RYBREVANT - Resistance Mechanisms in EGFR Exon 20 Insertion-Mutated NSCLC

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-mutated 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-mutated 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 prospective, single-center study evaluated the clinical utility of ctDNA levels and molecular profiling in predicting clinical outcomes and assessment of resistance mechanisms using longitudinal paired ctDNA analysis of 62 samples from 25 patients with advanced EGFR Exon20ins mutation-positive NSCLC treated with RYBREVANT.⁴
  • Matched baseline and progression samples were available for 12 patients. Among these, 7 (58.3%) patients exhibited ≥1 de novo putative resistance mechanism to RYBREVANT that was not detected at baseline but emerged at progression.
  • The most frequently observed resistance alteration was EP300 deletion (n=3, 25%). Pathway-level analysis showed alterations in the RTK/RAS/PI3K/AKT and cell cycle gene alterations in 5 (41.6%) patients each. Alterations in the p53 and Hippo/NOTCH pathways were observed in 5 (41.6%) and 3 (25%) patients, respectively.
• 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 progression⁵:
  • 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 17 June 2026.