11P Preclinical evaluation of DS-2087b, a novel and selective inhibitor of EGFR/HER2 exon 20 insertions

Abstract

Methods: Human BC tissue sections and tissue array were used to ascertain the clinical relevance of Angiomotin-p130 expressing in tumor cells and the formation of VM. We utilized MCF7 and MD-MBA-231 human tumor cells to observe VM in an orthotopic BC model and bevacizumab (anti-VEGF) was used to identify the resistance mechanism of antiangiogenic therapies in breast cancer. Later, tube formation assay was used to explore the efficacy of bevacizumab and anlotinib (anti-VEGFR,PDGFR,FGFR and c-Kit) in the inhibition of VM.Results: According to human datasets and histological analysis Angiomotin-p130 was identified as a bonafide candidate to regulation VM formation through in vitro and in vivo experiments. Stable overexpression of Angiomotin-p130 in tumor cells led to decreased tumor growth as well as incomplete VM structures in the animal models. We identified highly downregulated Angiomotin-p130 in human breast tumor cells and AAT-treated orthotopic mammary tumors. AAT-treated (bevacizumab and anlotinib) tumors displayed a higher number of Angiomotin-p130-negative tumor cells than endothelial-like phenotypes. Tube formation assay showed that the bevacizumab and anlotinib had no significant difference in inhibition on VM, though anlotinib inhibited the proliferation of tumor cells. Conclusions:The present study suggests that tumor cell autonomous Angiomotin-p130 pathway may play an important role in AAT-mediated resistance and VM formation in BC. Therefore, targeting Angiomotin-p130 can be combined with standard antiangiogenic therapies to improve the therapeutic outcomes in clinical trials.

Activity and Safety of Mobocertinib (TAK-788) in Previously Treated Non–Small Cell Lung Cancer with EGFR Exon 20 Insertion Mutations from a Phase I/II Trial

“…EGFRex20ins and demonstrated selectivity over WT EGFR (36) (40). Here, we present the results of a dose-escalation phase 1/2 trial with expansion cohorts that assessed the safety, tolerability, and antitumor activity of mobocertinib in patients with metastatic EGFRex20ins-mutated NSCLC.…”

Epidemiological and clinical burden of EGFR Exon 20 insertion in advanced non-small cell lung cancer: A systematic literature review

“…Results from our review showed limited data on the effectiveness and/or safety of IOs in patients with Exon 20ins, however, ongoing research will further assess the impact of PD-1/PD-L1 blockade in these patients, given recent findings that patients with EGFR Exon 20ins had increased PD-L1 expression and improved outcomes compared to those with HER2 Exon 20ins [ 61 ]. In addition, several emerging compounds, such as DS-2087b [ 62 ] and BLU-945 [ 63 ], have demonstrated anti-tumour activity in preclinical studies. It should be noted that most studies identified in this SLR included a small number of patients with Exon 20ins, and there was considerable heterogeneity in the clinical and demographic characteristics of the enrolled patients.…”

TargetingHER2Exon 20 Insertion–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib

“…Tarloxotinib, a hypoxia-activated prodrug of a pan-HER TKI, exhibits antitumor activity in HER2 activating mutant NSCLC patient (33). DS-2087b, a selective inhibitor of EGFR/HER2 exon 20 insertions, demonstrated in vitro and in vivo inhibition in preclinical assays (34). Poziotinib demonstrated some efficacy in patients with HER2 mutations, but it was associated with high rates of WT EGFRmediated toxicity (23,35).…”