amivantamab: prescribing information – dosing, contraindications, interactions, side effects

Rybrevant is indicated:
 in combination with lazertinib for the first-line treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations.
 in combination with carboplatin and pemetrexed for the treatment of adult patients with advanced NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations after failure of prior therapy including an EGFR tyrosine kinase inhibitor (TKI).
 in combination with carboplatin and pemetrexed for the first-line treatment of adult patients with advanced NSCLC with activating EGFR Exon 20 insertion mutations.
 as monotherapy for treatment of adult patients with advanced NSCLC with activating EGFR Exon 20 insertion mutations, after failure of platinum-based therapy.

Rybrevant subcutaneous formulation is indicated:
 in combination with lazertinib for the first-line treatment of adult patients with advanced non-small cell lung cancer (NSCLC) with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations.

 in combination with carboplatin and pemetrexed for the treatment of adult patients with advanced NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations after failure of prior therapy including an EGFR tyrosine kinase inhibitor (TKI).
 in combination with carboplatin and pemetrexed for the first-line treatment of adult patients with advanced NSCLC with activating EGFR Exon 20 insertion mutations.
 as monotherapy for treatment of adult patients with advanced NSCLC with activating EGFR Exon 20 insertion mutations, after failure of platinum-based therapy.

Treatment with Rybrevant should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.
Rybrevant should be administered by a healthcare professional with access to appropriate medical support to manage infusion-related reactions (IRRs) if they occur.

Before initiation of Rybrevant therapy, EGFR mutation status in tumour tissue or plasma specimens must be established using a validated test method. If no mutation is detected in a plasma specimen, tumour tissue should be tested if available in sufficient amount and quality due to the potential for false negative results using a plasma-test. Testing may be performed at any time from initial diagnosis until the initiation of therapy; testing does not need to be repeated once EGFR mutation status has been established (see section 5.1).
Posology
Premedications should be administered to reduce the risk of IRRs with Rybrevant (see below “Dose modifications” and “Recommended concomitant medicinal products”).
Every 3 weeks
The recommended dosages of Rybrevant, when used in combination with carboplatin and pemetrexed, is provided in Table 1 (see below “Infusion rates” and Table 5).
Table 1:
Recommended dosage of Rybrevant every 3 weeks
Body weight at baselinea
Rybrevant dose
Schedule
Number of vials
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
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
2 100 mg
Every 3 weeks starting at Week 7 onwards a
Dose adjustments not required for subsequent body weight changes.
When used in combination with carboplatin and pemetrexed, Rybrevant should be administered after carboplatin and pemetrexed in the following order: pemetrexed, carboplatin and then Rybrevant. See section 5.1 and the manufacturer’s prescribing information for dosing instructions for carboplatin and pemetrexed.
Every 2 weeks
The recommended dosages of Rybrevant monotherapy or in combination with lazertinib is provided in Table 2 (see below “Infusion rates” and Table 6).
Table 2:
Recommended dosage of Rybrevant every 2 weeks
Body weight at baselinea
Rybrevant dose
Schedule
Number of
350 mg/7 mL
Rybrevant vials
Less than 80 kg
1 050 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
Every 2 weeks starting at Week 5 onwards
Greater than or equal to 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
Every 2 weeks starting at Week 5 onwards a
Dose adjustments not required for subsequent body weight changes.
When given in combination with lazertinib, it is recommended to administer Rybrevant any time after lazertinib when given on the same day. Refer to section 4.2 of the lazertinib Summary of Product Characteristics for recommended lazertinib dosing information.

Duration of treatment
It is recommended that patients are treated with Rybrevant until disease progression or unacceptable toxicity.
Missed dose
If a planned dose is missed, the dose should be administered as soon as possible and the dosing schedule should be adjusted accordingly, maintaining the treatment interval.
Dose modifications
Dosing should be interrupted for Grade 3 or 4 adverse reactions until the adverse reaction resolves to ≤Grade 1 or baseline. If an interruption is 7 days or less, restart at the current dose. If an interruption is longer than 7 days, it is recommended restarting at a reduced dose as presented in Table 3. See also specific dose modifications for specific adverse reactions below Table 3.
If used in combination with lazertinib, refer to section 4.2 of the lazertinib Summary of Product Characteristics for information about dose modifications.
Table 3:
Recommended dose modifications for adverse reactions
Dose at which the adverse reaction occurred
Dose after 1st interruption for adverse reaction
Dose after 2nd interruption for adverse reaction
Dose after 3rd interruption for adverse reaction
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
Infusion-related reactions
Infusion should be interrupted at the first sign of IRRs. Additional supportive medicinal products (e.g., additional glucocorticoids, antihistamine, antipyretics and antiemetics) should be administered as clinically indicated (see section 4.4).

Grade 1-3 (mild-severe): Upon recovery from symptoms, resume infusion at 50% of the previous rate. If there are no additional symptoms, the rate may be increased per the recommended infusion rate (see Tables 5 and 6). Concomitant medicinal products should be administered at the next dose (including dexamethasone (20 mg) or equivalent (see Table 4).

Recurrent Grade 3 or Grade 4 (life-threatening): Permanently discontinue Rybrevant.
Venous thromboembolic (VTE) events with concomitant use with lazertinib
At the initiation of treatment, prophylactic anticoagulants should be administered to prevent VTE events in patients receiving Rybrevant in combination with lazertinib. Consistent with clinical guidelines, patients should receive prophylactic dosing of either a direct acting oral anticoagulant (DOAC) or a low-molecular weight heparin (LMWH). Use of Vitamin K antagonists is not recommended.
For VTE events associated with clinical instability (e.g., respiratory failure or cardiac dysfunction), both drugs should be withheld until the patient is clinically stable. Thereafter, both medicinal products can be resumed at the same dose. In the event of recurrence despite appropriate anticoagulation, discontinue Rybrevant. Treatment can continue with lazertinib at the same dose.
Skin and nail reactions
Prophylactic therapy with oral and topical antibiotics is recommended to reduce the risk and severity of skin and nail reactions in patients receiving Rybrevant. Non-comedogenic skin moisturiser (ceramide-based or other formulations that provide long lasting skin hydration and exclude drying agents are preferred) on the face and whole body (except scalp) and chlorhexidine solution to wash hands and feet is also recommended. Patients should be instructed to limit sun exposure during and for 2 months after Rybrevant therapy. For further information about prophylaxis for skin and nail reactions, see section 4.4.

If the patient develops a Grade 1-2 skin or nail reaction, supportive care should be initiated as clinically indicated; if there is no improvement after 2 weeks, dose reduction should be considered for persistent Grade 2 rash (see Table 3). If the patient develops a Grade 3 skin or nail reaction, supportive care should be initiated as clinically indicated, and interruption of Rybrevant should be considered until the adverse reaction improves. Upon recovery of the skin or nail reaction to ≤Grade 2, Rybrevant should be resumed at a reduced dose. If the patient develops Grade 4 skin reactions, permanently discontinue Rybrevant (see section 4.4).
Interstitial lung disease
Rybrevant should be withheld if interstitial lung disease (ILD) or ILD-like adverse reactions (pneumonitis) is suspected. If the patient is confirmed to have ILD or ILD-like adverse reactions (e.g., pneumonitis), permanently discontinue Rybrevant (see section 4.4).
Recommended concomitant medicinal products
Two days before the first infusion:
During the two days prior to the initial Rybrevant infusion, patients should receive 8 mg dexamethasone orally, twice daily.
Day of infusion:
On the day of the initial infusion (Week 1, Day 1), patients should receive 8 mg dexamethasone orally, one hour prior to infusion in addition to intravenous dexamethasone to further reduce the risk of IRRs.
Prior to infusion (Week 1, Days 1 and 2), antihistamines, antipyretics, and glucocorticoids should be administered to reduce the risk of IRRs (see Table 4). For subsequent doses, antihistamines and antipyretics are required to be administered. Glucocorticoids should also be re-initiated after prolonged dose interruptions. Antiemetics should be administered as needed.
Table 4:
Dosing schedule of premedications
Premedication
Dose
Route of administration
Recommended dosing window prior to Rybrevant administration
Antihistamine*
Diphenhydramine (25 to 50 mg) or equivalent
Intravenous
15 to 30 minutes
Oral
30 to 60 minutes
Antipyretic*
Paracetamol/Acetaminophen (650 to 1 000 mg)
Intravenous
15 to 30 minutes
Oral
30 to 60 minutes
Glucocorticoid‡
Dexamethasone (8 mg)
Oral
60 minutes
Glucocorticoid‡
Dexamethasone (20 mg) or equivalent
Intravenous
60 to 120 minutes
Glucocorticoid+
Dexamethasone (10 mg) or equivalent
Intravenous
45 to 60 minutes
*
Required at all doses.
‡
Required at initial dose (Week 1, Day 1) or at the next subsequent dose in the event of an IRR.
+
Required at second dose (Week 1, Day 2); optional for subsequent doses.
Special populations
Paediatric population
There is no relevant use of amivantamab in the paediatric population in the treatment of non-small cell lung cancer.
Elderly
No dose adjustments are necessary (see section 4.8, section 5.1, and section 5.2).
Renal impairment
No formal studies of amivantamab in patients with renal impairment have been conducted. Based on population pharmacokinetic (PK) analyses, no dose adjustment is necessary for patients with mild or

moderate renal impairment. Caution is required in patients with severe renal impairment as amivantamab has not been studied in this patient population (see section 5.2). If treatment is started, patients should be monitored for adverse reactions with dose modifications per the recommendations above.
Hepatic impairment
No formal studies of amivantamab in patients with hepatic impairment have been conducted. Based on population PK analyses, no dose adjustment is necessary for patients with mild hepatic impairment.
Caution is required in patients with moderate or severe hepatic impairment as amivantamab has not been studied in this patient population (see section 5.2). If treatment is started, patients should be monitored for adverse reactions with dose modifications per the recommendations above.
Method of administration
Rybrevant is for intravenous use. It is administered as an intravenous infusion following dilution with sterile 5% glucose solution or sodium chloride 9 mg/mL (0.9%) solution for injection. Rybrevant must be administered with in-line filtration.
For instructions on dilution of the medicinal product before administration, see section 6.6.
Infusion rates
Following dilution, the infusion should be administered intravenously at the infusion rates presented in Table 5 or 6 below. Due to the frequency of IRRs at the first dose, amivantamab should be infused via a peripheral vein at Week 1 and Week 2; infusion via a central line may be administered for subsequent weeks when the risk of IRR is lower (see section 6.6). It is recommended for the first dose to be prepared as close to administration as possible to maximise the likelihood of completing the infusion in the event of an IRR.
Table 5:
Infusion rates for Rybrevant every 3 weeks
Body weight less than 80 kg
Week
Dose
(per 250 mL bag)
Initial infusion rate
Subsequent infusion rate†
Week 1 (split dose infusion)
Week 1 Day 1
350 mg
50 mL/hr
75 mL/hr
Week 1 Day 2
1 050 mg
33 mL/hr
50 mL/hr
Week 2
1 400 mg
65 mL/hr
Week 3
1 400 mg
85 mL/hr
Week 4
1 400 mg
125 mL/hr
Subsequent weeks*
1 750 mg
125 mL/hr
Body weight greater than or equal to 80 kg
Week
Dose
(per 250 mL bag)
Initial infusion rate
Subsequent infusion rate†
Week 1 (split dose infusion)
Week 1 Day 1
350 mg
50 mL/hr
75 mL/hr
Week 1 Day 2
1 400 mg
25 mL/hr
50 mL/hr
Week 2
1 750 mg
65 mL/hr
Week 3
1 750 mg
85 mL/hr
Week 4
1 750 mg
125 mL/hr
Subsequent weeks*
2 100 mg
125 mL/hr
*
Starting at Week 7, patients are dosed every 3 weeks.
†
Increase the initial infusion rate to the subsequent infusion rate after 2 hours in the absence of infusion-related reactions.

Table 6:
Infusion rates for Rybrevant every 2 weeks
Body weight less than 80 kg
Week
Dose
(per 250 mL bag)
Initial infusion rate
Subsequent infusion rate‡
Week 1 (split dose infusion)
Week 1 Day 1
350 mg
50 mL/hr
75 mL/hr
Week 1 Day 2
700 mg
50 mL/hr
75 mL/hr
Week 2
1 050 mg
85 mL/hr
Subsequent weeks*
1 050 mg
125 mL/hr
Body weight greater than or equal to 80 kg
Week
Dose
(per 250 mL bag)
Initial infusion rate
Subsequent infusion rate‡
Week 1 (split dose infusion)
Week 1 Day 1
350 mg
50 mL/hr
75 mL/hr
Week 1 Day 2
1 050 mg
35 mL/hr
50 mL/hr
Week 2
1 400 mg
65 mL/hr
Week 3
1 400 mg
85 mL/hr
Subsequent weeks*
1 400 mg
125 mL/hr
*
After Week 5, patients are dosed every 2 weeks.
‡
Increase the initial infusion rate to the subsequent infusion rate after 2 hours in the absence of IRRs.

Treatment with Rybrevant subcutaneous formulation should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.
Before initiation of Rybrevant subcutaneous formulation, EGFR mutation status in tumour tissue or plasma specimens must be established using a validated test method. If no mutation is detected in a plasma specimen, tumour tissue should be tested if available in sufficient amount and quality due to the potential for false negative results using a plasma-test. Once EGFR mutation status has been established, testing does not need to be repeated (see section 5.1).
Rybrevant subcutaneous formulation should be administered by a healthcare professional with access to appropriate medical support to manage administration-related reactions if they occur.
For patients currently receiving amivantamab intravenous formulation, Rybrevant subcutaneous formulation may be used as an alternative to the intravenous amivantamab formulation starting at the next scheduled dose.
For patients currently receiving Rybrevant subcutaneous formulation at an every 2-week dosing regimen, an every 4-week dosing regimen may be used as an alternative starting at the next scheduled dose.
Posology
Premedications should be administered to reduce the risk of administration-related reactions with Rybrevant subcutaneous formulation (see below “Dose modifications” and “Recommended concomitant medicinal products”).
Rybrevant subcutaneous formulation in combination with lazertinib or as monotherapy The recommended dosages of Rybrevant subcutaneous formulation in combination with lazertinib or as monotherapy, based on baseline body weight, are provided in Table 1 (every 4-week dosing) and Table 2 (every 2-week dosing).
Table 1:
Recommended dosage of Rybrevant subcutaneous formulation in combination with lazertinib or as monotherapy (Every 4-week dosing) Body weight at baseline* Recommended dose Dosing schedule Less than 80 kg 1 600 mg Weekly (total of 4 doses) from Weeks 1 to 4 3 520 mg Every 4 weeks starting at Week 5 onwards Greater than or equal to 80 kg 2 240 mg Weekly (total of 4 doses) from Weeks 1 to 4 4 640 mg Every 4 weeks starting at Week 5 onwards * Dose adjustments not required for subsequent body weight changes.

Table 2:
Recommended dosage of Rybrevant subcutaneous formulation in combination with lazertinib or as monotherapy (Every 2-week dosing) Body weight at baseline* Recommended dose Dosing schedule Less than 80 kg 1 600 mg Weekly (total of 4 doses) from Weeks 1 to 4 Every 2 weeks starting at Week 5 onwards Greater than or equal to 80 kg 2 240 mg Weekly (total of 4 doses) from Weeks 1 to 4 Every 2 weeks starting at Week 5 onwards * Dose adjustments not required for subsequent body weight changes.
When given in combination with lazertinib, it is recommended to administer Rybrevant subcutaneous formulation any time after lazertinib when given on the same day. Refer to section 4.2 of the lazertinib Summary of Product Characteristics for recommended lazertinib dosing information.
Rybrevant subcutaneous formulation in combination with carboplatin and pemetrexed The recommended dosages of Rybrevant subcutaneous formulation when used in combination with carboplatin and pemetrexed, based on baseline body weight, are provided in Table 3.
Table 3:
Recommended dosage of Rybrevant subcutaneous formulation in combination with carboplatin and pemetrexed (Every 3-week dosing) Body weight at baseline* Recommended dose Dosing schedule Less than 80 kg 1 600 mg First dose at Week 1 Day 1 2 400 mg Weekly (total of 3 doses) from Weeks 2 to 4 Every 3 weeks starting at Week 7 onwards Greater than or equal to 80 kg 2 240 mg First dose at Week 1 Day 1 3 360 mg Weekly (total of 3 doses) from Weeks 2 to 4 Every 3 weeks starting at Week 7 onwards * Dose adjustments not required for subsequent body weight changes.
When used in combination with carboplatin and pemetrexed, Rybrevant subcutaneous formulation should be administered after carboplatin and pemetrexed in the following order: pemetrexed, carboplatin and then Rybrevant. See section 5.1 and the manufacturer’s prescribing information for dosing instructions for carboplatin and pemetrexed.
Duration of treatment
It is recommended that patients are treated with Rybrevant subcutaneous formulation until disease progression or unacceptable toxicity.
Missed dose
Every 4-week or every 2-week dosing: If a dose of Rybrevant subcutaneous formulation is missed between Weeks 1 to 4, it should be administered within 24 hours. If a dose of Rybrevant subcutaneous formulation is missed from Week 5 onward, it should be administered within 7 days.
Every 3-week dosing: If a dose of Rybrevant subcutaneous formulation is missed between Weeks 1 to 3, it should be administered within 24 hours. If a dose of Rybrevant subcutaneous formulation is missed from Week 4 onward, it should be administered within 7 days.
If the missed dose is not administered according to this guidance, the missed dose should not be administered and the next dose should be administered per the usual dosing schedule.
Dose modifications
Dosing should be interrupted for Grade 3 or 4 adverse reactions until the adverse reaction resolves to ≤Grade 1 or baseline. If an interruption is 7 days or less, restart at the current dose. If an interruption is longer than 7 days, it is recommended restarting at a reduced dose as presented in Table 4. See also specific dose modifications for specific adverse reactions below Table 4.

If used in combination with lazertinib, refer to section 4.2 of the lazertinib Summary of Product Characteristics for information about dose modifications.
Table 4:
Recommended dose modifications for adverse reactions
Dose*
Dose after 1st interruption for adverse reaction
Dose after 2nd interruption for adverse reaction
Dose after 3rd interruption for adverse reaction
1 600 mg
1 050 mg
700 mg
Discontinue Rybrevant subcutaneous formulation
2 240 mg
1 600 mg
1 050 mg
2 400 mg
1 600 mg
1 050 mg
3 360 mg
2 240 mg
1 600 mg
3 520 mg
2 400 mg
1 600 mg
4 640 mg
3 360 mg
2 240 mg
*
Dose at which the adverse reaction occurred
Administration-related reactions
Premedications should be administered to reduce the risk of administration-related reactions with Rybrevant subcutaneous formulation (see “Recommended concomitant medicinal products”).
Injections should be interrupted at the first sign of administration-related reactions. Additional supportive medicinal products (e.g., additional glucocorticoids, antihistamine, antipyretics and antiemetics) should be administered as clinically indicated (see section 4.4).

Grade 1-3 (mild-severe): Upon recovery of symptoms, resume Rybrevant subcutaneous formulation injections. Concomitant medicinal products should be administered at the next dose, including dexamethasone (20 mg) or equivalent (see Table 5).

Recurrent Grade 3 or Grade 4 (life-threatening): Permanently discontinue Rybrevant.
Venous thromboembolic (VTE) events with concomitant use with lazertinib
At the initiation of treatment, prophylactic anticoagulants should be administered to prevent VTE events in patients receiving Rybrevant subcutaneous formulation in combination with lazertinib.
Consistent with clinical guidelines, patients should receive prophylactic dosing of either a direct acting oral anticoagulant (DOAC) or a low‑molecular weight heparin (LMWH). Use of Vitamin K antagonists is not recommended.
For VTE events associated with clinical instability (e.g., respiratory failure or cardiac dysfunction), both drugs should be withheld until the patient is clinically stable. Thereafter, both medicinal products can be resumed at the same dose. In the event of recurrence despite appropriate anticoagulation, discontinue Rybrevant. Treatment can continue with lazertinib at the same dose (see section 4.4).
Skin and nail reactions
Prophylactic therapy with oral and topical antibiotics is recommended to reduce the risk and severity of skin and nail reactions in patients receiving Rybrevant. Non-comedogenic skin moisturiser (ceramide-based or other formulations that provide long lasting skin hydration and exclude drying agents are preferred) on the face and whole body (except scalp) and chlorhexidine solution to wash hands and feet is also recommended. Patients should be instructed to limit sun exposure during and for 2 months after Rybrevant therapy. For further information about prophylaxis for skin and nail reactions, see section 4.4.
If the patient develops a Grade 1-2 skin or nail reaction, supportive care should be initiated as clinically indicated; if there is no improvement after 2 weeks, dose reduction should be considered for persistent Grade 2 rash (see Table 4). If the patient develops a Grade 3 skin or nail reaction, supportive care should be initiated as clinically indicated, and interruption of Rybrevant subcutaneous formulation should be considered until the adverse reaction improves. Upon recovery of the skin or nail reaction to ≤Grade 2, Rybrevant subcutaneous formulation should be resumed at a reduced dose.
If the patient develops Grade 4 skin reactions, permanently discontinue Rybrevant (see section 4.4).

Interstitial lung disease
Rybrevant subcutaneous formulation should be withheld if interstitial lung disease (ILD) or ILD-like adverse reactions (pneumonitis) is suspected. If the patient is confirmed to have ILD or ILD-like adverse reactions (e.g., pneumonitis), permanently discontinue Rybrevant (see section 4.4).
Recommended concomitant medicinal products
Prior to the initial dose (Week 1, Day 1), antihistamines, antipyretics, and glucocorticoids should be administered to reduce the risk of administration-related reactions (see Table 5). For subsequent doses, antihistamines and antipyretics are required to be administered. Glucocorticoids should also be re-initiated after prolonged dose interruptions. Antiemetics should be administered as needed.
Table 5:
Dosing schedule of premedications
Premedication
Dose
Route of administration
Recommended dosing window prior to
Rybrevant subcutaneous formulation administration
Antihistamine*
Diphenhydramine (25 to
50 mg) or equivalent
Intravenous
15 to 30 minutes
Oral
30 to 60 minutes
Antipyretic*
Paracetamol/Acetaminophen
(650 to 1 000 mg) or equivalent
Intravenous
15 to 30 minutes
Oral
30 to 60 minutes
Glucocorticoid†
Dexamethasone (20 mg) or equivalent
Intravenous
45 to 60 minutes
Oral
At least 60 minutes
Glucocorticoid‡
Dexamethasone (10 mg) or equivalent
Intravenous
45 to 60 minutes
Oral
60 to 90 minutes
*
Required at all doses.
†
Required at initial dose (Week 1, Day 1) or at the next subsequent dose in the event of an administration-related reaction.
‡
Optional for subsequent doses.
Special populations
Paediatric population
There is no relevant use of amivantamab in the paediatric population in the treatment of NSCLC.
Elderly
No dose adjustments are necessary (see section 4.8, section 5.1, and section 5.2).
Renal impairment
No formal studies of amivantamab in patients with renal impairment have been conducted. Based on population pharmacokinetic (PK) analyses, no dose adjustment is necessary for patients with mild or moderate renal impairment. Caution is required in patients with severe renal impairment as amivantamab has not been studied in this patient population (see section 5.2). If treatment is started, patients should be monitored for adverse reactions with dose modifications per the recommendations above.
Hepatic impairment
No formal studies of amivantamab in patients with hepatic impairment have been conducted. Based on population PK analyses, no dose adjustment is necessary for patients with mild hepatic impairment.
Caution is required in patients with moderate or severe hepatic impairment as amivantamab has not been studied in this patient population (see section 5.2). If treatment is started, patients should be monitored for adverse reactions with dose modifications per the recommendations above.

Method of administration
Rybrevant solution for injection is for subcutaneous use only.
Rybrevant subcutaneous formulation is not intended for intravenous administration and should be given by subcutaneous injection only, using the doses specified. See section 6.6 for instructions on handling of the medicinal product before administration.
Inject the required volume of Rybrevant subcutaneous formulation into the subcutaneous tissue of the abdomen over approximately 5 minutes. Do not administer at other sites of the body as no data are available.
Pause or slow delivery rate if the patient experiences pain. In the event pain is not alleviated by pausing or slowing down delivery rate, a second injection site may be chosen on the opposite side of the abdomen to deliver the remainder of the dose.
If administering with a subcutaneous infusion set, ensure that the full dose is delivered through the infusion set. Sodium chloride 9 mg/mL (0.9%) solution may be utilised to flush remaining medicinal product through the line.
Do not inject into tattoos or scars or areas where the skin is red, bruised, tender, hard, not intact or within 5 cm around the periumbilical area.
Injection sites should be rotated for successive injections.

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

Summary of the safety profile
In the dataset of amivantamab as monotherapy (N=380), the most frequent adverse reactions in all grades were rash (76%), infusion-related reactions (67%), nail toxicity (47%), hypoalbuminaemia (31%), oedema (26%), fatigue (26%), stomatitis (24%), nausea (23%), and constipation (23%).
Serious adverse reactions included ILD (1.3%), IRR (1.1%), and rash (1.1%). Three percent of patients discontinued Rybrevant due to adverse reactions. The most frequent adverse reactions leading to treatment discontinuation were IRR (1.1%), ILD (0.5%), and nail toxicity (0.5%).
Tabulated list of adverse reactions
Table 7 summarises the adverse drug reactions that occurred in patients receiving amivantamab as monotherapy.

The data reflects exposure to amivantamab in 380 patients with locally advanced or metastatic non-small cell lung cancer after failure of platinum-based chemotherapy. Patients received amivantamab 1 050 mg (for patients < 80 kg) or 1 400 mg (for patients ≥80 kg). The median exposure to amivantamab was 4.1 months (range: 0.0 to 39.7 months).
Adverse reactions observed during clinical studies are listed below by frequency category. Frequency categories are defined as follows: very common (≥1/10); common (≥1/100 to < 1/10); uncommon (≥1/1 000 to < 1/100); rare (≥1/10 000 to < 1/1 000); very rare (< 1/10 000); and not known (frequency cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.
Table 7:
Adverse reactions in patients receiving amivantamab as monotherapy
System organ class
Adverse reaction
Frequency category
Any grade
(%)
Grade 3-4
(%)
Metabolism and nutrition disorders
Hypoalbuminaemia* (see section 5.1)
Very common
2†
Decreased appetite
0.5†
Hypocalcaemia
0.3†
Hypokalaemia
Common
Hypomagnesaemia
Nervous system disorders
Dizziness*
Very common
0.3†
Eye disorders
Visual impairment*
Common
Growth of eyelashes*
Other eye disorders*
Keratitis
Uncommon

Summary of the safety profile
Rybrevant as monotherapy
In the dataset of Rybrevant intravenous formulation as monotherapy (N=380), the most frequent adverse reactions in all grades were rash (76%), infusion-related reactions (67%), nail toxicity (47%), hypoalbuminaemia (31%), oedema (26%), fatigue (26%), stomatitis (24%), nausea (23%), and constipation (23%). Serious adverse reactions included ILD (1.3%), IRR (1.1%), and rash (1.1%).
Three percent of patients discontinued Rybrevant due to adverse reactions. The most frequent adverse reactions leading to treatment discontinuation were IRR (1.1%), ILD (0.5%), and nail toxicity (0.5%).
Tabulated list of adverse reactions
Table 6 summarises the adverse drug reactions that occurred in patients receiving Rybrevant as monotherapy.
The data reflects exposure to Rybrevant intravenous formulation in 380 patients with locally advanced or metastatic non-small cell lung cancer after failure of platinum-based chemotherapy. Patients received amivantamab 1 050 mg (for patients < 80 kg) or 1 400 mg (for patients ≥80 kg). The median exposure to amivantamab was 4.1 months (range: 0.0 to 39.7 months).
Adverse reactions observed during clinical studies are listed below by frequency category. Frequency categories are defined as follows: very common (≥1/10); common (≥1/100 to < 1/10); uncommon (≥1/1 000 to < 1/100); rare (≥1/10 000 to < 1/1 000); very rare (< 1/10 000); and not known (frequency cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.
Table 6:
Adverse reactions in patients receiving Rybrevant as monotherapy (N=380)
System organ class
Adverse reaction
Frequency category
Any grade
(%)
Grade 3-4
(%)
Metabolism and nutrition disorders
Hypoalbuminaemia* (see section 5.1)
Very common
2†
Decreased appetite
0.5†
Hypocalcaemia
0.3†
Hypokalaemia
Common
Hypomagnesaemia
Nervous system disorders
Dizziness*
Very common
0.3†
Eye disorders
Visual impairment*
Common
Growth of eyelashes*
Other eye disorders*
Keratitis
Uncommon

Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Infusion-related reactions
Infusion-related reactions commonly occurred in patients treated with amivantamab (see section 4.8).
Prior to initial infusion (Week 1), antihistamines, antipyretics, and glucocorticoids should be administered to reduce the risk of IRRs. For subsequent doses, antihistamines and antipyretics should be administered. The initial infusion should be administered in split doses on Week 1, Day 1 and 2.
Patients should be treated in a setting with appropriate medical support to treat IRRs. Infusions should be interrupted at the first sign of IRRs of any severity and post-infusion medicinal products should be administered as clinically indicated. Upon resolution of symptoms, the infusion should be resumed at 50% of the previous rate. For recurrent Grade 3 or Grade 4 IRRs, Rybrevant should be permanently discontinued (see section 4.2).
Interstitial lung disease
Interstitial lung disease (ILD) or ILD-like adverse reactions (e.g., pneumonitis) have been reported in patients treated with amivantamab, including fatal events (see section 4.8). Patients should be monitored for symptoms indicative of ILD/pneumonitis (e.g., dyspnoea, cough, fever). If symptoms develop, treatment with Rybrevant should be interrupted pending investigation of these symptoms.
Suspected ILD or ILD-like adverse reactions should be evaluated and appropriate treatment should be initiated as necessary. Rybrevant should be permanently discontinued in patients with confirmed ILD or ILD-like adverse reactions (see section 4.2).
Venous thromboembolic (VTE) events with concomitant use with lazertinib
In patients receiving Rybrevant in combination with lazertinib, VTE events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), including fatal events, were reported (see section 4.8). Consistent with clinical guidelines, patients should receive prophylactic dosing of either a

direct acting oral anticoagulant (DOAC) or a low-molecular weight heparin (LMWH). Use of Vitamin K antagonists is not recommended.
Signs and symptoms of VTE events should be monitored. Patients with VTE events should be treated with anticoagulation as clinically indicated. For VTE events associated with clinical instability treatment should be withheld until the patient is clinically stable. Thereafter, both drugs can be resumed at the same dose.
In the event of recurrence despite appropriate anticoagulation, Rybrevant should be discontinued.
Treatment can continue with lazertinib at the same dose (see section 4.2).
Skin and nail reactions
Rash (including dermatitis acneiform), pruritus, dry skin, and skin ulcer occurred in patients treated with amivantamab (see section 4.8). Patients should be instructed to limit sun exposure during and for 2 months after Rybrevant therapy. Protective clothing and use of broad-spectrum UVA/UVB sunscreen are advisable. A prophylactic approach to rash prevention is recommended. This includes prophylactic therapy, at treatment initiation, with an oral antibiotic (e.g., doxycycline or minocycline, 100 mg twice daily) starting on Day 1 for the first 12 weeks of treatment and after completion of oral antibiotic therapy, topical antibiotic lotion to the scalp (e.g., clindamycin 1%) for the next 9 months of treatment. Non-comedogenic skin moisturiser (ceramide-based or other formulations that provide long-lasting skin hydration and exclude drying agents are preferred) on the face and whole body (except scalp) and chlorhexidine solution to wash hands and feet is recommended beginning on Day 1 and continued for the duration of treatment.
Prescriptions for topical and/or oral antibiotics and topical corticosteroids are recommended to be available at the time of initial dosing to minimise any delay in reactive management should rash develop despite prophylactic treatment. If skin reactions develop, supportive care, topical corticosteroids and topical and/or oral antibiotics should be administered. For Grade 3 or poorly-tolerated Grade 2 events, systemic antibiotics and oral steroids should also be administered.
Patients presenting with severe rash that has an atypical appearance or distribution or lack improvement within 2 weeks should be referred promptly to a dermatologist. Rybrevant should be dose reduced, interrupted, or permanently discontinued based on severity (see section 4.2).
Toxic epidermal necrolysis (TEN) has been reported. Treatment with this medicinal product should be discontinued if TEN is confirmed.
Eye disorders
Eye disorders, including keratitis, occurred in patients treated with amivantamab (see section 4.8).
Patients presenting with worsening eye symptoms should promptly be referred to an ophthalmologist and should discontinue use of contact lenses until symptoms are evaluated. For dose modifications for Grade 3 or 4 eye disorders, see section 4.2.
Sodium content
This medicinal product contains less than 1 mmol (23 mg) sodium per dose, that is to say essentially “sodium-free”. This medicinal product may be diluted in sodium chloride 9 mg/mL (0.9%) solution for infusion. This should be taken into consideration for patients on a controlled sodium diet (see section 6.6).
Polysorbate content
This medicinal product contains 0.6 mg of polysorbate 80 in each mL, which is equivalent to 4.2 mg per 7 mL vial. Polysorbates may cause hypersensitivity reactions.

Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Administration-related reactions
Administration-related reactions occurred in patients treated with Rybrevant subcutaneous formulation (see section 4.8).
Prior to the initial injection (Week 1 Day 1), antihistamines, antipyretics, and glucocorticoids should be administered to reduce the risk of administration-related reactions. For subsequent doses, antihistamines and antipyretics should be administered.
Patients should be treated in a setting with appropriate medical support to treat administration-related reactions. At the first sign of administration-related reactions of any severity, injections should be interrupted, if ongoing, and post-injection medicinal products should be administered as clinically indicated. Upon resolution of symptoms, the injection should be resumed. For Grade 4 or recurrent Grade 3 administration-related reactions, Rybrevant should be permanently discontinued (see section 4.2).
Interstitial lung disease
Interstitial lung disease (ILD) or ILD-like adverse reactions (e.g., pneumonitis) have been reported in patients treated with amivantamab, including fatal events (see section 4.8). Patients should be monitored for symptoms indicative of ILD/pneumonitis (e.g., dyspnoea, cough, fever). If symptoms develop, treatment with Rybrevant should be interrupted pending investigation of these symptoms.
Suspected ILD or ILD-like adverse reactions should be evaluated and appropriate treatment should be

initiated as necessary. Rybrevant should be permanently discontinued in patients with confirmed ILD or ILD-like adverse reactions (see section 4.2).
Venous thromboembolic (VTE) events with concomitant use with lazertinib
In patients receiving amivantamab in combination with lazertinib, VTE events, including deep vein thrombosis (DVT) and pulmonary embolism (PE), were reported (see section 4.8). Fatal events were observed with amivantamab intravenous formulation.
Consistent with clinical guidelines, patients should receive prophylactic dosing of either a direct acting oral anticoagulant (DOAC) or a low molecular weight heparin (LMWH). Use of Vitamin K antagonists is not recommended.
Signs and symptoms of VTE events should be monitored. Patients with VTE events should be treated with anticoagulation as clinically indicated. For VTE events associated with clinical instability, treatment should be withheld until the patient is clinically stable. Thereafter, both drugs can be resumed at the same dose.
In the event of recurrence despite appropriate anticoagulation, Rybrevant should be discontinued.
Treatment can continue with lazertinib at the same dose (see section 4.2).
Skin and nail reactions
Rash (including dermatitis acneiform), pruritus, dry skin, and skin ulcer occurred in patients treated with amivantamab (see section 4.8). Patients should be instructed to limit sun exposure during and for 2 months after Rybrevant therapy. Protective clothing and use of broad-spectrum UVA/UVB sunscreen are advisable. A prophylactic approach to rash prevention is recommended. This includes prophylactic therapy, at treatment initiation, with an oral antibiotic (e.g., doxycycline or minocycline, 100 mg twice daily) starting on Day 1 for the first 12 weeks of treatment and after completion of oral antibiotic therapy, topical antibiotic lotion to the scalp (e.g., clindamycin 1%) for the next 9 months of treatment. Non‑comedogenic skin moisturiser (ceramide-based or other formulations that provide long-lasting skin hydration and exclude drying agents are preferred) on the face and whole body (except scalp) and chlorhexidine solution to wash hands and feet is recommended beginning on Day 1 and continued for the duration of treatment.
Prescriptions for topical and/or oral antibiotics and topical corticosteroids are recommended to be available at the time of initial dosing to minimise any delay in reactive management should rash develop despite prophylactic treatment. If skin reactions develop, supportive care, topical corticosteroids and topical and/or oral antibiotics should be administered. For Grade 3 or poorly-tolerated Grade 2 events, systemic antibiotics and oral steroids should also be administered.
Patients presenting with severe rash that has an atypical appearance or distribution or lack improvement within 2 weeks should be referred promptly to a dermatologist. Rybrevant should be dose reduced, interrupted, or permanently discontinued based on severity (see section 4.2).
Toxic epidermal necrolysis (TEN) has been reported. Treatment with this medicinal product should be discontinued if TEN is confirmed.
Eye disorders
Eye disorders, including keratitis, occurred in patients treated with amivantamab (see section 4.8).
Patients presenting with worsening eye symptoms should promptly be referred to an ophthalmologist and should discontinue use of contact lenses until symptoms are evaluated. For dose modifications for Grade 3 or 4 eye disorders, see section 4.2.
Sodium content
This medicinal product contains less than 1 mmol (23 mg) sodium per dose, that is to say essentially “sodium-free” (see section 6.6).

Polysorbate content
This medicinal product contains 0.6 mg of polysorbate 80 in each mL, which is equivalent to 6 mg per 10 mL vial, 8.4 mg per 14 mL vial, 9 mg per 15 mL vial, or 13.2 mg per 22 mL vial. Polysorbates may cause hypersensitivity reactions.

No drug interaction studies have been performed. As an IgG1 monoclonal antibody, renal excretion and hepatic enzyme-mediated metabolism of intact amivantamab are unlikely to be major elimination routes. As such, variations in drug-metabolising enzymes are not expected to affect the elimination of

amivantamab. Due to the high affinity to a unique epitope on EGFR and MET, amivantamab is not anticipated to alter drug-metabolising enzymes.
Vaccines
No clinical data are available on the efficacy and safety of vaccinations in patients taking amivantamab. Avoid the use of live or live-attenuated vaccines while patients are taking amivantamab.

Women of child-bearing potential/Contraception
Women of child-bearing potential should use effective contraception during and for 3 months after cessation of amivantamab treatment.
Pregnancy
There are no human data to assess the risk of amivantamab use during pregnancy. No animal reproductive studies were conducted to inform a drug-associated risk. Administration of EGFR and MET inhibitor molecules in pregnant animals resulted in an increased incidence of impairment of embryo-foetal development, embryo lethality, and abortion. Therefore, based on its mechanism of action and findings in animal models, amivantamab could cause foetal harm when administered to a pregnant woman. Amivantamab should not be given during pregnancy unless the benefit of treatment of the woman is considered to outweigh potential risks to the foetus. If the patient becomes pregnant while taking this medicinal product the patient should be informed of the potential risk to the foetus (see section 5.3).
Breast-feeding
It is unknown whether amivantamab is excreted in human milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which is decreasing to low concentrations soon afterwards. A risk to the breast-fed child cannot be excluded during this short period just after birth, although IgGs are likely to be degraded in the gastrointestinal tract of the breast-fed child and not absorbed. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from amivantamab therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility
There are no data on the effect of amivantamab on human fertility. Effects on male and female fertility have not been evaluated in animal studies.

Women of child-bearing potential/Contraception
Women of child-bearing potential should use effective contraception during and for 3 months after cessation of amivantamab treatment.
Pregnancy
There are no human data to assess the risk of amivantamab use during pregnancy. No animal reproductive studies were conducted to inform a drug-associated risk. Administration of EGFR and MET inhibitor molecules in pregnant animals resulted in an increased incidence of impairment of embryo-foetal development, embryo lethality, and abortion. Therefore, based on its mechanism of action and findings in animal models, amivantamab could cause foetal harm when administered to a pregnant woman. Amivantamab should not be given during pregnancy unless the benefit of treatment of the woman is considered to outweigh potential risks to the foetus. If the patient becomes pregnant while taking this medicinal product, the patient should be informed of the potential risk to the foetus (see section 5.3).
Breast-feeding
It is unknown whether amivantamab is excreted in human milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which is decreasing to low concentrations soon afterwards. A risk to the breast-fed child cannot be excluded during this short period just after birth, although IgGs are likely to be degraded in the gastrointestinal tract of the breast-fed child and not absorbed. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from amivantamab therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility
There are no data on the effect of amivantamab on human fertility. Effects on male and female fertility have not been evaluated in animal studies.

Rybrevant may have moderate influence on the ability to drive and use machines. Please see section 4.8 (e.g., dizziness, fatigue, visual impairment). If patients experience treatment-related symptoms, including vision-related adverse reactions, affecting their ability to concentrate and react, it is recommended that they do not drive or use machines until the effect subsides.

No maximum tolerated dose has been determined in a clinical study in which patients received up to 2 100 mg administered intravenously. There is no known specific antidote for amivantamab overdose.
In the event of an overdose, treatment with Rybrevant should be stopped, the patient should be monitored for any signs or symptoms of adverse events and appropriate general supportive measures should be instituted immediately until clinical toxicity has diminished or resolved.
5.
PHARMACOLOGICAL PROPERTIES

There is no information on overdose with Rybrevant subcutaneous formulation and no known specific antidote for overdose. In the event of an overdose, treatment with Rybrevant should be stopped, the patient should be monitored for any signs or symptoms of adverse events and appropriate general supportive measures should be instituted immediately until clinical toxicity has diminished or resolved.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Monoclonal antibodies and antibody drug conjugates, ATC code:
L01FX18.
Mechanism of action
Amivantamab is a low-fucose, fully-human IgG1-based EGFR-MET bispecific antibody with immune cell-directing activity that targets tumours with activating EGFR mutations such as Exon 19 deletions, Exon 21 L858R substitution, and Exon 20 insertion mutations. Amivantamab binds to the extracellular domains of EGFR and MET.
Amivantamab disrupts EGFR and MET signalling functions through blocking ligand binding and enhancing degradation of EGFR and MET, thereby preventing tumour growth and progression. The presence of EGFR and MET on the surface of tumour 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.
Pharmacodynamic effects
Albumin
Amivantamab decreased serum albumin concentration, a pharmacodynamic effect of MET inhibition, typically during the first 8 weeks (see section 4.8); thereafter, albumin concentration stabilised for the remainder of amivantamab treatment.
Clinical efficacy and safety
Previously-untreated NSCLC with EGFR Exon 19 deletions or Exon 21 L858R substitution mutations (MARIPOSA) NSC3003 (MARIPOSA) is a randomised, open-label, active-controlled, multicentre phase 3 study assessing the efficacy and safety of Rybrevant in combination with lazertinib as compared to osimertinib monotherapy as first-line treatment in patients with EGFR-mutated locally advanced or metastatic NSCLC not amenable to curative therapy. Patient samples were required to have one of the two common EGFR mutations (Exon 19 deletion or Exon 21 L858R substitution mutation), as

identified by local testing. Tumour tissue (94%) and/or plasma (6%) samples for all patients were tested locally to determine EGFR Exon 19 deletion and/or Exon 21 L858R substitution mutation status using polymerase chain reaction (PCR) in 65% and next generation sequencing (NGS) in 35% of patients.
A total of 1 074 patients were randomised (2:2:1) to receive Rybrevant in combination with lazertinib, osimertinib monotherapy, or lazertinib monotherapy until disease progression or unacceptable toxicity.
Rybrevant was 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. Lazertinib was administered at 240 mg orally once daily. Osimertinib was administered at a dose of 80 mg orally once daily. Randomisation was stratified by EGFR mutation type (Exon 19 deletion or Exon 21 L858R), race (Asian or non-Asian), and history of brain metastasis (yes or no).

Pharmacotherapeutic group: Monoclonal antibodies and antibody drug conjugates, ATC code:
L01FX18.
Rybrevant subcutaneous formulation contains recombinant human hyaluronidase (rHuPH20).
rHuPH20 works locally and transiently to degrade hyaluronan ((HA), a naturally occurring glycoaminoglycan found throughout the body) in the extracellular matrix of the subcutaneous space by cleaving the linkage between the two sugars (N-acetylglucosamine and glucuronic acid), which comprise HA.
Mechanism of action
Amivantamab is a low-fucose, fully-human IgG1-based EGFR-MET bispecific antibody with immune cell-directing activity that targets tumours with activating EGFR mutations such as Exon 19 deletions, Exon 21 L858R substitution and Exon 20 insertion mutations. Amivantamab binds to the extracellular domains of EGFR and MET.
Amivantamab disrupts EGFR and MET signalling functions through blocking ligand binding and enhancing degradation of EGFR and MET, thereby preventing tumour growth and progression. The presence of EGFR and MET on the surface of tumour 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.
Pharmacodynamic effects
After the first full dose of Rybrevant subcutaneous formulation, mean serum EGFR and MET concentrations decreased substantially and remained suppressed for the duration of treatment for all studied doses.
Albumin
Rybrevant subcutaneous formulation decreased serum albumin concentration, a pharmacodynamic effect of MET inhibition, typically during the first 8 weeks (see section 4.8); thereafter, albumin concentration stabilised for the remainder of amivantamab treatment.
Clinical experience of Rybrevant subcutaneous formulation
The efficacy of Rybrevant subcutaneous formulation in patients with EGFR-mutated locally advanced or metastatic NSCLC is based on achieving non-inferior PK exposure to intravenous amivantamab in the non-inferiority study PALOMA-3 (see section 5.2). The study demonstrated non-inferior efficacy of subcutaneous to intravenous amivantamab given in combination with lazertinib in patients with EGFR-mutated locally advanced or metastatic NSCLC whose disease has progressed on or after treatment with osimertinib and platinum-based chemotherapy.
Clinical experience of Rybrevant intravenous formulation

Based on Rybrevant monotherapy data, amivantamab area under the concentration-time curve (AUC1 week) increases proportionally over a dose range from 350 to 1 750 mg.
Based on simulations from the population pharmacokinetic model, AUC1 week was approximately 2.8-fold higher after the fifth dose for the 2-week dosing regimen and 2.6-fold higher after the fourth dose for the 3-week dosing regimen. Steady-state concentrations of amivantamab were reached by Week 13 for both the 3-week and 2-week dosing regimen and the systemic accumulation was 1.9-fold.
Distribution
Based on the individual amivantamab PK parameter estimates in population PK analysis, the geometric mean (CV%) total volume of distribution, is 5.12 (27.8%) L, following administration of the recommended dose of Rybrevant.
Elimination
Based on the individual amivantamab PK parameter estimates in population PK analysis, the geometric mean (CV%) linear clearance (CL) and terminal half-life associated with linear clearance is 0.266 (30.4%) L/day and 13.7 (31.9%) days respectively.

Special populations
Elderly
No clinically meaningful differences in the pharmacokinetics of amivantamab were observed based on age (21-88 years).
Renal impairment
No clinically meaningful effect on the pharmacokinetics of amivantamab was observed in patients with mild (60 ≤ creatinine clearance [CrCl] < 90 mL/min), moderate (29 ≤ CrCl < 60 mL/min) or severe (15 ≤ CrCl < 29 mL/min) renal impairment. Data in patients with severe renal impairment are limited (n=1), but there is no evidence to suggest that dose adjustment is required in these patients.
The effect of end-stage renal disease (CrCl < 15 mL/min) on amivantamab pharmacokinetics is unknown.
Hepatic impairment
Changes in hepatic function are unlikely to have any effect on the elimination of amivantamab since IgG1-based molecules such as amivantamab are not metabolised through hepatic pathways.

Absorption
Following subcutaneous administration, the geometric mean (%CV) of amivantamab bioavailability is 66.6% (14.9%) with a median time to reach maximum concentration of 3 days, based on the individual amivantamab PK parameter estimates for participants receiving subcutaneous administration in the population PK analysis.
For the every 2-week subcutaneous dosing regimen, the geometric mean (%CV) maximum trough concentration of amivantamab after the 4th weekly dose was 335 µg/mL (32.7%). The mean AUC1 week increased 3.5-fold from the first dose to Cycle 2 Day 1. Maximum trough concentration of amivantamab after subcutaneous administration as monotherapy and in combination with lazertinib is typically observed at the end of the weekly dosing (Cycle 2 Day 1). Amivantamab steady-state concentration is reached by approximately Week 13. The geometric mean (%CV) steady-state trough concentration of amivantamab at Cycle 4 Day 1 was 206 µg/mL (39.1%).
Table 14 lists the observed geometric mean (%CV) maximum trough concentrations (Cycle 2 Day 1 Ctrough) and Cycle 2 area under the concentration time curve (AUCDay 1-15) following the recommended doses of amivantamab administered subcutaneously and intravenously in patients with NSCLC. These PK endpoints were the basis for the demonstration of non-inferiority that supports the intravenous to subcutaneous bridging.
Table 14:
Summary of serum pharmacokinetics parameters of amivantamab in patients with
NSCLC (PALOMA-3 Study)
Parameter
Rybrevant subcutaneous formulation
1 600 mg
(2 240 mg for body weight ≥80 kg)
Rybrevant intravenous formulation
1 050 mg
(1 400 mg for body weight ≥80 kg)
Geometric mean (%CV)
Cycle 2 Day 1 Ctrough
(µg/mL)
335 (32.7%)
293 (31.7%)
Cycle 2 AUC(Day1-15)
(µg/mL)
135 861 (30.7%)
131 704 (24.0%)