SUMMARY

• RYBREVANT (amivantamab-vmjw) is a low fucose, fully-human immunoglobulin G1 (IgG1)-based bispecific antibody with immune cell-directing activity that targets epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition (MET) mutations and amplifications in non-small cell lung cancer (NSCLC).¹
• A whole-genome and targeted sequencing study used tumor tissue DNA and cell-free (cf) DNA, respectively, to investigate the mechanism of resistance to EGFR Exon 20 insertion (Exon20ins)-specific inhibitors among 9 patients with EGFR Exon20ins-mutant NSCLC.²
  • DNA sequencing analysis before and after RYBREVANT treatment in 3 patients who experienced RYBREVANT failure revealed that 2 patients had chromosome 7p amplification, including EGFR and MACC1, after RYBREVANT failure.
• An exploratory analysis used plasma circulating tumor (ct) DNA samples from 27 patients with EGFR Exon20ins-mutant NSCLC to study the genomic landscape of the disease.³
  • Pairwise analysis using data collected at baseline and at the time of disease progression from 14 patients suggested that the putative mechanisms for resistance to RYBREVANT were:
    • PDGFRB mutations (28.5%)
    • PTEN mutations (21.4%)
    • CHEK2 mutations (21.4%)
• A retrospective case series identified potential mechanisms of resistance to anti-EGFR therapies in patients with EGFR-mutated NSCLC, including 2 patients with EGFR Exon20ins with disease progression under RYBREVANT treatment. At disease progression⁴:
  • One patient presented a gain on mutated EGFR allele frequency at progression (51%) compared to baseline (10%).
    • The TP53 signaling pathway was altered due to an acquired inactivating mutation in the TP53 gene (allele frequency: 37%) that was associated with a loss of heterozygosity (LOH).
    • There was an acquired mutation in the RB1 gene (allele frequency: 35%) that was associated with a LOH.
    • Ki67 expression was elevated (>90%) compared to baseline (20%). Tumor histology remained comparable to baseline (differentiated adenocarcinoma) and neuroendocrine markers were not seen.
  • One patient had a similar mutated EGFR allele frequency at progression (16%) compared to baseline (18%).
    • The TP53 signaling pathway was altered due to an acquired mutation in the TP53BP1 gene (allele frequency: 12%).
    • There was an acquired mutation in the FGFR1 gene (allele frequency: 2%).
    • Ki67 expression was elevated (50%) compared to baseline (10%) and neuroendocrine markers were not seen.

Literature Search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 29 July 2024.