Rybrevant

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 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.
  • 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.
  • 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.
  • 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.

  1.1 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.
  ,
  
  
  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
  )
  
• 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 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.
  • 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.
  • 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.
  • 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.

  1.1 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.
  ,
  
  
  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
  )
  
• 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 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.
  • 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.
  • 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.
  • 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.

  1.1 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.
  ,
  
  
  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
  )
  
• 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 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.
  • 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.
  • 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.
  • 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.

  1.1 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.
  ,
  
  
  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
  )
  

• The recommended dosage of RYBREVANT is based on baseline body weight and administered as an intravenous infusion after dilution. (
  
  
  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 BaselineDose 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 BaselineDose 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/m2intravenously 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.
  )
  
• Administer prophylactic and concomitant medications as recommended to reduce the risk of dermatologic adverse reactions. (
  
  
  2.6 Prophylactic and Concomitant Medications to Reduce the Risk of Dermatologic Adverse Reactions

  When initiating treatment with RYBREVANT, prophylactic and concomitant medications are recommended to reduce the risk and severity of dermatologic adverse reactions

  [see Warnings and Precautions (5.4)].

  • Administer an oral antibiotic (doxycycline or minocycline, 100 mg orally twice daily) starting on Day 1 for the first 12 weeks of treatment.
  • After completion of oral antibiotic treatment, administer antibiotic lotion to the scalp (clindamycin 1% topical once daily) for the next 9 months of treatment.
  • Administer non-comedogenic skin moisturizer (ceramide-based or other formulations that provide long-lasting skin hydration and exclude drying agents) on the face and whole body (except scalp).
  • Wash hands and feet with 4% chlorhexidine solution once daily.
  • Limit sun exposure during and for 2 months after treatment. Advise patients to wear protective clothing and use broad-spectrum UVA/UVB sunscreen to reduce the risk of dermatologic adverse reactions.
  )
  
• Administer via a peripheral line on Week 1 and Week 2 to reduce the risk of infusion-related reactions. (
  
  
  2.10 Administration

  • Administer the diluted RYBREVANT solution
    [see Dosage and Administration (2.9)]
    by intravenous infusion using an infusion set fitted with a flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.2 micrometer).
  • Administration sets must be made of either polyurethane (PU), polybutadiene (PBD), PVC, PP, or PE.
  • The administration set with filter,
    must
    be primed with either 5% Dextrose Injection or 0.9% Sodium Chloride Injection prior to the initiation of each RYBREVANT infusion.
  • Do not infuse RYBREVANT concomitantly in the same intravenous line with other agents.

  RYBREVANT in Combination with Lazertinib or RYBREVANT as a Single Agent

  • Administer RYBREVANT as a single agent infusion every 2 weeks intravenously until disease progression or unacceptable toxicity according to the infusion rates in Table 8.
  • Administer RYBREVANT via a peripheral line on Week 1 and Week 2, to reduce the risk of infusion-related reactions during initial treatment
    [see Warnings and Precautions (5.1)].
  • RYBREVANT may be administered via central line for subsequent weeks.
  • For the initial infusion, prepare RYBREVANT as close to administration time as possible to allow for the possibility of extended infusion time in the event of an infusion-related reaction.
  • When given in combination with lazertinib, administer RYBREVANT any time after lazertinib when given on the same day.

  Table 8: Infusion Rates of RYBREVANT in Combination with Lazertinib or RYBREVANT as Single Agent

  Body Weight Less Than 80 kg
  Week	Dose (per 250 mL bag)	Initial Infusion Rate (mL/hr)	Subsequent Infusion RateIn the absence of infusion-related reactions, increase the initial infusion rate to the subsequent infusion rate after 2 hours based on patient tolerance. Total infusion time is approximately 4–6 hours for day 1 and 6–8 hours for day 2. Subsequent infusion time is approximately 2 hours. (mL/hr)
  Week 1 (split dose infusion)
  Week 1 Day 1	350 mg	50	75
  Week 1 Day 2	700 mg	50	75
  Week 2	1,050 mg	85
  Week 3	1,050 mg	125
  Week 4	1,050 mg	125
  Week 5	1,050 mg	125
  Week 6	No dose
  Week 7 and every 2 weeks thereafter	1,050 mg	125
  Body Weight Greater Than or Equal to 80 kg
  Week	Dose (per 250 mL bag)	Initial Infusion Rate (mL/hr)	Subsequent Infusion Rate (mL/hr)
  Week 1 (split dose infusion)
  Week 1 Day 1	350 mg	50	75
  Week 1 Day 2	1,050 mg	35	50
  Week 2	1,400 mg	65
  Week 3	1,400 mg	85
  Week 4	1,400 mg	125
  Week 5	1,400 mg	125
  Week 6	No dose
  Week 7 and every 2 weeks thereafter	1,400 mg	125

  RYBREVANT in Combination with Carboplatin and Pemetrexed

  • Administer RYBREVANT in combination with carboplatin and pemetrexed infusions every 3 weeks intravenously until disease progression or unacceptable toxicity according to the infusion rates in Table 9.
  • Administer RYBREVANT via a peripheral line on Week 1 and Week 2 to reduce the risk of infusion-related reactions during initial treatment
    [see Warnings and Precautions (5.1)].
  • RYBREVANT may be administered via central line for subsequent weeks.
  • For the initial infusion, prepare RYBREVANT as close to administration time as possible to allow for the possibility of extended infusion time in the event of an infusion-related reaction.
  • Administer the pemetrexed infusion first, carboplatin infusion second, and the RYBREVANT infusion last.

  Table 9: Infusion Rates of RYBREVANT in Combination with Carboplatin and Pemetrexed for Treatment of NSCLC

  Body Weight Less Than 80 kg
  Week	Dose (per 250 mL bag)	Initial Infusion Rate (mL/hr)	Subsequent Infusion Rate In the absence of infusion-related reactions, increase the initial infusion rate to the subsequent infusion rate after 2 hours based on patient tolerance. Total infusion time is approximately 4–6 hours for day 1 and 6–8 hours for day 2. Subsequent infusion time is approximately 2 hours. (mL/hr)
  Week 1 (split dose infusion)
  Week 1 Day 1	350 mg	50	75
  Week 1 Day 2	1,050 mg	33	50
  Week 2	1,400 mg	65
  Week 3	1,400 mg	85
  Week 4	1,400 mg	125
  Weeks 5 and 6		No dose
  Week 7 and every 3 weeks thereafter	1,750 mg	125
  Body Weight Greater Than or Equal to 80 kg
  Week	Dose (per 250 mL bag)	Initial Infusion Rate (mL/hr)	Subsequent Infusion Rate (mL/hr)
  Week 1 (split dose infusion)
  Week 1 Day 1	350 mg	50	75
  Week 1 Day 2	1,400 mg	25	50
  Week 2	1,750 mg	65
  Week 3	1,750 mg	85
  Week 4	1,750 mg	125
  Week 5 and 6		No dose
  Week 7 and every 3 weeks thereafter	2,100 mg	125
  )
  
• 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 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 BaselineDose 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.
  )
  
• 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 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 BaselineDose 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/m2intravenously 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.
  )
• 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 RYBREVANT in Combination with Lazertinib: Concomitant Medications to Reduce the Risk of Venous Thromboembolic Events

  When initiating treatment with RYBREVANT in combination with lazertinib, administer anticoagulant prophylaxis to reduce the risk of venous thromboembolic (VTE) events for the first four months of treatment

  [see Warnings and Precautions (5.3)].

  If there are no signs or symptoms of VTE during the first four months of treatment, consider discontinuation of anticoagulant prophylaxis at the discretion of the healthcare provider. Refer to the lazertinib prescribing information for information about concomitant medications.
  )
  
• Administer diluted RYBREVANT intravenously according to the infusion rates in Tables 8 and 9. (
  
  
  2.9 Preparation

  Dilute and prepare RYBREVANT for intravenous infusion before administration.

  • Check that the RYBREVANT solution is colorless to pale yellow. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if discoloration or visible particles are present.
  • Determine the dose required and number of RYBREVANT vials needed based on patient's baseline weight
    [see Dosage and Administration (2.3, 2.4)]
    . Each vial of RYBREVANT contains 350 mg of amivantamab-vmjw.
  • Withdraw and then discard a volume of either 5% Dextrose Injection or 0.9% Sodium Chloride Injection from the 250 mL infusion bag equal to the volume of RYBREVANT to be added (i.e., discard 7 mL diluent from the infusion bag for each RYBREVANT vial). Only use infusion bags made of polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE), or polyolefin blend (PP+PE).
  • Withdraw 7 mL of RYBREVANT from each vial and add it to the infusion bag. The final volume in the infusion bag should be 250 mL. Discard any unused portion left in the vial.
  • Gently invert the bag to mix the solution. Do not shake.
  • Diluted solutions should be administered within 10 hours (including infusion time) at room temperature 15°C to 25°C (59°F to 77°F).
  ,
  2.10 Administration

  • Administer the diluted RYBREVANT solution
    [see Dosage and Administration (2.9)]
    by intravenous infusion using an infusion set fitted with a flow regulator and with an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter (pore size 0.2 micrometer).
  • Administration sets must be made of either polyurethane (PU), polybutadiene (PBD), PVC, PP, or PE.
  • The administration set with filter,
    must
    be primed with either 5% Dextrose Injection or 0.9% Sodium Chloride Injection prior to the initiation of each RYBREVANT infusion.
  • Do not infuse RYBREVANT concomitantly in the same intravenous line with other agents.

  RYBREVANT in Combination with Lazertinib or RYBREVANT as a Single Agent

  • Administer RYBREVANT as a single agent infusion every 2 weeks intravenously until disease progression or unacceptable toxicity according to the infusion rates in Table 8.
  • Administer RYBREVANT via a peripheral line on Week 1 and Week 2, to reduce the risk of infusion-related reactions during initial treatment
    [see Warnings and Precautions (5.1)].
  • RYBREVANT may be administered via central line for subsequent weeks.
  • For the initial infusion, prepare RYBREVANT as close to administration time as possible to allow for the possibility of extended infusion time in the event of an infusion-related reaction.
  • When given in combination with lazertinib, administer RYBREVANT any time after lazertinib when given on the same day.

  Table 8: Infusion Rates of RYBREVANT in Combination with Lazertinib or RYBREVANT as Single Agent

  Body Weight Less Than 80 kg
  Week	Dose (per 250 mL bag)	Initial Infusion Rate (mL/hr)	Subsequent Infusion RateIn the absence of infusion-related reactions, increase the initial infusion rate to the subsequent infusion rate after 2 hours based on patient tolerance. Total infusion time is approximately 4–6 hours for day 1 and 6–8 hours for day 2. Subsequent infusion time is approximately 2 hours. (mL/hr)
  Week 1 (split dose infusion)
  Week 1 Day 1	350 mg	50	75
  Week 1 Day 2	700 mg	50	75
  Week 2	1,050 mg	85
  Week 3	1,050 mg	125
  Week 4	1,050 mg	125
  Week 5	1,050 mg	125
  Week 6	No dose
  Week 7 and every 2 weeks thereafter	1,050 mg	125
  Body Weight Greater Than or Equal to 80 kg
  Week	Dose (per 250 mL bag)	Initial Infusion Rate (mL/hr)	Subsequent Infusion Rate (mL/hr)
  Week 1 (split dose infusion)
  Week 1 Day 1	350 mg	50	75
  Week 1 Day 2	1,050 mg	35	50
  Week 2	1,400 mg	65
  Week 3	1,400 mg	85
  Week 4	1,400 mg	125
  Week 5	1,400 mg	125
  Week 6	No dose
  Week 7 and every 2 weeks thereafter	1,400 mg	125

  RYBREVANT in Combination with Carboplatin and Pemetrexed

  • Administer RYBREVANT in combination with carboplatin and pemetrexed infusions every 3 weeks intravenously until disease progression or unacceptable toxicity according to the infusion rates in Table 9.
  • Administer RYBREVANT via a peripheral line on Week 1 and Week 2 to reduce the risk of infusion-related reactions during initial treatment
    [see Warnings and Precautions (5.1)].
  • RYBREVANT may be administered via central line for subsequent weeks.
  • For the initial infusion, prepare RYBREVANT as close to administration time as possible to allow for the possibility of extended infusion time in the event of an infusion-related reaction.
  • Administer the pemetrexed infusion first, carboplatin infusion second, and the RYBREVANT infusion last.

  Table 9: Infusion Rates of RYBREVANT in Combination with Carboplatin and Pemetrexed for Treatment of NSCLC

  Body Weight Less Than 80 kg
  Week	Dose (per 250 mL bag)	Initial Infusion Rate (mL/hr)	Subsequent Infusion Rate In the absence of infusion-related reactions, increase the initial infusion rate to the subsequent infusion rate after 2 hours based on patient tolerance. Total infusion time is approximately 4–6 hours for day 1 and 6–8 hours for day 2. Subsequent infusion time is approximately 2 hours. (mL/hr)
  Week 1 (split dose infusion)
  Week 1 Day 1	350 mg	50	75
  Week 1 Day 2	1,050 mg	33	50
  Week 2	1,400 mg	65
  Week 3	1,400 mg	85
  Week 4	1,400 mg	125
  Weeks 5 and 6		No dose
  Week 7 and every 3 weeks thereafter	1,750 mg	125
  Body Weight Greater Than or Equal to 80 kg
  Week	Dose (per 250 mL bag)	Initial Infusion Rate (mL/hr)	Subsequent Infusion Rate (mL/hr)
  Week 1 (split dose infusion)
  Week 1 Day 1	350 mg	50	75
  Week 1 Day 2	1,400 mg	25	50
  Week 2	1,750 mg	65
  Week 3	1,750 mg	85
  Week 4	1,750 mg	125
  Week 5 and 6		No dose
  Week 7 and every 3 weeks thereafter	2,100 mg	125
  )
  

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