Abstract 1326: WSD0922: A BBB penetrable EGFR/EGFRVIII inhibitor for the treatment of GBM and metastatic CNS tumor

Abstract

Abstract Aberrant activity caused by EGFRm+ (EGFRvIII/Del19/L858R) is implicated in the brain tumors such as GBM and DIPG, and metastatic CNS tumors of NSCLC, and cancer of HNSCC. To date, approved EGFRi has limited efficacy against brain tumors due to insufficient BBB penetration and/or poor activity against EGFRvIII. Moreover, GBM is a whole-brain disease and needs a BBB penetrable therapy for killing tumor cells beyond intact BBB. We report that WSD0922, a novel selective EGFRi, displays potent activity, excellent CNS penetration, good safety profile and preclinical anti-tumor efficacy. The IC50 of WSD0922 against EGFRm+ <10nM and the ex-vivo GI50 in GBM PDX with EGFRvIII is ~20nM. WSD0922 is highly selective over other kinases. WSD0922 treatment resulted in dose dependent inhibition on EGFRvIII phosphorylation and AKT phosphorylation in GBM PDX model and the in vivo PD modulation correlated well with PK and efficacy. WSD0922 treatment significantly prolonged the survival of mice with intracranial tumor of EGFRm+ NSCLC. WSD0922 treatment resulted in tumor regression on cetuximab resistant PDX model of HNSCC. In screening platform of squamous lung cancer PDX models, WSD0922 demonstrated remarkable tumor regression in 3 PDX models (platinum sensitive/insensitive/EGFRm+). WSD0922 is well tolerated in GLP tox at dose ~10x clinical equivalent dose. In addition, WSD0922 is predicted to be CNS penetrable with decent PK in human. The phase 1 clinical trial in US will be initiated in early 2019 with a design of 3+3 basket trial. Taken together, our data provide a good rationale for WSD0922 to be developed toward clinic for the treatment of patients with GBM, HNSCC (EGFR and/or EGFRvIII) and CNS metastasis of NSCLC (EGFRm+). Citation Format: Wei Zhong, Jinqiang Zhang, Ahihua Mu, Claire Sun. WSD0922: A BBB penetrable EGFR/EGFRVIII inhibitor for the treatment of GBM and metastatic CNS tumor [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 1326.