Commercial

Medical Policy

Title:

Amivantamab-vmjw (Rybrevant®) and Amivantamab and hyaluronidase-lpuj (Rybrevant Faspro™)

Policy #:

08.01.90c

Policy

The Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member's medical needs and condition.

MEDICALLY NECESSARY

INITIAL APPROVAL

Non-Small Cell Lung Cancer (NSCLC)

Amivantamab-vmjw (Rybrevant) and amivantamab and hyaluronidase-lpuj (Rybrevant Faspro) is considered medically necessary and, therefore, covered for the treatment of adult individuals with non-small cell lung cancer (NSCLC) when one of the following criteria is met:

As a single agent when ALL of the following criteria are met:

The individual has recurrent, locally advanced or metastatic disease; and
The individual has EGFR exon 20 insertion pathogenic variations*; and
Disease has progressed on or after platinum-based chemotherapy; or as subsequent therapy

In combination with carboplatin and pemetrexed in adult individuals with NSCLC when one of the following criteria is met:

First-line treatment with recurrent, advanced or metastatic disease with epidermal growth factor receptor (EGFR) exon 20 insertion mutations* as National Comprehensive Cancer Network (NCCN)-preferred therapy
Subsequent therapy for EGFR exon 19 deletion or exon 21 L858R mutation–positive recurrent, advanced, or metastatic disease (nonsquamous) following disease progression on osimertinib (Tagrisso) or lazertinib (Lazcluze) for symptomatic systemic disease with multiple lesions as NCCN-preferred therapy.
Subsequent therapy for advanced or metastatic disease EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, following disease progression on or after treatment with an EGFR tyrosine kinase inhibitor.

In combination with lazertinib (Lazcluze) for EGFR exon 19 deletion or exon 21 L858R* recurrent, advanced, or metastatic disease when either of the following criteria are met:

First-line treatment (NCCN-preferred)
Continuation of treatment following disease progression on amivantamab-vmjw plus lazertinib for asymptomatic disease, symptomatic brain lesions, or symptomatic systemic limited progression
Subsequent therapy following disease progression on osimertinib for symptomatic systemic disease with multiple lesions
Subsequent therapy in those with PS 0–2 following progression on prior (carboplatin or cisplatin)/osimertinib/pemetrexed (if not previously given)

*As detected by a US Food and Drug Administration (FDA)-approved test.

Central Nervous System Cancers (CNS)

Limited and Extensive Brain Metastases in Adults

Amivantamab-vmjw (Rybrevant) and amivantamab and hyaluronidase-lpuj (Rybrevant Faspro) is considered medically necessary in NCSLC with exon 19 deletion or L858R and, therefore, covered for the following:

In combination with lazertinib (Lacluze) or in combination with carboplatin and pemetrexed (both NCCN- preferred regimens) as

Initial treatment in select cases (i.e, small asymptomatic brain metastases) for newly diagnosed or stable systemic disease or if reasonable systemic treatment options exist
Treatment option for recurrent brain metastases

CONTINUATION OF THERAPY

Continuation of amivantamab-vmjw (Rybrevant) and amivantamab and hyaluronidase-lpuj (Rybrevant Faspro) therapy is medically necessary in individuals requesting reauthorization for an indication listed above when any of the following criteria are met:

There is no evidence of unacceptable toxicity or disease progression while on the current regimen, OR
Individual is requesting the medication in combination with lazertinib (Lazcluze) and there is no evidence of unacceptable toxicity while on the current regimen.

EXPERIMENTAL/INVESTIGATIONAL

All other uses for amivantamab-vmjw (Rybrevant) and amivantamab and hyaluronidase-lpuj (Rybrevant Faspro) , including but not limited to when medical necessity criteria are not met, for the treatment of gastroesophageal cancer, are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.

MANDATES

PENNSYLVANIA MEMBERS

In accordance with the Commonwealth of Pennsylvania's Act 6 of 2020 or Fair Access to Cancer Treatment Act, for members who are enrolled in Pennsylvania commercial products who have Stage 4, advanced metastatic cancer, refer to the Medical Policy titled "Coverage of Anticancer Prescription Oral and Injectable Drugs and Biologics and Supportive Agents" (08.01.08) for additional information regarding the applicable coverage of drugs and biologics.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.

Guidelines

BLACK BOX WARNINGS

Refer to the specific manufacturer's prescribing information for any applicable Black Box Warnings.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, amivantamab (Rybrevant) and amivantamab and hyaluronidase-lpuj (Rybrevant Faspro) is covered under the medical benefits of the Company's products when the medical necessity criteria listed in this medical policy are met.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

Amivantamab-vmjw (Rybrevant) intravenous (IV) was approved by the FDA on May 21, 2021, for the treatment of adult individuals with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. On March 1, 2024, the FDA approved amivantamab (Rybrevant) in combination with carboplatin and pemetrexed for the first-line treatment of adult individuals with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. Supplemental approvals have since been approved.

Amivantamab and hyaluronidase-lpuj (Rybrevant Faspro) subcutaneous (SC) formulation was approved by the FDA on December 17, 2025 across all the same indications as the existing IV amivantamab (Rybrevant).

Dosage and Administration

Amivantamab-vmjw (Rybrevant) IV is available as 350 mg/7 mL (50 mg/mL) solution in a single-dose vial for intravenous infusion.

Amivantamab and hyaluronidase-lpuj (Rybrevant Faspro) SC is available in a single-dose vial as

2,240 mg amivantamab and 28,000 units hyaluronidase per 14 mL (160 mg and 2,000 units/mL) solution
2,400 mg amivantamab and 30,000 units hyaluronidase per 15 mL (160 mg and 2,000 units/mL) solution
3,520 mg amivantamab and 44,000 units hyaluronidase per 22 mL (160 mg and 2,000 units/mL) solution

Amivantamab-vmjw (Rybrevant) IV is administered weekly (total of four doses) during weeks 1 to 4, with the initial dose as split infusion in week 1 on day 1 and day 2. During weeks 2 to 4, the infusion is on day 1, then given every 2 weeks starting at week 5 until disease progression or unacceptable toxicity. The recommended doses of amivantamab-vmjw (Rybrevant) IV are based on baseline body weight as the following:

For less than 80 kg, the recommended dose is 1050 mg
For greater than or equal to 80 kg, the recommended dose is 1400 mg

Amivantamab and hyaluronidase-lpuj (Rybrevant Faspro) SC in combination with Carboplatin and Pemetrexed is administered every 3 weeks and in combination with Lazertinib or as a single agent can be administered every 4 weeks or every 2 weeks based on body weight at baseline. RYBREVANT FASPRO must be administered by a healthcare professional.

PEDIATRIC USE

The safety and effectiveness of amivantamab-vmjw (Rybrevant) and amivantamab and hyaluronidase-lpuj (Rybrevant Faspro) have not been established in pediatric individuals less than 18 years of age.

Description

NON-SMALL CELL LUNG CANCER (NSCLC)

Globally, lung cancer is the most prevalent cancer type and the leading cause of cancer-related mortality. According to the American Cancer Society, NSCLC is responsible for 80% to 85% of all lung cancers. An estimated 2% to 3% of individuals with NSCLC will have epidermal growth factor receptor (EGFR) exon 20 insertion mutations, which are a group of mutations on a protein that result in rapid cell proliferation and ensuing cancer spread. EGFR exon 20 insertion mutations are the third most prevalent type of EGFR mutation (US Food and Drug Administration [FDA], 2021).

AMIVANTAMAB-VMJW (RYBREVANT)

Amivantamab-vmjw (Rybrevant) is a low-fucose human immunoglobulin G (IgG) 1–based bispecific antibody that binds the extracellular domains of EGFR and mesenchymal-epithelial transition (MET). In in vitro and in vivo studies, amivantamab-vmjw (Rybrevant) was able to disrupt EGFR and MET signaling functions through blocking ligand binding and, in exon 20 insertion mutation models, degradation of EGFR and MET. Tumor cells with EGFR and MET on their surface are targeted for destruction by immune effector cells through antibody-dependent cellular cytotoxicity (ADCC) and trogocytosis mechanisms. Amivantamab-vmjw is produced by mammalian cell line (Chinese Hamster Ovary [CHO] using recombinant DNA technology (Janssen Biotech Inc., 2021a).

PEER-REVIEWED LITERATURE

SUMMARY

Previously Treated NSCLC with Exon 20 Insertion Mutations

The phase I CHRYSALIS study consisted of a multicenter, open-label, multicohort clinical trial that included individuals with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy. Amivantamab-vmjw (Rybrevant) was administered as an intravenous infusion at 1050 mg (for individual baseline body weight <80 kg) or 1400 mg (for individual baseline body weight ≥80 kg) once weekly for 4 weeks, then every 2 weeks thereafter until disease progression or unacceptable toxicity. The efficacy of amivantamab-vmjw (Rybrevant) was evaluated in a population of 81 individuals with NSCLC with EGFR exon 20 insertion mutation with measurable disease who received prior platinum-based chemotherapy. The primary efficacy outcome measure was overall response rate (ORR) with an additional efficacy outcome measure as duration of response (DOR). The confirmed ORR was 40% (95% confidence interval [CI], 29%–51%), with 3.7% achieving complete responses (CRs) and 36% having partial responses (PR). The median DOR was 11.1 months (95% CI, 6.9 months to not estimable) with 63% of individuals having a DOR of 6 months or more (Janssen Biotech Inc., 2021a).

First Line Treatment of NSCLC with Exon 20 Insertion Mutations

The safety and efficacy was evaluated in the phase III PAPILLON trial (Zhou et al.), which included 308 participants with advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, Eastern Cooperative Oncology Group performance status (PS) ≤1, and adequate organ and bone marrow function. Study participants were randomly assigned to receive amivantamab with carboplatin and pemetrexed (n=153) or carboplatin and pemetrexed (n=155). The primary endpoint was progression-free survival (PFS). Results showed a statistically significant improvement in PFS for participants treated with amivantamab with carboplatin and pemetrexed compared with those who received carboplatin and pemetrexed (hazard ratio, 0.40 [95% CI, 0.30–0.53]; P<0.0001). Median PFS was 11.4 months (95% CI, 9.8–13.7) and 6.7 months (95% CI, 5.6–7.3) in the respective arms. The ORRs were 67% (95% CI, 59–75) for the amivantamab with carboplatin and pemetrexed group (4% CR, 63% PR) and 36% (95% CI, 29–44) for the carboplatin and pemetrexed group (1% CR, 36% PR). Median DOR was 10.1 months (95% CI, 8.5–13.9) and 5.6 months (95% CI, 4.4–6.9) in the respective arms.

Previously Treated NSCLC Patients with EGFR Exon 19 Deletions or Exon 21 L858R Substitution Mutations

The efficacy of amivantamab-vmjw (Rybrevant) in combination with carboplatin and pemetrexed was evaluated in MARIPOSA-2 (NCT04988295), a randomized, open-label, multicenter trial. Eligible participants 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 (Tagrisso). Participants with asymptomatic or previously treated and stable intracranial metastases were eligible to enroll. Participants were randomly assigned (1:2:2) to receive amivantamab-vmjw (Rybrevant) in combination with carboplatin and pemetrexed (N=131), carboplatin and pemetrexed (N=263) or part of another combination regimen. The trial demonstrated a statistically significant improvement in PFS by Blinded Independent Central Review 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 amivantamab with carboplatin and pemetrexed arm and 15.3 months (95% CI, 13.7–16.8) in the carboplatin and pemetrexed arm, with a hazard ratio of 0.73 (95% CI, 0.54–0.99).

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

The efficacy of amivantamab-vmjw (Rybrevant) was evaluated in MARIPOSA [NCT04487080], a randomized, active-controlled, multicenter trial. The study conducted was in combination with lazertinib (Lazcluze) as first-line therapy for NSCLC with EGFR mutations, specifically exon 19 deletions (ex19del) or L858R substitution mutations. The chemotherapy-free combination regimen of amivantamab-vmjw (Rybrevant) and lazertinib (Lazcluze) met the secondary endpoint of OS, demonstrating a statistically significant improvement (reduced the risk of progression or death by 30%) over osimertinib (Tagrisso) monotherapy, the current standard of care. These findings build on earlier positive results for PFS and interim OS analysis for amivantamab-vmjw (Rybrevant) in combination with lazertinib (Lazcluze) for EGFR-mutated NSCLC.

Rybrevant Faspro (amivantamab and hyaluronidase-lpuj) 

The PALOMA‑3 trial evaluated subcutaneous (SC) amivantamab and hyaluronidase‑lpuj in adults with EGFR‑mutated locally advanced or metastatic NSCLC and demonstrated pharmacokinetic non‑inferiority to the intravenous (IV) formulation, with key PK measures—such as the Cycle 2 AUC geometric mean ratio of 1.03 (90% CI 0.98–1.09) and steady‑state Ctrough of 1.43 (90% CI 1.27–1.61)—meeting prespecified comparability thresholds; efficacy outcomes showed no notable differences in overall response rate, progression‑free survival, or overall survival between SC and IV arms, and safety profiles were similar, though SC administration resulted in markedly fewer administration‑related reactions (13% vs 66% with IV), reduced VTE rates with prophylactic anticoagulation, and significantly greater convenience, including a ~5‑minute injection time compared with ~5 hours for IV infusion, supporting FDA approval across all amivantamab indications.

OFF-LABEL INDICATIONS

There may be additional indications contained in the Policy section of this document due to the evaluation of criteria highlighted in the Company's off-label policy, and/or review of clinical guidelines issues by leading professional organizations and government entities.

References

American Hospital Formulary Service (AHFS). Drug Information 2023. Amivantamab-vmjw (Rybrevant). [Lexicomp Online Web Site] Updated 03/15/2024. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed February 17, 2026.

Cho BC, Felip E, Hayashi H, et al. MARIPOSA: Phase 3 study of first-line amivantamab + lazertinib versus osimertinib in EGFR-mutant non-small-cell lung cancer. Future Oncol. 2022;18(6):639-647.

Elsevier's Clinical Pharmacology Compendium. Amivantamab-vmjw (Rybrevant). 04/30/2024. [Clinical Pharmacology Web site]. Available at: https://www.clinicalkey.com/pharmacology/ [via subscription only]. Accessed February 17, 2026.

Janssen Biotech, Inc. Rybrevant (amivantamab-vmjw) receives FDA approval as the first targeted treatment for patients with non-small cell lung cancer with EGFR exon 20 insertion mutations. Press Release. Horsham, PA: Janssen; May 21, 2021.

Kwon CS, Lin HM, Crossland V, et al. Non-small cell lung cancer with EGFR exon 20 insertion mutation: A systematic literature review and meta-analysis of patient outcomes. Curr Med Res Opin. 2022;38(8):1341-1350.

Lexi-Drugs Compendium. Amivantamab-vmjw (Rybrevant). 05/05/2025. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed February 17, 2026.

Maron SB, Moya S, Morano F, et al. Epidermal growth factor receptor inhibition in epidermal growth factor receptor-amplified gastroesophageal cancer: Retrospective global experience. J Clin Oncol. 2022;40(22):2458-2467.

National Comprehensive Cancer Network (NCCN). Amivantamab-vmjw. NCCN Drugs and Biologics Compendium, Plymouth Meeting, PA: NCCN; 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology – Non-Small Cell Lung Cancer. V3.2026. [NCCN Web site]. 12/24/2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf [via subscription only]. Accessed February 13, 2026.

National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology – Central Nervous System Cancers. V3.2025. [NCCN Web site]. 12/05/2025. Available at: https://www.nccn.org/professionals/physician_gls/pdf/cns.pdf [via subscription only]. Accessed February 13, 2026.

PA House Bill – HB 427; Act 6. Signed February 12, 2020. Available at: https://www.legis.state.pa.us/cfdocs/billinfo/billinfo.cfm?syear=2019&sind=0&body=H&type=B&bn=0427. Accessed February 17, 2026.

Truven Health Analytics Inc. Micromedex DrugDex® Compendium. Amivantamab-vmjw (Rybrevant). [Micromedex® Solutions Web site]. Updated 03/11/2025. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed February 17, 2026.

U.S. Food and Drug Administration (FDA). FDA approves first targeted therapy for subset of non-small cell lung cancer. FDA News Release. Silver Spring, MD: FDA; May 21, 2021.

US Food and Drug Administration (FDA). Amivantamab-vmjw (Rybrevant) prescribing information & approval letter. [FDA Web site]. 11/2025. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761210s007lbl.pdf. Accessed February 13, 2026.

US Food and Drug Administration (FDA). RYBREVANT FASPRO™ (amivantamab and hyaluronidase-lpuj) . [FDA Web site]. 12/2025. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761210s007lbl.pdf. Accessed February 13, 2026.

Zhou C, Tang K-J, Cho BC, et al. Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions. N Engl J Med. 2023;389:2039-2051.

Coding

CPT Procedure Code Number(s)

N/A

ICD - 10 Procedure Code Number(s)

N/A

ICD - 10 Diagnosis Code Number(s)

Report the most appropriate diagnosis code in support of medically necessary criteria as listed in the policy.

HCPCS Level II Code Number(s)

J9061 Injection, amivantamab-vmjw, 2 mg

THE FOLLOWING CODES ARE USED TO REPRESENT Rybrevant Faspro™ (Amivantamab and hyaluronidase-lpuj):

C9399 Unclassified drugs or biologics

J3590 Unclassified biologics

Revenue Code Number(s)

N/A

MPMiscCodesNarrativesPub

Coding and Billing Requirements

BILLING REQUIREMENTS (new)

If there is no specific HCPCS code available for the drug administered, then the drug must be reported with the most appropriate unlisted code along with the corresponding National Drug Code (NDC).

Cross Reference

Policy History

Revisions From 08.01.90c:

04/20/2026

This version of the policy will become effective 04/20/2026.

The following drug was added to this policy:

Amivantamab and hyaluronidase-lpuj (Rybrevant Faspro™) with the same indications as amivantamab-vmjw (Rybrevant®) in accordance with the US Food and Drug Administration (FDA) labeling 12/17/2025.

The title of the policy was changed as follows:
FROM: Amivantamab-vmjw (Rybrevant®)
TO: Amivantamab-vmjw (Rybrevant®) and Amivantamab and hyaluronidase-lpuj (Rybrevant Faspro™)

The following criterion has been revised to this policy in accordance with NCCN recommendations:

Added lazertinib to a subsequent therapy regimen and removed EGFR S768I, L861Q, and G719X from this regimen.
Subsequent-line amivantamab + lazertinib after osimertinib.
Subsequent-line amivantamab + lazertinib after (platinum)/osimertinib/pemetrexed.

The following indication has been added to this policy in accordance with NCCN recommendations:

CNS/brain metastases systemic therapy

The following NOC code has been added to this policy, which is used to represent Amivantamab and hyaluronidase-lpuj (Rybrevant Faspro™):

C9399 Unclassified drugs or biologics
J3590 Unclassified biologics

Revisions From 08.01.90b:

07/28/2025

This version of the policy will become effective 07/28/2025.

This policy has been updated to communicate the Company's coverage position for amivantamab-vmjw (Rybrevant®), in accordance with US Food and Drug Administration (FDA) prescribing information and National Comprehensive Cancer Network (NCCN) compendia.

The following criteria have been added to this policy in accordance with FDA labeling:

First-line treatment in combination with lazertinib (Lazcluze) for locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R substitution mutations
Subsequent therapy for advanced or metastatic NSCLC disease EGFR exon 19 deletions or exon 21 (L858R) substitution mutations, following disease progression on or after treatment with an EGFR tyrosine kinase inhibitor.

The following criterion has been added to this policy in accordance with NCCN recommendations:

Continuation of treatment for EGFR exon 19 deletion or exon 21 L858R* recurrent, advanced, or metastatic NSCLC disease following disease progression on amivantamab-vmjw plus lazertinib for asymptomatic disease, symptomatic brain lesions, or symptomatic systemic limited progression

All of the ICD-10 CM codes have been removed from this policy, since they are informational. Report the most appropriate diagnosis code in su pport of medically necessary criteria as listed in the policy.

Revisions From 08.01.90a:

05/20/2024

This version of the policy will become effective 05/20/2024.

This policy has been updated to communicate the Company's coverage position for Amivantamab-vmjw (Rybrevant®), in accordance with US Food and Drug Administration (FDA) prescribing information and National Comprehensive Cancer Network (NCCN) compendia.

Policy criteria was updated to include new recommendations from FDA:

First-line treatment in combination with carboplatin and pemetrexed

Policy criteria was updated to include new recommendations from NCCN:

Subsequent therapy in combination with carboplatin and pemetrexed

Both regimens identified as a NCCN-preferrred regimen.

The following ICD-10 CM codes have been removed from this policy, due to specificity:

C34.00 Malignant neoplasm of unspecified main bronchus

C34.10 Malignant neoplasm of upper lobe, unspecified bronchus or lung

C34.30 Malignant neoplasm of lower lobe, unspecified bronchus or lung

C34.80 Malignant neoplasm of overlapping sites of unspecified bronchus and lung

C34.90 Malignant neoplasm of unspecified part of unspecified bronchus or lung

C78.00 Secondary malignant neoplasm of unspecified lung

Revisions From 08.01.90:

01/02/2024

The following new policy has been developed to communicate the Company’s coverage criteria for Amivantamab-vmjw (Rybrevant™). The policy will become effective on 01/02/2024.

Version Effective Date:

4/20/2026

Version Issued Date: