Amivantamab

RYBREVANT is a bispecific EGF receptor-directed and MET receptor-directed antibody indicated: in combination with lazertinib 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. ( 1 , 2.2 ) in combination with carboplatin and pemetrexed 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. ( 1 , 2.2 ) in combination with carboplatin and pemetrexed 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. ( 1 , 2.2 ) 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. ( 1 , 2.2 )

1.1 First-Line Treatment of NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations 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 (2.2) ] .

1.2 Previously Treated NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations 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 EGFR tyrosine kinase inhibitor [see Dosage and Administration (2.2) ] .

1.3 First-Line Treatment of NSCLC with EGFR Exon 20 Insertion Mutations 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 (2.2) ] .

1.4 Previously Treated NSCLC with EGFR Exon 20 Insertion Mutations RYBREVANT is indicated as a single agent for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test [see Dosage and Administration (2.2) ] , whose disease has progressed on or after platinum-based chemotherapy.

Injection: 350 mg/7 mL (50 mg/mL) colorless to pale yellow solution in a single-dose vial. Injection : 350 mg/7 mL (50 mg/mL) solution in a single-dose vial ( 3 )

None. None. ( 4 )

Infusion-Related Reactions (IRR) : Interrupt infusion at the first sign of IRRs. Reduce the infusion rate or permanently discontinue RYBREVANT based on severity. ( 2.5 , 2.8 , 5.1 ) Interstitial Lung Disease (ILD)/Pneumonitis : Monitor for new or worsening symptoms indicative of ILD. Immediately withhold RYBREVANT in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed. ( 2.8 , 5.2 ) Venous Thromboembolic (VTE) Events with Concomitant Use with Lazertinib: Prophylactic anticoagulation is recommended for the first four months of treatment. Monitor for signs and symptoms of VTE and treat as medically appropriate. Withhold RYBREVANT and lazertinib based on severity. Once anticoagulant treatment has been initiated, resume RYBREVANT and lazertinib at the same dose at the discretion of the healthcare provider. Permanently discontinue RYBREVANT and continue lazertinib for recurrent VTE despite therapeutic anticoagulation. ( 2.7 , 2.8 , 5.3 ) Dermatologic Adverse Reactions : Can cause severe rash including toxic epidermal necrolysis (TEN) and acneiform dermatitis. At treatment initiation, prophylactic and concomitant medications are recommended. Withhold, reduce the dose, or permanently discontinue RYBREVANT based on severity. ( 2.6 , 2.8 , 5.4 ) Ocular Toxicity : Promptly refer patients with worsening eye symptoms to an ophthalmologist. Withhold, reduce the dose, or permanently discontinue RYBREVANT based on severity. ( 2.8 , 5.5 ) Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception. ( 5.6 , 8.1 , 8.3 )

5.1 Infusion-Related Reactions RYBREVANT can cause infusion-related reactions (IRR) including anaphylaxis; 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 with Lazertinib RYBREVANT in combination with lazertinib can cause infusion-related reactions. In MARIPOSA, [see Adverse Reactions (6.1) ] , 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. RYBREVANT with Carboplatin and Pemetrexed Based on the pooled safety population [see Adverse Reactions (6.1) ] , IRR occurred in 50% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed, including Grade 3 (3.2%) adverse reactions. The incidence of infusion modifications due to IRR was 46%, and 2.8% of patients permanently discontinued RYBREVANT due to IRR. RYBREVANT as a Single Agent In CHRYSALIS, [see Adverse Reactions (6.1) ], IRR occurred in 66% of patients treated with RYBREVANT as a single agent. Among patients receiving treatment on Week 1 Day 1, 65% experienced an IRR, while the incidence of IRR was 3.4% with the Day 2 infusion, 0.4% with the Week 2 infusion, and cumulatively 1.1% with subsequent infusions. Of the reported IRRs, 97% were Grade 1–2, 2.2% were Grade 3, and 0.4% were Grade 4. The median time to onset was 1 hour (range 0.1 to 18 hours) after start of infusion. The incidence of infusion modifications due to IRR was 62%, and 1.3% of patients permanently discontinued RYBREVANT due to IRR. Premedicate with antihistamines, antipyretics, and glucocorticoids and infuse RYBREVANT as recommended [see Dosage and Administration (2.5) ] . Administer RYBREVANT via a peripheral line on Week 1 and Week 2 to reduce the risk of infusion-related reactions [see Dosage and Administration (2.10) ] . 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 (2.8) ]. If an anaphylactic reaction occurs, permanently discontinue RYBREVANT.

5.2 Interstitial Lung Disease/Pneumonitis RYBREVANT can cause severe and fatal interstitial lung disease (ILD)/pneumonitis. RYBREVANT with Lazertinib In MARIPOSA [see Adverse Reactions (6.1) ] , ILD/pneumonitis occurred in 3.1% of patients treated with RYBREVANT in combination with lazertinib, 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 RYBREVANT and lazertinib due to ILD/pneumonitis [see Adverse Reactions (6.1) ]. RYBREVANT with Carboplatin and Pemetrexed Based on the pooled safety population [see Adverse Reactions (6.1) ], ILD/pneumonitis occurred in 2.1% treated with RYBREVANT in combination with carboplatin and pemetrexed with 1.8% of patients experiencing Grade 3 ILD/pneumonitis. 2.1% discontinued RYBREVANT due to ILD/pneumonitis. RYBREVANT as a Single Agent In CHRYSALIS, [see Adverse Reactions (6.1) ] , ILD/pneumonitis occurred in 3.3% of patients treated with RYBREVANT as a single agent, with 0.7% of patients experiencing Grade 3 ILD/pneumonitis. Three patients (1%) permanently discontinued RYBREVANT due to ILD/pneumonitis. Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold RYBREVANT in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed [see Dosage and Administration (2.8) ] .

5.3 Venous Thromboembolic (VTE) Events with Concomitant Use of RYBREVANT and Lazertinib RYBREVANT in combination with lazertinib can cause serious and fatal venous thromboembolic (VTE) events, including deep vein thrombosis and pulmonary embolism. The majority of these events occurred during the first four months of treatment [see Adverse Reactions (6.1) ] . In MARIPOSA [see Adverse Reactions (6.1) ], 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 (2.7) ]. 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 (2.8) ] . Once anticoagulant treatment has been initiated, resume RYBREVANT 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. Treatment can continue with lazertinib at the same dose level at the discretion of the healthcare provider [see Dosage and Administration (2.8) ]. Refer to the lazertinib prescribing information for recommended lazertinib dosage modification.

5.4 Dermatologic Adverse Reactions RYBREVANT can cause severe rash including toxic epidermal necrolysis (TEN), dermatitis acneiform, pruritus, and dry skin. RYBREVANT with Lazertinib In MARIPOSA, [see Adverse Reactions (6.1) ] , 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). […]

The following adverse reactions are discussed elsewhere in the labeling: Infusion-Related Reactions [see Warnings and Precautions (5.1) ] Interstitial Lung Disease/Pneumonitis [see Warnings and Precautions (5.2) ] Venous Thromboembolic Events [see Warnings and Precautions (5.3) ] Dermatologic Adverse Reactions [see Warnings and Precautions (5.4) ] Ocular Toxicity [see Warnings and Precautions (5.5) ] RYBREVANT in Combination with Lazertinib 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. ( 6.1 ) 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. ( 6.1 ) RYBREVANT in Combination with Carboplatin and Pemetrexed The most common adverse reactions (≥ 20%) were rash, nail toxicity, infusion-related reaction, fatigue, nausea, stomatitis, constipation, edema, decreased appetite, musculoskeletal pain, vomiting, and COVID-19. ( 6.1 ) The most common Grade 3 or 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. ( 6.1 ) RYBREVANT as a Single Agent The most common adverse reactions (≥ 20%) were rash, IRR, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting. ( 6.1 ) The most common Grade 3 or 4 laboratory abnormalities (≥ 2%) were decreased lymphocytes, decreased albumin, decreased phosphate, decreased potassium, increased alkaline phosphatase, increased glucose, increased gamma-glutamyl transferase, and decreased sodium. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen Biotech, Inc. at 1-800-526-7736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 in Combination with Lazertinib 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 (14.1) ] . 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, 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, and nausea. 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. RYBREVANT in Combination with Carboplatin and Pemetrexed 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: MARIPOSA-2 [see Clinical Studies (14.2) ] 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 [see Clinical Studies (14.3) ] in 151 patients with previously untreated, locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. Patients received RYBREVANT 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, 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 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. RYBREVANT as a Single Agent The data in the WARNINGS AND PRECAUTIONS also reflect exposure to RYBREVANT as a single agent in CHRYSALIS [see Clinical Studies (14.4) ] in 302 patients with locally advanced or metastatic NSCLC. Patients received RYBREVANT 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 RYBREVANT as a single agent, 36% were exposed for 6 months or longer and 12% were exposed for greater than one year. In the safety population, the most common (≥ 20%) adverse reactions were rash, infusion-related reaction, paronychia, musculoskeletal pain, dyspnea, nausea, edema, cough, fatigue, stomatitis, constipation, vomiting and pruritus. The most common Grade 3 to 4 laboratory abnormalities (≥ 2%) were increased gamma glutamyl transference, decreased sodium, decreased potassium and increased alkaline phosphatase. First-line Treatment of NSCLC with Exon 19 deletions or Exon 21 L858R substitution mutations 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 (14.1) ]. 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. […]

Lactation : Advise not to breastfeed. ( 8.2 )

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

8.2 Lactation Risk Summary There are no data on the presence of amivantamab-vmjw in human milk, the effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions from RYBREVANT in breast-fed children, advise women not to breastfeed during treatment with RYBREVANT and for 3 months after the last dose.

8.3 Females and Males of Reproductive Potential RYBREVANT can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ]. Pregnancy Testing Verify pregnancy status of females of reproductive potential prior to initiating RYBREVANT. Contraception Females Advise females of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of RYBREVANT.

8.4 Pediatric Use The safety and efficacy of RYBREVANT have not been established in pediatric patients.

8.5 Geriatric Use Of the 421 patients with locally advanced or metastatic NSCLC treated with RYBREVANT in combination with lazertinib in the MARIPOSA study, 45% were ≥ 65 years of age and 12% were ≥ 75 years of age. Of the 130 patients with locally advanced or metastatic NSCLC treated with RYBREVANT in combination with carboplatin and pemetrexed in the MARIPOSA-2 study, 40% were ≥ 65 years of age and 10% were ≥ 75 years of age. Of the 151 patients with locally advanced or metastatic NSCLC treated with RYBREVANT in combination with carboplatin and pemetrexed in the PAPILLON study, 37% were ≥ 65 years of age and 8% were ≥ 75 years of age. Of the 302 patients with locally advanced or metastatic NSCLC treated with RYBREVANT as a single agent in the CHRYSALIS study, 39% were ≥ 65 years of age and 11% were ≥ 75 years of age. No clinically important differences in safety or efficacy were observed between patients who were ≥ 65 years of age and younger patients.

Amivantamab-vmjw is a 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.