Rybrevant Faspro Drug Information
Generic name: AMIVANTAMAB AND HYALURONIDASE-LPUJ (HUMAN RECOMBINANT)
Endoglycosidase [EPC]
Uses of Rybrevant Faspro
First-Line Treatment of
NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations RYBREVANT FASPRO, 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 .
Previously Treated
NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations RYBREVANT FASPRO, 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 EGFR tyrosine kinase inhibitor.
First-Line Treatment of
NSCLC with EGFR Exon 20 Insertion Mutations RYBREVANT FASPRO, 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 .
Previously Treated
NSCLC with EGFR Exon 20 Insertion Mutations RYBREVANT FASPRO 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 , whose disease has progressed on or after platinum-based chemotherapy.
Dosage & Administration of Rybrevant Faspro
| Information on FDA-approved tests is available at: | |
|---|---|
| First-Line Treatment of NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations | RYBREVANT FASPRO 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) | RYBREVANT FASPRO in combination with carboplatin and pemetrexed |
| First-Line Treatment of NSCLC with EGFR Exon 20 Insertion Mutations | RYBREVANT FASPRO in combination with carboplatin and pemetrexed |
| Previously Treated NSCLC with EGFR Exon 20 Insertion Mutations | RYBREVANT FASPRO as a single agent |
Side Effects of Rybrevant Faspro
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. RYBREVANT FASPRO in Combination with Lazertinib The safety population described in the WARNINGS AND PRECAUTIONS reflect exposure to RYBREVANT FASPRO in combination with lazertinib in 206 patients with previously treated locally advanced or metastatic NSCLC whose tumors have either an EGFR exon 19 deletion or an exon 21 L858R substitution mutation in PALOMA-3. Patients received RYBREVANT FASPRO (N=206) or intravenous amivantamab (N=210), both in combination with lazertinib, at the recommended dosages until disease progression or unacceptable toxicity. Among 206 patients who received RYBREVANT FASPRO in combination with lazertinib, 47% were exposed for 6 months or longer and 12% were exposed for greater than one year.
The most common adverse reactions (≥ 20%) were rash, nail toxicity, musculoskeletal pain, fatigue, stomatitis, edema, nausea, diarrhea, vomiting, constipation, decreased appetite, and headache. The most common Grade 3 or 4 laboratory abnormalities (≥ 2%) were decreased lymphocyte count, decreased sodium, decreased potassium, decreased albumin, increased alanine aminotransferase, increased aspartate aminotransferase, decreased platelet count, increased gamma-glutamyl transferase, and decreased hemoglobin. Intravenous Amivantamab in Combination with Lazertinib The data described in the WARNINGS AND PRECAUTIONS also reflect exposure to intravenous amivantamab 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 . Patients received intravenous amivantamab 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, until disease progression or unacceptable toxicity.
Among 421 patients who received intravenous amivantamab 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, 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.
Intravenous Amivantamab in Combination with Carboplatin and Pemetrexed The pooled safety population described in the WARNINGS AND PRECAUTIONS also reflect exposure to intravenous amivantamab in combination with carboplatin and pemetrexed in 281 patients in two studies: MARIPOSA-2 in 130 patients with previously treated 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 osimertinib. PAPILLON in 151 patients with previously untreated, locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. Patients received intravenous amivantamab at 1,400 mg (for patients < 80 kg) or 1,750 mg (for patients ≥ 80 kg) once weekly through 4 weeks, then every 3 weeks with a dose of 1,750 mg (for patients < 80 kg) or 2,100 mg (for 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/m 2 once every 3 weeks until disease progression or unacceptable toxicity.
Among 281 patients who received intravenous amivantamab 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. Intravenous Amivantamab as a Single Agent The pooled safety population described in the WARNINGS AND PRECAUTIONS also reflect exposure to intravenous amivantamab as a single agent in CHRYSALIS in 302 patients with locally advanced or metastatic NSCLC. Patients received intravenous amivantamab at 1,050 mg (for patient baseline body weight < 80 kg) or 1,400 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 intravenous amivantamab 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 transferase, decreased sodium, decreased potassium and increased alkaline phosphatase.
Subcutaneous RYBREVANT FASPRO Previously Treated NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations – RYBREVANT FASPRO In Combination with Lazertinib PALOMA-3 (Every 2-week dosing) The safety of RYBREVANT FASPRO in combination with lazertinib was evaluated in the PALOMA-3 study . Eligible patients were required to have locally advanced or metastatic NSCLC whose tumors have either an EGFR exon 19 deletion or an exon 21 L858R substitution mutation and whose disease has progressed on prior treatment with osimertinib and platinum-based chemotherapy. Patients were randomized to receive lazertinib 240 mg orally once daily in combination with either RYBREVANT FASPRO (N=206) or intravenous amivantamab (N=210) at the recommended dosages until disease progression or unacceptable toxicity. In total, 164 patients (80%) receiving RYBREVANT FASPRO and 171 patients (81%) receiving intravenous amivantamab received prophylactic anticoagulants with a direct oral anticoagulant or low molecular weight heparin during the first four months of study treatment.
Among patients receiving RYBREVANT FASPRO, 47% were exposed for ≥ 6 months and 12% were exposed for ≥ 1 year. The median age of patients who received RYBREVANT FASPRO was 61 years (range: 35–82); 67% were female; 61% Asian, 38% White, 0.5% Black, and 0.5% did not report race; 6% were Hispanic or Latino. Serious adverse reactions occurred in 33% of patients who received RYBREVANT FASPRO in combination with lazertinib.
Serious adverse reactions in ≥ 2% of patients who received RYBREVANT FASPRO in combination with lazertinib included ILD/pneumonitis (6%); and pneumonia, VTE and fatigue (2.4% each). Death due to adverse reactions occurred in 5% of patients treated with RYBREVANT FASPRO, including ILD/pneumonitis (1.9%), pneumonia (1.5%), and respiratory failure and sudden death (1% each). Permanent discontinuations of RYBREVANT FASPRO due to an adverse reaction occurred in 13% of patients. Adverse reactions leading to RYBREVANT FASPRO discontinuation in ≥ 1% of patients were ILD/pneumonitis (5%), rash (1.9%) and pneumonia 1%. Dosage interruptions of RYBREVANT FASPRO due to an adverse reaction occurred in 54% of patients. Adverse reactions requiring RYBREVANT FASPRO dose interruption in ≥ 5% of patients were rash (21%) and nail toxicity (13%). Dose reductions of RYBREVANT FASPRO due to an adverse reaction occurred in 20% of patients.
Adverse reactions requiring RYBREVANT FASPRO dose reductions in ≥ 5% of patients were rash (11%) and nail toxicity (8%). Table 10 summarizes the adverse reactions (≥ 10%) in PALOMA-3. Table 10: Adverse Reactions (≥ 10%) in Patients with Previously Treated NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations Who Received RYBREVANT FASPRO in Combination with Lazertinib in PALOMA-3 Adverse Reaction RYBREVANT FASPRO with lazertinib (N=206) Intravenous amivantamab with lazertinib (N=210) All Grades (%) Grades 3 or 4 (%) All Grades (%) Grades 3 or 4 (%) Skin and subcutaneous tissue disorders Rash Grouped terms 80 17 78 13 Nail toxicity 58 3.9 56
Dry skin 18 0 18 0 Pruritus 17 0 12 0 Musculoskeletal
and connective tissue disorders Musculoskeletal pain 50 2.4 35
General disorders and administration site conditions Fatigue 37 3.4 31 2.4 Edema
34 2.9 34 1 Pyrexia 13 0 11 0 Local injection site reactions 11 0 0 0 Gastrointestinal disorders Stomatitis 36 0.5 38
Nausea 30 0.5 25 1.4 Diarrhea 22 1.5 19 1 Vomiting 22
1 20
Constipation 22 0 20 0.5 Metabolism and nutrition disorders Decreased appetite 22
0.5 25
Nervous system disorders Headache 21 0.5 19 0.5 Peripheral neuropathy 19 1.5
23
Dizziness 12 0 12 0 Injury, poisoning and procedural complications Administration-related reactions
13 0.5 66
Eye disorders Ocular toxicity 13 0.5 11 0.5 Vascular disorders Venous thromboembolism
11 1.5 18 5 Clinically relevant adverse reactions in < 10% of patients who received RYBREVANT FASPRO in combination with lazertinib not included in the table above were abdominal pain, hemorrhoids, ILD/pneumonitis, and skin ulcer. Table 11 summarizes the laboratory abnormalities in PALOMA-3. Table 11: Select Laboratory Abnormalities (≥ 20%) that Worsened from Baseline in Patients with NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations in PALOMA-3 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. Laboratory Abnormality RYBREVANT FASPRO with lazertinib (N=206) Intravenous amivantamab with lazertinib (N=210) All Grades (%) Grades 3 or 4 (%) All Grades (%) Grades 3 or 4 (%) Chemistry Decreased Albumin 92 4.9 91 5 Increased Alkaline Phosphatase 47 1.5 37 0 Increased Alanine Aminotransferase 45 3.4 50 5 Decreased Sodium 36 5 43 8 Increased Aspartate Aminotransferase 36 2 40
Hematology Decreased Lymphocyte Count 57 6 60 29 Decreased Platelet Count 37
2.4 42
Decreased White Blood Cell 36 0.5 31 0.5 Decreased Hemoglobin 34 2
36
Clinical Trials Experience of Amivantamab Intravenous Formulation Below is a description of
adverse reactions of intravenous amivantamab in these adequate and well-controlled NSCLC studies. First-line Treatment of NSCLC with Exon 19 Deletions or Exon 21 L858R Substitution Mutations – Intravenous Amivantamab in Combination with Lazertinib MARIPOSA The safety data described below reflect exposure to intravenous amivantamab 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 . Patients received intravenous amivantamab 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 intravenous amivantamab in combination with lazertinib, 73% were exposed to intravenous amivantamab for ≥ 6 months and 59% were exposed to intravenous amivantamab for > 1 year.
The median age of patients who received intravenous amivantamab 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 intravenous amivantamab 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 intravenous amivantamab 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 intravenous amivantamab 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 intravenous amivantamab 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 intravenous amivantamab 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 12 summarizes the adverse reactions (≥ 10%) in MARIPOSA. Table 12: Adverse Reactions (≥ 10%) in Patients with NSCLC with Exon 19 Deletion or Exon 21 L858R Substitution Mutations in MARIPOSA Adverse Reaction Intravenous amivantamab 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 Grouped terms 86 26 48
Nail toxicity 71 11 34 0.7 Dry skin 25 1 18 0.2
Pruritus 24 0.5 17
Injury, poisoning and procedural complications Infusion-related reaction Applicable for intravenous amivantamab only
63 6 0 0 Musculoskeletal and connective tissue disorders Musculoskeletal pain 47 2.1 39
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
Vomiting 12 0.5 5 0 Abdominal pain 11 0 10 0 Hemorrhoids
10 0.2 2.1
General disorders and administration site conditions Edema 43 2.6 8 0 Fatigue
32 3.8 20
Dizziness 14 0 10 0 Headache 13 0.2 13 0 Infections and
infestations COVID-19 26 1.7 24
Conjunctivitis 11 0.2 1.6 0 Metabolism and nutrition disorders Decreased appetite 24
1 18
Respiratory, thoracic, and mediastinal disorders Cough 19 0 23 0 Dyspnea 14
1.7 17
Eye disorders Ocular toxicity 16 0.7 7 0 Psychiatric disorders Insomnia 10
0 11 0 Clinically relevant adverse reactions in < 10% of patients who received intravenous amivantamab in combination with lazertinib included skin ulcer and ILD/pneumonitis. Table 13 summarizes the laboratory abnormalities in MARIPOSA. Table 13: 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 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. Intravenous amivantamab in combination with lazertinib (N=421) Osimertinib (N=428) Laboratory Abnormality All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Chemistry Decreased albumin 89 8 22
Increased
ALT 65 7 29
Increased
AST 52 3.8 36
Increased alkaline phosphatase 45 0.5 15 0.5 Decreased calcium (corrected) 41 1.4
27
Increased
GGT 39 2.6 24
Decreased sodium 38 7 35 5 Decreased potassium 30 5 15 1.2
Increased creatinine 26 0.7 35
Decreased magnesium 25 0.7 10 0.2 Increased magnesium 12 2.6 20 4.8
Hematology Decreased platelet count 52 0.7 57
Decreased hemoglobin 47 3.8 56 1.9 Decreased white blood cell 38 1
66
Decreased neutrophils 15 1.4 33 1.4 Previously Treated
NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations – Intravenous Amivantamab in Combination with Carboplatin and Pemetrexed MARIPOSA-2 The safety data described below reflect exposure to intravenous amivantamab in combination with carboplatin and pemetrexed was evaluated in MARIPOSA-2. 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 intravenous amivantamab at 1,400 mg (for patients < 80 kg) or 1,750 mg (for patients ≥ 80 kg) once weekly through 4 weeks, then every 3 weeks with a dose of 1,750 mg (for patients < 80 kg) or 2,100 mg (for 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/m 2 once every 3 weeks until disease progression or unacceptable toxicity.
Among patients who received intravenous amivantamab (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 intravenous amivantamab 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 intravenous amivantamab in combination with carboplatin and pemetrexed; these included respiratory failure, sepsis, and ventricular fibrillation (0.8% each). Permanent discontinuation of intravenous amivantamab due to adverse reactions occurred in 11% of patients. The most frequent adverse reactions leading to discontinuation of intravenous amivantamab in ≥ 5% of patients were infusion-related reactions. Dose interruptions of intravenous amivantamab 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 intravenous amivantamab 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 14 summarizes the adverse reactions in MARIPOSA-2. Table 14: Adverse Reactions (≥ 10%) in Previously Treated Patients with NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations Treated with Intravenous Amivantamab in Combination with Carboplatin and Pemetrexed in MARIPOSA-2 Intravenous Amivantamab With Carboplatin and Pemetrexed (N=130) Carboplatin and Pemetrexed (N=243) Adverse Reaction All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade 3 or 4 (%) Skin and subcutaneous tissue disorders Rash Grouped term 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
Edema 36 1.5 11 0.4 Pyrexia 12 0 10 0 Gastrointestinal disorders
Nausea 45 0.8 37
Constipation 39 0.8 30 0 Stomatitis 35 2.3 11 0 Vomiting 25
0.8 17
Diarrhea 15 1.5 7 0.8 Metabolism and nutrition disorders Decreased appetite 31
0 21
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
Respiratory, thoracic, and mediastinal disorders Cough 14 0 16 0.4 Dyspnea 13
1.5 8
Clinically relevant adverse reactions in < 10% of patients who received intravenous
amivantamab in combination with carboplatin and pemetrexed include: abdominal pain, hemorrhoids, dizziness, visual impairment, trichomegaly, keratitis, interstitial lung disease, and skin ulcer. Table 15 summarizes the laboratory abnormalities in MARIPOSA-2. Table 15: 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 Intravenous Amivantamab in Combination with Carboplatin and Pemetrexed in MARIPOSA-2 Intravenous Amivantamab with Carboplatin and Pemetrexed (N=130) Carboplatin and Pemetrexed (N=243) Laboratory Abnormality 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
Increased alkaline phosphatase 42 0 29 0.4 Increased alanine aminotransferase 39 3.9
56 6 Decreased magnesium 38 0.8 17
Decreased calcium (corrected) 25 0 11 0.9 First-Line Treatment of
NSCLC with EGFR Exon 20 Insertion Mutations – Intravenous Amivantamab in Combination with Carboplatin and Pemetrexed PAPILLON The safety data described below reflect exposure to intravenous amivantamab in combination with carboplatin and pemetrexed at the recommended dosage in the PAPILLON trial in 151 patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. Among patients who received intravenous amivantamab 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 intravenous amivantamab 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 intravenous amivantamab due to an adverse reaction occurred in 11% of patients. Adverse reactions resulting in permanent discontinuation of intravenous amivantamab in ≥ 1% of patients were rash and ILD. Dose interruptions of intravenous amivantamab 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 intravenous amivantamab 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 16 summarizes the adverse reactions in PAPILLON. Table 16: Adverse Reactions (≥ 10%) in Patients with Metastatic NSCLC with Exon 20 Insertion Mutations Who Received Intravenous Amivantamab in Combination with Carboplatin and Pemetrexed in PAPILLON Intravenous Amivantamab in Combination with Carboplatin and Pemetrexed (N=151) Carboplatin and Pemetrexed (N=155) Adverse Reaction Adverse reactions were graded using CTCAE version
All Grades (%) Grade 3 or 4 (%) All Grades (%) Grade
3 or 4 (%) Skin and subcutaneous tissue disorders Rash Grouped Term 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
Nausea 36 0.7 42 0 Vomiting 21 3.3 19 0.7 Diarrhea 21
3 13
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
Edema 40 1.3 19 0 Pyrexia 17 0 6 0 Metabolism and
nutrition disorders Decreased appetite 36 2.6 28
Infections and infestations
COVID-19 24 2 14
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
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 intravenous amivantamab in combination with carboplatin and pemetrexed included pulmonary embolism, deep vein thrombosis, skin ulcer, conjunctivitis, and interstitial lung disease (ILD)/pneumonitis. Table 17 summarizes the laboratory abnormalities in PAPILLON. Table 17: Select Laboratory Abnormalities (≥ 20%) That Worsened from Baseline in Patients with Metastatic NSCLC with EGFR Exon 20 Insertion Mutations Who Received Intravenous Amivantamab in Combination with Carboplatin and Pemetrexed in PAPILLON Intravenous Amivantamab in Combination with Carboplatin and Pemetrexed 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. Carboplatin in Combination with Pemetrexed 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.
Laboratory Abnormality Adverse reactions were graded using CTCAE version
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 with EGFR Exon 20 Insertion Mutations – Intravenous Amivantamab as a Single Agent CHRYSALIS The safety data described below reflect exposure to intravenous amivantamab at the recommended dosage in 129 patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations in the CHRYSALIS trial, whose disease had progressed on or after platinum-based chemotherapy. Patients received intravenous amivantamab at 1,050 mg (for patient baseline body weight < 80 kg) or 1,400 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 patients who received intravenous amivantamab, 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 intravenous amivantamab. 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 intravenous amivantamab due to an adverse reaction occurred in 11% of patients. Adverse reactions resulting in permanent discontinuation of intravenous amivantamab in ≥ 1% of patients were pneumonia, IRR, pneumonitis/ILD, dyspnea, pleural effusion, and rash.
Dose interruptions of intravenous amivantamab 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 intravenous amivantamab 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 18 summarizes the adverse reactions in CHRYSALIS. Table 18: Adverse Reactions (≥ 10%) in Patients with NSCLC with Exon 20 Insertion Mutations Whose Disease Has Progressed on or after Platinum-based Chemotherapy and Received Intravenous Amivantamab in CHRYSALIS Adverse Reactions Intravenous Amivantamab Adverse reactions were graded using CTCAE version 4.03 (N=129) All Grades (%) Grades 3 or 4 (%) Skin and subcutaneous tissue disorders Rash Grouped term 84
Pruritus 18 0 Dry skin 14 0 General disorders and administration site
conditions Infusion-related reaction 64
Fatigue 33 2.3 Edema 27 0.8 Pyrexia 13 0 Infections and infestations
Paronychia 50
Pneumonia 10 0.8 Musculoskeletal and connective tissue disorders Musculoskeletal pain 47 0
Respiratory, thoracic, and mediastinal disorders Dyspnea 37
Cough 25 0 Gastrointestinal disorders Nausea 36 0 Stomatitis 26 0.8 Constipation
23 0 Vomiting 22 0 Diarrhea 16
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
Headache 10 0.8 Clinically relevant adverse reactions in < 10% of patients
who received intravenous amivantamab included ocular toxicity, ILD/pneumonitis, and toxic epidermal necrolysis (TEN). Table 19 summarizes the laboratory abnormalities in CHRYSALIS. Table 19: 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 Intravenous Amivantamab in CHRYSALIS Laboratory Abnormality Intravenous Amivantamab 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. (N=129) All Grades (%) Grades 3 or 4 (%) Chemistry Decreased albumin 79 8 Increased glucose 56 4 Increased alkaline phosphatase 53
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
Warnings & Cautions for Rybrevant Faspro
Hypersensitivity and Administration-Related Reactions
RYBREVANT FASPRO can cause hypersensitivity and administration-related reactions (ARR); signs and symptoms of ARR include dyspnea, flushing, fever, chills, chest discomfort, hypotension, and vomiting. The median time to ARR onset is approximately 2 hours. Local injection site reactions are described separately in Section 6.1. RYBREVANT FASPRO (Subcutaneous Amivantamab) with Lazertinib In PALOMA-3 , in the 206 patients who received RYBREVANT FASPRO in combination with lazertinib, all Grade ARR occurred in 13%, including 0.5% Grade 3. Of the patients who experienced ARR, 89% occurred with the initial dose (Week 1, Day 1). Premedicate with antihistamines, antipyretics, and glucocorticoids and administer RYBREVANT FASPRO as recommended . Monitor patients for any signs and symptoms of administration-related reactions during injection in a setting where cardiopulmonary resuscitation medication and equipment are available.
Interrupt RYBREVANT FASPRO injection, if ARR is suspected. Resume treatment upon resolution of symptoms or permanently discontinue RYBREVANT FASPRO based on severity .
Interstitial Lung Disease/Pneumonitis
RYBREVANT FASPRO can cause severe and fatal interstitial lung disease (ILD)/pneumonitis. RYBREVANT FASPRO (Subcutaneous Amivantamab) with Lazertinib In PALOMA-3 , in 206 patients who received RYBREVANT FASPRO in combination with lazertinib, ILD/pneumonitis occurred in 6%, including Grade 3 in 1%, Grade 4 in 1.5%, and fatal cases in 1.9%. In total, 5% of patients permanently discontinued RYBREVANT FASPRO and lazertinib due to ILD/pneumonitis. Intravenous Amivantamab with Lazertinib In MARIPOSA , in 421 patients who received intravenous amivantamab in combination with lazertinib, ILD/pneumonitis occurred in 3.1%, including Grade 3 in 1% and Grade 4 in 0.2% of patients.
There was one fatal case of ILD/pneumonitis and 2.9% of patients permanently discontinued intravenous amivantamab and lazertinib due to ILD/pneumonitis. Intravenous Amivantamab with Carboplatin and Pemetrexed Based on the pooled safety population , in 281 patients who received intravenous amivantamab in combination with carboplatin and pemetrexed, ILD/pneumonitis occurred in 2.1%, including 1.8% Grade 3 ILD/pneumonitis. Of these, 2.1% of patients permanently discontinued intravenous amivantamab due to ILD/pneumonitis.
Intravenous Amivantamab as a Single Agent In CHRYSALIS , in 302 patients who received intravenous amivantamab as a single agent, ILD/pneumonitis occurred in 3.3%, including 0.7% Grade 3. Three patients (1%) permanently discontinued intravenous amivantamab due to ILD/pneumonitis. Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold RYBREVANT FASPRO in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed .
Venous Thromboembolic (VTE) Events with
Concomitant Use with Lazertinib RYBREVANT FASPRO in combination with lazertinib can cause serious and fatal venous thromboembolic (VTE) events, including deep vein thrombosis and pulmonary embolism. Without prophylactic anticoagulation, the majority of these events occurred during the first four months of therapy . RYBREVANT FASPRO (Subcutaneous Amivantamab) with Lazertinib In PALOMA-3 , in the 206 patients who received RYBREVANT FASPRO in combination with lazertinib, all Grade VTE occurred in 11% and 1.5% were Grade 3. Of the 206 patients treated with RYBREVANT FASPRO in combination with lazertinib, 80% received prophylactic anticoagulation at study entry. In the 164 patients treated with RYBREVANT FASPRO in combination with lazertinib who received prophylactic anticoagulation, all Grade VTE occurred in 7%. In the 42 patients treated with RYBREVANT FASPRO in combination with lazertinib who did not receive prophylactic anticoagulation, all Grade VTE occurred in 17%. In total, 0.5% of patients had VTE leading to dose reductions of RYBREVANT FASPRO and no patients required permanent discontinuation.
The median time to onset of VTEs was 95 days (range: 17 to 390). Intravenous Amivantamab with Lazertinib In MARIPOSA , in 421 patients who received intravenous amivantamab in combination with lazertinib, VTEs occurred in 36%, 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 intravenous amivantamab, 1% of patients had VTE leading to dose reductions of intravenous amivantamab, and 3.1% of patients had VTE leading to permanent discontinuation of intravenous amivantamab.
The median time to onset of VTEs was 84 days (range: 6 to 777). Administer prophylactic anticoagulation for the first four months of treatment. The use of Vitamin K antagonists is not recommended. Monitor for signs and symptoms of VTE events and treat as medically appropriate.
Withhold RYBREVANT FASPRO and lazertinib based on severity . Once anticoagulant treatment has been initiated, resume RYBREVANT FASPRO and lazertinib at the same dose level at the discretion of the healthcare provider . In the event of VTE recurrence despite therapeutic anticoagulation, permanently discontinue RYBREVANT FASPRO. Treatment can continue with lazertinib at the same dose level at the discretion of the healthcare provider . Refer to the lazertinib prescribing information for recommended lazertinib dosage modification.
Dermatologic Adverse Reactions
RYBREVANT FASPRO can cause severe rash including toxic epidermal necrolysis (TEN), dermatitis acneiform, pruritus and dry skin. RYBREVANT FASPRO (Subcutaneous Amivantamab) with Lazertinib In PALOMA-3 , in the 206 patients who received RYBREVANT FASPRO in combination with lazertinib, rash occurred in 80% of patients, including Grade 3 in 17% and Grade 4 in 0.5%. Rash leading to dose reduction occurred in 11% of patients, and RYBREVANT FASPRO was permanently discontinued due to rash in 1.5% of patients. Intravenous Amivantamab with Lazertinib In MARIPOSA , in 421 patients who received intravenous amivantamab in combination with lazertinib, rash occurred in 86%, including 26% Grade 3. The median time to onset of rash was 14 days (range: 1 to 556 days). Rash leading to dose interruptions of intravenous amivantamab occurred in 37% of patients, rash leading to dose reductions of intravenous amivantamab occurred in 23% of patients, and rash leading to permanent discontinuation of intravenous amivantamab occurred in 5% of patients.
Intravenous Amivantamab with Carboplatin and Pemetrexed Based on the pooled safety population , in 281 patients who received intravenous amivantamab in combination with carboplatin and pemetrexed, rash occurred in 82%, including 15% Grade 3. Rash leading to dose reductions occurred in 14% of patients, and 2.5% permanently discontinued intravenous amivantamab and 3.1% discontinued pemetrexed. Intravenous Amivantamab as a Single Agent In CHRYSALIS , in 302 patients who received intravenous amivantamab as a single agent, rash occurred in 74%, including 3.3% Grade 3. 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 intravenous amivantamab was permanently discontinued due to rash in 0.7% of patients. Toxic epidermal necrolysis (TEN) occurred in one patient (0.3%) treated with intravenous amivantamab as a single agent.
When initiating treatment with RYBREVANT FASPRO, prophylactic and concomitant medications are recommended to reduce the risk and severity of dermatologic adverse reactions . Instruct patients to limit sun exposure during and for 2 months after treatment with RYBREVANT FASPRO. Advise patients to wear protective clothing and use broad-spectrum UVA/UVB sunscreen. If skin reactions develop, administer supportive care including 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 FASPRO based on severity .
Ocular Toxicity
RYBREVANT FASPRO can cause ocular toxicity including keratitis, blepharitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, eye pruritus and uveitis. RYBREVANT FASPRO (Subcutaneous Amivantamab) with Lazertinib In PALOMA-3 , in the 206 patients who received RYBREVANT FASPRO in combination with lazertinib, all Grade ocular toxicity occurred in 13%, including 0.5% Grade 3. Intravenous Amivantamab with Lazertinib In MARIPOSA , in 421 patients treated with intravenous amivantamab in combination with lazertinib, ocular toxicity occurred in 16%, including 0.7% Grade 3 or 4 ocular toxicity. Intravenous Amivantamab with Carboplatin and Pemetrexed Based on the pooled safety population , in 281 patients who received intravenous amivantamab in combination with carboplatin and pemetrexed, ocular toxicity occurred in 16%. All events were Grade 1 or 2. Intravenous Amivantamab as a Single Agent In CHRYSALIS , in 302 patients treated with intravenous amivantamab, keratitis occurred in 0.7% and uveitis occurred in 0.3%. All events were Grade 1– 2. Promptly refer patients presenting with new or worsening eye symptoms to an ophthalmologist.
Withhold, dose reduce or permanently discontinue RYBREVANT FASPRO based on severity .
Embryo-Fetal Toxicity
Based on its mechanism of action and findings from animal models, RYBREVANT FASPRO 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. Verify pregnancy status of females of reproductive potential prior to initiating RYBREVANT FASPRO. Advise pregnant women and 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 FASPRO .
Pregnancy Safety for Rybrevant Faspro
Pregnancy Risk Summary Based on the mechanism of action and findings in animal models, RYBREVANT FASPRO can cause fetal harm when administered to a pregnant woman. There are no available data on the use of RYBREVANT FASPRO in pregnant women or animal data to assess the risk of RYBREVANT FASPRO 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 and females of reproductive potential 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 RYBREVANT FASPRO for subcutaneous injection contains amivantamab and hyaluronidase.
Amivantamab: No animal studies have been conducted to evaluate the effects of amivantamab on reproduction and fetal development; however, based on its mechanism of action, RYBREVANT FASPRO 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 has the potential to be transmitted from the mother to the developing fetus.
Hyaluronidase: In an embryo-fetal study, mice were dosed daily by subcutaneous injection during the period of organogenesis with hyaluronidase (recombinant human) at dose levels up to 2,200,000 U/kg, which is > 3600 times higher than the human dose. The study found no evidence of teratogenicity. Reduced fetal weight and increased numbers of fetal resorptions were observed, with no effects found at a daily dose of 360,000 U/kg, which is > 600 times higher than the human dose.
In a peri-and post-natal reproduction study, mice have been dosed daily by subcutaneous injection, with hyaluronidase (recombinant human) from implantation through lactation and weaning at dose levels up to 1,100,000 U/kg, which is > 1800 times higher than the human dose. The study found no adverse effects on sexual maturation, learning and memory or fertility of the offspring.
Pediatric Use of Rybrevant Faspro
Pediatric Use The safety and efficacy of RYBREVANT FASPRO have not been established in pediatric patients.
Contraindications for Rybrevant Faspro
is contraindicated in patients with known hypersensitivity to hyaluronidase or to any of its excipients. Patients with known hypersensitivity to hyaluronidase or to any of its excipients.
Clinical Studies of Rybrevant Faspro
First-Line Treatment of
NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations – Intravenous Amivantamab in Combination with Lazertinib MARIPOSA The efficacy of intravenous amivantamab, 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 intravenous amivantamab 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: Amivantamab administered 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 administered at 240 mg orally once daily. Osimertinib administered at a dose of 80 mg orally once daily.
Randomization was stratified by EGFR mutation type (exon 19 deletion or exon 21 L858R substitution mutation), Asian race (yes or no), and history of brain metastasis (yes or no). Tumor assessments were performed every 8 weeks for 30 months, and then every 12 weeks until disease progression. The major efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review (BICR). Additional efficacy outcome measures included overall survival (OS), overall response rate (ORR), and duration of response (DOR). A total of 858 patients were randomized between the two study arms, 429 to the intravenous amivantamab 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 intravenous amivantamab 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 and OS for intravenous amivantamab in combination with lazertinib compared to osimertinib (see Table 21 and Figures 1 and 2 ). Efficacy results for intravenous amivantamab in combination with lazertinib are provided in Table 21. Table 21: Efficacy Results in MARIPOSA by BICR Assessment Intravenous amivantamab in combination with lazertinib (N=429) Osimertinib (N=429) CI = confidence interval; NR = not reached; NE = not estimable Progression-free survival (PFS) Number of events (%) 192 252 Median, months (95% CI) 23.7
HR Stratified by mutation type (Exon 19del or Exon 21 L858R), prior
brain metastases (yes or no), and Asian race (yes or no)., Stratified Cox proportional hazards regression. (95% CI); p-value, Stratified log-rank test. 0.70 ; p=0.0002 Overall survival (OS) Number of events (%) 173 217 Median, months (95% CI) NR (42.9, NE)
HR, (95% CI); p-value, 0.75 ; p=0.0048 Overall response rate (ORR) Confirmed
responses based on the ITT population. ORR, % (95% CI) 78 73 Complete response, % 5.4
Partial response, % 73 70 Duration of response (DOR)
In confirmed responders. Median (95% CI), months 25.8 (20.1, NE)
Patients with
DOR ≥ 6 months Based on observed rates., % 86 85 Patients with DOR ≥ 12 months, % 68 57 Figure 1: Kaplan-Meier Curves of PFS by BICR Assessment in Patients with Previously Untreated NSCLC Figure 2: Kaplan-Meier Curves of OS in Patients with Previously Untreated NSCLC 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 intravenous amivantamab in combination with lazertinib arm and the osimertinib arm are summarized in Table 22. Table 22: Exploratory Analysis of Intracranial ORR and DOR by BICR Assessment in Subjects with Intracranial Lesions at Baseline Intravenous amivantamab in combination with lazertinib (N=180) Osimertinib (N=187) CI = confidence interval Intracranial tumor response assessment Intracranial ORR Confirmed responses, % (95% CI) 68 69 Complete response % 55 52 Intracranial DOR In confirmed responders Number of responders 122 129 Patients with DOR ≥ 12 months Based on observed rates, % 66 59 Patients with DOR ≥ 18 months, % 35 23 Figure 1 Figure 2
Previously Treated
NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations – Intravenous Amivantamab in Combination with Carboplatin and Pemetrexed MARIPOSA-2 The efficacy of intravenous amivantamab 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 intravenous amivantamab in combination with carboplatin and pemetrexed (intravenous amivantamab-CP, N=131), carboplatin and pemetrexed (CP, N=263), or intravenous amivantamab as part of another combination regimen. The evaluation of efficacy for metastatic NSCLC relied upon comparison between: Intravenous amivantamab in combination with carboplatin and pemetrexed. Amivantamab was administered intravenously at 1,400 mg (for patients < 80 kg) or 1,750 mg (for patients ≥ 80 kg) once weekly through 4 weeks, then every 3 weeks with a dose of 1,750 mg (for patients < 80 kg) or 2,100 mg (for patients ≥ 80 kg) starting at Week 7 until disease progression or unacceptable toxicity.
Platinum-based chemotherapy with carboplatin and pemetrexed. 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/m 2 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 intravenous amivantamab-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 intravenous amivantamab in combination with carboplatin and pemetrexed compared to carboplatin and pemetrexed. Efficacy results are summarized in Table 23. Table 23: Efficacy Results in MARIPOSA-2 Intravenous amivantamab with carboplatin and pemetrexed (N=131) carboplatin and pemetrexed (N=263) CI = confidence interval; NE = not estimatable Progression-free survival (PFS) Blinded Independent Central Review by RECIST v1.1. Number of events 74 (56%) 171 (65%) Median, months (95% CI) 6.3
HR (95% CI) Stratified by osimertinib line of therapy (first-line or second-line)
prior brain metastases (yes or no), and Asian race (yes or no)., Stratified Cox proportional hazards regression. ; p-value, Stratified log-rank test. 0.48 ; p<0.0001 Overall response rate, Confirmed responses. ORR, % (95% CI) 53% 29% p-value, Stratified logistic regression analysis. p<0.0001 Complete response 0.8% 0% Partial response 52% 29% Duration of response, (DOR) Median (95% CI), months 6.9 (5.5, NE)
Figure 3: Kaplan-Meier Curve of
PFS in Previously Treated NSCLC Patients by BICR Assessment - MARIPOSA-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. Figure 3
First-Line Treatment of
NSCLC with EGFR Exon 20 Insertion Mutations – Intravenous Amivantamab in Combination with Carboplatin and Pemetrexed PAPILLON The efficacy of intravenous amivantamab 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 intravenous amivantamab in combination with carboplatin and pemetrexed (n=153) or carboplatin and pemetrexed (n=155). Patients received amivantamab intravenously at 1,400 mg (for patients < 80 kg) or 1,750 mg (for patients ≥ 80 kg) once weekly through 4 weeks, then every 3 weeks with a dose of 1,750 mg (for patients < 80 kg) or 2,100 mg (for 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 2 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 intravenous amivantamab 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 intravenous amivantamab in combination with carboplatin and pemetrexed compared with carboplatin and pemetrexed. Efficacy results are summarized in Table 24 and Figure 4. Table 24: Efficacy Results in PAPILLON Intravenous amivantamab with carboplatin and pemetrexed (N=153) carboplatin and pemetrexed (N=155) CI = confidence interval Progression-Free Survival (PFS) Number of events (%) 84 132 Median, months (95% CI) 11.4
HR (95% CI) 0.40 p-value p<0.0001 Overall Response Rate (ORR) Confirmed responses.
ORR, % (95% CI) 67 36 Complete response, % 4 1 Partial response, % 63 36 Duration of response (DOR) In confirmed responders. Median (95% CI), months 10.1
Figure 4: 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 intravenous amivantamab as a single agent. Figure 4
Previously Treated
NSCLC with EGFR Exon 20 Insertion Mutations – Intravenous Amivantamab as a Single Agent CHRYSALIS The efficacy of intravenous amivantamab 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 intravenous amivantamab at 1,050 mg (for patient baseline body weight < 80 kg) or 1,400 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 25. Table 25: Efficacy Results for CHRYSALIS Prior Platinum-based Chemotherapy Treated (N=81) Based on Kaplan-Meier estimates.
NE=Not Estimable, CI=confidence interval. Overall Response Rate (95% CI) 40% (29%, 51%) Complete response (CR) 3.7% Partial response (PR) 36% Duration of Response (DOR) Median (95% CI), months 11.1 (6.9, NE) Patients with DOR ≥ 6 months 63%
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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