Amivantamab is a bispecific epidermal growth factor receptor (EGFR) and MET receptor-directed antibody indicated as first-line treatment in combination with pemetrexed and carboplatin for the treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutation, and as monotherapy for locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations in patients whose disease has progressed on or after platinum-based chemotherapy. Infusion-related reactions are common with the first dose. Because of this, the first dose should be divided and administered on 2 days. Premedication with an antihistamine and acetaminophen is required for all doses; the addition of a glucocorticoid is necessary for the first dose (days 1 and 2).
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
-Amivantamab dosing should be based on the patient's baseline weight. Dose adjustments are not required for subsequent body weight changes.
-Split administration of the Week 1 dose on days 1 and 2; thereafter, the total dose may be infused on day 1.
-Glucocorticoid premedication is required for week 1, days 1 and 2 and upon reinitiation of therapy after a prolonged interruption; it may be administered as necessary for subsequent infusions. Administer diphenhydramine and acetaminophen prior to all amivantamab doses.
-Premedicate with diphenhydramine 25 to 50 mg IV (or equivalent) and acetaminophen 650 to 1,000 mg IV 15 to 30 minutes prior to each dose of amivantamab; alternatively, oral diphenhydramine and acetaminophen may be given 30 to 60 minutes prior to amivantamab administration.
-On week 1, day 1, additionally premedicate with dexamethasone 20 mg IV (or equivalent) 45 to 60 minutes before amivantamab administration. On week 1, day 2 additionally premedicate with dexamethasone 10 mg IV (or equivalent) 45 to 60 minutes before amivantamab administration.
-Do not infuse amivantamab concomitantly in the same IV line with other agents.
Dilution:
-For the initial infusion, prepare amivantamab as close as possible to administration time to allow for the possibility of an extended infusion due to an infusion-related reaction.
-Withdraw and discard a volume of either 5% Dextrose Injection or 0.9% Sodium Chloride Injection from a 250 mL infusion bag equal to the volume of amivantamab to be added (7 mL per vial). Only use polyvinylchloride (PVC), polypropylene (PP), polyethylene (PE), or polyolefin blend (PP+PE) infusion bags.
-Withdraw 7 mL (350 mg) of amivantamab from each vial to reach the appropriate dose and add it to the infusion bag; the final volume should be 250 mL. Discard any unused portion or overfill left in the vial.
-Gently invert the bag to mix; do not shake.
-Storage following dilution: Diluted solutions should be administered within 10 hours (including infusion time) at room temperature (59 to 77 degrees F; 15 to 25 degrees C).
Intravenous Infusion:
-Infuse using an infusion set fitted with a flow regulator and with a 0.2 micrometer in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone (PES) filter primed with diluent only.
-Administration sets must be made of either polyurethane (PU), polybutadiene (PBD) PVC, PP, or PE.
-Administer amivantamab via a peripheral line on weeks 1 and 2, given the high incidence of infusion-related reactions during initial treatment. Amivantamab may be administered via central line for subsequent weeks.
-The total infusion time is 4 to 6 hours on week 1, day 1 and 6 to 8 hours on week 1, day 2. Subsequent infusion time is approximately 2 hours.
Monotherapy:
-Week 1, Day 1: Infuse 350 mg at an initial infusion rate of 50 mL/hour; the rate may be increased to 75 mL/hour after 2 hours in the absence of infusion-related reactions.
-Week 1, Day 2: If the day 2 dose is 700 mg, infuse at an initial rate of 50 mL/hour; the rate may be increased to 75 mL/hour after 2 hours in the absence of infusion-related reactions. If the day 2 dose is 1,050 mg, infuse at an initial rate of 35 mL/hour; the rate may be increased to 50 mL/hour after 2 hours in the absence of infusion-related reactions.
-Week 2: If the dose is 1,050 mg, infuse at a rate of 85 mL/hour. If the dose is 1,400 mg, infuse at a rate of 65 mL/hour.
-Week 3: If the dose is 1,050 mg, infuse at a rate of 125 mL/hour. If the dose is 1,400 mg, infuse at a rate of 85 mL/hour.
-Week 4 and subsequent doses: Infuse at a rate of 125 mL/hour.
Combination therapy with pemetrexed and carboplatin:
-Sequence of administration: Administer pemetrexed first, carboplatin second, amivantamab last.
-Week 1, Day 1: Infuse 350 mg at an initial infusion rate of 50 mL/hour; the rate may be increased to 75 mL/hour after 2 hours in the absence of infusion-related reactions.
-Week 1, Day 2: If the day 2 dose is 1,050 mg, infuse at an initial rate of 35 mL/hour; the rate may be increased to 50 mL/hour after 2 hours in the absence of infusion-related reactions. If the day 2 dose is 1,400 mg, infuse at an initial rate of 25 mL/hour; the rate may be increased to 50 mL/hour after 2 hours in the absence of infusion-related reactions.
-Week 2: Infuse at a rate of 65 mL/hour.
-Week 3: Infuse at a rate of 85 mL/hour.
-Week 4 and subsequent doses: Infuse at a rate of 125 mL/hour.
Interstitial lung disease (ILD)/pneumonitis occurred in 3.3% (grade 3, 0.7%) of patients with previously treated, locally advanced or metastatic NSCLC treated with amivantamab in a multicenter, multicohort clinical trial. While reported in fewer than 10% of patients receiving amivantamab in combination with pemetrexed and carboplatin for advanced NSCLC, the incidence of grade 3 ILD/pneumonitis was 2.6% in this population. Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis and immediately interrupt therapy if ILD/pneumonitis is suspected; permanently discontinue amivantamab if ILD/pneumonitis is confirmed. Dyspnea was reported in 11% to 37% (grade 3 or 4, 1.3% to 2.3%) and cough in 17% to 25% of NSCLC patients who received amivantamab in clinical trials.
Rash commonly occurs in patients treated with amivantamab (74% to 89%; grade 3, 3.3% to 19%), with a median time to onset of 14 days after administration; the term rash included acneiform rash, eczema, asteatotic eczema, palmar-plantar erythrodysesthesia (hand and foot syndrome), perineal rash, maculopapular rash, vesicular rash, skin exfoliation, and toxic epidermal necrolysis. Toxic epidermal necrolysis occurred in 1 patient (0.3%) in a multicenter, multicohort trial (n = 302). Instruct patients to limit sunlight (UV) exposure, use broad-spectrum UVA/UVB sunscreen, and wear protective clothing. Patients with dry skin may use alcohol-free emollient cream. If skin reactions develop, begin treatment with topical corticosteroids and topical and/or oral antibiotics; add oral steroids and consider a dermatologic consultation for grade 3 reactions. Promptly refer patients presenting with severe rash, atypical appearance or distribution, or lack of improvement within 2 weeks to a dermatologist. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary depending on the severity of the reaction. Xerosis occurred in 14% to 17% of NSCLC patients who received amivantamab in clinical trials. Nail toxicity occurred in 62% of NSCLC patients treated with amivantamab plus pemetrexed and carboplatin compared with 3% of those receiving pemetrexed and carboplatin alone (grade 3 or 4, 7% vs. 0%) in one randomized clinical trial; fewer than 10% of patients reported a skin ulcer. Pruritus was reported in 18% of amivantamab-treated patients in an open-label, multicohort trial.
Amivantamab caused ocular toxicity in less than 10% of patients treated in a multicenter, multicohort clinical trial including keratitis (0.7%), dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular pruritus, and uveitis (0.3%). Promptly refer patients presenting with ocular symptoms to an ophthalmologist. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for ocular adverse reactions.
Musculoskeletal pain was reported in 47% of patients with previously treated, locally advanced or metastatic NSCLC with exon 20 insertion mutations treated with amivantamab in a multicenter, multicohort clinical trial, including arthralgia, arthritis, back pain, bone pain, non-cardiac chest pain, myalgia, neck pain, extremity pain, and spinal pain. Serious cases of muscle weakness occurred in 2% of patients or more.
Gastrointestinal adverse reactions reported in patients with previously treated, locally advanced or metastatic NSCLC treated with amivantamab monotherapy in a multicenter, multicohort clinical trial include nausea (36%), stomatitis (26%; grade 3 or 4, 0.8%), constipation (23%), vomiting (22%), diarrhea (16%; grade 3 or 4, 3.1%), and abdominal pain (11%; grade 3 or 4, 0.8%). The term stomatitis included aphthous ulcer, cheilitis, glossitis, oral ulceration, oral inflammation, and pharyngeal inflammation. The addition of amivantamab to pemetrexed and carboplatin increased the incidence of stomatitis (43% vs. 11%; grade 3 or 4, 4% vs. 0%), constipation (40% vs. 30%; grade 3 or 4, 0% vs. 0.7%), vomiting (21% vs. 19%; grade 3 or 4, 3.3% vs. 0.7%), diarrhea (21% vs. 13%; grade 3 or 4, 3% vs. 1.3%), and abdominal pain (11% vs. 8%; grade 3 or 4, 0.7% vs. 0%) compared with pemetrexed and carboplatin alone in a randomized clinical trial; nausea occurred in 36% vs. 42% of patients, respectively (grade 3 or 4, 0.7% vs. 0%).
Fatigue (including asthenia) occurred in 33% to 42% (grade 3 or 4, 2.3% to 6%) of patients with previously treated, locally advanced or metastatic NSCLC treated with amivantamab in clinical trials.
Edema occurred in 27% to 40% (grade 3 or 4, 0.8% to 1.3%) of patients with previously treated, locally advanced or metastatic NSCLC treated with amivantamab in clinical trials. The term edema included eyelid edema, facial edema, lip edema, peripheral edema, and periorbital edema.
Bleeding occurred in 18% to 19% of patients with previously treated, locally advanced or metastatic NSCLC treated with amivantamab in clinical trials (grade 3 or 4, 0.7% or less); hemorrhoids were also reported in 12% (grade 3 or 4, 1%) of amivantamab-treated patients in 1 clinical trial. The term bleeding included epistaxis, gingival bleeding, hematuria, hemoptysis, hemorrhage, mouth hemorrhage, and mucosal hemorrhage.
Infection including COVID-19 (24% vs. 14%; grade 3 or 4, 2% vs. 0.6%) and pneumonia (13% vs. 6%; grade 3 or 4, 5% vs. 1.9%) occurred more often in patients treated with amivantamab plus pemetrexed and carboplatin compared with pemetrexed and carboplatin alone in a randomized clinical trial; conjunctivitis was reported in fewer than 10% of amivantamab-treated patients in this trial. Paronychia (50%; grade 3 or 4, 3.1%) and pneumonia (10%; grade 3 or 4, 0.8%) were also reported in patients who received amivantamab monotherapy in a multicenter, multicohort clinical trial. Fever has been reported in 13% to 17% of patients who received amivantamab.
Anorexia (36% vs. 28%; grade 3 or 4, 2.6% vs. 1.3%) and weight loss (14% vs. 8%; grade 3 or 4, 0.7% vs. 0%) were more common in patients with advanced NSCLC treated with amivantamab plus pemetrexed and carboplatin compared with those who received pemetrexed and carboplatin alone in a randomized clinical trial. Decreased appetite was reported in 15% of patients with advanced NSCLC who received amivantamab monotherapy in a separate clinical trial.
Peripheral neuropathy occurred in 13% of patients with previously treated, locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations who received amivantamab in a multicenter, multicohort clinical trial, including hypoesthesia, neuralgia, and paresthesias.
Dizziness occurred in 11% to 12% (grade 3 or 4, 0.8% or less) of patients with previously treated, locally advanced or metastatic NSCLC who received amivantamab in clinical trials. Headache (including migraine) was also reported in 10% (grade 3 or 4, 0.8%) of amivantamab-treated patients in a multicenter, multicohort clinical trial.
Deep vein thrombosis and pulmonary embolism were each reported in fewer than 10% of patients with advanced NSCLC treated with amivantamab in combination with pemetrexed and carboplatin in a randomized clinical trial. Pulmonary embolism was also reported in at least 2% of patients with advanced NSCLC who received amivantamab in a multicenter, multicohort clinical trial.
Elevated hepatic enzymes occurred in patients with previously treated, locally advanced or metastatic NSCLC who received amivantamab in clinical trials including increased alkaline phosphatase (51% to 53%; grade 3 or 4, 1% to 4.8%), increased ALT (38% to 57%; grade 3 or 4, 1.6% to 4%), increased AST (33% to 60%; grade 3 or 4, 1% or less), and increased GGT (27% to 38%; grade 3 or 4, 4%).
Electrolyte abnormalities including hyperglycemia, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia, and hypophosphatemia occurred in patients with previously treated locally advanced or metastatic NSCLC s who received amivantamab in clinical trials including decreases from baseline in magnesium (27% to 39%; grade 3 or 4, 2% or less), sodium (27% to 55%; grade 3 or 4, 4% to 7%), and potassium (26% to 44%; grade 3 or 4, 6% to 11%). A decrease in corrected calcium from baseline was also reported in 27% of patients with advanced NSCLC treated with amivantamab plus pemetrexed and carboplatin compared with 18% of those who received pemetrexed and carboplatin alone in a randomized clinical trial (grade 3 or 4, 1% vs. 1%). Increased creatinine (46%), increased blood glucose (56%; grade 3 or 4, 4%), and decreased phosphate (33%; grade 3 or 4, 8%) were also reported in amivantamab-treated patients in a multicenter, multicohort clinical trial.
Hypoalbuminemia has been reported in patients with previously treated, locally advanced or metastatic NSCLC who received amivantamab in clinical trials, with 79% to 87% reporting decreased albumin concentrations from baseline (grade 3 or 4, 7% to 8%).
Hematologic abnormalities including leukopenia, lymphopenia, neutropenia, and thrombocytopenia, occurred in patients with previously treated locally advanced or metastatic NSCLC s who received amivantamab in clinical trials. In a randomized clinical trial, decreases from baseline in white blood cells (89% vs. 76%; grade 3 or 4, 17% vs. 10%), neutrophils (76% vs. 61%; grade 3 or 4, 36% vs. 23%), platelets (70% vs. 54%; grade 3 or 4, 10% vs. 12%), and lymphocytes (61% vs. 49% (grade 3 or 4, 11% vs. 13%) were more common in patients with advanced NSCLC treated with amivantamab plus pemetrexed and carboplatin compared with those who received pemetrexed and carboplatin alone. Decreased lymphocyte counts were also reported in 36% (grade 3 or 4, 8%) of patients with previously treated, locally advanced or metastatic NSCLC who received amivantamab monotherapy in a multicenter, multicohort clinical trial.
Infusion-related reactions occurred in 42% to 66% (grade 3 or 4, 1.3% to 2.6%) of patients treated with amivantamab in clinical trials; symptoms include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting. The incidence was higher on week 1, day 1 of therapy (65%), and decreasing to 3.4% on week 1, day 2, 0.4% with week 2, and cumulatively 1.1% with subsequent infusions. Premedicate with antihistamines, antipyretics before every dose; additionally administer glucocorticoids prior to the first 2 doses (week 1, days 1 and 2) and after prolonged interruptions of therapy. Administer amivantamab via a peripheral line for the first 2 weeks of therapy; follow recommendations regarding the rate of infusion. Monitor patients for signs and symptoms of infusion reactions during amivantamab administration in a setting where cardiopulmonary resuscitation medication and equipment are available. Interrupt the infusion if an infusion-related reaction is suspected; a rate reduction or discontinuation of therapy may be necessary. The median time to onset was 1 hour (range, 0.1 to 18 hours) after the start of the infusion.
Treatment-emergent anti-amivantamab antibody formation was reported in 0.5% of patients who received amivantamab as monotherapy or in combination with chemotherapy in clinical trials (n = 663). The effect of anti-drug antibodies on the efficacy of amivantamab is unknown.
Amivantamab can cause infusion-related reactions, most commonly with the first dose. Symptoms are typically mild (grade 1 or 2), and include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting. The median time to onset was 1 hour (range, 0.1 to 18 hours) after the start of infusion. Premedicate with antihistamines, antipyretics before every dose; additionally administer glucocorticoids prior to the first 2 doses (week 1, days 1 and 2). Administer amivantamab via a peripheral line for the first 2 weeks of therapy; follow recommendations regarding the rate of infusion. Monitor patients for signs and symptoms of infusion reactions during amivantamab administration in a setting where cardiopulmonary resuscitation medication and equipment are available. Interrupt the infusion if an infusion-related reaction is suspected; a rate reduction or discontinuation of therapy may be necessary.
Use amivantamab with caution in patients who have a history of pre-existing chronic lung disease (CLD); severe pneumonitis/interstitial lung disease (ILD) has been reported in patients treated with amivantamab. Advise patients to immediately report any new or worsening respiratory symptoms including cough, dyspnea, or fever. Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis and immediately interrupt therapy if ILD/pneumonitis is suspected; permanently discontinue amivantamab if ILD/pneumonitis is confirmed.
The occurrence of a rash is common in patients treated with amivantamab, with a median time to onset of 14 days after administration; toxic epidermal necrolysis occurred in 1 patient in a multicenter, multicohort trial (n = 302). Instruct patients to limit sunlight (UV) exposure, use broad-spectrum UVA/UVB sunscreen, and wear protective clothing. Patients with dry skin may use alcohol-free emollient cream. If skin reactions develop, begin treatment with topical corticosteroids and topical and/or oral antibiotics; add oral steroids and consider a dermatologic consultation for grade 3 reactions. Promptly refer patients presenting with serious rash, atypical appearance or distribution, or lack of improvement within 2 weeks to a dermatologist. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary depending on the severity of the reaction.
Use amivantamab with caution in patients with a history of ocular disease. Amivantamab can cause ocular toxicity, including keratitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, and uveitis. Promptly refer patients presenting with ocular symptoms to an ophthalmologist. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for ocular adverse reactions.
Pregnancy should be avoided by females of reproductive potential during amivantamab treatment and for at least 3 months after the last dose. Although there are no adequately controlled studies in pregnant women or animals, amivantamab can cause fetal harm, developmental anomalies, or death based on its mechanism of action. Women who are pregnant or who become pregnant while receiving amivantamab should be apprised of the potential hazard to the fetus. In mice, EGFR is critically important in reproductive and developmental processes including blastocyst implantation, placental development, and embryofetal/postnatal survival and development. Reduction or elimination of embryofetal or maternal EGFR signaling can prevent implantation, can cause embryofetal loss during various stages of gestation, and can cause developmental anomalies and early death in surviving fetuses. Similarly, knock out of MET or its ligand HGF caused embryonic death due to severe defects in placental development; fetuses also displayed defects in muscle development in multiple organs. Human IgG1 is known to cross the placenta; therefore, amivantamab has the potential to be transmitted from the mother to the developing fetus.
Counsel patients about the reproductive risk and contraception requirements during amivantamab treatment. Amivantamab can cause fetal harm if taken by the mother during pregnancy. Females of reproductive potential should avoid pregnancy and use effective contraception during and for at least 3 months after treatment with amivantamab. Females of reproductive potential should undergo pregnancy testing prior to initiation of amivantamab. Women who become pregnant while receiving amivantamab should be apprised of the potential hazard to the fetus. There are no data regarding the effect of amivantamab on fertility.
Due to the potential for serious adverse reactions in nursing infants from amivantamab, advise women to discontinue breast-feeding during treatment and for 3 months after the final dose. It is not known whether amivantamab is present in human milk, although many drugs are excreted in human milk.
For the treatment of non-small cell lung cancer (NSCLC):
-for the first-line treatment of locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, in combination with carboplatin and pemetrexed:
NOTE: Patients should be selected based on the presence of EGFR exon 20 insertion mutations in tumor or plasma specimens. If no mutation is detected in a plasma specimen, test tumor tissue. Information on FDA-approved tests is available at www.fda.gov/CompanionDiagnostics.
Intravenous dosage:
Adults weighing 80 kg or more: 350 mg IV on day 1 of week 1; 1,400 mg IV on day 2 of week 1. On day 1 of weeks 2 through 4, administer amivantamab 1,750 mg IV once weekly; do not administer amivantamab during weeks 5 and 6. Beginning on day 1 of week 7, give amivantamab 2,100 mg IV every 3 weeks until disease progression or unacceptable toxicity. Dose adjustments are not required for subsequent body weight changes. Premedicate with diphenhydramine and acetaminophen prior to each dose of amivantamab; premedication with a glucocorticoid is only required on week 1 day 1 and 2 and after prolonged dose interruptions. Administer in combination with carboplatin (AUC 5 IV every 3 weeks for up to 12 cycles) and pemetrexed (500 mg/m2 IV every 3 weeks until disease progression or unacceptable toxicity). Infuse pemetrexed first, followed by carboplatin, and then amivantamab. Treatment with amivantamab, carboplatin, and pemetrexed significantly improved the median progression-free survival (PFS) compared with carboplatin and pemetrexed alone in patients with previously untreated locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations (11.4 months vs. 6.7 months). The objective response rate was 67% (complete response [CR], 4%) in the amivantamab plus chemotherapy arm compared with 36% (CR, 1%) in the chemotherapy alone arm, for a median duration of 10.1 months versus 5.6 months, respectively.
Adults weighing less than 80 kg: 350 mg IV on day 1 of week 1; 1,050 mg IV on day 2 of week 1. On day 1 of weeks 2 through 4, administer amivantamab 1,400 mg IV once weekly; do not administer amivantamab during weeks 5 and 6. Beginning on day 1 of week 7, give amivantamab 1,750 mg IV every 3 weeks until disease progression or unacceptable toxicity. Dose adjustments are not required for subsequent body weight changes. Premedicate with diphenhydramine and acetaminophen prior to each dose of amivantamab; premedication with a glucocorticoid is only required on week 1 day 1 and 2 and after prolonged dose interruptions. Administer in combination with carboplatin (AUC 5 IV every 3 weeks for up to 12 cycles) and pemetrexed (500 mg/m2 IV every 3 weeks until disease progression or unacceptable toxicity). Infuse pemetrexed first, followed by carboplatin, and then amivantamab. Treatment with amivantamab, carboplatin, and pemetrexed significantly improved the median progression-free survival (PFS) compared with carboplatin and pemetrexed alone in patients with previously untreated locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations (11.4 months vs. 6.7 months). The objective response rate was 67% (complete response [CR], 4%) in the amivantamab plus chemotherapy arm compared with 36% (CR, 1%) in the chemotherapy alone arm, for a median duration of 10.1 months versus 5.6 months, respectively.
-for the treatment of locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, with progression on or after platinum-based chemotherapy:
NOTE: Patients should be selected based on the presence of EGFR exon 20 insertion mutations in tumor or plasma specimens. If no mutation is detected in a plasma specimen, test tumor tissue. Information on FDA-approved tests is available at www.fda.gov/CompanionDiagnostics.
Intravenous dosage:
Adults weighing 80 kg or more: 350 mg IV on day 1 of week 1; 1,050 mg IV on day 2 of week 1. On day 1 of weeks 2 through 5, administer amivantamab 1,400 mg IV once weekly; do not administer amivantamab during week 6. Beginning on day 1 of week 7, give amivantamab 1,400 mg IV every 2 weeks until disease progression or unacceptable toxicity. Dose adjustments are not required for subsequent body weight changes. Premedicate with diphenhydramine and acetaminophen prior to each dose of amivantamab; premedication with a glucocorticoid is only required on week 1 day 1 and 2 and after prolonged dose interruptions. In a multicenter, open-label, multicohort clinical trial (CHRYSALIS), treatment with amivantamab resulted in an overall response rate of 40% (complete response, 3.7%) for a median duration of 11.1 months in 81 patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy; the duration of response was at least 6 months in 63% of patients. At a median follow-up time of 9.7 months, the median progression-free survival and overall survival times were 8.3 months and 22.8 months, respectively. In this trial, patients had received a median of 2 prior therapies.
Adults weighing less than 80 kg: 350 mg IV on day 1 of week 1; 700 mg IV on day 2 of week 1. On day 1 of weeks 2 through 5, administer 1,050 mg IV once weekly; do not administer amivantamab during week 6. Beginning on day 1 of week 7, give 1,050 mg IV every 2 weeks until disease progression or unacceptable toxicity. Dose adjustments are not required for subsequent body weight changes. Premedicate with diphenhydramine (25 mg to 50 mg) and acetaminophen (650 mg to 1,000 mg) prior to each dose of amivantamab. Additionally, administer either dexamethasone (10 mg IV) or methylprednisolone (40 mg IV) or equivalent prior to the initial 2 infusions of amivantamab (week 1, days 1 and 2); glucocorticoid premedication is optional for subsequent doses. In a multicenter, open-label, multicohort clinical trial (CHRYSALIS trial), treatment with amivantamab resulted in an overall response rate of 40% (complete response, 3.7%) for a median duration of 11.1 months in 81 patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy; the duration of response was at least 6 months in 63% of patients. At a median follow-up time of 9.7 months (range, 1.1 to 29.3 months), the median progression-free survival and overall survival times were 8.3 months and 22.8 months, respectively. In this trial, patients (median age, 62 years; range, 42 to 84 years) had received a median of 2 (range, 1 to 7) prior therapies.
Therapeutic Drug Monitoring:
Dosage Adjustments for Treatment-Related Toxicities:
Monotherapy
-First dose reduction: If the initial dose was 1,050 mg, reduce the dose to 700 mg. If the initial dose was 1,400 mg, reduce the dose to 1,050 mg.
-Second dose reduction: If the initial dose was 1,050 mg, reduce the dose to 350 mg. If the initial dose was 1,400 mg, reduce the dose to 700 mg.
-Subsequent reduction: Permanently discontinue amivantamab.
Combination therapy with Pemetrexed and Carboplatin
-First dose reduction: If the initial dose was 2,100 mg, reduce the dose to 1,750 mg.If the initial dose was 1,750 mg, reduce the dose to 1,400 mg.
-Second dose reduction: If the initial dose was 2,100 mg, reduce the dose to 1,400 mg. If the initial dose was 1,750 mg, reduce the dose to 1,050 mg.
-Subsequent reduction: Permanently discontinue amivantamab.
Dermatologic (including acneiform rash, pruritus, and dry skin)
-Grade 1: Initiate supportive care management including topical corticosteroids and topical and/or oral antibiotics. Alcohol-free emollient cream is recommended for dry skin. Reassess after 2 weeks.
-Grade 2: Initiate supportive care management including topical corticosteroids and topical and/or oral antibiotics. Alcohol-free emollient cream is recommended for dry skin. Reassess after 2 weeks; if the rash does not improve, consider a dose reduction of amivantamab.
-Grade 3: Hold amivantamab therapy and initiate supportive care management including topical corticosteroids, oral corticosteroids, and topical and/or oral antibiotics. Consider a dermatologic consultation. Upon recovery to grade 2 or less, resume amivantamab at a reduced dose. If there is no improvement in 2 weeks, permanently discontinue amivantamab.
-Grade 4 or severe bullous, blistering, or exfoliating skin conditions (e.g., toxic epidermal necrolysis): Permanently discontinue amivantamab.
Infusion-Related Reactions
-Grade 1 or 2: Interrupt the amivantamab infusion and monitor until symptoms resolve. Resume the infusion at 50% of the infusion rate at which the reaction occurred. After 30 minutes, if there are no additional symptoms the infusion rate may be escalated. Include corticosteroids with the premedications for the subsequent dose.
-Grade 3: Interrupt the amivantamab infusion and administer supportive care medications; continuously monitor until symptoms resolve. Resume the infusion at 50% of the infusion rate at which the reaction occurred. After 30 minutes, if there are no additional symptoms the infusion rate may be escalated. Include corticosteroids with the premedications for the subsequent dose. Permanently discontinue amivantamab for recurrent grade 3 infusion-related reactions.
-Grade 4: Permanently discontinue amivantamab.
Interstitial Lung Disease (ILD) / Pneumonitis
-Any Grade: Hold amivantamab if ILD/pneumonitis is suspected. Permanently discontinue amivantamab if ILD/pneumonitis is confirmed.
Other Adverse Reactions
-Grade 3: Hold amivantamab therapy. Upon recovery to grade 1 or less, or baseline, resume amivantamab. If recovery occurs within 1 week, therapy may be resumed at the same dose. If recovery occurs after 1 week but within 4 weeks, resume treatment a reduced dose. If recovery does not occur within 4 weeks, permanently discontinue amivantamab.
-Grade 4: Hold amivantamab therapy. Upon recovery to grade 1 or less, or baseline, resume amivantamab. If recovery occurs within 4 weeks, resume treatment a reduced dose. If recovery does not occur within 4 weeks, permanently discontinue amivantamab. Permanently discontinue amivantamab for recurrent grade 4 adverse reactions.
Maximum Dosage Limits:
-Adults
Weight of less than 80 kg: 1,750 mg IV.
Weight of 80 kg or more: 2,100 mg IV.
-Geriatric
Weight of less than 80 kg: 1,750 mg IV.
Weight of 80 kg or more: 2,100 mg IV.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed. The pharmacokinetics of amivantamab have not been studied in patients with moderate (total bilirubin 1.5 to 3 times the upper limit of normal [ULN]) to severe (total bilirubin greater than 3 times ULN) hepatic impairment.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. The pharmacokinetics of amivantamab have not been studied in patients with severe renal impairment (CrCl 15 to 29 mL/min).
*non-FDA-approved indication
Cholera Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the live cholera vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to cholera bacteria after receiving the vaccine.
Dengue Tetravalent Vaccine, Live: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the dengue virus vaccine. When feasible, administer indicated vaccines at least 2 weeks prior to initiating immunosuppressant medications. If vaccine administration is necessary, consider revaccination following restoration of immune competence. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure after receiving the vaccine.
SARS-CoV-2 (COVID-19) vaccines: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Adenovirus Vector Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) mRNA Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
SARS-CoV-2 Virus (COVID-19) Recombinant Spike Protein Nanoparticle Vaccine: (Moderate) Patients receiving immunosuppressant medications may have a diminished response to the SARS-CoV-2 virus vaccine. When feasible, administer indicated vaccines prior to initiating immunosuppressant medications. Counsel patients receiving immunosuppressant medications about the possibility of a diminished vaccine response and to continue to follow precautions to avoid exposure to SARS-CoV-2 virus after receiving the vaccine.
Amivantamab is a low-fucose human immunoglobulin G1-based bispecific antibody that binds to the extracellular domains of EGFR and MET. In vitro and in vivo, amivantamab was able to disrupt EGFR and MET signaling functions through blocking ligand binding and, in exon 20 insertion mutation models, 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 (e.g., natural killer cells and macrophages) through antibody-dependent cellular cytotoxicity and trogocytosis mechanisms, respectively.
Amivantamab is administered intravenously. Exposure increases proportionally over a dose range of 350 mg to 1,750 mg (0.25 to 1.25 times the maximum recommended dose). Steady-state was achieved by the 9th infusion; the accumulation ratio at steady-state was 2.4. The mean volume of distribution of amivantamab is 5.13 liters (+/- 1.78 liters). The mean clearance of amivantamab is 360 mL/day (+/- 144 mL/day) and the terminal half-life is 11.3 days (+/- 4.53 days).
Affected cytochrome P450 isoenzymes and drug transporters:
Formal drug interaction studies have not been conducted with amivantamab.
-Special Populations
Hepatic Impairment
Mild hepatic impairment (total bilirubin less than or equal to the upper limit of normal [ULN] and AST greater than ULN; or total bilirubin greater than ULN but less than or equal to 1.5 times ULN) did not have a clinically meaningful effect on the pharmacokinetics of amivantamab. The pharmacokinetics of amivantamab have not been studied in patients with moderate to severe hepatic impairment (total bilirubin 1.5 times ULN or higher).
Renal Impairment
Mild to moderate renal impairment (CrCl 30 mL/min or higher) did not have a clinically meaningful effect on the pharmacokinetics of amivantamab. The pharmacokinetics of amivantamab have not been studied in patients with severe renal impairment (CrCl 15 to 29 mL/min).
Geriatric
Age (32 to 87 years) did not have a clinically meaningful effect on the pharmacokinetics of amivantamab.
Gender Differences
Sex did not have a clinically meaningful effect on the pharmacokinetics of amivantamab.
Ethnic Differences
Race did not have a clinically meaningful effect on the pharmacokinetics of amivantamab.
Obesity
Increased body weight increases the volume of distribution and clearance of amivantamab. Amivantamab exposure was 30% to 40% lower in patients weighing 80 kg or more compared to patients weighing less than 80 kg at the same dose; exposure was comparable between patients weighing less than 80 kg who received 1,050 mg and patients weighing 80 kg or more who received 1,400 mg.