Rybrevant (Amivantamab) injection
Janssen Biotech, Inc.

Janssen Biotech, Inc.
Janssen Pharmaceutical Sciences Unlimited Company
Cilag AG
Rybrevant
Amivantamab
EDETATE DISODIUM
HISTIDINE
HISTIDINE MONOHYDROCHLORIDE MONOHYDRATE
METHIONINE
POLYSORBATE 20
SUCROSE
WATER
AMIVANTAMAB
AMIVANTAMAB
Colorlous to Pale Yellow

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. ( 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 EGFRExon 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 DOSAGE AND ADMINISTRATION

  • The recommended dosage of RYBREVANT is based on baseline body weight and administered as an intravenous infusion after dilution. ( 2.3, 2.5, 2.6, 2.7)
  • Administer premedications as recommended. ( 2.5)
  • Administer via a peripheral line on Week 1 and Week 2 to reduce the risk of infusion-related reactions. ( 2.8)
  • 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. ( 2.3)
  • 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. ( 2.4)
  • When administering RYBREVANT in combination with lazertinib, administer anticoagulant prophylaxis to prevent venous thromboembolic (VTE) events for the first four months of treatment. ( 2.4)
  • Administer diluted RYBREVANT intravenously according to the infusion rates in Tables 8 and 9. ( 2.8)
Body Weight (at Baseline) Dosage Recommended Dose
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
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

2.1 Important Dosage Information

  • Administer premedications before each RYBREVANT infusion as recommended [see Dosage and Administration (2.5)].
  • 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 (2.8)].
  • Administer RYBREVANT via peripheral line for Week 1 Day 1 and 2 and Week 2 to reduce the risk of infusion-related reactions [see Dosage and Administration (2.8)].
  • When administering RYBREVANT in combination with carboplatin and pemetrexed, infuse pemetrexed first, carboplatin second, and RYBREVANT last [see Dosage and Administration (2.8)].
  • When administering RYBREVANT in combination with lazertinib, administer lazertinib orally any time before the RYBREVANT infusion [see Dosage and Administration (2.8)].
  • When administering RYBREVANT in combination with lazertinib, administer anticoagulant prophylaxis to prevent venous thromboembolic (VTE) events for the first four months of treatment [see Dosage and Administration (2.4)].

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 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 2.

Table 2: 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 3.

Table 3: Order of Administration and Regimen for RYBREVANT in Combination with Carboplatin and Pemetrexed
RYBREVANT in Combination with Carboplatin and Pemetrexed
Administer the regimen in the following order: pemetrexed first, carboplatin second, and RYBREVANT last.
Drug Dose Duration/Timing of Treatment
Pemetrexed Pemetrexed 500 mg/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 2. 		Every 3 weeks, continue until disease progression or unacceptable toxicity.

2.4 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 4. Administer RYBREVANT until disease progression or unacceptable toxicity.

Table 4: Recommended Dosage Schedule for RYBREVANT in Combination with Lazertinib or RYBREVANT as a Single Agent
Body weight at 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.

Concomitant Medications

When initiating treatment with RYBREVANT in combination with lazertinib, administer anticoagulant prophylaxis to prevent venous thromboembolic (VTE) events for the first four months of treatment [see Warnings and Precautions (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.

When initiating treatment with RYBREVANT in combination with lazertinib, administer alcohol-free (e.g., isopropanol-free, ethanol-free) emollient cream and encourage patients to limit sun exposure during and for 2 months after treatment, to wear protective clothing and use broad-spectrum UVA/UVB sunscreen to reduce the risk of dermatologic adverse reactions [see Warnings and Precautions (5.4)]. Consider prophylactic measures (e.g., use of oral antibiotics) to reduce the risk of dermatologic adverse reactions. Refer to the lazertinib prescribing information for information about concomitant medications.

2.5 Recommended Premedications

Prior to the initial infusion of RYBREVANT (Week 1, Day 1 and 2), administer premedications as described in Table 5 to reduce the risk of infusion-related reactions [see Warnings and Precautions (5.1)].

Glucocorticoid administration is required for Week 1, Day 1 and 2 dose only and upon re-initiation after prolonged dose interruptions, then as necessary for subsequent infusions (see Table 5) . Administer both antihistamine and antipyretic prior to all infusions.

Table 5: Premedications
Medication Dose Route of Administration Dosing Window Prior to RYBREVANT Administration
Antihistamine Required at all doses. Diphenhydramine (25 to 50 mg) or equivalent Intravenous 15 to 30 minutes

Oral

30 to 60 minutes
Antipyretic
Acetaminophen (650 to 1,000 mg) Intravenous 15 to 30 minutes

Oral

30 to 60 minutes
Glucocorticoid Required at initial dose (Week 1 Day 1). Dexamethasone (20 mg) or equivalent Intravenous 45 to 60 minutes
Glucocorticoid Required at second dose (Week 1 Day 2); optional for subsequent doses. Dexamethasone (10 mg) or equivalent Intravenous 45 to 60 minutes

2.6 Dosage Modifications for Adverse Reactions

The recommended dose reductions for adverse reactions for RYBREVANT are listed in Table 6.

Table 6: Dose Reductions for Adverse Reactions for RYBREVANT
Dose at which the adverse reaction occurred 1 st Dose Reduction 2 nd Dose Reduction 3 rd Dose Reduction
1,050 mg 700 mg 350 mg Discontinue RYBREVANT
1,400 mg 1,050 mg 700 mg
1,750 mg 1,400 mg 1,050 mg
2,100 mg 1,750 mg 1,400 mg

The recommended dosage modifications and management for adverse reactions for RYBREVANT are provided in Table 7.

Table 7: Recommended Dosage Modifications and Management for Adverse Reactions for RYBREVANT
Adverse Reaction Severity Dosage Modifications
Infusion-related reactions (IRR) [see Warnings and Precautions (5.1)] Grade 1 to 2
  • Interrupt RYBREVANT infusion if IRR is suspected and monitor patient until reaction symptoms resolve.
  • Resume the infusion at 50% of the infusion rate at which the reaction occurred.
  • If there are no additional symptoms after 30 minutes, the infusion rate may be escalated (see Tables 8 and 9).
  • Include corticosteroid with premedications for subsequent dose (see Table 5).
Grade 3
  • Interrupt RYBREVANT infusion and administer supportive care medications. Continuously monitor patient until reaction symptoms resolve.
  • Resume the infusion at 50% of the infusion rate at which the reaction occurred.
  • If there are no additional symptoms after 30 minutes, the infusion rate may be escalated (see Tables 8 and 9).
  • Include corticosteroid with premedications for subsequent dose (see Table 5). For recurrent Grade 3, permanently discontinue RYBREVANT.
Grade 4
  • Permanently discontinue RYBREVANT.
Interstitial Lung Disease (ILD)/pneumonitis [see Warnings and Precautions (5.2)] Any Grade
  • Withhold RYBREVANT if ILD/pneumonitis is suspected.
  • Permanently discontinue RYBREVANT if ILD/pneumonitis is confirmed.
Venous Thromboembolic (VTE) Events [Applies to the combination with lazertinib, see Warnings and Precautions (5.3)] Grade 2 or 3
  • Withhold RYBREVANT and lazertinib.
  • Administer anticoagulant treatment as clinically indicated.
  • Once anticoagulant treatment has been initiated, resume RYBREVANT and lazertinib at the same dose level, at the discretion of the healthcare provider.
Grade 4 or recurrent Grade 2 or 3 despite therapeutic level anticoagulation
  • Withhold lazertinib and permanently discontinue RYBREVANT.
  • Administer anticoagulant treatment as clinically indicated.
  • Once anticoagulant treatment has been initiated, treatment can continue with lazertinib at the same dose level at the discretion of the healthcare provider.
Dermatologic Adverse Reactions (including dermatitis acneiform, pruritus, dry skin) [see Warnings and Precautions (5.4)] Grade 1 or Grade 2
  • Initiate supportive care management.
  • Reassess after 2 weeks; if rash does not improve, consider dose reduction.
Grade 3
  • Withhold RYBREVANT and initiate supportive care management.
  • Upon recovery to ≤ Grade 2, resume RYBREVANT at reduced dose.
  • If no improvement within 2 weeks, permanently discontinue treatment.
Grade 4
  • Permanently discontinue RYBREVANT.
Severe bullous, blistering or exfoliating skin conditions (including toxic epidermal necrolysis (TEN)
  • Permanently discontinue RYBREVANT.
Other Adverse Reactions [see Adverse Reactions (6.1)] Grade 3
  • Withhold RYBREVANT until recovery to ≤ Grade 1 or baseline.
  • Resume at the same dose if recovery occurs within 1 week.
  • Resume at reduced dose if recovery occurs after 1 week but within 4 weeks.
  • Permanently discontinue if recovery does not occur within 4 weeks.
Grade 4
  • Withhold RYBREVANT until recovery to ≤ Grade 1 or baseline.
  • Resume at reduced dose if recovery occurs within 4 weeks.
  • Permanently discontinue if recovery does not occur within 4 weeks.
  • Permanently discontinue for recurrent Grade 4 reactions.

Recommended Dosage Modifications for Adverse Reactions for RYBREVANT in Combination with Lazertinib

When administering RYBREVANT in combination with lazertinib, if there is an adverse reaction requiring dose reduction after withholding treatment and resolution, reduce the dose of RYBREVANT first.

Refer to the lazertinib prescribing information for information about dosage modifications for lazertinib.

Recommended Dosage Modifications for Adverse Reactions for RYBREVANT in Combination with Carboplatin and Pemetrexed

When administering RYBREVANT in combination with carboplatin and pemetrexed, modify the dosage of one or more drugs. Withhold or discontinue RYBREVANT as shown in Table 7. Refer to prescribing information for carboplatin and pemetrexed for additional dosage modification information.

2.7 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)] . 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).

2.8 Administration

  • Administer the diluted RYBREVANT solution [see Dosage and Administration (2.7)] 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.

3 DOSAGE FORMS AND STRENGTHS

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)

4 CONTRAINDICATIONS

None.

None. ( 4)

5 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. ( 2.6, 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. ( 2.6, 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. ( 2.6, 5.3)
  • Dermatologic Adverse Reactions: Can cause severe rash including toxic epidermal necrolysis (TEN) and acneiform dermatitis. Withhold, reduce the dose, or permanently discontinue RYBREVANT based on severity. ( 2.6, 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. ( 2.6, 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); 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.

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 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 (2.6)] .

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 therapy [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 (2.4)]. 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 (2.6)] . Once anticoagulant treatment has been initiated, resume RYBREVANT and lazertinib at the same dose level at the discretion of the healthcare provider [see Dosage and Administration (2.4)]. 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 (2.6)]. 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 dose interruptions of RYBREVANT occurred in 37% of patients, rash leading to dose reductions of RYBREVANT occurred in 23% of patients, and rash leading to permanent discontinuation of RYBREVANT occurred in 5% of patients.

RYBREVANT with Carboplatin and Pemetrexed

Based on the pooled safety population [see Adverse Reactions (6.1)] , rash occurred in 82% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed, including Grade 3 (15%) adverse reactions. Rash leading to dose reductions occurred in 14% of patients, and 2.5% permanently discontinued RYBREVANT and 3.1% discontinued pemetrexed.

RYBREVANT as a Single Agent

In CHRYSALIS, [see Adverse Reactions (6.1)] , rash occurred in 74% of patients treated with RYBREVANT as a single agent, including Grade 3 rash in 3.3% of patients. The median time to onset of rash was 14 days (range: 1 to 276 days). Rash leading to dose reduction occurred in 5% of patients, and RYBREVANT was permanently discontinued due to rash in 0.7% of patients [see Adverse Reactions (6.1)].

Toxic epidermal necrolysis (TEN) occurred in one patient (0.3%) treated with RYBREVANT as a single agent.

Instruct patients to limit sun exposure during and for 2 months after treatment with RYBREVANT. Advise patients to wear protective clothing and use broad-spectrum UVA/UVB sunscreen. Alcohol-free (e.g., isopropanol-free, ethanol-free) emollient cream is recommended for dry skin.

When initiating treatment with RYBREVANT, administer alcohol-free (e.g., isopropanol-free, ethanol-free) emollient cream to reduce the risk of dermatologic adverse reactions. Consider prophylactic measures (e.g., use of oral antibiotics) to reduce the risk of dermatologic adverse reactions. If skin reactions develop, start topical corticosteroids and topical and/or oral antibiotics. For Grade 3 reactions, add oral steroids and consider dermatologic consultation. Promptly refer patients presenting with severe rash, atypical appearance or distribution, or lack of improvement within 2 weeks to a dermatologist. Withhold, reduce the dose, or permanently discontinue RYBREVANT based on severity [see Dosage and Administration (2.6)] .

5.5 Ocular Toxicity

RYBREVANT can cause ocular toxicity including keratitis, blepharitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, eye pruritus, and uveitis.

RYBREVANT with Lazertinib

In MARIPOSA [see Adverse Reactions (6.1)] , ocular toxicity occurred in 16% of patients treated with RYBREVANT in combination with lazertinib, including Grade 3 or 4 ocular toxicity in 0.7% of patients. Withhold, reduce the dose, or permanently discontinue RYBREVANT and continue lazertinib based on severity [see Dosage and Administration (2.4)] .

RYBREVANT with Carboplatin and Pemetrexed

Based on the pooled safety population [see Adverse Reactions (6.1)], ocular toxicity occurred in 16% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed. All events were Grade 1 or 2.

RYBREVANT as a Single Agent

In CHRYSALIS, [see Adverse Reactions (6.1)], keratitis occurred in 0.7% and uveitis occurred in 0.3% of patients treated with RYBREVANT. All events were Grade 1–2.

Promptly refer patients with new or worsening eye symptoms to an ophthalmologist. Withhold, reduce the dose, or permanently discontinue RYBREVANT based on severity [see Dosage and Administration (2.6)] .

5.6 Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal models, RYBREVANT can cause fetal harm when administered to a pregnant woman. Administration of other EGFR inhibitor molecules to pregnant animals has resulted in an increased incidence of impairment of embryo-fetal development, embryo lethality, and abortion. Advise females of reproductive potential of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of RYBREVANT. [see Use in Specific Populations (8.1, 8.3)] .

6 ADVERSE REACTIONS

The following adverse reactions are discussed elsewhere in the labeling:

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, nausea, and ocular toxicity. ( 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.

8 USE IN SPECIFIC POPULATIONS

Lactation: Advise not to breastfeed. ( 8.2)

8.1 Pregnancy

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.

11 DESCRIPTION

Amivantamab-vmjw is a low-fucose human immunoglobulin G1-based bispecific antibody directed against the EGF and MET receptors, produced by mammalian cell line (Chinese Hamster Ovary [CHO]) using recombinant DNA technology that has a molecular weight of approximately 148 kDa. RYBREVANT ® (amivantamab-vmjw) injection for intravenous infusion is a sterile, preservative-free, colorless to pale yellow solution in single-dose vials. The pH is 5.7.

Each RYBREVANT vial contains 350 mg (50 mg/mL) amivantamab-vmjw, EDTA disodium salt dihydrate (0.14 mg), L-histidine (2.3 mg), L-histidine hydrochloride monohydrate (8.6 mg), L-methionine (7 mg), polysorbate 80 (4.2 mg), sucrose (595 mg), and water for injection, USP.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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.

12.2 Pharmacodynamics

The exposure-response relationship and time-course of pharmacodynamic response of amivantamab-vmjw have not been fully characterized in patients with NSCLC with EGFR mutations.

12.3 Pharmacokinetics

Amivantamab-vmjw exposures increased proportionally over a dosage range from 350 to 1,750 mg (0.33 to 1.7 times the lowest approved recommended dosage) when RYBREVANT was administered as a single agent. Steady-state concentrations of RYBREVANT were reached by week 13 for both the 3-week and 2-week dosing regimen and the systemic accumulation was 1.9-fold.

Distribution

The amivantamab-vmjw mean (%CV) volume of distribution is 5 (24%) L.

Elimination

The mean (% CV) linear clearance (CL) is 0.26 L/day (30%) and mean terminal half-life is 14 days (33%).

12.4 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies (ADA) in the studies described below with the incidence of anti-drug antibodies in other studies, including those of amivantamab-vmjw or amivantamab products.

During treatment in studies CHRYSALIS, CHRYSALIS-2, PAPILLON, MARIPOSA, and MARIPOSA-2 (up to 39 months), 4 of the 1,862 (0.2%) patients who received RYBREVANT as a single agent or in combination developed a treatment-emergent anti-amivantamab-vmjw antibodies. Given the low occurrence of anti-drug antibodies, the effect of these antibodies on the pharmacokinetics, safety or efficacy of RYBREVANT is unknown.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies have been performed to assess the potential of amivantamab-vmjw for carcinogenicity or genotoxicity. Fertility studies have not been performed to evaluate the potential effects of amivantamab-vmjw. In 6-week and 3-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs.

14 CLINICAL STUDIES

14.1 First Line Treatment of NSCLC with Exon 19 deletion or Exon 21 L858R Substitution Mutation - MARIPOSA

The efficacy of RYBREVANT, in combination with lazertinib, was evaluated in MARIPOSA [NCT04487080], a randomized, active-controlled, multicenter trial. Eligible patients were required to have untreated locally advanced or metastatic NSCLC with either exon 19 deletions or exon 21 L858R substitution EGFR mutations identified by local testing, not amenable to curative therapy. Patients with asymptomatic or previously treated and stable intracranial metastases were eligible to enroll.

Patients were randomized (2:2:1) to receive RYBREVANT in combination with lazertinib (N=429), osimertinib monotherapy (N=429), or lazertinib monotherapy (an unapproved regimen for NSCLC) until disease progression or unacceptable toxicity. The evaluation of efficacy for the treatment of untreated metastatic NSCLC relied upon comparison between:

  • RYBREVANT administered intravenously at 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 RYBREVANT in combination with lazertinib arm and 429 to the osimertinib arm. The median age was 63 (range: 25–88) years; 61% were female; 58% were Asian, 38% were White, 1.6% were American Indian or Alaska Native, 0.8% were Black or African American, 0.2% were Native Hawaiian or other Pacific Islander, 0.6% were unknown race or multiple races; and 12% were Hispanic or Latino. Eastern Cooperative Oncology Group (ECOG) performance status was 0 (34%) or 1 (66%); 69% never smoked; 41% had prior brain metastases; and 89% had Stage IV cancer at initial diagnosis. Sixty percent of patients had tumors harboring exon 19 deletions and the remaining 40% had exon 21 L858R substitution mutations.

Among the 858 patients with EGFR exon 19 deletion or L858R substitution mutations that were randomized between the RYBREVANT plus lazertinib arm versus the osimertinib arm, available tissue samples from 544 (63%) patients had evaluable results when tested retrospectively using the cobas EGFR Mutation Test v2. Of the 544 patients with evaluable results, 527 (97%) patients were positive for EGFR exon 19 deletion or L858R substitution mutations, while 17 (3%) patients were negative. Available plasma samples from patients were retrospectively tested using an FDA-approved test to confirm the biomarker status.

The trial demonstrated a statistically significant improvement in PFS by BICR assessment for RYBREVANT in combination with lazertinib compared to osimertinib.

Efficacy results for RYBREVANT in combination with lazertinib are provided in Table 18.

Table 18: Efficacy Results in MARIPOSA by BICR Assessment
RYBREVANT in combination with lazertinib
(N=429) 		Osimertinib
(N=429)
CI = confidence interval; NE = not estimable
Progression-free survival (PFS)
Number of events (%) 192 (45) 252 (59)
Median, months (95% CI) 23.7 (19.1, 27.7) 16.6 (14.8, 18.5)
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 (0.58, 0.85); p=0.0002
Overall response rate (ORR) Confirmed responses based on the ITT population.
ORR, % (95% CI) 78 (74, 82) 73 (69, 78)
Complete response, % 5.4 3.5
Partial response, % 73 70
Duration of response (DOR) In confirmed responders.
Median (95% CI), months 25.8 (20.1, NE) 16.7 (14.8, 18.5)
Patients with DOR ≥ 6 months Based on observed rates., % 86 85
Patients with DOR ≥ 12 months
, % 		68 57

Figure 1: Kaplan-Meier curve of PFS in previously untreated NSCLC patients by BICR assessment

Figure 1

While OS results were immature at the current analysis, with 55% of pre-specified deaths for the final analysis reported, no trend towards a detriment was observed.

Out of all randomized patients (n=858), 367 (43%) had baseline intracranial lesions assessed by BICR using modified RECIST. Results of pre-specified analyses of intracranial ORR and DOR by BICR in the subset of patients with intracranial lesions at baseline for the RYBREVANT in combination with lazertinib arm and the osimertinib arm are summarized in Table 19.

Table 19: Exploratory Analysis of Intracranial ORR and DOR by BICR assessment in subjects with intracranial lesions at baseline
RYBREVANT in combination with lazertinib
(N=180) 		Osimertinib
(N=187)
CI = confidence interval
Intracranial Tumor Response Assessment
Intracranial ORR Confirmed responses, % (95% CI) 68
(60, 75) 		69
(62, 76)
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

14.2 Previously Treated NSCLC Patients with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations - MARIPOSA-2

The efficacy of RYBREVANT in combination with carboplatin and pemetrexed was evaluated in MARIPOSA-2 (NCT04988295), a randomized, open-label, multicenter trial. Eligible patients were required to have locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations and progressive disease on or after receiving osimertinib. Patients with asymptomatic or previously treated and stable intracranial metastases were eligible to enroll. Patients were randomized (1:2:2) to receive RYBREVANT in combination with carboplatin and pemetrexed (RYBREVANT-CP, N=131), carboplatin and pemetrexed (CP, N=263), or RYBREVANT as part of another combination regimen. The evaluation of efficacy for metastatic NSCLC relied upon comparison between:

  • RYBREVANT in combination with carboplatin and pemetrexed.
    RYBREVANT 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 2once every 3 weeks until disease progression or unacceptable toxicity.

Randomization was stratified by osimertinib line of therapy (first-line or second-line), prior brain metastases (yes or no), and Asian race (yes or no). Tumor assessments were performed every 6 weeks for the first 12 months and every 12 weeks thereafter.

The major efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review (BICR). Overall survival (OS) and overall response rate (ORR) as assessed by BICR were key secondary outcome measures.

A total of 394 patients were randomized between the two arms, 131 to the RYBREVANT-CP arm and 263 to the CP arm. The median age was 62 (range: 31 to 85) years, with 38% of patients ≥ 65 years of age; 60% were female; and 48% were Asian and 46% were White, 1% were American Indian or Alaska Native, 1% were Black or African American, 0.5% were multiple races and 2.8% were race not reported or race unknown; 8% were Hispanic or Latino. Baseline Eastern Cooperative Oncology Group (ECOG) performance status was 0 (40%) or 1 (60%); 65% never smoked; 45% had history of brain metastasis, and 99.7% had Stage IV cancer at study enrollment.

The trial demonstrated a statistically significant improvement in PFS by BICR for RYBREVANT in combination with carboplatin and pemetrexed compared to carboplatin and pemetrexed.

Efficacy results are summarized in Table 20.

Table 20: Efficacy results in MARIPOSA-2
RYBREVANT + carboplatin + pemetrexed
(N=131) 		carboplatin + pemetrexed
(N=263)
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 (5.6, 8.4) 4.2 (4.0, 4.4)
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 (0.36, 0.64); p<0.0001
Overall response rate
, Confirmed responses.
ORR, % (95% CI) 53% (44, 62) 29% (23, 35)
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) 5.6 (4.2, 9.6)

Figure 2: Kaplan-Meier curve of PFS in Previously Treated NSCLC Patients by BICR assessment- MARIPOSA-2

Figure 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 2

14.3 First Line Treatment of NSCLC with Exon 20 Insertion Mutations - PAPILLON

The efficacy of RYBREVANT was evaluated in PAPILLON (NCT04538664), in a randomized, open-label, multicenter study. Eligible patients were required to have previously untreated locally advanced or metastatic NSCLC with EGFR Exon 20 insertion mutations measurable disease per RECIST v1.1, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1, and adequate organ and bone marrow function. Patients with brain metastases at screening were eligible for participation once they were definitively treated, clinically stable, asymptomatic, and off corticosteroid treatment for at least 2 weeks prior to randomization. Patients with a medical history of interstitial lung disease or active ILD were excluded from the clinical study.

A total of 308 patients were randomized 1:1 to receive RYBREVANT in combination with carboplatin and pemetrexed (n=153) or carboplatin and pemetrexed (n=155). Patients received RYBREVANT intravenously at 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 RYBREVANT was permitted for patients who had confirmed disease progression on carboplatin and pemetrexed.

The median age was 62 (range: 27 to 92) years, with 40% of the patients ≥ 65 years of age; 58% were female; 61% were Asian and 36% were White, 0.7% were Black or African American and race was not reported in 2.3% of patients; 93% were not Hispanic or Latino. Baseline ECOG performance status was 0 (35%) or 1 (65%); 58% were never smokers; 23% had history of brain metastasis and 84% had Stage IV cancer at initial diagnosis.

PAPILLON demonstrated a statistically significant improvement in progression free survival for patients randomized to RYBREVANT in combination with carboplatin and pemetrexed compared with carboplatin and pemetrexed.

Efficacy results are summarized in Table 21 and Figure 3.

Table 21: Efficacy Results in PAPILLON
RYBREVANT+ carboplatin+ pemetrexed
(N=153) 		carboplatin+ pemetrexed
(N=155)
CI = confidence interval
Progression-Free Survival (PFS)
Number of events (%) 84 (55) 132 (85)
Median, months (95% CI) 11.4 (9.8, 13.7) 6.7 (5.6, 7.3)
HR (95% CI) 0.40 (0.30, 0.53)
p-value p<0.0001
Overall Response Rate (ORR) Confirmed responses.
ORR, % (95% CI) 67 (59, 75) 36 (29, 44)
Complete response, % 4 1
Partial response, % 63 36
Duration of response (DOR) In confirmed responders.
Median (95% CI), months 10.1 (8.5, 13.9) 5.6 (4.4, 6.9)

Figure 3: Kaplan-Meier Curve of PFS in Previously Untreated NSCLC Patients by BICR Assessment – Papillon Study

Figure 3

While OS results were immature at the current analysis, with 44% of pre-specified deaths for the final analysis reported, no trend towards a detriment was observed. Seventy-five (48%) of the treated patients crossed over from the carboplatin and pemetrexed arm after confirmation of disease progression to receive RYBREVANT as a single agent.

Figure 3

14.4 Previously Treated NSCLC with Exon 20 Insertion Mutations - CHRYSALIS

The efficacy of RYBREVANT was evaluated in patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations in a multicenter, open-label, multi-cohort clinical trial (CHRYSALIS, NCT02609776). The study included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy. Patients with untreated brain metastases and patients with a history of ILD requiring treatment with prolonged steroids or other immunosuppressive agents within the last 2 years were not eligible for the study.

In the efficacy population, EGFR exon 20 insertion mutation status was determined by prospective local testing using tissue (94%) and/or plasma (6%) samples. Of the 81 patients with EGFR exon 20 insertion mutations identified by local testing, plasma samples from 78/81 (96%) patients were tested retrospectively using Guardant360 ® CDx, identifying 62/78 (79%) samples with an EGFR exon 20 insertion mutation; 16/78 (21%) samples did not have an EGFR exon 20 insertion mutation identified.

Patients received RYBREVANT at 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 22.

Table 22: 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, months (95% CI), months 11.1 (6.9, NE)
Patients with DOR ≥ 6 months 63%

16 HOW SUPPLIED/STORAGE AND HANDLING

Storage and Handling

Store in a refrigerator at 2°C to 8°C (36°F to 46°F) in original carton to protect from light. Do not freeze.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Infusion-Related Reactions

Advise patients that RYBREVANT can cause infusion-related reactions, the majority of which may occur with the first infusion. Advise patients to alert their healthcare provider immediately for any signs or symptoms of infusion-related reactions [see Warnings and Precautions (5.1)] .

Interstitial Lung Disease/Pneumonitis

Advise patients of the risks of interstitial lung disease (ILD)/pneumonitis. Advise patients to immediately contact their healthcare provider for new or worsening respiratory symptoms [see Warnings and Precautions (5.2)] .

Venous Thromboembolic Events with Concomitant Use with Lazertinib

When RYBREVANT is used in combination with lazertinib, advise patients of the risks of serious and life threatening venous thromboembolic (VTE) events, including deep venous thrombosis and pulmonary embolism. Advise patients that prophylactic anticoagulants are recommended to be used for the first four months of treatment. Advise patients to immediately contact their healthcare provider for signs and symptoms of venous thromboembolism [see Warnings and Precautions (5.3)] .

Dermatologic Adverse Reactions

Advise patients of the risk of dermatologic adverse reactions. Advise patients to apply alcohol-free (e.g., isopropanol-free, ethanol-free) emollient cream to reduce the risk of skin reactions. Consider prophylactic measures (e.g., use of oral antibiotics) to reduce the risk of dermatologic adverse reactions. Advise patients to limit direct sun exposure during and for 2 months after treatment, to use broad-spectrum UVA/UVB sunscreen, and to wear protective clothing during treatment with RYBREVANT [see Warnings and Precautions (5.4)] .

Ocular Toxicity

Advise patients of the risk of ocular toxicity. Advise patients to contact their ophthalmologist if they develop eye symptoms and advise discontinuation of contact lenses until symptoms are evaluated [see Warnings and Precautions (5.5)] .

Paronychia/Nail Toxicity

Advise patients of the risk of paronychia. Advise patients to contact their healthcare provider for signs or symptoms of paronychia [see Adverse Reactions (6.1)].

Embryo-Fetal Toxicity

Advise females of reproductive potential of the potential risk to a fetus, to use effective contraception during treatment with RYBREVANT and for 3 months after the last dose, and to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions (5.6), Use in Specific Populations (8.1, 8.3)].

Lactation

Advise women not to breastfeed during treatment with RYBREVANT and for 3 months after the last dose [see Use in Specific Populations (8.2)] .