Found 1 Presentation For Request "999P"
999P - JIN-A02, a fourth-generation, highly effective tyrosine kinase inhibitor with intracranial activity, targeting EGFR C797S mutations in NSCLC
- Mi Ran Yun (Seoul, Korea, Republic of)
Abstract
Background
Even though epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have improved treatment outcomes for EGFR-driven NSCLC, resistance inevitably emerges and disease often progresses due to brain metastasis. The C797S is the most significant resistance mutation to occur after 3rd generation TKIs treatment. JIN-A02 is an orally available EGFR-TKI targeting C797S mutation with high brain penetration.
Methods
Cellular activities of JIN-A02 were evaluated on phosphorylation-EGFR expression with AlphaLISA assay and on EGFR mutants with patients-derived cell (PDC) and patients-derived organoid (PDO). Different type of allelic relationship was also assessed in all models by whole exome sequencing. Patients-derived xenografts (PDX) was used to assess antitumor activities of JIN-A02. For
Results
In AlphaLISA assay, JIN-A02 showed high potency in EGFRex19del/T790M/C797S (IC50=4.7 nM, Ba/F3), EGFRL858R/T790M/C797S (IC50=12.8 nM, NCI-H1975 LTC). JIN-A02 strongly inhibited cellular activity of in trans model (IC50=89.7 nM, PDO) and in cis model (IC50=92.1 nM, PDC) of EGFRex19del/T790M/C797S. It appears to be superior to osimertinib (IC50 >4,000 nM for both cells). In addition, JIN-A02 showed comparable potency to osimertinib in EGFRex19del/T790M (IC50=84.4 nM for PC-9GR), and EGFRL858R/T790M (IC50=73.3 nM for NCI-H1975). In the PDX mouse model (YHIM-1094, EGFRex19del/T790M/C797S), JIN-A02 delayed tumor growth at a dose of 30 mg/kg. In the brain metastases model, antitumor activity of JIN-A02 was observed with intracranial implanted NCI-H1975 tumors.
Conclusions
JIN-A02 is highly potent EGFR-TKI for various EGFR targeted mutations including in cis and trans EGFRex19del/T790M/C797S and shows intracranial activity. Based on these robust activities for EGFR mutants, JIN-A02 is expected to provide a potential therapeutic opportunity for NSCLC.
Legal entity responsible for the study
Ji Eun Jung, Daan Cancer Laboratory, Yonsei University College of Medicine.
Funding
J INTS Bio.
Disclosure
All authors have declared no conflicts of interest.