BEBT-109

EGFR mutation-positive NSCLC tumors are highly heterogeneous, therefore, exploring an agent simultaneously targeting multiple EGFR mutations may be valuable for clinical practice. Compared with osimertinib, BEBT-109 shows more sensitive and extensive antitumor activity in EGFR mutant NSCLC, while sparing wild-type EGFR cell lines. Meanwhile, unlike the metabolite of osimertinib AZ5104, the main metabolites of BEBT-109 are found lacking in activity against wild-type EGFR cell lines. Preclinical and clinical studies demonstrate a unique pharmacokinetic profiles of BEBT-109 with rapid absorption and quick in vivo clearance without accumulation, which are conducive to minimizing the off-target toxicity of the covalent irreversible EGFR inhibitor. Oral administration of BEBT-109 induces tumor regression in EGFR exon 20 insertion xenografts, and even tumor disappearance in PC-9, HCC827 and H1975 xenograft models. Furthermore, in clinical trials, the objective responses were observed in NSCLC patients with EGFR T790M mutation in the first and second dosing cohorts. These findings demonstrate that BEBT-109, a potent pan-mutant-selective EGFR inhibitor with improved pharmacokinetic properties, might offer a promising new option for the treatment of multiple mutant-EGFR-driven NSCLC.

Lung cancer remains a leading cause of mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for ~85% of all lung cancer cases. Epidermal growth factor receptor (EGFR) exon 20 insertion mutant NSCLC is rare and associated with poor outcomes. Several novel generations (third-generation) of EGFR-tyrosine kinase inhibitors (TKIs) have been developed for the treatment of NSCLC and have shown antitumour potential. Therefore, the present study reviewed their efficacy and safety outcomes for this condition. A thorough literature searching was performed using the Cochrane Library, Web of Science, PubMed and Embase databases. Clinical trials published in English and reporting overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and treatment relevant adverse events (TRAEs) of grade ≥3 were included for further analysis. A total of 13 studies were included. All included studies reported ORRs with a pooled ORR of 0.486 [95% confidence interval (CI), 0.369-0.602]. Subgroup analysis revealed the following ORRs: 0.731 (95% CI, 0.560-0.901; I²=0%) for YK-029A; 0.608 (95% CI, 0.511-0.705; I²=0%) for sunvozertinib; 0.602 (95% CI, 0.440-0.764; I²=80.2%) for furmonertinib; 0.602 (95% CI, 0.486-0.718; I²=84.5%) for befotertinib; 0.566 (95% CI, 0.236-0.896; I²=96.3%) for amivantamab; 0.444 (95% CI, 0.215-0.674; I²=0%) for BEBT-109; and 0.256 (95% CI, 0.178-0.334; I²=75.0%) for poziotinib. The pooled DCR, median PFS and median OS were 0.843 (95% CI, 0.740-0.946), 10.11 months (95% CI, 9.58-10.64 months; I²=78.8%; P<0.001) and 23.00 months (95% CI, 20.30-25.69 months; I²=44.8; P=0.178), respectively. The pooled incidence of TRAEs of grade ≥3 was 0.458 (95% CI, 0.336-0.580; I²=96.9%; P<0.001), with the incidence of the three most reported TRAEs (diarrhoea, thrombocytopenia and anaemia) demonstrated to be 0.112 (95% CI, 0.060-0.164), 0.065 (95% CI, -0.012-0.141) and 0.040 (95% CI, 0.005-0.076), respectively. In conclusion, the emerging EGFR-TKIs for NSCLC with EGFR exon 20 insertion have a promising treatment outcome with a manageable safety profile. However, further analysis is needed when more clinical data are released.