Abstract 3081: DZD9008, an oral, wild type selective EGFR inhibitor for the treatment of non-small-cell lung cancer with Exon20 insertion and other activating mutations

Background: Several EGFR TKIs have been approved for the treatment of non-small cell lung cancer (NSCLC) with L858R mutation, Exon 19 deletion, and T790M mutations. However, for patients with uncommon mutations, such as EGFR or HER2 Exon20ins, there lacks safe and effective therapy. All Exon20ins inhibitors under clinical development have a negative selectivity profile, inhibiting wild type EGFR more potently than mutant ones. Consequently, severe wild type EGFR-driven toxicities have been observed in patients. DZD9008 is an oral, potent, irreversible, wild type-selective EGFR TKI against EGFR or HER2 Exon20ins and other mutations. The present study shows anti-tumor activity of DZD9008 in tumor cell lines and xenograft models. Materials and Methods: The enzyme assay was performed by incubating DZD9008 with recombinant enzymes at 2 mM ATP concentrations. The cellular activity of DZD9008, including phosphorylation of EGFR or HER2 and cell proliferation, was evaluated in a panel of cell lines expressing wild type EGFR, mutant EGFR or HER2, using MSD assay and CellTiter-Glo assays. DZD9008 in vivo anti-tumor activity was evaluated in both cell line-derived (CDX) and patient-derived xenograft (PDX) models, carrying EGFR single or double mutations, Exon20ins mutations, and wild type EGFR. Results: The enzymatic IC50 of DZD9008 in mutant EGFR ranges from 0.4 to 2.1 nM. DZD9008 downregulated pEGFR with IC50 ranging from 1 to 22 nM in a panel of tumor cell lines expressing EGFR L858R, Exon19del, L858R/T790M, various Exon20ins or uncommon mutations. Similar activity against pHER2 was observed in tumor cells with HER2 Exon20ins mutation, with IC50 at 7 nM. In contrast, DZD9008 was less potent in modulating pEGFR in tumor cells expressing wild type EGFR, with IC50 greater than 80 nM. In cell proliferation assays, DZD9008 suppressed cell proliferation with GI50 of 1 to 60 nM in tumor cells carrying EGFR L858R, Exon19del, L858R/T790M, various Exon20ins or uncommon mutations. In CDX and PDX models carrying EGFR Exon19del single mutation, L858R/T790M double mutations, and PDX models harboring G719S/L861Q or Exon20ins, DZD9008 induced dose dependent tumor growth inhibition and regression. Good PK/PD relationship was established across these tumor models. Conclusion: DZD9008 is a potential EGFR TKI for NSCLC patients with EGFR or HER2 Exon20ins and other activating mutations. Citation Format: Yan Xu, Lin Zhang, Lifang Zhu, Yingchun Wang, Mei Wang, Zhenfan Yang. DZD9008, an oral, wild type selective EGFR inhibitor for the treatment of non-small-cell lung cancer with Exon20 insertion and other activating mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3081.