39P Preliminary clinical investigations and mechanism exploration of furmonertinib in NSCLC with EGFR exon 20 insertion

Here we analyzed the clinical efficacy of furmonertinib, a novel 3rd generation EGFR TKI, in advanced NSCLC patients (pts) who harboring EGFRex20ins and explored mechanism. A retrospective single-arm analysis was performed to evaluate the efficacy of 20 NSCLC pts harboring EGFRex20ins receiving furmonertinib treatment from three institutions. Meanwhile, we investigated the clinical efficacy of furmonertinib versus osimertinib as second-line treatment, because pts about furmonertinib as first-line treatment were immature. In addition, the binding activity of different EGFR TKIs to EGFRex20ins were computationally constructed based on the crystal structure of EGFR_D770_N771insNPG/V948R (PDB ID: 7LGS) by the Schrödinger software (2021–2 Release). Of the 20 pts selected, we found that EGFRex20ins p. S768_D770dup (n = 5) variants were more common. Six first-line pts all achieved PR (ORR: 100%), five of the eight second-line pts achieved PR (ORR: 62.5%), and three of the six multiple-line pts achieved PR (ORR: 50.0%). We observed 14 pts with PR and six pts with SD as best response to furmonertinib (ORR: 70.0%, DCR: 100%). All pts showed tumor shrinkage in target lesions (median best percent change, –36.43% [–74.78%, –5.56%]). Median PFS was 10.2 (95% CI, 7.19–13.21) months (mo). Median DOR was 8.5 (95% CI, 4.97–12.03) mo. Comparative analysis of the efficacy of different groups showed that median PFS was significantly longer in furmonertinib group than in osimertinib (10.2 vs 3.8 mo, p = 0.008). Median OS was numerically longer in furmonertinib group than in osimertinib (18.9 vs 11.7 mo, p = 0.207). No grade 3 or above adverse events were observed. Furthermore, rather than erlotinib (GlideScore: –5.564; MM/GBSA: –52.8044), gefitinib (–7.68; –47.317), and afatinib (–5.075; –44.64), furmonertinib (–11.085; –68.1575) and osimertinib (–10.031; –63.87) revealed favorable binding activity to EGFRex20ins, with furmonertinib being the most significant. Furmonertinib has positive clinical efficacy to advanced NSCLC pts with EGFRex20ins probably based on its favorable binding activity to EGFRex20ins. Furmonertinib may be the optimal choice for these pts in the future.