Prospective investigation of biomarker and resistance mechanism using longitudinal cell-free NGS in non-small cell lung cancer with EGFR exon 20 insertion treated with amivantamab.

BACKGROUND

There has been little investigation of predictive biomarkers and resistance mechanisms of amivantamab, an EGFR, and MET targeting bispecific antibody in EGFR ex20ins. Here, we investigated the correlation of molecular profile with clinical outcome using cell-free NGS (cf-NGS) in patients treated with amivantamab.

METHODS

Plasma samples from PCR or NGS-confirmed EGFR ex20ins patients (n = 30) treated with amivantamab were prospectively and longitudinally collected for analysis. The Guardant OMNI research-use-only assay was used for molecular profiling.

RESULTS

cfNGS analysis was performed on 62 samples from 25 patients. Baseline cfDNA-based NGS results demonstrated that patients with an EGFR ex20ins variant allele frequency (VAF) < 1 % (n = 11) showed higher objective response rate (45.4 vs 35.7 %), durable clinical benefit ratio (81.8 vs 21.4 %), and longer progression-free survival (PFS) (16.5 vs 2.6 months, hazard ratio [HR] 0.40, p < 0.01) compared to those with VAF ≥ 1 % (n = 14). The most common concurrent alteration was TP53 (n = 14, 56.0 %) which showed no correlation with clinical outcome while concomitant EGFR amplification (n = 9, 36.0 %) showed significantly shorter PFS (11.1 vs 2.7 months, HR 0.35, p < 0.05). Paired analysis showed a significant difference in PFS based on the dynamics of EGFR ex20ins VAF compared to the baseline and during treatment. Additionally, we identified several acquired resistance mechanisms to amivantamab.

CONCLUSIONS

Our findings underscore the significant predictive value of baseline EGFR ex20ins VAF for amivantamab treatment. Furthermore, changes in ctDNA VAF during treatment emphasize the role of early ctDNA dynamics as critical predictors of therapeutic response and long-term outcomes, which may inform treatment strategies.