U.S. Food and Drug Administration (FDA)-Approved Indications

Rybrevant is indicated for the treatment of adult patients 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.

Compendial Uses

Recurrent, advanced, or metastatic EGFR exon 20 insertion mutation positive NSCLC

Amivantamab-vmjw is available as Rybrevant (Janssen Biotech, Inc.) and is a low-fucose human immunoglobulin GI-based bispecific antibody that binds the extracellular domains of epidermal growth receptor factor (EGFR) and mesenchymal-epithelial transition (MET). In

and

studies, amivantamab-vmjw 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, 2021a).

Per the prescribing information, amivantamab-vmjw (Rybrevant) carries the following warnings and precautions:

The most frequent adverse reactions (≥20%) were rash, IRR, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting (Janssen, 2021a).

The most frequent Grade 3 or 4 laboratory abnormalities (≥2%) were decreased lymphocytes, decreased albumin, decreased phosphate, decreased potassium, increased alkaline phosphatase, increased glucose, increased gamma-glutamyl transferase, and decreased sodium(Janssen, 2021a).

Non-Small Cell Lung Cancer (NSCLC)

Globally, lung cancer is the most prevalent cancer type and the leading cause cancer-related mortality, of which, non-small cell lung cancer is responsible for 80% to 85% of all lung cancers per the American Cancer Society. An estimated 2% to 3% of patients with non-small cell lung cancer 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 (FDA, 2021).

On May 21, 2021, the U.S. Food and Drug Administration (FDA) approved Rybrevant (amivantamab-vmjw) for the treatment of adult patients 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. The FDA granted accelerated approval based on Priority Review and Breakthrough Therapy designation for the non-small cell lung cancer indication. The FDA approval was based on supporting data from the ongoing Phase I CHRYSALIS study (Janssen, 2021).

The Phase I CHRYSALIS study consisted of a multicenter, open-label, multi-cohort clinical trial which included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy. Rybrevant was administered as an intravenous infusion 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 efficacy of Rybrevant was evaluated in a population of 81 patients 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% to 51%), with 3.7% achieving complete responses (CR) and 36% having partial responses (PR). The median DOR was 11.1 months (95% CI, 6.9 months to not estimable) with 63% of patients having a DOR of 6 months or more (Janssen, 2021a).

Combined Amivantamab and Lazertinib for the Treatment of EGFR Mutation-Positive Non-Small-Cell Lung Cancer

Cho et al (2022) stated that 3rd-generation EGFR tyrosine kinase inhibitors (TKIs), such as osimertinib, have shown effectiveness in patients with EGFR-mutant NSCLC; however, almost all patients will eventually relapse. Amivantamab is an EGFR-MET bi-specific antibody with immune cell-directing activity that targets activating and resistance EGFR mutations and MET mutations and amplifications. In the ongoing CHRYSALIS Trial, amivantamab in combination with lazertinib, a potent, brain-penetrant 3rd-generation EGFR TKI, demonstrated anti-tumor activity in the treatment-naive and osimertinib-relapsed setting. These researchers presented the methodology for the MARIPOSA Trial, a randomized, multi-center, phase-III clinical trial designed to compare the safety and effectiveness of amivantamab and lazertinib combination therapy versus single-agent osimertinib as 1st-line treatment for EGFR-mutant NSCLC.

Gastro-Esophageal Cancer

Maron et al (2022) noted that subset analyses from phase-III clinical trials of EGFRi suggested improved outcomes in patients with EGFR-amplified gastro-esophageal adenocarcinoma (GEA); however, large-scale analyses are lacking. In a multi-center analysis , these investigators examined the role of EGFRi in the largest cohort of patients with EGFR-amplified GEA to-date. A total of 60 patients from 15 tertiary cancer centers in 6 countries met the inclusion criteria. These criteria required histologically confirmed GEA in the metastatic or unresectable setting with EGFR amplification identified by using a Clinical Laboratory Improvement Amendments (CLIA)-approved assay, and who received on- or off-protocol EGFRi. Testing could be by tissue next-generation sequencing (NGS), plasma circulating tumor DNA NGS, and/or fluorescence in-situ hybridization (FISH) carried out by a CLIA- approved laboratory. Treatment patterns and outcomes analysis was also carried out using a de-identified clinic-genomic database (CGDB). A total of 60 patients with EGFR-amplified GEA received EGFRi, including 31 of 60 patients (52 %) with concurrent chemotherapy. Across treatment lines, patients achieved a 43 % ORR with a median progression-free survival (PFS) of 4.6 months (95 % CI: 3.5 to 6.4). Patients receiving EGFRi in 1st-, 2nd-, and 3rd-line therapy achieved a median overall survival (OS) of 20.6 months (95 % CI: 13.5 to not reached [NR]), 9 months (95 % CI: 7.9 to NR), and 8.4 months (7.6 to NR), respectively. This survival far exceeded the 11.2-month (95 % CI: 8.7 to 14.2) median OS from 1st-line initiation of non-EGFRi therapy in patients with EGFR-amplified GEA in the CGDB. Despite this benefit, analysis of the CGDB (January 2011 to December 2020) suggested that only 5 % of patients with EGFR-amplified GEA received EGFRi. The authors concluded that patients with EGFR-amplified GEA derived significant benefit from EGFRi. Moreover, these researchers stated that further prospective investigation of EGFRi in a well-selected patient population is ongoing in an upcoming trial of amivantamab in EGFR and/or MET amplified GEA.

: Requires Precertification:

Precertification of amivantamab-vmjw (Rybrevant) is required of all Aetna participating providers and members in applicable plan designs. For precertification of amivantamab-vmjw (Rybrevant), call (866) 752-7021 (commercial), or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see

.

For Medicare Part B plans, call (866) 503-0857, or fax (844) 268-7263.

Criteria for Initial Approval

Non-Small Cell Lung Cancer (NSCLC)

Aetna considers amivantamab-vmjw (Rybrevant) medically necessary for treatment of NSCLC when

of the following criteria are met:

Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

Continuation of Therapy

Aetna considers continuation of amivantamab-vmjw (Rybrevant) therapy medically necessary in members requesting reauthorization for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Dosage and Administration

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

Non-Small Cell Lung Cancer (NSCLC)

The recommended doses of Rybrevant are based on baseline body weight as the following:

Rybrevant is administered weekly (total of 4 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.

Source: Janssen, 2021a

Experimental and Investigational

Aetna considers amivantamab experimental and investigational for the treatment of gastro-esophageal cancer.

Aetna considers combined combined amivantamab and lazertinib experimental and investigational for the treatment of EGFR mutation-positive non-small-cell lung cancer.