic (VTEs) events, including deep vein thrombosis and pulmonary embolism. The majority of these events occurred during the first four months of therapy [see ADVERSE REACTION].
In MARIPOSA [see ADVERSE REACTIONS], VTEs occurred in 36% of patients receiving RYBREVANT in combination with lazertinib, including Grade 3 in 10% and Grade 4 in 0.5% of patients. On-study VTEs occurred in 1.2% of patients (n=5) while receiving anticoagulation therapy. There were two fatal cases of VTE (0.5%), 9% of patients had VTE leading to dose interruptions of RYBREVANT, 1% of patients had VTE leading to dose reductions of RYBREVANT, and 3.1% of patients had VTE leading to permanent discontinuation of RYBREVANT. The median time to onset of VTEs was 84 days (range: 6 to 777).Administer prophylactic anticoagulation for the first four months of treatment [see DOSAGE AND ADMINISTRATION]. The use of Vitamin K antagonists is not recommended. Monitor for signs and symptoms of VTE events and treat as medically appropriate.
Withhold RYBREVANT and lazertinib based on severity [see DOSAGE AND ADMINISTRATION]. Once anticoagulant treatment has been initiated, resume RYBREVANT and lazertinib at the same dose level at the discretion of the healthcare provider [see DOSAGE AND ADMINISTRATION]. In the event of VTE recurrence despite therapeutic anticoagulation, permanently discontinue RYBREVANT. Treatment can continue with lazertinib at the same dose level at the discretion of the healthcare provider [see DOSAGE AND ADMINISTRATION]. Refer to the lazertinib prescribing information for recommended lazertinib dosage modification.
RYBREVANT can cause severe rash including toxic epidermal necrolysis (TEN), dermatitis acneiform, pruritus and dry skin.
In MARIPOSA, [see ADVERSE REACTIONS], rash occurred in 86% of patients treated with RYBREVANT in combination with lazertinib, including Grade 3 in 26% of patients. The median time to onset of rash was 14 days (range: 1 to 556 days). Rash leading to dose interruptions of RYBREVANT occurred in 37% of patients, rash leading to dose reductions of RYBREVANT occurred in 23% of patients, and rash leading to permanent discontinuation of RYBREVANT occurred in 5% of patients.
In PAPILLON [see ADVERSE REACTIONS], 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.
In CHRYSALIS [see ADVERSE REACTIONS], 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].
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 (e.g., isopropanol-free, ethanol-free) emollient cream is recommended for dry skin.
When initiating treatment with RYBREVANT, administer alcohol-free (e.g., isopropanol-free, ethanol-free) emollient cream to reduce the risk of dermatologic adverse reactions. Consider prophylactic measures (e.g., use of oral antibiotics) to reduce the risk of dermatologic adverse reactions. 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].
RYBREVANT can cause ocular toxicity including keratitis, blepharitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, eye pruritus and uveitis.
In MARIPOSA [see ADVERSE REACTIONS], ocular toxicity occurred in 16% of patients treated with RYBREVANT in combination with lazertinib, including Grade 3 or 4 ocular toxicity in 0.7% of patients. Withhold, reduce the dose, or permanently discontinue RYBREVANT and continue lazertinib based on severity [see DOSAGE AND ADMINISTRATION].
In PAPILLON [see ADVERSE REACTIONS], ocular toxicity including blepharitis, dry eye, conjunctival redness, blurred vision, and eye pruritus occurred in 9%. All events were Grade 1-2.
In CHRYSALIS [see 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 with new or worsening eye symptoms to an ophthalmologist. Withhold, dose reduce or permanently discontinue RYBREVANT based on severity [see DOSAGE AND ADMINISTRATION].
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].
Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).
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].
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].
When RYBREVANT is used in combination with lazertinib, advise patients of the risks of serious and life threatening venous thromboembolic (VTE) events, including deep venous thrombosis and pulmonary embolism. Advise patients that prophylactic anticoagulants are recommended to be used for the first four months of treatment. Advise patients to immediately contact their healthcare provider for signs and symptoms of venous thromboembolism [see WARNINGS AND PRECAUTIONS].
Advise patients of the risk of dermatologic adverse reactions. Advise patients to apply alcohol-free (e.g., isopropanol-free, ethanol-free) emollient cream to reduce the risk of skin reactions. Consider prophylactic measures (e.g., use of oral antibiotics) to reduce the risk of dermatologic adverse reactions. Advise patients to limit direct sun exposure during and for 2 months after treatment, to use broad-spectrum UVA/UVB sunscreen, and to wear protective clothing during treatment with RYBREVANT [see WARNINGS AND PRECAUTIONS].
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].
Advise patients of the risk of paronychia. Advise patients to contact their healthcare provider for signs or symptoms of paronychia [see ADVERSE REACTIONS].
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, Use In Specific Populations].
Advise women not to breastfeed during treatment with RYBREVANT and for 3 months after the last dose [see Use In Specific Populations].
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.
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.
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.
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].
Verify pregnancy status of females of reproductive potential prior to initiating RYBREVANT.
Females
Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of RYBREVANT.
The safety and efficacy of RYBREVANT have not been established in pediatric patients.
No clinically important differences in safety or efficacy were observed between patients who were ≥65 years of age and younger patients.
No Information provided
None.
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 in mutation models of exon 19 deletions, exon 21 L858R substitutions, and exon 20 insertions through blocking ligand binding or 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. Treatment with amivantamab in combination with lazertinib increased in vivo anti-tumor activity compared to either agent alone in a mouse xenograft model of human NSCLC with an EGFR L858R mutation.
The exposure-response relationship and time-course of pharmacodynamic response of amivantamab-vmjw have not been fully characterized in patients with NSCLC with EGFR mutations.
Amivantamab-vmjw exposures increased proportionally over a dosage range from 350 to 1750 mg (0.33 to 1.7 times the lowest approved recommended dosage) when RYBREVANT was administered as a single agent. 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 1.9Âfold.
The amivantamab-vmjw mean (%CV) volume of distribution is 5 (24%) L.
The mean (% CV) linear clearance (CL) is 0.26 L/day (30%) and mean terminal half-life is 14 days (33%).
No clinically meaningful differences in the pharmacokinetics of amivantamab-vmjw were observed based on age (range: 21-88 years), body weight (31 to 140 kg), sex, race (White, Asian or Black or African American) and ethnicity (Hispanic/Latino or not Hispanic/Latino), mild or moderate renal impairment (eGFR 30 to 89 mL/min) or mild hepatic impairment [(total bilirubin ≤ ULN and AST > ULN) or (ULN < total bilirubin ≤ 1.5 times ULN)]. The effect of severe renal impairment (eGFR 15 to 29 mL/min), end-stage renal disease (eGFR < 15 mL/min) or moderate to severe hepatic impairment (total bilirubin > 1.5 times ULN and any AST) on amivantamabÂvmjw pharmacokinetics has not been studied.
Increases in body weight increased the volume of distribution and clearance of amivantamab-vmjw. Amivantamab-vmjw exposures are 30 to 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.
During treatment in studies CHRYSALIS, CHRYSALIS-2, PAPILLON, MARIPOSA, and MARIPOSA-2 (up to 39 months), 4 of the 1862 (0.2%) patients who received RYBREVANT as a single agent or in combination developed a treatment-emergent anti-amivantamab-vmjw antibodies. Given the low occurrence of anti-drug antibodies, the effect of these antibodies on the pharmacokinetics, safety or efficacy of RYBREVANT is unknown.
The efficacy of RYBREVANT, in combination with lazertinib, was evaluated in MARIPOSA [NCT04487080], a randomized, active-controlled, multicenter trial. Eligible patients were required to have untreated locally advanced or metastatic NSCLC with either exon 19 deletions or exon 21 L858R substitution EGFR mutations identified by local testing, not amenable to curative therapy. Patients with asymptomatic or previously treated and stable intracranial metastases were eligible to enroll.
Patients were randomized (2:2:1) to receive RYBREVANT in combination with lazertinib (N=429), osimertinib monotherapy (N=429), or lazertinib monotherapy (an unapproved regimen for NSCLC) until disease progression or unacceptable toxicity. The evaluation of efficacy for the treatment of untreated metastatic NSCLC relied upon comparison between:
RYBREVANT administered intravenously at 1050 mg (for patients < 80 kg) or 1400 mg (for patients ≥ 80 kg) once weekly for 4 weeks, then every 2 weeks thereafter starting at week 5 in combination with lazertinib administered at 240 mg orally once daily.
Osimertinib administered at a dose of 80 mg orally once daily.
A total of 858 patients were randomized between the two study arms, 429 to the RYBREVANT in combination with lazertinib arm and 429 to the osimertinib arm. The median age was 63 (range: 25–88) years; 61% were female; 58% were Asian, 38% were White, 1.6% were American Indian or Alaska Native, 0.8% were Black or African American, 0.2% were Native Hawaiian or other Pacific Islander, 0.6% were unknown race or multiple races; and 12% were Hispanic or Latino. Eastern Cooperative Oncology Group (ECOG) performance status was 0 (34%) or 1 (66%); 69% never smoked; 41% had prior brain metastases; and 89% had Stage IV cancer at initial diagnosis. Sixty percent of patients had tumors harboring exon 19 deletions and the remaining 40% had exon 21 L858R substitution mutations.
Among the 858 patients with EGFR exon 19 deletion or L858R substitution mutations that were randomized between the RYBREVANT plus lazertinib arm versus the osimertinib arm, available tissue samples from 544 (63%) patients had evaluable results when tested retrospectively using the cobas EGFR Mutation Test v2. Of the 544 patients with evaluable results, 527 (97%) patients were positive for EGFR exon 19 deletion or L858R substitution mutations, while 17 (3%) patients were negative. Available plasma samples from patients were retrospectively tested using an FDA-approved test to confirm the biomarker status.
The trial demonstrated a statistically significant improvement in PFS by BICR assessment for RYBREVANT in combination with lazertinib compared to osimertinib.
Efficacy results for RYBREVANT in combination with lazertinib are provided in Table 18.
Table 18: Efficacy Results in MARIPOSA by BICR Assessment
| RYBREVANT in combination with lazertinib (N=429) |
Osimertinib (N=429) |
|
| Progression-free survival (PFS) | ||
| Number of events (%) | 192 (45) | 252 (59) |
| Median, months (95% CI) | 23.7 (19.1, 27.7) | 16.6 (14.8, 18.5) |
| HR1,2 (95% CI); p-value1,3 | 0.70 (0.58, 0.85); p=0.0002 | |
| Overall response rate (ORR)4 | ||
| ORR, % (95% CI) | 78 (74, 82) | 73 (69, 78) |
| Complete response, % | 5.4 | 3.5 |
| Partial response, % | 73 | 70 |
| Duration of response (DOR)5 | ||
| Median (95% CI), months | 25.8 (20.1, NE) | 16.7 (14.8, 18.5) |
| Patients with DOR ≥ 6 months6, % | 86 | 85 |
| Patients with DOR ≥ 12 months6,% | 68 | 57 |
| CI = confidence interval; NE = not estimable 1 Stratified by mutation type (Exon 19del or Exon 21 L858R), prior brain metastases (yes or no), and Asian race (yes or no). 2 Stratified Cox proportional hazards regression. 3 Stratified log-rank test. 4 Confirmed responses based on the ITT population. 5 In confirmed responders. 6 Based on observed rates. |
||
Figure 1: Kaplan-Meier curve of PFS in previously untreated NSCLC patients by BICR assessment
 |
While OS results were immature at the current analysis, with 55% of pre-specified deaths for the final analysis reported, no trend towards a detriment was observed.
Out of all randomized patients (n=858), 367 (43%) had baseline intracranial lesions assessed by BICR using modified RECIST. Results of pre-specified analyses of intracranial ORR and DOR by BICR in the subset of patients with intracranial lesions at baseline for the RYBREVANT in combination with lazertinib arm and the osimertinib arm are summarized in Table 19.
Table 19: Exploratory Analysis of Intracranial ORR and DOR by BICR assessment in subjects with intracranial lesions at baseline
| RYBREVANT in combination with lazertinib (N=180) |
Osimertinib (N=187) |
||
| Intracranial Tumor Response Assessment | |||
| Intracranial ORR1, % (95% CI) | 68 (60, 75) | 69 (62, 76) | |
| Complete response % | 55 | 52 | |
| Intracranial DOR2 | |||
| Number of responders | 122 | 129 | |
| Patients with DOR ≥ 12 months3, % | 66 | 59 | |
| Patients with DOR ≥ 18 months3, % | 35 | 23 | |
| CI = confidence interval 1 Confirmed responses 2 In confirmed responders 3 Based on observed rates |
|||
The efficacy of RYBREVANT in combination with carboplatin and pemetrexed was evaluated in MARIPOSA-2 (NCT04988295), a randomized, open-label, multicenter trial. Eligible patients were required to have locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations and progressive disease on or after receiving osimertinib. Patients with asymptomatic or previously treated and stable intracranial metastases were eligible to enroll. Patients were randomized (1:2:2) to receive RYBREVANT in combination with carboplatin and pemetrexed (RYBREVANT-CP, N=131), carboplatin and pemetrexed (CP, N=263), or RYBREVANT as part of another combination regimen. The evaluation of efficacy for metastatic NSCLC relied upon comparison between:
For both arms, 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 and pemetrexed was administered intravenously at 500 mg/m² once every 3 weeks until disease progression or unacceptable toxicity.
Randomization was stratified by osimertinib line of therapy (first-line or second-line), prior brain metastases (yes or no), and Asian race (yes or no). Tumor assessments were performed every 6 weeks for the first 12 months and every 12 weeks thereafter.
The major efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review (BICR). Overall survival (OS) and overall response rate (ORR) as assessed by BICR were key secondary outcome measures.
A total of 394 patients were randomized between the two arms, 131 to the RYBREVANT-CP arm and 263 to the CP arm. The median age was 62 (range: 31 to 85) years, with 38% of patients ≥ 65 years of age; 60% were female; and 48% were Asian and 46% were White, 1% were American Indian or Alaska Native, 1% were Black or African American, 0.5% were multiple races and 2.8% were race not reported or race unknown; 8% were Hispanic or Latino. Baseline Eastern Cooperative Oncology Group (ECOG) performance status was 0 (40%) or 1 (60%); 65% never smoked; 45% had history of brain metastasis, and 99.7% had Stage IV cancer at study enrollment.
The trial demonstrated a statistically significant improvement in PFS by BICR for RYBREVANT in combination with carboplatin and pemetrexed compared to carboplatin and pemetrexed.
Efficacy results are summarized in Table 20.
Table 20: Efficacy results in MARIPOSA-2
| RYBREVANT + carboplatin+ pemetrexed (N=131) |
carboplatin+ pemetrexed (N=263) |
|
| Progression-free survival (PFS)1 | ||
| Number of events | 74 (56%) | 171 (65%) |
| Median, months (95% CI) | 6.3 (5.6, 8.4) | 4.2 (4.0, 4.4) |
| HR (95% CI)2,3; p-value2,4 | 0.48 (0.36, 0.64); p<0.0001 | |
| Overall response rate1,5 | ||
| ORR, % (95% CI) | 53% (44, 62) | 29% (23, 35) |
| p-value2,6 | p<0.0001 | |
| Complete response | 0.8% | 0% |
| Partial response | 52% | 29% |
| Duration of response1,5 (DOR) | ||
| Median (95% CI), months | 6.9 (5.5, NE) | 5.6 (4.2, 9.6) |
| CI = confidence interval NE = not estimatable 1 Blinded Independent Central Review by RECIST v1.1 2 Stratified by osimertinib line of therapy (first-line or second-line), prior brain metastases (yes or no), and Asian race (yes or no). 3 Stratified Cox proportional hazards regression. 4 Stratified log-rank test. 5 Confirmed responses. 6 Stratified logistic regression analysis. |
||
Figure 2: Kaplan-Meier curve of PFS in Previously Treated NSCLC Patients by BICR assessment ÂMARIPOSA-2
 |
At the prespecified second interim analysis of OS, with 85% of the deaths needed for the final analysis, there was no statistically significant difference in OS. The median OS was 17.7 months (95% CI: 16.0, 22.4) in the ACP arm and 15.3 months (95% CI: 13.7, 16.8) in the CP arm, with a hazard ratio of 0.73 (95% CI: 0.54, 0.99).
Patients with asymptomatic or previously treated and stable intracranial metastases were eligible to be randomized in MARIPOSA-2. Baseline disease assessment, including brain magnetic resonance imaging (MRI) was performed at treatment initiation. All patients underwent serial brain MRI during the trial.
Pre-specified secondary analyses of intracranial ORR by BICR in the subset of 91 (23%) patients with baseline intracranial disease were performed. Data were only available for intracranial complete responses and not available for intracranial partial responses. Intracranial ORR was 20% (95% CI: 8, 39) in the 30 patients with baseline intracranial disease in the ACP arm and 7% (95% CI:1.8, 16) in the 61 patients with baseline intracranial disease in the CP arm.
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/m² on 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 21 and Figure 3.
Table 21: Efficacy Results in PAPILLON
| RYBREVANT+ carboplatin+ pemetrexed (N=153) |
carboplatin+ pemetrexed (N=155) |
|
| 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)1 | ||
| ORR, % (95% CI) | 67 (59, 75) | 36 (29, 44) |
| Complete response, % | 4 | 1 |
| Partial response, % | 63 | 36 |
| Duration of response (DOR) 2 | ||
| Median (95% CI), months | 10.1 (8.5, 13.9) | 5.6 (4.4, 6.9) |
| CI = confidence interval 1 Confirmed responses. 2 In confirmed responders. |
||
Figure 3: 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 22.
Table 22: Efficacy Results for CHRYSALIS
| Prior Platinum-based Chemotherapy Treated (N=81) |
|
| 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% |
| Based on Kaplan-Meier estimates. NE=Not Estimable, CI=confidence interval. |
|
RYBREVANT®
(RYE-breh-vant)
(amivantamab-vmjw) injection, for intravenous use
What is RYBREVANT?
RYBREVANT is a prescription medicine used to treat adults with non-small cell lung cancer (NSCLC) that has spread to other parts of the body (metastatic) or cannot be removed by surgery, and has certain abnormal epidermal growth factor receptor (EGFR) gene(s):
Your healthcare provider will perform a test to make sure that RYBREVANT is right for you.
It is not known if RYBREVANT is safe and effective in children.
Before you receive RYBREVANT, tell your healthcare provider about all of your medicalconditions, including if you:
Females who are able to become pregnant:
Tell your healthcare provider about all the medicines you take, including prescription and over-thecounter medicines, vitamins, and herbal supplements.
How will I receive RYBREVANT?
What should I avoid while receiving RYBREVANT?
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:
Your healthcare provider may send you to see an eye specialist (ophthalmologist) if you get new or worsening 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 when given in combination with lazertinib include:
The most common side effects of RYBREVANT when given in combination with carboplatin and pemetrexed include:
The most common side effects of RYBREVANT when given alone:
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.
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.
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.
This Patient Information has been approved by the U.S. Food and Drug Administration
