Abstract 1962: PH009-1, a highly potent, selective and brain-penetrable fourth-generation EGFR-TKI that overcome classic and resistant EGFR mutations in NSCLC
Authors: Gao Feng , Wang Jing , Liu Bin , Wu Yongyong , Jing Liandong , Zhang Pengzhi , Gao Yu , Li Zhizhong , Guo Yongqi 
Published: March 2024

Background: Epidermal growth factor receptor (EGFR) inhibitors, especially 3rd Gen inhibitor such as osimertinib (Osi), have become the first line therapy for non-small cell lung cancer (NSCLC) patients with EGFR activating mutations. However, treatments with 3rd Gen EGFR inhibitors lead to occurrence of acquired C797S mutation in 10-24% of patients. Though studies showed that double mutations 19Del/C797S (DC) and L858R/C797S (LC) could be inhibited by 1st Gen EGFR TKIs, appearance of triple mutations 19Del/T790M/C797S (DTC) and L858R/T790M/C797S (LTC) always leads to treatment failure. In recent years, 4th Gen EGFR inhibitors have been developed such as BLU-945 and PH009-1. PH009-1 had been reported on AACR annual meeting 2023.

Methods: Cell activity and selectivity were determined in engineered Ba/F3 cell lines carrying EGFR wild type (WT, stimulated with EGF), 19Del (D), L858R (L), 19Del/T790M (DT), L858R/T790M (LT), DC, LC, DTC and LTC. The in vivo anti-tumor efficacy and PK-PD studies were performed in cell or patient derived xenograft (CDX or PDX) cancer models (HCC827, D; Ba/F3, LC; PDX, DTC). Brain penetration capability was tested in mice orally treated with PH009-1 for 7 days. Systemic safety of PH009-1 was evaluated in 28-day repeated dosing toxicity studies in rats and dogs following GLP guidelines.

Results: PH009-1 displayed potent anti-proliferation activity against Ba/F3 cells harboring EGFR mutations (L, D, LC, DC, LT, DT, LTC, DTC) with IC50 of 2.4, 1.3, 5.2, 1.2, 1.1, 1.5, 2.8, 1.9 nM, respectively, but had very weak effect on EGFR WT Ba/F3 cells (IC50, 1135 nM), suggesting excellent potency and selectivity. In contrast, though BLU-945 potently inhibited DT, LT, DTC, LTC with IC50 less than 5 nM, but its activities on L, D, LC, DC were not strong with IC50 of 31.6, 81.2, 46.2, and 52.0 nM. In in vivo efficacy studies, PH009-1 at a dose of 20 mg/kg BID led to potent inhibition on tumor growth and EGFR phosphorylation, and tumor regression was observed at higher doses in all tested models. In HCC827 model with 19Del (first line therapy setting), mice were treated for more than 200 days, and one tumor relapsed in BLU-945 group but not in PH009-1 or Osi group. Also, deaths were observed in Osi group, but not with PH009-1. After treated mice with PH009-1 at efficacious dose for 7 days, concentrations in cerebrospinal fluids (CSF) at 0-8 h post final dose were more than enough (≥1.5 fold) to cover IC80 on all tested mutations. In GLP toxicity studies, no unexpected toxicity was observed. In dogs. the highest tested dose was determined as highest non-severely toxic dose (HNSTD) and based on high plasma exposure, wide safety margin was confirmed with PH009-1.

Conclusion: Our data suggested that PH009-1 overcome T790M/C797S resistant mutations, and also have potential to become a potent and safe approach for first line therapy of NSCLC with EGFR mutations.

Citation Format: Feng Gao, Jing Wang, Bin Liu, Yongyong Wu, Liandong Jing, Pengzhi Zhang, Yu Gao, Zhizhong Li, Yongqi Guo. PH009-1, a highly potent, selective and brain-penetrable fourth-generation EGFR-TKI that overcome classic and resistant EGFR mutations in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1962.