Coverage Policy Manual
Policy #: 2021040
Category: Pharmacy
Initiated: August 2021
Last Review: August 2025
  Amivantamab-vmjw (e.g., Rybrevant)
Description:
Amivantamab-vmjw (e.g., Rybrevant) is an epidermal growth factor (EGF) and mesenchymal epithelial transition (MET) factor bispecific antibody that targets activating and resistant epidermal growth factor receptor (EGFR) exon 20 insertion mutations and MET mutations. Amivantamab is the first available treatment for individuals with EGFR exon 20 insertion mutations.
 
Non-small cell lung cancer (NSCLC) attributes to approximately 80-85% of all lung cancer cases; 2-3% of individuals with NSCLC have EFGR exon 20 insertion genetic mutations. Tumors with the EGFR exon 20 mutation are more aggressive than other types of EGFR tumor mutations.
 
Regulatory Status
 
Amivantamab-vmjw (e.g., Rybrevant) was approved by the U.S. Food and Drug Administration (FDA) on May 21, 2021, for the treatment of adult individuals with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease has progressed on or after platinum-based chemotherapy.
 
This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.
 
On August 19, 2024, the Food and Drug Administration approved amivantamab-vmjw (e.g., Rybrevant)  in combination with lazertinib for first-line treatment of adult individuals with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R substitution mutations, as detected by an FDA-approved test.
 
On September 19, 2024, the Food and Drug Administration approved a new indication for amivantamab-vmjw (e.g., Rybrevant) in combination with carboplatin and pemetrexed, for the treatment of adult individuals with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations, whose disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor.
 
Coding
 
See CPT/HCPCS Code section below.
Policy/
Coverage:
Prior Approval is required for Amivantamab-vmjw (e.g., Rybrevant).
 
For members of plans that utilize an oncology benefits management program, Prior Approval is required for this service when rendered for oncologic indications and is managed through the oncology benefits management program.
 
INITIAL AND CONTINUATION APPROVAL will be for duration of treatment course or 12 months (whichever comes first). Approval timeframes may differ for members/participants of Self-Insured plans.
 
Effective October 15, 2025
 
Meets Primary Coverage Criteria or Is Covered for Contracts Without Primary Coverage Criteria
 
Amivantamab-vmjw (e.g., Rybrevant) meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:
 
FDA Labeled Indications:
 
The use of this drug is covered if an FDA-approved oncologic indication exists [not listed as an indication below with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”).
 
INITIAL APPROVAL
 
1. Individual is 18 years of age or older; AND
2. Individual has a diagnosis of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutation (documentation submitted) (NCCN 2A, Rybrevant, 2025); AND
a. Individual’s disease has progressed on or after receiving at least one prior platinum-based chemotherapy (Rybrevant, 2024); AND
b. Will be used as a single agent (NCCN 2A); OR
3. Individual has a diagnosis of locally advanced or metastatic NSCLC with (Rybrevant, 2025; NCCN 1 and 2A):
a. EFGR exon 19 deletions; OR
b. EGFR exon  21 L858R substitution mutations; AND
c. Will be used as first-line therapy in combination with Lazertinib; OR
4. Individual has a diagnosis of locally advanced or metastatic NSCLC with (Rybrevant, 2025; NCCN 1):
a. EGFR exon 19 deletions; OR
b. EGFR exon 21 L858R substitution mutations; AND
c. Individual’s disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor; AND
d. Will be used in combination with carboplatin and pemetrexed; OR
5. Individual has a diagnosis of locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations; AND
a. Will be used as first-line therapy in combination with carboplatin and pemetrexed (Rybrevant, 2025; NCCN 1); AND
6. Individual has a current ECOG (see policy guidelines) performance status of 1 or lower.
 
CONTINUATION OF THERAPY
 
1. Individual continues to meet the initial approval criteria; AND
2. Documentation indicating disease response to treatment, by stabilization of disease and decrease in size of tumor or tumor spread.
 
Off-label Indications:
 
The use of this drug for off-label indications not listed below is subject to policy 2000030.
 
INITIAL APPROVAL
 
1. Central Nervous System Cancers:
a. Limited Brain Metastases (NCCN 2A):
i. Used in combination with lazertinib or in combination with carboplatin and pemetrexed for limited brain metastases in non-small cell lung cancer with exon 19 deletion or L858R:
1. May be considered as initial treatment in select cases for new diagnosed or stable systemic disease or if reasonable systemic treatment options exist; OR
2. Consider as treatment for recurrent brain metastases; OR
b. Extensive Brain Metastases (NCCN 2A):
i. Used in combination with lazertinib or in combination with carboplatin and pemetrexed for extensive brain metastases in non-small cell lung cancer with exon 19 deletion or L858R:
1. May be conserved as primary treatment in select cases (e.g., small asymptomatic brain metastases); OR
2. As treatment for recurrent disease with stable systemic disease or reasonable systemic treatment options.
 
CONTINUATION OF THERAPY
 
1. Individual continues to meet the initial approval criteria; AND
2. Documentation indicating disease response to treatment, by stabilization of disease and decrease in size of tumor or tumor spread.
 
Please see the NCCN Drugs and Biologics Compendium for a complete list of NCCN 1 & 2A indications. To view the most recent and complete version of the guideline or Compendium, go online to NCCN.org. Please note, NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
 
Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria
 
Amivantamab-vmjw (e.g., Rybrevant) for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, Amivantamab-vmjw (e.g., Rybrevant)  for any indication or circumstance other than those described above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
POLICY GUIDELINES
 
There should be an absence of unacceptable toxicity from the drug, including severe infusion reactions such as Infusion-Related Reactions (IRR), Interstitial Lung Disease ((ILD)/Pneumonitis, Venous Thromboembolic (VTE) Events with Concomitant Use with Lazertinib Dermatologic Adverse Reactions (e.g., toxic epidermal necrolysis (TEN), acneiform dermatitis), and Ocular Toxicity.
 
*The ECOG or Eastern Cooperative Oncology Group Performance Status is based on the following scale:
    •  0 = Fully active, able to carry on all pre-disease performance without restriction
    •  1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light housework, office work
    •  2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
    •  3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
    •  4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
    •  5 = Dead
 
DOSAGE AND ADMINISTRATION
 
For FDA labeled indications, Amivantamab-vmjw (e.g., Rybrevant) must be dosed in accordance with the indication specific recommended dose per FDA label unless otherwise specified below.
 
For off-label indications, authorizations will not exceed the maximum FDA labeled dose and frequency across all the FDA labeled indications unless higher dose is allowed for the specific indication below.
 
The recommended dose of amivantamab is based on weight.
 
IN COMBINATION WITH CARBOPLATIN AND PEMTREXED:
 
Body Weight (at Baseline)          Dosage                                           Recommended Dose
Less than 80 kg                            Weeks 1-4                                       1400 mg
                                                   Weeks 5 and 6                                 No dose
                                                   Week 7 onwards (every 3 weeks)       1750 mg
Greater than or equal to 80 kg        Weeks 1-4                                       1750 mg
                                                   Weeks 5 and 6                                 No dose
                                                   Week 7 onwards (every 3 weeks)       2100 mg
 
IN COMBINATION WITH LAZERTINIB or AS A SINGLE AGENT:
 
Body Weight (at Baseline)        Dosage                                             Recommended Dose
Less than 80 kg                          Weeks 1-5                                         1050 mg
                                                 Week 6                                              No dose
                                                 Week 7 onwards (every 2 weeks)         1050 mg
Greater than or equal to 80 kg      Weeks 1-5                                         1400 mg
                                                 Week 6                                              No dose
                                                 Week 7 onwards (every 2 weeks)         1400 mg
 
Amivantamab (e.g., Rybrevant) is available as 350 mg/7 mL (50 mg/mL) solution in a single-dose vial.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Effective December 18, 2024 to October 14, 2025
 
Meets Primary Coverage Criteria or Is Covered for Contracts Without Primary Coverage Criteria
 
Amivantamab (e.g., Rybrevant)  meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:
 
FDA Labeled Indications:
 
For FDA labeled indications, all products must be dosed in accordance with the FDA label unless otherwise specified.
 
1. Individual is 18 years of age or older; AND
2. Individual has a diagnosis of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutation (documentation submitted) (NCCN 2A, Rybrevant, 2024); AND
a. Individual’s disease has progressed on or after receiving at least one prior platinum-based chemotherapy (Rybrevant, 2024); AND
b. Will be used as a single agent (NCCN 2A); OR
3. Individual has a diagnosis of locally advanced or metastatic NSCLC with (Rybrevant, 2024; NCCN 1):
a. EFGR exon 19 deletions; OR
b. EGFR exon  21 L858R substitution mutations; AND
c. Will be used as first-line therapy in combination with Lazertinib; OR
4. Individual has a diagnosis of locally advanced or metastatic NSCLC with (Rybrevant, 2024; NCCN 1):
a. EGFR exon 19 deletions; OR
b. EGFR exon 21 L858R substitution mutations; AND
c. Individual’s disease has progressed on or after treatment with an EGFR tyrosine kinase inhibitor; AND
d. Will be used in combination with carboplatin and pemetrexed; OR
5. Individual has a diagnosis of locally advanced or metastatic NSCLC with EGFR exon 20 mutations; AND
a. Will be used as first-line therapy in combination with carboplatin and pemetrexed (Rybrevant, 2024; NCCN 1); AND
6. Individual has a current ECOG (see policy guidelines) performance status of 1 or lower.
 
Off-label Indications:
 
For off-label indications, authorizations will not exceed 1750 mg unless medical literature supports a higher dose.
 
1. Non-Small Cell Lung Cancer (NSCLC) (NCCN 1 and 2A)
 
Please see the NCCN Drugs and Biologics Compendium for a complete list of NCCN 1 & 2A indications.
 
Policy Guidelines
 
*The ECOG or Eastern Cooperative Oncology Group Performance Status is based on the following scale:
      •  0 = Fully active, able to carry on all pre-disease performance without restriction
      •  1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light housework, office work
      •  2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
      •  3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
      •  4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
      •  5 = Dead
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting all of specified criteria (See policy #2000030).
 
Dosage and Administration
Dosing per FDA Guidelines
 
The recommended dose of amivantamab is based on weight.
 
IN COMBINATION WITH CARBOPLATIN AND PEMTREXED:
 
Body Weight (at Baseline)         Dosage                                          Recommended Dose
Less than 80 kg                           Weeks 1-4                                      1400 mg
                                                  Weeks 5 and 6                                No dose
                                                  Week 7 onwards (every 3 weeks)      1750 mg
Greater than or equal to 80 kg       Weeks 1-4                                      1750 mg
                                                  Weeks 5 and 6                                No dose
                                                  Week 7 onwards (every 3 weeks)      2100 mg
 
IN COMBINATION WITH LAZERTINIB or AS A SINGLE AGENT
 
Body Weight (at Baseline)         Dosage                                             Recommended Dose
Less than 80 kg                           Weeks 1-5                                         1050 mg
                                                  Week 6                                             No dose
                                                  Week 7 onwards (every 2 weeks)        1050 mg
Greater than or equal to 80 kg       Weeks 1-5                                        1400 mg
                                                  Week 6                                             No dose
                                                  Week 7 onwards (every 2 weeks)        1400 mg
 
Amivantamab (e.g., Rybrevant) is available as 350 mg/7 mL (50 mg/mL) solution in a single-dose vial.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Amivantamab (e.g., Rybrevant)  for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, Amivantamab (e.g., Rybrevant)  for any indication or circumstance other than those described above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective August 28, 2024 to December 17, 2024
 
Meets Primary Coverage Criteria or Is Covered for Contracts Without Primary Coverage Criteria
 
Amivantamab meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations and ALL the following criteria are met:
 
FDA Labeled Indications:
 
For FDA labeled indications, all products must be dosed in accordance with the FDA label unless otherwise specified.
 
1. Individual is diagnosed with locally advanced, recurrent, or metastatic NSCLC with EGFR exon 20 insertion mutation (documentation submitted) [NCCN 2A, FDA 2021]; AND
2. Individual’s disease has progressed on or after receiving at least one prior platinum-based chemotherapy (FDA 2021); AND
3. The drug is used as a single agent (NCCN 2A); AND
4. Individual has a current ECOG* performance status of 1 or lower.
 
*The ECOG or Eastern Cooperative Oncology Group Performance Status is based on the following scale:
    •  0 = Fully active, able to carry on all pre-disease performance without restriction
    •  1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light housework, office work
    •  2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
    •  3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
    •  4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
    •  5 = Dead
 
Off-label Indications:
 
For off-label indications, authorizations will not exceed 1050 mg for individuals weighing less than 80 kg and 1400 mg for individuals weighing 80 kg or more weekly for the first four weeks and then every 2 weeks thereafter unless medical literature supports a higher dose.
 
1. Individual is diagnosed with NSCLC:
a. Preferred first-line therapy for EGFR exon 20 insertion mutation positive recurrent, advanced, or metastatic disease (nonsquamous) in combination with carboplatin and pemetrexed inclusive of mediastinal lymph node recurrence with prior radiation therapy (NCCN 1); OR
b. Preferred subsequent therapy for EGFR exon 19 deletion or exon 21 L858R or EGFR S768I, L861Q, and/or G719X mutation positive recurrent, advanced, or metastatic disease (nonsquamous) in combination with carboplatin and pemetrexed following disease progression on Osimertinib for symptomatic systemic disease with multiple lesions inclusive of mediastinal lymph node recurrence with prior radiation therapy (NCCN 1); OR
c. Subsequent therapy as a single agent for EGFR exon 20 insertion mutation positive recurrent, advanced, or metastatic disease inclusive of mediastinal lymph node recurrence with prior radiation therapy (NCCN 1).
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting all of specified criteria (See policy #2000030).
 
Dosage and Administration
Dosing per FDA Guidelines
 
The recommended dose of amivantamab is based on weight; less than 80kg is 1050mg and greater than or equal to 80kg is 1400mg. Amivantamab is administered weekly for four weeks, with the initial dose as a split infusion in Week 1 on Day 1 and Day 2, then administer every 2 weeks thereafter until disease progression or unacceptable toxicity.
 
Amivantamab-vmjw is available as 350 mg/7 mL (50 mg/mL) solution in a single-dose vial.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Amivantamab for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, amivantamab for any indication or circumstance other than those described above is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective August 4, 2022 to August 27, 2024
 
Meets Primary Coverage Criteria or Is Covered for Contracts Without Primary Coverage Criteria
 
The use of amivantamab meets primary coverage criteria that there be scientific evidence of effectivenss in improving health outcomes for locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations and ALL of the following criteria are met:
    1. Individual is diagnosed with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutation (documentation submitted) [NCCN 2A, FDA 2021] AND  
    2. Individual’s disease has progressed on or after receiving at least one prior platinum-based chemotherapy (FDA 2021) AND  
    3. The drug is used as a single agent (NCCN 2A]
    4. Individual has a current ECOG* performance status of 1 or lower AND
    5. Must be dosed in accordance with the FDA label.
 
*The ECOG or Eastern Cooperative Oncology Group Performance Status is based on the following scale:
    • 0 = Fully active, able to carry on all pre-disease performance without restriction
    • 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, for example, light housework, office work
    • 2 = Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours
    • 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
    • 4 = Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
    • 5 = Dead
 
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting all of specified criteria (See policy #2000030).
 
Dosage and Administration
Dosing per FDA Guidelines
 
The recommended dose of amivantamab is based on weight; less than 80kg is 1050mg and greater than or equal to 80kg is 1400mg. Amivantamab is administered weekly for four weeks, with the initial dose as a split infusion in Week 1 on Day 1 and Day 2, then administer every 2 weeks thereafter until disease progression or unacceptable toxicity.
 
Amivantamab-vmjw is available as 350 mg/7 mL (50 mg/mL) solution in a single-dose vial.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Amivantamab for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.  
 
For members with contracts without primary coverage criteria, the use of amivantamab for any indication or circumstance other than those described above is considered investigational.
 
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Rationale:
The safety and efficacy of amivantamab was evaluated in a phase 1, multicenter, open-label, multi-cohort clinical trial. Inclusion criteria included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy. Patients with untreated brain metastases and patients with a history of interstitial lung disease requiring treatment with prolonged steroids or other immunosuppressive agents within the last 2 years were excluded from the study.
 
Patients received 1050mg (body weight <80kg) or 1400mg (body weight ≥80kg) once weekly for four weeks, then every 2 weeks thereafter until disease progression or unacceptable toxicity. 81 patients in the post-platinum cohort were assessed for efficacy. Overall response rate (ORR) for patients receiving amivantamab was 40% [3.7% CR and 36% PR]. The median duration of response (DOR) was 11.1 months, with 63% of patients having a DOR of 6 months or more.
 
The most common adverse effects were rash, infusion related reaction, and paronychia. No treatment related deaths were reported. The incidence of treatment-related adverse effects leading to dose reduction and discontinuation was 15% and 11%, respectively. (Rybrevant, 2021)
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2023. No new literature was identified that would prompt a change in the coverage statement.
 
2024 Update
In a phase 3, international, randomized trial, patients with advanced NSCLC with EGFR exon 20 insertions who had not received previous systemic therapy were assigned in a 1:1 ratio to receive intravenous amivantamab plus chemotherapy (amivantamab-chemotherapy) or chemotherapy alone. The primary outcome was progression-free survival according to blinded independent central review. Patients in the chemotherapy group who had disease progression were allowed to cross over to receive amivantamab monotherapy.
 
A total of 308 patients underwent randomization (153 to receive amivantamab-chemotherapy and 155 to receive chemotherapy alone). Progression-free survival was significantly longer in the amivantamab-chemotherapy group than in the chemotherapy group (median, 11.4 months and 6.7 months, respectively; hazard ratio for disease progression or death, 0.40; 95% confidence interval [CI], 0.30 to 0.53; P<0.001). At 18 months, progression-free survival was reported in 31% of the patients in the amivantamab-chemotherapy group and in 3% in the chemotherapy group; a complete or partial response at data cutoff was reported in 73% and 47%, respectively (rate ratio, 1.50; 95% CI, 1.32 to 1.68; P<0.001). In the interim overall survival analysis (33% maturity), the hazard ratio for death for amivantamab-chemotherapy as compared with chemotherapy was 0.67 (95% CI, 0.42 to 1.09; P = 0.11). The predominant adverse events associated with amivantamab-chemotherapy were reversible hematologic and EGFR-related toxic effects; 7% of patients discontinued amivantamab owing to adverse reactions.
 
The use of amivantamab-chemotherapy resulted in superior efficacy as compared with chemotherapy alone as first-line treatment of patients with advanced NSCLC with EGFR exon 20 insertions. (Zhou C, Tang KJ, Cho BC, et.al., 2023)
 
December 2024 Update
The efficacy of RYBREVANT, in combination with lazertinib, was evaluated in MARIPOSA [NCT04487080], a randomized, active-controlled, multicenter trial. Eligible patients were required to have untreated locally advanced or metastatic NSCLC with either exon 19 deletions or exon 21 L858R substitution EGFR mutations identified by local testing, not amenable to curative therapy.
 
Patients with asymptomatic or previously treated and stable intracranial metastases were eligible to enroll. Patients were randomized (2:2:1) to receive RYBREVANT in combination with lazertinib (N=429), osimertinib monotherapy (N=429), or lazertinib monotherapy (an unapproved regimen for NSCLC) until disease progression or unacceptable toxicity. The evaluation of efficacy for the treatment of untreated metastatic NSCLC relied upon comparison between:
    • RYBREVANT administered intravenously at 1050 mg (for patients < 80 kg) or 1400 mg (for patients ≥ 80 kg) once weekly for 4 weeks, then every 2 weeks thereafter starting at week 5 in combination with lazertinib administered at 240 mg orally once daily.
    • Osimertinib administered at a dose of 80 mg orally once daily.
 
Randomization was stratified by EGFR mutation type (exon 19 deletion or exon 21 L858R substitution mutation), Asian race (yes or no), and history of brain metastasis (yes or no). Tumor assessments were performed every 8 weeks for 30 months, and then every 12 weeks until disease progression.
 
The major efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review (BICR). Additional efficacy outcome measures included overall survival (OS), overall response rate (ORR), and duration of response (DOR).
 
A total of 858 patients were randomized between the two study arms, 429 to the RYBREVANT in combination with lazertinib arm and 429 to the osimertinib arm. The median age was 63 (range: 25–88) years; 61% were female; 58% were Asian, 38% were White, 1.6% were American Indian or Alaska Native, 0.8% were Black or African American, 0.2% were Native Hawaiian or other Pacific Islander, 0.6% were unknown race or multiple races; and 12% were Hispanic or Latino. Eastern Cooperative Oncology Group (ECOG) performance status was 0 (34%) or 1 (66%); 69% never smoked; 41% had prior brain metastases; and 89% had Stage IV cancer at initial diagnosis. Sixty percent of patients had tumors harboring exon 19 deletions and the remaining 40% had exon 21 L858R substitution mutations.
 
Among the 858 patients with EGFR exon 19 deletion or L858R substitution mutations that were randomized between the RYBREVANT plus lazertinib arm versus the osimertinib arm, available tissue samples from 544 (63%) patients had evaluable results when tested retrospectively using the cobas EGFR Mutation Test v2. Of the 544 patients with evaluable results, 527 (97%) patients were positive for EGFR exon 19 deletion or L858R substitution mutations, while 17 (3%) patients were negative. Available plasma samples from patients were retrospectively tested using an FDAapproved test to confirm the biomarker status.
 
The trial demonstrated a statistically significant improvement in PFS by BICR assessment for RYBREVANT in combination with lazertinib compared to osimertinib.
 
While OS results were immature at the current analysis, with 55% of pre-specified deaths for the final analysis reported, no trend towards a detriment was observed.
 
Out of all randomized patients (n=858), 367 (43%) had baseline intracranial lesions assessed by BICR using modified RECIST. (Rybrevant, 2024)
 
The efficacy of RYBREVANT in combination with carboplatin and pemetrexed was evaluated in MARIPOSA-2 (NCT04988295), a randomized, open-label, multicenter trial. Eligible patients were required to have locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations and progressive disease on or after receiving osimertinib. Patients with asymptomatic or previously treated and stable intracranial metastases were eligible to enroll. Patients were randomized (1:2:2) to receive RYBREVANT in combination with carboplatin and pemetrexed (RYBREVANT-CP, N=131), carboplatin and pemetrexed (CP, N=263), or RYBREVANT as part of another combination regimen. The evaluation of efficacy for metastatic NSCLC relied upon comparison between:
    • RYBREVANT in combination with carboplatin and pemetrexed. RYBREVANT was administered intravenously at 1400 mg (for patients < 80 kg) or 1750 mg (for patients ≥ 80 kg) once weekly through 4 weeks, then every 3 weeks with a dose of 1750 mg (for patients < 80 kg) or 2100 mg (for patients ≥ 80 kg) starting at Week 7 until disease progression or unacceptable toxicity.
    • Platinum-based chemotherapy with carboplatin and pemetrexed.
 
For both arms, carboplatin was administered intravenously at area under the concentration-time curve 5 mg/mL per minute (AUC 5) once every 3 weeks, for up to 12 weeks and pemetrexed was administered intravenously at 500 mg/m2 once every 3 weeks until disease progression or unacceptable toxicity.
 
Randomization was stratified by osimertinib line of therapy (first-line or second-line), prior brain metastases (yes or no), and Asian race (yes or no). Tumor assessments were performed every 6 weeks for the first 12 months and every 12 weeks thereafter.
 
The major efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review (BICR). Overall survival (OS) and overall response rate (ORR) as assessed by BICR were key secondary outcome measures.
 
A total of 394 patients were randomized between the two arms, 131 to the RYBREVANT-CP arm and 263 to the CP arm. The median age was 62 (range: 31 to 85) years, with 38% of patients ≥ 65 years of age; 60% were female; and 48% were Asian and 46% were White, 1% were American Indian or Alaska Native, 1% were Black or African American, 0.5% were multiple races and 2.8% were race not reported or race unknown; 8% were Hispanic or Latino. Baseline Eastern Cooperative Oncology Group (ECOG) performance status was 0 (40%) or 1 (60%); 65% never smoked; 45% had history of brain metastasis, and 99.7% had Stage IV cancer at study enrollment.
 
The trial demonstrated a statistically significant improvement in PFS by BICR for RYBREVANT in combination with carboplatin and pemetrexed compared to carboplatin and pemetrexed.
 
At the prespecified second interim analysis of OS, with 85% of the deaths needed for the final analysis, there was no statistically significant difference in OS. The median OS was 17.7 months (95% CI: 16.0, 22.4) in the ACP arm and 15.3 months (95% CI: 13.7, 16.8) in the CP arm, with a hazard ratio of 0.73 (95% CI: 0.54, 0.99).
 
Patients with asymptomatic or previously treated and stable intracranial metastases were eligible to be randomized in MARIPOSA-2. Baseline disease assessment, including brain magnetic resonance imaging (MRI) was performed at treatment initiation. All patients underwent serial brain MRI during the trial.
 
Pre-specified secondary analyses of intracranial ORR by BICR in the subset of 91 (23%) patients with baseline intracranial disease were performed. Data were only available for intracranial complete responses and not available for intracranial partial responses. Intracranial ORR was 20% (95% CI: 8, 39) in the 30 patients with baseline intracranial disease in the ACP arm and 7% (95% CI: 1.8, 16) in the 61 patients with baseline intracranial disease in the CP arm. (Rybrevant, 2024)
 
The efficacy of RYBREVANT was evaluated in PAPILLON (NCT04538664), in a randomized, open-label, multicenter study. Eligible patients were required to have previously untreated locally advanced or metastatic NSCLC with EGFR Exon 20 insertion mutations measurable disease per RECIST v1.1, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 1, and adequate organ and bone marrow function. Patients with brain metastases at screening were eligible for participation once they were definitively treated, clinically stable, asymptomatic, and off corticosteroid treatment for at least 2 weeks prior to randomization. Patients with a medical history of interstitial lung disease or active ILD were excluded from the clinical study.
 
A total of 308 patients were randomized 1:1 to receive RYBREVANT in combination with carboplatin and pemetrexed (n=153) or carboplatin and pemetrexed (n=155). Patients received RYBREVANT intravenously at 1400 mg (for patients < 80 kg) or 1750 mg (for patients ≥ 80 kg) once weekly through 4 weeks, then every 3 weeks with a dose of 1750 mg (for patients < 80 kg) or 2100 mg (for patients ≥ 80 kg) starting at Week 7 until disease progression or unacceptable toxicity. Carboplatin was administered intravenously at area under the concentration-time curve 5 mg/mL per minute (AUC 5) once every 3 weeks, for up to 12 weeks. Pemetrexed was administered intravenously at 500 mg/m2 on once every 3 weeks until disease progression or unacceptable toxicity. Patients were stratified by Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1) and prior brain metastases (yes or no).
 
The primary efficacy outcome measure was progression-free survival (PFS) as assessed by blinded independent central review (BICR). Additional efficacy outcome measures included overall response rate (ORR), duration of response (DOR) and overall survival (OS). Cross-over to single agent RYBREVANT was permitted for patients who had confirmed disease progression on carboplatin and pemetrexed.
 
The median age was 62 (range: 27 to 92) years, with 40% of the patients ≥ 65 years of age; 58% were female; 61% were Asian and 36% were White, 0.7% were Black or African American and race was not reported in 2.3% of patients; 93% were not Hispanic or Latino. Baseline ECOG performance status was 0 (35%) or 1 (65%); 58% were never smokers; 23% had history of brain metastasis and 84% had Stage IV cancer at initial diagnosis.
 
PAPILLON demonstrated a statistically significant improvement in progression free survival for patients randomized to RYBREVANT in combination with carboplatin and pemetrexed compared with carboplatin and pemetrexed. (Rybrevant, 2024)
 
The efficacy of RYBREVANT was evaluated in patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations in a multicenter, open-label, multi-cohort clinical trial (CHRYSALIS, NCT02609776). The study included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy. Patients with untreated brain metastases and patients with a history of ILD requiring treatment with prolonged steroids or other immunosuppressive agents within the last 2 years were not eligible for the study.
 
In the efficacy population, EGFR exon 20 insertion mutation status was determined by prospective local testing using tissue (94%) and/or plasma (6%) samples. Of the 81 patients with EGFR exon 20 insertion mutations identified by local testing, plasma samples from 78/81 (96%) patients were tested retrospectively using Guardant360® CDx, identifying 62/78 (79%) samples with an EGFR exon 20 insertion mutation; 16/78 (21%) samples did not have an EGFR exon 20 insertion mutation identified.
 
Patients received RYBREVANT at 1050 mg (for patient baseline body weight < 80 kg) or 1400 mg (for patient baseline body weight ≥ 80 kg) once weekly for 4 weeks, then every 2 weeks thereafter until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST v1.1) as evaluated by Blinded Independent Central Review (BICR). An additional efficacy outcome measure was duration of response (DOR) by BICR.
 
The efficacy population included 81 patients with NSCLC with EGFR exon 20 insertion mutation with measurable disease who were previously treated with platinum-based chemotherapy. The median age was 62 (range: 42 to 84) years, 59% were female; 49% were Asian, 37% were White, 2.5% were Black; 74% had baseline body weight < 80 kg; 95% had adenocarcinoma; and 46% had received prior immunotherapy. The median number of prior therapies was 2 (range: 1 to 7). At baseline, 67% had Eastern Cooperative Oncology Group (ECOG) performance status of 1; 53% never smoked; all patients had metastatic disease; and 22% had previously treated brain metastases. (Rybrevant, 2024)
 
2025 Update
An analysis included patients with treatment-naive, EGFR-mutant advanced NSCLC randomized to amivantamab-lazertinib (n = 429) or osimertinib (n = 429) in MARIPOSA. Pathogenic alterations were identified by next-generation sequencing (NGS) of baseline blood ctDNA with Guardant360 CDx. Ex19del and L858R ctDNA in blood was analyzed at baseline and cycle 3 day 1 (C3D1) with Biodesix droplet digital polymerase chain reaction (ddPCR).
 
Baseline ctDNA for NGS of pathogenic alterations was available for 636 patients (amivantamab-lazertinib, n = 320; osimertinib, n = 316). Amivantamab-lazertinib improved median PFS (mPFS) versus osimertinib for patients with TP53 co-mutations {18.2 versus 12.9 months; HR 0.65 [95% confidence interval (CI) 0.48-0.87]; P = 0.003} and for patients with wild-type TP53 [22.1 versus 19.9 months; HR 0.75 (95% CI 0.52-1.07)]. In patients with EGFR-mutant, ddPCR-detectable baseline ctDNA, amivantamab-lazertinib significantly prolonged mPFS versus osimertinib [20.3 versus 14.8 months; HR 0.68 (95% CI 0.53-0.86); P = 0.002]. Amivantamab-lazertinib significantly improved mPFS versus osimertinib in patients without ctDNA clearance at C3D1 [16.5 versus 9.1 months; HR 0.49 (95% CI 0.27-0.87); P = 0.015] and with clearance [24.0 versus 16.5 months; HR 0.64 (95% CI 0.48-0.87); P = 0.004]. Amivantamab-lazertinib significantly prolonged mPFS versus osimertinib among randomized patients with [18.2 versus 11.0 months; HR 0.58 (95% CI 0.37-0.91); P = 0.017] and without baseline liver metastases [24.0 versus 18.3 months; HR 0.74 (95% CI 0.60-0.91); P = 0.004].
 
Amivantamab-lazertinib effectively overcomes the effect of high-risk features and represents a promising new standard of care for patients with EGFR-mutant advanced NSCLC. (Felip, 2024)
CPT/HCPCS:
J9061Injection, amivantamab-vmjw, 2 mg
J9999Not otherwise classified, antineoplastic drugs
References: Cho BC, Felip E, Hayashi H, Thomas M, Lu S, Besse B, Sun T, Martinez M, Sethi SN, Shreeve SM, Spira AI.(2022) MARIPOSA: phase 3 study of first-line amivantamab+lazertinib versus osimertinib in EGFR-mutant non-small-cell lung cancer. Future Oncol. 2022 Feb;18(6):639-647. doi: 10.2217/fon-2021-0923. Epub 2021 Dec 16. PMID: 34911336.

Felip E, Cho BC, Gutiérrez V, et.al(2024) Amivantamab plus lazertinib versus osimertinib in first-line EGFR-mutant advanced non-small-cell lung cancer with biomarkers of high-risk disease: a secondary analysis from MARIPOSA. Ann Oncol. 2024 Sep;35(9):805-816. doi: 10.1016/j.annonc.2024.05.541. Epub 2024 Jun 26. PMID: 38942080.

Jatkoe T, Wang S, Odegaard JI, Velasco Roth AM, Osgood D, Martinez G, Lucas P, Curtin JC, Karkera J.(2022) Clinical Validation of Companion Diagnostics for the Selection of Patients with Non-Small Cell Lung Cancer Tumors Harboring Epidermal Growth Factor Receptor Exon 20 Insertion Mutations for Treatment with Amivantamab. J Mol Diagn. 2022 Nov;24(11):1181-1188. doi: 10.1016/j.jmoldx.2022.07.003. Epub 2022 Aug 10. PMID: 35963523.

multiple authors; PAPILLON Investigators.(2023) Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions. N Engl J Med. 2023 Nov 30;389(22):2039-2051. doi: 10.1056/NEJMoa2306441. Epub 2023 Oct 21. PMID: 37870976.

National Comprehensive Cancer Network(2021) NCCN Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer. Version 5.2021. June 15, 2021. Accessed August 1, 2021

NCCN(2025) NCCN Drugs & Biologics Compendium for Amivantamab-vmjw (e.g., Rybevant) NCCN Inc. 2025. All rights reserved. Accessed [July 31, 2025]. To view the most recent and complete version of the Compendium, go online to NCCN.org.

Rybrevant [package insert] Horsham, PA. Janssen Biotech, Inc., 2021.

Rybrevant(2024) package insert Horsham, PA. Janssen Biotech, Inc., 2024.

Rybrevant(2025) package insert Horsham, PA. Janssen Biotech, Inc., 2025.

Sabari JK, et al.(2021) Amivantamab in post-platinum EGFR exon 20 insertion mutant non-small cell lung cancer. J Thorac Oncol. 2021;16(3 suppl):S108-S109.

Study of Amivantamab, a Human Bispecific EGFR and cMet Antibody, in Participants With Advanced Non-Small Cell Lung Cancer (CHRYSALIS). 2015 November 15 [last updated 2021 May 18; cited 2021 August 2]. In: ClinicalTrials.gov [Internet]. Bethesda (MD): U.S. National Library of Medicine. 2000 - . Available from: https://clinicaltrials.gov/ct2/show/NCT02609776
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