Amivantamab, a human immunoglobulin G1-based bispecific antibody directed against the epidermal growth factor receptor (EGFR) and the mesenchymal-epithelial transition (MET) receptor, is an antineoplastic agent.1
Amivantamab-vmjw is used in several clinical scenarios involving adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC).1 It is used in combination with lazertinib for the first-line treatment of patients whose tumors harbor epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations (as detected by an FDA-approved test).1 Additionally, it is used in combination with carboplatin and pemetrexed for patients with exon 19 deletions or exon 21 L858R substitution mutations whose disease has progressed following treatment with an EGFR tyrosine kinase inhibitor.1 For patients with EGFR exon 20 insertion mutations (as detected by an FDA-approved test), the treatment is used both in combination with carboplatin and pemetrexed as a first-line therapy, and as a single agent for those whose disease has progressed after platinum-based chemotherapy.1
Information about FDA-approved tests to detect EGFR exon mutations is available at [Web].1
NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations
The efficacy and safety of amivantamab-vmjw in combination with lazertinib as a first-line therapy for the treatment of NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations were evaluated in the MARIPOSA trial, a randomized, active-controlled, multicenter, phase 3 trial.1, 11 Eligible patients had not received prior systemic therapy for advanced disease and had confirmed EGFR exon 19 deletion or exon 21 L858R substitution mutations based on local testing.1 Patients with untreated, symptomatic brain metastases or those requiring urgent local therapy were excluded, although those with treated and stable intracranial metastases were eligible.1, 11 Patients were randomized in a 2:2:1 ratio to receive either amivantamab-vmjw (administered IV at 1050 mg for patients weighing <80 kg or 1400 mg for those weighing ≥80 kg once weekly for 4 weeks, then every 2 weeks) plus lazertinib (240 mg orally once daily), osimertinib monotherapy (80 mg orally once daily), or lazertinib monotherapy (an unapproved regimen for NSCLC).1, 11 Treatment continued until disease progression or unacceptable toxicity occurred.1, 11 Randomization was stratified by EGFR mutation type, Asian race, and history of brain metastasis.1, 11 Tumor assessments were conducted every 8 weeks for 30 months, then every 12 weeks thereafter.1, 11
The primary efficacy endpoint was progression-free survival (PFS) as assessed by Blinded Independent Central Review (BICR); additional endpoints included overall survival (OS), overall response rate (ORR), and duration of response (DOR).1, 11 The efficacy population included 858 patients (429 in the amivantamab-vmjw plus lazertinib arm and 429 in the osimertinib arm), with a median age of 63 years (range, 25-88 years).1, 11 Among these, 61% were female, 58% were Asian, 38% were white, and 12% were Hispanic or Latino; 69% were never-smokers, and 89% were diagnosed with stage IV NSCLC at baseline.1, 11 EGFR mutation distribution included 60% with exon 19 deletions and 40% with exon 21 L858R substitution mutations.1 The median PFS duration was longer in the amivantamab-lazertinib group than in the osimertinib group (23.7 versus 16.6 months).1, 11 The ORR was 78% among patients treated with the amivantamab-lazertinib combination and 73% among those treated with osimertinib; the median DOR was 25.8 months and 16.8 months, respectively.1, 11 In a planned interim OS analysis of amivantamab-lazertinib as compared with osimertinib, no trend towards a detriment was observed.1, 11
The efficacy and safety of amivantamab-vmjw used in combination with carboplatin and pemetrexed for the treatment of NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations in patients whose disease has progressed following treatment with an EGFR tyrosine kinase inhibitor were evaluated in the MARIPOSA-2 trial, a randomized, open-label, multicenter, phase 3 trial.1, 12 Patients were eligible for enrollment if they had confirmed EGFR exon 19 deletion or exon 21 L858R substitution mutations and experienced disease progression after treatment with osimertinib; patients with asymptomatic or previously treated and stable brain metastases were permitted to enroll.1, 12 Patients were randomized in a 1:2:2 ratio to receive amivantamab-vmjw plus carboplatin and pemetrexed (amivantamab-CP), carboplatin plus pemetrexed alone (CP), or amivantamab-vmjw as part of another combination regimen.1, 12 Amivantamab-vmjw was administered IV at 1400 mg for patients weighing <80 kg or 1750 mg for those weighing ≥80 kg once weekly for the first 4 weeks; beginning at week 7, doses were increased to 1750 mg or 2100 mg, respectively, and given every 3 weeks thereafter until disease progression or unacceptable toxicity occurred.1, 12 Carboplatin was administered IV every 3 weeks at an AUC of 5 mg/mL per minute for up to 12 weeks, and pemetrexed was given IV at 500 mg/m² every 3 weeks until progression or intolerance occurred in both treatment arms.1, 12 Randomization was stratified by prior line of osimertinib therapy, history of brain metastases, and Asian race.1, 12 Tumor assessments were conducted every 6 weeks for the first 12 months and every 12 weeks thereafter.1, 12
The primary efficacy endpoint was PFS, as evaluated by a BICR, while OS and ORR were key secondary endpoints.1, 12 The efficacy population included 394 patients (131 in the amivantamab-CP arm and 263 in the CP arm), with a median age of 62 years (range, 31-85 years).1 Among these, 60% were female, 48% were Asian, 46% were white, and 8% were Hispanic or Latino; additional racial groups included 1% American Indian or Alaska Native and 1% Black or African American.1 Sixty-five percent of patients were never-smokers, 45% had a history of brain metastases, and 99.7% had stage IV NSCLC at baseline.1 At the time of analysis, treatment with amivantamab-CP resulted in a longer median PFS (6.3 months) compared with CP alone (4.2 months).1, 12 The ORR was higher for the amivantamab-CP arm (53%) versus CP alone (29%); the median DOR was 6.9 months and 5.6 months, respectively.1 There was no substantial difference in OS between groups.1, 12
NSCLC with EGFR Exon 20 Insertion Mutations
The efficacy and safety of amivantamab-vmjw used in combination with carboplatin and pemetrexed as a first-line therapy for the treatment of locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations are supported by findings from PAPILLON, a randomized, open-label, multicenter, phase 3 study.1, 13 Eligible patients had previously untreated, locally advanced or metastatic NSCLC with confirmed EGFR exon 20 insertion mutations, measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate organ and bone marrow function.1, 13 Patients with brain metastases at screening were eligible if they received definitive treatment and were clinically stable, asymptomatic, and off corticosteroids for at least 2 weeks prior to randomization.1 Patients with a history or presence of active interstitial lung disease (ILD) were excluded.1, 13 A total of 308 patients were randomized in a 1:1 ratio to receive either amivantamab-CP (n=153) or CP (n=155).1, 13 Amivantamab-vmjw was administered IV at 1400 mg for patients weighing <80 kg or 1750 mg for those ≥80 kg once weekly for the first 4 weeks.1, 13 Beginning in week 7, dosing increased to 1750 mg or 2100 mg, respectively, and continued every 3 weeks until disease progression or unacceptable toxicity occurred.1, 13 Carboplatin was administered every 3 weeks at an AUC of 5 mg/mL per minute for up to 12 weeks, and pemetrexed was administered at 500 mg/m² every 3 weeks until progression or unacceptable toxicity occurred.1, 13 Patients were stratified based on ECOG performance status and history of brain metastases.1, 13
The primary endpoint was PFS, assessed by BICR, while secondary efficacy outcomes included ORR, DOR, and OS.1, 13 Patients in the CP arm with confirmed disease progression were permitted to cross over to receive single-agent amivantamab-vmjw.1, 13 The median age of patients was 62 years (range: 27-92 years), with 40% aged 65 years or older.1 Among the study population, 58% were female, 61% were Asian, and 36% were white; 0.7% were Black or African American.1 At baseline, ECOG performance status was 0 in 35% of patients and 1 in 65%; 58% were never-smokers, 23% had a history of brain metastases, and 84% were diagnosed with stage IV disease.1 Progression-free survival was longer in the amivantamab-CP arm compared to the CP arm (median, 11.4 months and 6.7 months, respectively).1, 13 The ORR was higher for the amivantamab-CP arm (67%) versus CP alone (36%); the median DOR was 10.1 months and 5.6 months, respectively.1 There was no substantial difference in OS between groups.1, 13 Seventy-five patients (48% of those treated) transitioned from the CP arm to receive amivantamab-vmjw monotherapy following confirmed disease progression.1
The efficacy and safety of amivantamab-vmjw for the treatment of locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations in patients whose disease has progressed on or after platinum-based chemotherapy are based primarily on the results of the phase I, open-label, multicenter, multi-cohort, CHRYSALIS trial.1, 2 The study evaluated a subset of patients with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy.1, 2 Patients with untreated brain metastases or a history of ILD that required treatment with steroids or immunosuppressants within the prior 2 years were excluded.1 Patients in the EGFR exon 20 insertion mutation cohort received amivantamab-vmjw monotherapy (1050 mg in those with body weight <80 kg or 1400 mg in those with body weight ≥80 kg) once weekly for 4 weeks, then every 2 weeks thereafter until disease progression or unacceptable toxicity.1, 2
The major efficacy outcome was ORR according to RECIST v1.1 as evaluated by BICR; DOR by BICR was also assessed.1 The median age of patients was 62 years (range: 42-84), with 59% being female.1 Among the study population, 49% were Asian, 37% were white, and 2.5% were Black.1 Seventy-four percent of patients had a baseline body weight <80 kg, and 95% had adenocarcinoma histology.1 At study entry, 46% received prior immunotherapy, and the median number of previous treatments was 2 (range: 1-7).1 Baseline ECOG performance status was 1 in 67% of patients, 53% were never-smokers, all had metastatic disease, and 22% had a history of previously treated brain metastases.1 The efficacy population included 81 patients with a median follow-up of 9.7 months (range 1.1-29.3 months).2 At baseline, the median time from initial diagnosis was 17 months in the efficacy population; 95% of patients had adenocarcinoma, and 22% had previously treated brain metastases.1, 2 All patients had previously received platinum-based chemotherapy; 46% received prior immunotherapy and 25% received prior EGFR tyrosine kinase inhibitor therapy.2 The ORR with amivantamab was 40%.1, 2 Disease progression or death occurred in 47 patients (58%).2 Complete response and partial response occurred in 3.7% and 36% of patients, respectively.2 Median PFS, DOR, and OS were 8.3 months, 11.1 months, and 22.8 months, respectively.2 A DOR of ≥6 months occurred in 63% of patients.1
EGFR-activating mutations are present in approximately 15-22% of NSCLC cases in North America and Europe and are present in up to 30-50% of cases in patients of East Asian descent.100 The majority of EGFR mutations are exon 19 deletions and an L858R substitution in exon 21, which together account for about 90% of EGFR mutations in patients with NSCLC.101 EGFR mutations are identified in a large proportion of NSCLC cases in nonsmokers (49.3%), female patients (43.7%), and those with adenocarcinoma histology (38%).102
The American Society of Clinical Oncology (ASCO) 2024 guideline specifically addresses treatment of stage IV NSCLC harboring driver alterations such as EGFR mutations.103 Clinicians may consider offering either osimertinib with platinum-based doublet chemotherapy or the combination of amivantamab and lazertinib as first-line treatment options for patients with EGFR exon 19 deletion or L858R-positive NSCLC.103 To note, combination regimens tend to carry a higher risk of toxicity compared to osimertinib monotherapy.103 For instance, 75% of patients receiving amivantamab plus lazertinib and 64% of those on osimertinib with chemotherapy experienced grade ≥3 adverse events, compared to 43% and 27%, respectively, in patients treated with osimertinib alone.103 Regarding second-line therapy for patients who experience disease progression on osimertinib or other EGFR tyrosine kinase inhibitors without the development of a T790M mutation or other actionable genetic alterations, clinicians may consider offering platinum-based chemotherapy, with or without the addition of amivantamab.103
For EGFR exon 20 insertions, clinicians may offer chemotherapy and amivantamab; if amivantamab is not available, clinicians should offer standard treatment following the non-driver alteration guideline.103 Regarding second line therapy for EGFR exon 20 insertions, clinicians may offer treatment with amivantamab in patients with an exon 20 insertion alteration who have received prior treatment with platinum chemotherapy.103
Indication | Treatment Regimen | Source for Testing |
|---|---|---|
First-line treatment of NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations | Amivantamab-vmjw in combination with lazertinib | Tumor or plasma specimens Testing may be performed at any time from initial diagnosis Testing does not need to be repeated once EGFR mutation status has been confirmed |
Previously treated locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations (progressive disease on an EGFR tyrosine kinase inhibitor) | Amivantamab-vmjw in combination with carboplatin and pemetrexed | Tumor or plasma specimens Testing may be performed at any time from initial diagnosis Testing does not need to be repeated once EGFR mutation status has been confirmed |
First-line treatment of NSCLC with EGFR exon 20 insertion mutations | Amivantamab-vmjw in combination with carboplatin and pemetrexed | Tumor or plasma specimens Testing may be performed at any time from initial diagnosis Testing does not need to be repeated once EGFR mutation status has been confirmed |
Previously treated NSCLC with EGFR exon 20 insertion mutations | Amivantamab-vmjw as a single agent | Tumor or plasma specimens Testing may be performed at any time from initial diagnosis Testing does not need to be repeated once EGFR mutation status has been confirmed |
Medication | Dose | Route and Timing of Administration |
|---|---|---|
Antihistamine | Diphenhydramine (25 to 50 mg) or equivalent | Administer IV 15-30 minutes prior to administration of amivantamab or orally 30-60 minutes prior to administration of amivantamab |
Antipyretic | Acetaminophen (650 to 1000 mg) | Administer IV 15-30 minutes prior to administration of amivantamab or orally 30-60 minutes prior to administration of amivantamab |
Glucocorticoid a | Dexamethasone (20 mg or equivalent) | Administer IV 45-60 minutes prior to administration of amivantamab |
Glucocortiocoidb | Dexamethasone (10 mg or equivalent) | Administer IV 45-60 minutes prior to administration of amivantamab |
aRequired at initial dose (week 1 day 1).
bRequired at second dose (week 1 day 2); optional for subsequent doses.
Amivantamab-vmjw is administered as an IV infusion after dilution.1 Administer IV infusions as described in Tables 3 and 4.1 During weeks 1 and 2, administer the infusion via a peripheral line due to the potential for infusion-related reactions during therapy initiation.1 Starting in week 3, amivantamab may be administered with a central line.1 Administer amivantamab-vmjw as a single agent or in combination with lazertinib every 2 weeks IV according to the infusion rates in Table 3.1
Administer amivantamab-vmjw in combination with carboplatin and pemetrexed infusions every 3 weeks IV according to the infusion rates in Table 4.1 Administer amivantamab-vmjw with an infusion set made of polyurethane, polybutadiene, polyvinyl chloride (PVC), polypropylene (PP), or polyethylene (PE) that contains a flow regulator and an in-line, sterile, non-pyrogenic, low protein-binding polyethersulfone 0.2 micron filter.1 Prime the infusion set with either 5% dextrose or 0.9% sodium chloride only.1 Do not infuse concurrently in the same IV line as other medications.1
Store amivantamab-vmjw vials in a refrigerator at 2-8°C in the original carton to protect from light.1 Do not freeze.1
Determine the dose required and number of amivantamab-vmjw vials needed based on the patient's baseline weight.1 Dilute amivantamab-vmjw injection in 250 mL of 5% dextrose or 0.9% sodium chloride injection.1 Remove and discard an amount of 5% dextrose Injection or 0.9% sodium chloride Injection from the 250 mL infusion bag that matches the volume of amivantamab-vmjw to be added (for example, discard 7 mL of diluent from the bag for each vial of amivantamab-vmjw).1 The final volume in the infusion bag should be 250 mL.1 The infusion bag must be made of one of the following materials PVC, PP, PE, or polyolefin blend (PP + PE).1 Administer the diluted solution within 10 hours (inclusive of the infusion time) at room temperature (15-25°C).1
Amivantamab is compatible with 5% dextrose and 0.9% sodium chloride for dilution prior to IV infusion.1 No other compatibility information is available.1
Recommended infusion rates for amivantamab-vmjw administration are summarized in Tables 3 and 4.1
Week | Dose (per 250 mL bag) | Initial Infusion Rate (mL/hour) | Subsequent Infusion Rate (mL/hour)a |
|---|---|---|---|
Body Weight <80 kg | |||
Week 1, Day 1 (split dose infusion) | 350 mg | 50 | 75 |
Week 1, Day 2 (split dose infusion) | 700 mg | 50 | 75 |
Week 2 | 1050 mg | 85 | 85 |
Week 3 | 1050 mg | 125 | 125 |
Week 4 | 1050 mg | 125 | 125 |
Week 5 | 1050 mg | 125 | 125 |
Week 6 | No dose administered | ||
Weeky 7 and every 2 weeks thereafter | 1050 mg | 125 | 125 |
Body Weight ≥80 kg | |||
Week 1, Day 1 (split dose infusion) | 350 mg | 50 | 75 |
Week 1, Day 2 (split dose infusion) | 1050 mg | 35 | 50 |
Week 2 | 1400 | 65 | 65 |
Week 3 | 1400 | 85 | 85 |
Week 4 | 1400 | 125 | 125 |
Week 5 | 1400 | 125 | 125 |
Week 6 | No dose administered | ||
Week 7 and every 2 weeks thereafter | 1400 mg | 125 | 125 |
aIn the absence of infusion-related reactions, increase the initial infusion rate to the subsequent infusion rate after 2 hours based on patient tolerance. Total infusion time is approximately 4-6 hours for day 1 and 6-8 hours for day 2. Subsequent infusion time is approximately 2 hours.
Week | Dose (per 250 mL bag) | Infusion Rate (mL/hour) | Subsequent Infusion Rate (mL/hour)a |
|---|---|---|---|
Body Weight (<80 kg) | |||
Week 1, Day 1 (split dose infusion) | 350 mg | 50 | 75 |
Week 1, Day 2 (split dose infusion) | 1050 mg | 33 | 50 |
Week 2 | 1400 mg | 65 | 65 |
Week 3 | 1400 mg | 85 | 85 |
Week 4 | 1400 mg | 125 | 125 |
Weeks 5 and 6 | No dose administered | ||
Week 7 and every 3 weeks thereafter | 1750 mg | 125 | 125 |
Body Weight ≥80 kg | |||
Week 1, Day 1 (split dose infusion) | 350 mg | 50 | 75 |
Week 1, Day 2 (split dose infusion) | 1400 mg | 25 | 50 |
Week 2 | 1750 mg | 65 | 65 |
Week 3 | 1750 mg | 85 | 85 |
Week 4 | 1750 mg | 125 | 125 |
Weeks 5 and 6 | No dose administered | ||
Week 7 and every 3 weeks thereafter | 2100 mg | 125 | 125 |
aIn the absence of infusion-related reactions, increase the initial infusion rate to the subsequent infusion rate after 2 hours based on patient tolerance. Total infusion time is approximately 4-6 hours for day 1 and 6-8 hours for day 2. Subsequent infusion time is approximately 2 hours.
When administering amivantamab-vmjw with lazertinib, give lazertinib orally at any time before the amivantamab-vmjw infusion.1 Administer amivantamab-vmjw any time after lazertinib when given on the same day.1 Refer to the lazertinib prescribing information for recommended lazertinib dosing information.1
When administering amivantamab-vmjw with carboplatin and pemetrexed, administer pemetrexed first, followed by carboplatin, and then infuse amivantamab-vmjw last.1
Non-small Cell Lung Cancer (NSCLC)
NSCLC with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations : The recommended adult dose of amivantamab-vmjw in combination with lazertinib as a first-line therapy for the treatment of NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations is based on baseline body weight.1 Recommended dosage is summarized in Table 5.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Body Weight (kg) at Baselinea | Recommended Dose | Dosing Schedule |
|---|---|---|
<80 | 1050 mg | Weekly (total of 5 doses) from weeks 1 to 5 Week 1: Split infusion on day 1 and day 2 Weeks 2 to 5: Infusion on day 1 Week 6: No dose Then every 2 weeks starting at week 7 onwards |
≥80 | 1400 mg | Weekly (total of 5 doses) from weeks 1 to 5 Week 1: Split infusion on day 1 and day 2 Weeks 2 to 5: Infusion on day 1 Week 6: No dose Then every 2 weeks starting at week 7 onwards |
aDose adjustment is not required for subsequent body weight change.
The recommended adult dose of amivantamab-vmjw used in combination with carboplatin and pemetrexed for the treatment of NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations in patients whose disease has progressed following treatment with an EGFR tyrosine kinase inhibitor is based on baseline body weight.1 Recommended dosage is summarized in Table 6.1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1 The recommended order of administration and regimen for amivantamab-vmjw in combination with carboplatin and pemetrexed are provided within the manufacturer's prescribing information.1
Body Weight (kg) at Baseline a | Recommended Dose | Dosing Schedule |
|---|---|---|
<80 | 1400 mg | Weekly (total of 4 doses) from weeks 1 to 4 Week 1: Split infusion on day 1 and day 2 Weeks 2 to 4: Infusion on day 1 Weeks 5 and 6: No dose |
1750 mg | Every 3 weeks starting at week 7 onwards | |
≥80 | 1750 mg | Weekly (total of 4 doses) from weeks 1 to 4 Week 1: Split infusion on day 1 and day 2 Weeks 2 to 4: Infusion on day 1 Weeks 5 and 6: No dose |
2100 mg | Every 3 weeks starting at week 7 onwards |
aDose adjustment is not required for subsequent body weight change.
NSCLC with EGFR Exon 20 Insertion Mutations : The recommended adult dose of amivantamab-vmjw, when used as a single agent for the treatment of locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations that has progressed on or after platinum-based chemotherapy is based on baseline body weight (see Table 7).1 Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Body Weight (kg) at Baseline a | Recommended Dose | Dosing Schedule |
|---|---|---|
<80 | 1050 mg | Weekly (total of 5 doses) from weeks 1 to 5 Week 1: Split infusion on day 1 and day 2 Weeks 2 to 5: Infusion on day 1 Week 6: No dose Then every 2 weeks starting at week 7 onwards |
≥80 | 1400 mg | Weekly (total of 5 doses) from weeks 1 to 5 Week 1: Split infusion on day 1 and day 2 Weeks 2 to 5: Infusion on day 1 Week 6: No dose Then every 2 weeks starting at week 7 onwards |
aDose adjustment is not required for subsequent body weight change
The recommended adult dose of amivantamab-vmjw used in combination with carboplatin and pemetrexed as a first-line therapy for the treatment of locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations is based on baseline body weight (see Table 8).1 The recommended order of administration and regimen for amivantamab-vmjw in combination with carboplatin and pemetrexed are provided within the manufacturer's prescribing information.1
Therapy should be continued until disease progression or unacceptable toxicity occurs.1
Body Weight (kg) at Baseline a | Recommended Dose | Dosing Schedule |
|---|---|---|
<80 | 1400 mg | Weekly (total of 4 doses) from weeks 1 to 4 Week 1: Split infusion on day 1 and day 2 Weeks 2 to 4: Infusion on day 1 Weeks 5 and 6: No dose |
1750 mg | Every 3 weeks starting at week 7 onwards | |
≥80 | 1750 mg | Weekly (total of 4 doses) from weeks 1 to 4 Week 1: Split infusion on day 1 and day 2 Weeks 2 to 4: Infusion on day 1 Weeks 5 and 6: No dose |
2100 mg | Every 3 weeks starting at week 7 onwards |
aDose adjustment is not required for subsequent body weight change.
Dosage Modification for Toxicity
If adverse effects occur during amivantamab-vmjw therapy, temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of the drug may be necessary.1 If dosage modification is required, the dosage of amivantamab-vmjw should be reduced as described in Table 9.1
Dose at Which the Adverse Reaction Occurred | First Dose Reduction | Second Dose Reduction | Third Dose Reduction |
|---|---|---|---|
1050 mg | 700 mg | 350 mg | Discontinue |
1400 mg | 1050 mg | 700 mg | Discontinue |
1750 mg | 1400 mg | 1050 mg | Discontinue |
2100 mg | 1750 mg | 1400 mg | Discontinue |
Temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of amivantamab-vmjw may be necessary in patients experiencing certain adverse effects as described in Table 10.1 When amivantamab-vmjw is used in combination with lazertinib, and an adverse reaction necessitates a dosage reduction after withholding treatment and resolution of the reaction, the amivantamab-vmjw dose should be reduced first.1 For guidance on modifying the dose of lazertinib, consult its prescribing information.1 For patients receiving amivantamab-vmjw alongside carboplatin and pemetrexed, dosage changes may be needed for one or more of these medications.1 Amivantamab-vmjw should be withheld or discontinued according to the guidelines in Table 10.1 Refer to the prescribing information for carboplatin and pemetrexed for further details on dosage adjustments.1
Adverse reaction and severity | Dosage modifications and management |
|---|---|
Infusion-related reactions (Grade 1 to 2) | Stop infusion and monitor until symptom resolution. Resume infusion at 50% of the infusion rate at which the reaction occurred. Increase the infusion rate if there are no additional symptoms after 30 minutes. Give corticosteroid premedication before subsequent infusions. |
Infusion-related reactions (Grade 3) | Stop infusion and administer supportive care medications. Monitor until resolution of symptoms. Resume infusion at 50% of the infusion rate at which the reaction occurred. Increase the infusion rate if there are no additional symptoms after 30 minutes. Give corticosteroid premedication before subsequent infusions. Permanently discontinue for recurrent Grade 3 infusion-related reactions. |
Infusion-related reactions (Grade 4 or any grade anaphylaxis/anaphylactic reactions) | Permanently discontinue therapy. |
Interstitial lung disease/pneumonitis (any grade) | Withhold therapy if interstitial lung disease/pneumonitis is suspected and permanently discontinue if confirmed. |
Venous thromboembolic events (Grade 2 or 3; applies to the combination with lazertinib) | Withhold amivantamab-vmjw and lazertinib therapy. Administer anticoagulant treatment as clinically indicated. Once anticoagulant treatment has been initiated, resume amivantamab-vmjw and lazertinib at the same dose level, at the discretion of the healthcare provider |
Venous thromboembolic events (Grade 4 or recurrent Grade 2 or 3 despite therapeutic level anticoagulation; applies to the combination with lazertinib) | Withhold lazertinib and permanently discontinue amivantamab-vmjw therapy. Administer anticoagulant treatment as clinically indicated. Once anticoagulant treatment has been initiated, resume lazertinib at the same dose level, at the discretion of the healthcare provider |
Dermatologic adverse reactions including dermatitis acneiform, pruritus, dry skin (Grade 1 or 2) | Provide supportive care. Consider dose reduction if rash does not improve after 2 weeks. |
Dermatologic adverse reactions (Grade 3) | Withhold therapy and provide supportive care. Resume therapy at a reduced dose upon recovery to ≤Grade 2. Permanently discontinue therapy if there is no improvement within 2 weeks. |
Dermatologic adverse reactions (Grade 4) | Permanently discontinue therapy. |
Dermatologic adverse reactions (severe bullous, blistering or exfoliating skin conditions including toxic epidermal necrolysis [TEN]) | Permanently discontinue therapy. |
Other adverse reactions (Grade 3) | Withhold therapy until recovery to ≤Grade 1 or baseline. Resume at the same dose if recovery occurs in <1 week. Resume at a reduced dose if recovery occurs after 1 but within 4 weeks. Permanently discontinue therapy if recovery does not occur within 4 weeks. |
Other adverse reactions (Grade 4) | Withhold therapy until recovery to ≤Grade 1 or baseline. Resume at a reduced dose if recovery occurs within 4 weeks. Permanently discontinue therapy if recovery does not occur within 4 weeks. Permanently discontinue therapy for recurrent Grade 4 reactions. |
The manufacturer makes no specific dosage recommendations for hepatic impairment.1
The manufacturer makes no specific dosage recommendations for renal impairment.1
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Amivantamab-vmjw can cause infusion-related reactions (IRRs), including anaphylaxis; signs and symptoms of IRR include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting.1 Median time to IRR onset is approximately 1 hour.1
In the CHRYSALIS study, IRRs occurred in 66% of patients in the amivantamab-vmjw monotherapy safety population.1 Among patients receiving treatment on week 1 day 1, 65% experienced an IRR, while the incidence of IRRs was 3.4% with the day 2 infusion, and 0.4% with the week 2 infusion.1 With subsequent infusions, the cumulative IRR incidence was 1.1%.1 The majority of IRRs (97%) were grade 1-2, 2.2% were grade 3, and 0.4% were grade 4.1 The median time to onset was 1 hour (range 0.1-18 hours) after the start of the amivantamab infusion.1 The infusion was modified in 62% of patients who experienced an IRR and 1.3% of patients permanently discontinued amivantamab-vmjw due to an IRR.1
In the MARIPOSA study, IRRs were reported in 63% of patients receiving amivantamab-vmjw and lazertinib combination therapy.1 Among these, 5% experienced grade 3 reactions, and 1% had grade 4 reactions.1 Infusion adjustments due to IRRs were required in 54% of patients, while only 0.7% needed a dose reduction of amivantamab-vmjw as a result of IRRs.1 Additionally, 4.5% of patients permanently discontinued amivantamab-vmjw due to IRRs.1
According to pooled safety population data, IRRs occurred in 50% of patients receiving amivantamab-vmjw in combination with carboplatin and pemetrexed.1 Grade 3 IRRs were reported in 3.2% of patients.1 Infusion adjustments due to IRRs were necessary in 46% of cases, and 2.8% of patients discontinued amivantamab-vmjw permanently as a result of IRRs.1
To minimize IRRs, administer premedication with antihistamines, antipyretics, and glucocorticoids; in addition, follow the manufacturer's recommended instructions for administration of the drug including rate recommendations.1 Administer amivantamab-vmjw via a peripheral line during week 1 and week 2.1
Monitor for signs and symptoms of IRRs during amivantamab-vmjw infusions in a setting where cardiopulmonary resuscitation medication and equipment are available.1 Interrupt the amivantamab-vmjw infusion if IRR is suspected.1 Reduce the infusion rate or permanently discontinue amivantamab-vmjw based on IRR severity.1
Interstitial Lung Disease/Pneumonitis
Amivantamab can cause severe and fatal interstitial lung disease (ILD)/pneumonitis.1 In the CHRYSALIS study, ILD/pneumonitis occurred in 3.3% of amivantamab-vmjw monotherapy patients in the safety population, with 0.7% of patients experiencing grade 3 ILD/pneumonitis.1 Three patients (1%) discontinued amivantamab-vmjw due to this adverse reaction.1
In the MARIPOSA study, ILD or pneumonitis was reported in 3.1% of patients treated with amivantamab-vmjw in combination with lazertinib.1 This included grade 3 events in 1% of patients and grade 4 events in 0.2%.1 There was one death attributed to ILD/pneumonitis, and 2.9% of patients permanently discontinued both amivantamab-vmjw and lazertinib due to this adverse reaction.1
From pooled safety population data, 2.1% of patients receiving amivantamab-vmjw along with carboplatin and pemetrexed experienced ILD/pneumonitis.1 Grade 3 severity was noted in 1.8% of patients.1 Due to ILD/pneumonitis, 2.1% of patients discontinued amivantamab-vmjw treatment.1
Monitor patients for new or worsening symptoms of ILD/pneumonitis (e.g., dyspnea, cough, fever).1 Immediately hold amivantamab-vmjw in patients with suspected ILD/pneumonitis and permanently discontinue if confirmed.1
The combination of amivantamab-vmjw and lazertinib has been associated with serious and potentially fatal venous thromboembolic (VTE) events, such as deep vein thrombosis and pulmonary embolism.1 Most of these events occurred within the initial 4 months of treatment.1
In the MARIPOSA study, 36% of patients treated with this combination experienced VTEs, including grade 3 events in 10% and grade 4 in 0.5% of patients.1 Among patients receiving anticoagulation, 1.2% (n=5) still experienced VTEs during the study period.1 There were 2 VTE-related deaths (0.5%).1
VTEs resulted in treatment interruptions of amivantamab-vmjw in 9% of patients, dose reductions in 1%, and permanent discontinuation in 3.1%.1 The median time to VTE onset was 84 days, ranging from 6 to 777 days.1 Prophylactic anticoagulation is advised during the first 4 months of therapy.1 The use of vitamin K antagonists is not recommended.1 Patients should be monitored for symptoms of VTE and managed accordingly.1
Treatment with amivantamab-vmjw and lazertinib should be paused based on the severity of the VTE.1 After initiating anticoagulation, therapy with both drugs may be resumed at the same dose if deemed appropriate by the healthcare provider.1 If VTE recurs despite therapeutic anticoagulation, permanently discontinue amivantamab-vmjw; however, lazertinib may be continued at the current dose if the provider determines it is suitable.1 For additional information on lazertinib dose adjustments, consult lazertinib's prescribing information.1
Amivantamab-vmjw can cause severe rash (including toxic epidermal necrolysis [TEN]), dermatitis acneiform, pruritus, and dry skin.1 In the CHRYSALIS study, rash occurred in 74% of amivantamab-vmjw monotherapy patients in the safety population.1 The median time to onset of rash was 14 days (range 1-276 days).1 Grade 3 rash occurred in 3.3% of patients.1 Rash leading to dose reduction and permanent therapy discontinuation occurred in 5% and 0.7% of patients, respectively.1 Toxic epidermal necrolysis occurred in one amivantamab-treated patient.1
In the MARIPOSA trial, rash was reported in 86% of patients receiving amivantamab-vmjw in combination with lazertinib.1 Grade 3 rash occurred in 26% of these patients.1 The median time to rash onset was 14 days, with a range from 1 to 556 days.1 Rash led to treatment interruptions of amivantamab-vmjw in 37% of patients, dose reductions in 23%, and permanent discontinuation in 5%.1
In pooled safety population data, 82% of patients treated with amivantamab-vmjw plus carboplatin and pemetrexed experienced rash.1 Grade 3 rashes were seen in 15% of patients.1 Rash led to dose reductions in 14% of patients, while 2.5% discontinued amivantamab-vmjw and 3.1% stopped pemetrexed treatment permanently.1
Instruct patients to limit sun exposure, wear protective clothing, and use broad spectrum UVA/UVB sunscreen during and for 2 months after treatment with amivantamab.1 Alcohol-free (e.g., isopropanol-free, ethanol-free) emollient cream is recommended for dry skin to reduce the risk of dermatologic adverse reactions.1 Consider prophylactic measures (e.g., use of oral antibiotics) to reduce the risk of dermatologic adverse reactions.1
If a skin reaction develops, treat with topical corticosteroids and topical and/or oral antibiotics.1 For grade 3 reactions, add oral steroids and consider a dermatologic consultation.1 Promptly refer patients presenting with severe rash, atypical appearance or distribution, or lack of improvement within 2 weeks to a dermatologist.1 Withhold, dose reduce, or permanently discontinue amivantamab-vmjw depending on the severity of the dermatologic reaction.1
Amivantamab-vmjw can cause ocular toxicity including keratitis, blepharitis, dry eye, conjunctival redness, blurred vision, visual impairment, ocular itching, eye pruritus, and uveitis.1 In the CHRYSALIS study, keratitis occurred in 0.7% and uveitis occurred in 0.3% of amivantamab-vmjw monotherapy patients in the safety population.1 All ocular toxicity events were grades 1 or 2.1
In the MARIPOSA study, 16% of patients receiving amivantamab-vmjw in combination with lazertinib experienced ocular toxicity.1 Grade 3 or 4 ocular events were observed in 0.7% of patients.1 Depending on the severity, amivantamab-vmjw should be withheld, dose-adjusted, or permanently discontinued, while treatment with lazertinib may continue.1
According to data from the pooled safety population, 16% of patients treated with amivantamab-vmjw in combination with carboplatin and pemetrexed experienced ocular toxicity.1 All reported events were mild or moderate in severity (grade 1 or 2).1
Promptly refer patients with new or worsening eye symptoms to an ophthalmologist.1 Withhold, dose reduce, or permanently discontinue amivantamab-vmjw based on ocular toxicity severity.1
Fetal/Neonatal Morbidity and Mortality
Based on its mechanism of action and findings from animal models, amivantamab-vmjw can cause fetal harm when administered to a pregnant woman.1 Administration of other epidermal growth factor receptor (EGFR) inhibitor molecules to pregnant animals has resulted in an increased incidence of impaired embryofetal development, embryolethality, and abortion.1 Advise females of reproductive potential of the potential risk to the fetus.1 Advise female patients of reproductive potential to use effective contraception during treatment with amivantamab-vmjw and for 3 months after the final dose.1 If the drug is used during pregnancy, apprise patient of the potential fetal harm.1
Amivantamab-vmjw is a therapeutic protein with the potential for immunogenicity.1 Across clinical trials covering up to 39 months of treatment, 4 out of 1,862 patients (0.2%) who received amivantamab-vmjw, either alone or in combination, developed treatment-emergent anti-drug antibodies.1 Due to the very low incidence of these anti-amivantamab-vmjw antibodies, their impact on the drug's pharmacokinetics, safety, or effectiveness remains unclear.1
Amivantamab-vmjw may cause fetal harm if administered to pregnant women based on its mechanism of action and animal findings.1 Disruption or depletion of EGFR in animal models resulted in impairment of embryofetal development, including effects on placental, lung, cardiac, skin, and neural development.1
It is not known whether amivantamab-vmjw or its metabolites are distributed into human milk.1 The effects of the drug on breastfed infants or on the production of milk are unknown.1
Because of the potential for serious adverse reactions to amivantamab-vmjw in nursing infants, advise women not to breastfeed while receiving the drug and for 3 months after the final dose.1
Females and Males of Reproductive Potential
Prior to initiation of amivantamab-vmjw therapy, verify pregnancy status of females of reproductive potential and advise such females to use effective contraceptive methods while receiving amivantamab-vmjw and for 3 months after the last dose. 1
Safety and efficacy of amivantamab-vmjw have not been established in pediatric patients.1
In clinical trials, no overall differences in safety and efficacy were observed between geriatric patients (≥65 years of age) and younger adults.1
Clinically meaningful differences in the pharmacokinetics of amivantamab-vmjw were not observed in patients with mild hepatic impairment (total bilirubin ≥ upper limit of normal [ULN] and AST > ULN) or (ULN < total bilirubin ≥1.5 times ULN).1 The pharmacokinetics of amivantamab-vmjw have not been studied in patients with moderate to severe hepatic impairment (total bilirubin >1.5 times ULN and any AST).1
Clinically meaningful differences in the pharmacokinetics of amivantamab-vmjw were not observed in patients with mild or moderate renal impairment (estimated glomerular filtration rate [eGFR] 30 to 89 mL/min).1 The pharmacokinetics of amivantamab-vmjw have not been studied in patients with severe renal impairment (eGFR 15 to 29 mL/min) or end-stage renal disease (eGFR <15 mL/min).1
Adverse effects reported in ≥20% of patients receiving amivantamab-vmjw in combination with lazertinib include rash, nail toxicity, infusion-related reaction, musculoskeletal pain, stomatitis, edema, VTE, paresthesia, fatigue, diarrhea, constipation, COVID-19, hemorrhage, dry skin, decreased appetite, pruritus, nausea, and ocular toxicity.1
Grade 3 or 4 laboratory abnormalities reported in ≥2% of patients receiving amivantamab-vmjw in combination with lazertinib include decreased albumin, decreased sodium, increased ALT, decreased potassium, decreased hemoglobin, increased AST, increased GGT, and increased magnesium.1
Adverse effects reported in ≥20% of patients receiving amivantamab-vmjw in combination with carboplatin and pemetrexed include rash, nail toxicity, infusion-related reaction, fatigue, nausea, stomatitis, constipation, edema, decreased appetite, musculoskeletal pain, vomiting, and COVID-19.1
Grade 3 or 4 laboratory abnormalities reported in ≥2% of patients receiving amivantamab-vmjw in combination with carboplatin and pemetrexed include decreased neutrophils, decreased leukocytes, decreased platelets, decreased hemoglobin, decreased potassium, decreased sodium, increased ALT, increased GGT, and decreased albumin.1
Adverse effects reported in ≥20% of patients receiving amivantamab-vmjw monotherapy include rash, infusion-related reactions, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting.1
Grade 3 or 4 laboratory abnormalities reported in ≥2% of patients receiving amivantamab-vmjw monotherapy include decreased lymphocytes, decreased albumin, decreased phosphate, decreased potassium, increased alkaline phosphatase, increased glucose, increased GGT, and decreased sodium.1
Amivantamab-vmjw is a bispecific antibody that binds to the extracellular domains of epidermal growth factor receptor (EGFR) and the mesenchymal-epithelial transition (MET) receptor.1 In in vitro and in vivo studies, amivantamab-vmjw disrupted EGFR and MET signaling functions through blocking ligand binding in mutation models of exon 19 deletions, exon 21 L858R substitutions, and exon 20 insertions.1 The presence of EGFR and MET on the surface of tumor cells allows these cells to be targeted for destruction by immune effector cells, such as natural killer cells and macrophages, through antibody-dependent cellular cytotoxicity and trogocytosis mechanisms, respectively.1 In a mouse xenograft model of human non-small cell lung cancer (NSCLC) harboring the EGFR L858R mutation, the combination of amivantamab-vmjw and lazertinib demonstrated greater anti-tumor activity in vivo compared to either drug administered individually.1
Amivantamab-vmjw monotherapy exposure increased proportionally over the dose range of 350-1750 mg (0.33-1.7 times the approved recommended dosage, respectively).1 Steady-state levels of amivantamab-vmjw were achieved by week 13 for both the 2-week and 3-week dosing schedules, with a systemic accumulation ratio of 1.9.1 The mean terminal half-life of amivantamab-vmjw is 14 days.1
Amivantamab-vmjw pharmacokinetics do not appear to be affected by age (range 21-88 years), body weight (31-140 kg), sex, race, creatinine clearance, or mild hepatic impairment.1 Volume of distribution and clearance of amivantamab increase with increasing body weight.1 Amivantamab-vmjw exposure is 30-40% lower in patients with body weight ≥80 kg compared to patients with lower body weight.1 Exposure to amivantamab-vmjw was similar between patients with body weight <80 kg who received a dose of 1050 mg and patients with body weight ≥80 kg who received a dose of 1400 mg.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Amivantamab-vmjw is obtained through a specialty distribution network.9 Contact manufacturer or consult the Janssen Medical Information website ([Web]) for specific availability information.9
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection concentrate, for IV infusion | 50 mg/mL | Rybrevant® | Janssen Biotech |
AHFS® Drug Information. © Copyright, 1959-2026, Selected Revisions August 10, 2025. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Janssen Biotech, Inc. Rybrevant® (amivantamab) intravenous prescribing information. 2025 Feb. [Web]
2. Park K, Haura EB, Leighl NB, et al. Amivantamab in EGFR exon 20 insertion-mutated non-small-cell lung cancer progressing on platinum chemotherapy: initial results from the CHRYSALIS Phase I study [published online ahead of print, 2021 Aug 2]. J Clin Oncol . 2021;JCO2100662. [Web]
9. Janssen. Rybrevant specialty distributors. From Janssen Medical Information website. Accessed 2025 June 3. [Web]
11. Cho BC, Lu S, Felip E, et al. Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC. N Engl J Med. 2024;391(16):1486-1498.
12. Passaro A, Wang J, Wang Y, et al. Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study. Ann Oncol. 2024;35(1):77-90.
13. Zhou C, Tang KJ, Cho BC, et al. Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions. N Engl J Med. 2023;389(22):2039-2051.
100. Midha A, Dearden S, McCormack R. EGFR mutation incidence in non-small-cell lung cancer of adenocarcinoma histology: a systematic review and global map by ethnicity (mutMapII). Am J Cancer Res. 2015; 5:2892-911
101. Jotte RM, Spigel DR. Advances in molecular-based personalized non-small-cell lung cancer therapy: targeting epidermal growth factor receptor and mechanisms of resistance. Cancer Med. 2015; 4:1621-32
102. Zhang YL, Yuan JQ, Wang KF, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget. 2016; 7:78985-78993.
103. Dwight H. Owen et al. Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.3. J Clin Oncol. 2025;43(10):e2-e16.