Amivantamab for Lung Cancer

INDICATIONS AND USAGE 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.

DOSAGE AND ADMINISTRATION The recommended dosage of RYBREVANT is based on baseline body weight and administered as an intravenous infusion after dilution. ( 2.3 , 2.4 ) Administer prophylactic and concomitant medications as recommended to reduce the risk of dermatologic adverse reactions. ( 2.6 ) Administer via a peripheral line on Week 1 and Week 2 to reduce the risk of infusion-related reactions. ( 2.10 ) Administer RYBREVANT in combination with lazertinib or RYBREVANT as a single agent weekly for 5 weeks, with the initial dose as a split infusion in Week 1 on Day 1 and Day 2, then administer every 2 weeks starting at Week 7. ( 2.3 ) Administer RYBREVANT in combination with chemotherapy weekly for 4 weeks, with the initial dose as a split infusion in Week 1 on Day 1 and Day 2, then administer every 3 weeks starting at Week 7. ( 2.4 ) When administering RYBREVANT in combination with lazertinib, administer anticoagulant prophylaxis to reduce the risk of venous thromboembolic (VTE) events for the first four months of treatment. ( 2.7 ) Administer diluted RYBREVANT intravenously according to the infusion rates in Tables 8 and 9. ( 2.9 , 2.10 ) Body Weight (at Baseline) Dosage Recommended Dose RYBREVANT in Combination with Lazertinib or RYBREVANT as a Single Agent Less than 80 kg Weeks 1–5 Week 7 onwards 1,050 mg Greater than or equal to 80 kg Weeks 1–5 Week 7 onwards 1,400 mg RYBREVANT in Combination with Carboplatin and Pemetrexed Less than 80 kg Weeks 1–4 1,400 mg Week 7 onwards 1,750 mg Greater than or equal to 80 kg Weeks 1–4 1,750 mg Week 7 onwards 2,100 mg 2.1 Important Dosage Information To reduce the risk of infusion-related reactions, administer premedications before each RYBREVANT infusion as recommended [see Dosage and Administration (2.5) ]. To reduce the risk of infusion-related reactions, administer RYBREVANT via peripheral line for Week 1 Day 1 and 2 and Week 2 [see Dosage and Administration (2.10) ]. To reduce the risk and severity of dermatologic adverse reactions with RYBREVANT, prophylactic and concomitant medications are recommended [see Dosage and Administration (2.6) ] . To reduce the risk of venous thromboembolic (VTE) events when administering RYBREVANT in combination with lazertinib, administer anticoagulant prophylaxis for the first four months of treatment [see Dosage and Administration (2.7) ]. Administer diluted RYBREVANT intravenously according to the infusion rates in Tables 8 and 9, with the initial dose as a split infusion on Week 1 on Day 1 and Day 2 [see Dosage and Administration (2.10) ]. When administering RYBREVANT in combination with lazertinib, administer lazertinib orally any time before the RYBREVANT infusion [see Dosage and Administration (2.10) ]. When administering RYBREVANT in combination with carboplatin and pemetrexed, infuse pemetrexed first, carboplatin second, and RYBREVANT last [see Dosage and Administration (2.10) ]. 2.2 Patient Selection 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 Information on FDA approved tests is available at: http://www.fda.gov/CompanionDiagnostics. First-Line Treatment of NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations [see Indications and Usage (1.1) ] RYBREVANT in combination with lazertinib Tumor or plasma specimens. Testing may be performed at any time from initial diagnosis. Testing does not need to be repeated once EGFR mutation status has been established. 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 and Usage (1.2) ] RYBREVANT in combination with carboplatin and pemetrexed First-Line Treatment of NSCLC with EGFR Exon 20 Insertion Mutations [see Indications and Usage (1.3) ] RYBREVANT in combination with carboplatin and pemetrexed Previously Treated NSCLC with EGFR Exon 20 Insertion Mutations [see Indications and Usage (1.4) ] RYBREVANT as a single agent 2.3 Recommended Dosage of RYBREVANT in Combination with Lazertinib or RYBREVANT as a Single Agent - Every 2-week dosing The recommended dosage of RYBREVANT in combination with lazertinib or RYBREVANT as a single agent, based on baseline body weight, are provided in Table 2. Administer RYBREVANT until disease progression or unacceptable toxicity. Table 2: Recommended Dosage Schedule for RYBREVANT in Combination with Lazertinib or RYBREVANT as a Single Agent Body weight at Baseline Dose adjustment is not required for subsequent body weight changes. Recommended Dose Dosing Schedule Less than 80 kg 1,050 mg Weekly (total of 5 doses) from Weeks 1 to 5 Week 1 - split infusion on Day 1 and Day 2 Weeks 2 to 5 - infusion on Day 1 Week 6 – no dose Every 2 weeks starting at Week 7 onwards Greater than or equal to 80 kg 1,400 mg Weekly (total of 5 doses) from Weeks 1 to 5 Week 1 - split infusion on Day 1 and Day 2 Weeks 2 to 5 - infusion on Day 1 Week 6 – no dose Every 2 weeks starting at Week 7 onwards RYBREVANT in Combination with Lazertinib 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. 2.4 Recommended Dosage of RYBREVANT in Combination with Carboplatin and Pemetrexed for the Treatment of NSCLC – Every 3-week dosing The recommended dosage of RYBREVANT, administered in combination with carboplatin and pemetrexed is based on baseline body weight is provided in Table 3. Table 3: Recommended Dosage for RYBREVANT in Combination with Carboplatin and Pemetrexed Body weight at Baseline Dose adjustment is not required for subsequent body weight changes. Recommended Dose Dosing Schedule Less than 80 kg 1,400 mg Weekly (total of 4 doses) from Weeks 1 to 4 Week 1 - split infusion on Day 1 and Day 2 Weeks 2 to 4 - infusion on Day 1 Weeks 5 and 6 – no dose 1,750 mg Every 3 weeks starting at Week 7 onwards Greater than or equal to 80 kg 1,750 mg Weekly (total of 4 doses) from Weeks 1 to 4 Week 1 - split infusion on Day 1 and Day 2 Weeks 2 to 4 - infusion on Day 1 Weeks 5 and 6 – no dose 2,100 mg Every 3 weeks starting at Week 7 onwards The recommended order of administration and regimen for RYBREVANT in combination with carboplatin and pemetrexed are provided in Table 4. Table 4: 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/m 2 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 3 . Every 3 weeks, continue until disease progression or unacceptable toxicity. 2.5 Recommended Premedications to Reduce the Risk of Infusion-Related Reactions Administer premedications as described in Table 5 . After prolonged dose interruptions, restart the following Week 1 Day 1 premedications upon re-initiation: intravenous dexamethasone, diphenhydramine, and acetaminophen. Table 5: Premedications Premedication Schedule Medication and Frequency Route of Administration Dosing Window Prior to RYBREVANT Administration Initial dose as a split infusion Dexamethasone 8 mg (or equivalent) Oral 48 hours Week 1 Day -2 twice daily Initial dose as a split infusion Dexamet

WARNINGS AND PRECAUTIONS 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). Rash leading to do

ADVERSE REACTIONS 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. Serious adverse reactions occurred in 49% of patients who received R