Dr Besse on Mechanisms of Acquired Resistance in EGFR+ Advanced NSCLC

Benjamin Besse, MD, PhD, director, clinical research, Gustave Roussy Institute; professor, medical oncology, Paris-Saclay University, discusses mechanisms of acquired resistance to frontline amivantamab-vmjw (Rybrevant) plus lazertinib (Lacluze) compared with osimertinib (Tagrisso) in patients with EGFR-mutant, advanced non–small cell lung cancer (NSCLC), as evaluated in an analysis of the phase 3 MARIPOSA trial (NCT04487080).

MARIPOSA enrolled patients with locally advanced or metastatic NSCLC who were treatment naive for advanced disease, had a documented EGFR exon 19 deletion or L858R mutation, and an ECOG performance status of 0 or 1. Patients were randomly assigned 2:2:1 to receive amivantamab plus lazertinib (n = 429), osimertinib monotherapy (n = 429), or lazertinib monotherapy (n = 216). Blood samples were collected from patients at baseline and at the end of treatment for analysis of detectable circulating tumor DNA by next-generation sequencing.

This analysis was the first to report mechanisms of acquired resistance to amivantamab plus lazertinib, Besse says. Treatment with the combination of amivantamab and lazertinib significantly reduced the incidence of acquired MET amplifications and EGFR resistance mutations compared with osimertinib. At the end of treatment, the rate of MET amplifications was 13.6% in the osimertinib arm (n = 140) vs 4.4% in the amivantamab plus lazertinib arm (n = 113; P = .017). Furthermore, the rates of secondary EGFR resistance mutations, including C797S, L718X, and G724X, were 7.9% and 0.9% in these respective arms (P = .014). These findings demonstrate that amivantamab operates both through the MET pathway and by inhibiting EGFR, Besse explains.

No statistically significant differences in the incidence of other resistance mutations was observed between treatment arms. These included HER2 amplifications, RAS/RAF mutations, PI3K pathway mutations, cell cycle mutations, and TP53/RB1 loss. Notably, the rate of TP53/RB1 loss, which is associated with small cell lung cancer transformation, was 0.9% in the amivantamab/lazertinib arm. Among patients with known resistance mechanisms, those who received osimertinib had a more heterogeneous mutational landscape than those who received amivantamab plus lazertinib.