NON-SMALL CELL LUNG CANCER (NSCLC)
Globally, lung cancer is the most prevalent cancer type and the leading cause cancer-related mortality, of which, NSCLC is responsible for 80% to 85% of all lung cancers per the American Cancer Society. 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 (FDA, 2021).
AMIVANTAMAB-VMJW (RYBREVANT)
Amivantamab-vmjw (Rybrevant) 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 in vitro and in vivo 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 Biotech Inc., 2021a).
PEER-REVIEWED LITERATURE
NON-SMALL CELL LUNG CANCER
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).
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 + pemetrexed (n=153) or carboplatin + 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 + pemetrexed compared with those who received carboplatin + 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 + pemetrexed group (4% CR, 63% PR) and 36% (95% CI, 29–44) for the carboplatin + 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.
COMBINED AMIVANTAMAB AND LAZERTINIB FOR THE TREATMENT OF EGFR MUTATION–POSITIVE NSCLC
Cho et al. (2022) stated that third-generation EGFR tyrosine kinase inhibitors (TKIs), such as osimertinib, have shown effectiveness in individuals with EGFR-mutant NSCLC; however, almost all individuals 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 third-generation EGFR TKI, demonstrated antitumor activity in the treatment-naive and osimertinib-relapsed setting. These researchers presented the methodology for the MARIPOSA Trial, a randomized, multicenter, phase III clinical trial designed to compare the safety and effectiveness of amivantamab and lazertinib combination therapy versus single-agent osimertinib as first-line treatment for EGFR-mutant NSCLC.
SUMMARY
Amivantamab-vmjw (Rybrevant), a bispecific epidermal growth factor receptor (EGFR) and MET receptor–directed antibody, was approved by the U.S. Food and Drug Administration (FDA) in May 2021 for the treatment of locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, in individuals whose disease has progressed on or after platinum-based chemotherapy. This indication is approved under accelerated approval based on ORR and DOR. The safety and efficacy of amivantamab was evaluated in a phase I, open-label study of individuals with metastatic or unresectable NSCLC and EGFR exon 20 mutations whose disease had progressed on or after platinum-based chemotherapy (CHRYSALIS, NCT02609776). Included individuals (median age, 62 years) received amivantamab 1050 mg (baseline body weight <80 kg) or 1400 mg (baseline body weight ≥80 kg) once weekly for 4 weeks, then every 2 weeks thereafter until disease progression or unacceptable toxicity. Amivantamab produced an ORR of 40% (CR, 3.7%) in cohort individuals with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations who had progressed on or after platinum-based chemotherapy (n=81) from the CHRYSALIS trial. The median DOR was 11.1 months, with 63% of individuals having a DOR of 6 months or longer. Individuals had adenocarcinoma (95%), had received prior immunotherapy (46%), had previously treated brain metastases (22%), and received a median of 2 prior therapies (range, 1 to 7). National Comprehensive Cancer Network (NCCN) Guidelines for Non-Small Cell Lung Cancer (Version 7.2021) contain recommendations for the use of amivantamab in NSCLC.
The most frequent adverse reactions (≥20%) were rash, IRR, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting (Janssen Biotech Inc., 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 Biotech Inc., 2021a).
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.
