999P - JIN-A02, a fourth-generation, highly effective tyrosine kinase inhibitor with intracranial activity, targeting EGFR C797S mutations in NSCLC

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 3^rd 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 in vivo intracranial activity, NCI-H1975 cell line derived tumor xenograft was used.

Results

In AlphaLISA assay, JIN-A02 showed high potency in EGFR^{ex19del/T790M/C797S} (IC₅₀=4.7 nM, Ba/F3), EGFR^{L858R/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 EGFR^{ex19del/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 EGFR^{ex19del/T790M} (IC₅₀=84.4 nM for PC-9GR), and EGFR^L858R/T790M (IC₅₀=73.3 nM for NCI-H1975). In the PDX mouse model (YHIM-1094, EGFR^{ex19del/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 EGFR^{ex19del/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.

Clinical trial identification

Editorial acknowledgement

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.