Background: Currently approved EGFR TKIs have dissatisfactory efficacy in most advanced NSCLC with EGFR exon 20 insertion mutations (EGFRex20ins). Whereas，preclinical studies have shown that furmonertinib demonstrated significantly antitumor activity in NSCLC with EGFRex20ins in vitro and in vivo. Here, we analyzed the clinical efficacy of furmonertinib in patients(pts) who harboring EGFRex20ins and explored mechanism. Methods: A retrospective single-arm analysis was performed to evaluate the efficacy of 20 NSCLC pts harboring EGFRex20ins receiving furmonertinib treatment who were determined at three institutions between Feb 2021 to Jul 2022. ORR, DCR, PFS, DOR and OS were analysed. The last follow-up time was February 1, 2023. Meanwhile, we investigated the clinical efficacy of furmonertinib (8 pts) versus osimertinib (8 pts) 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, Schrödinger Inc., Portland, Oregon). Results: There are 10 (50.0%) females and the median age was 51 (32-77) years old. Of the 20 pts selected, we found that EGFRex20ins p.S768_D770dup (n = 5) variants were more common. 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, 7.00-13.40) months(mo). Median DOR was 8.5 (95 % CI, 5.08-11.92) mo. 13 pts were still alive by the last follow-up date. 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 = 0.148). 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. Conclusions: Furmonertinib might have positive clinical efficacy to advanced NSCLC pts with EGFRex20ins on account of its favorable binding activity to EGFRex20ins. It may be the optimal choice for these pts in the future.