On July 4th, 2023, TYK Medicines stated that the Center for Drug Evaluation (CDE) has granted permission for the independently developed next-generation tyrosine kinase inhibitor (TKI) TY-4028 for clinical trials to be conducted in China.Previously, TY-4028 approved by the U.S. Food and Drug Administration (FDA) to conduct the clinical trial.

About TY-4028

TY-4028 is a novel, highly effective, and selective small-molecule tyrosine kinase inhibitor (TKI), independently developed by TYK Medicines, Inc, aiming for non-small cell lung cancer (NSCLC) harboring EGFR/HER2 exon 20 insertion mutations. Our preclinical data show that TY-4028 has a strong inhibitory effect on EGFR-sensitive mutations (e.g., EGFR exon 19 deletion, exon 21 mutation L858R) and exon 20 insertions, regulating the proliferation and apoptosis of tumor cells by inhibiting the phosphorylation of this transmembrane receptor protein and its downstream signaling molecules to achieve the effect of inhibiting tumor growth. TY-4028 has a weak inhibitory effect on wild-type EGFR (WT-EGFR), which avoids the toxic reactions associated with WT-EGFR. TY-4028 has demonstrated the marked antitumor effects in multiple types of lung cancer models with different exon 20 insertion mutations, as well as high tolerance and safety, laying a solid foundation for future clinical practice.

About EGFR exon 20 insertion mutations

In NSCLC, Epidermal growth factor receptor (EGFR) exon 20 insertions (EGFR exon 20ins) account for about 4-12% of EGFR mutations. The most common types are V769_D770insASV, D770_N771insSVD, and N771_H773dupNPH^[1,2,3]. However, in comparison to other common EGFR mutations (e.g., 19del, L858R mutation), existing 1st-3rd generation EGFR-TKIs are extremely ineffective in treating EGFR exon 20 insertions because of the shrink TKI-binding pocket, with semi-inhibitory concentrations (IC₅₀) as high as 0.1-10 mol/L, tens or even hundreds of times higher than the common resistance gene T790M, and only the A763Y764insFQEA mutation is highly sensitive, accounting for only 6% of all EGFR exon 20 insertions and 1% of all EGFR mutations^[4]. Therefore, there is an urgent need for effective targeted drugs for EGFR exon 20 insertions.

Figure1. Schematic of EGFR and HER2 exon 20 insertions ^[3]

Figure2. Mechanism of EGFR exon 20ins and 19del^[5]

About HER2 exon 20 insertion mutations

ErbB receptor tyrosine kinase (RTK) family has four members: epidermal growth factor receptor (EGFR), ErbB2 (HER 2), ErbB3, and ErbB4. HER2 combined with other members of the RTK family such as EGFR initiates signaling by causing specific homo- or heterodimeric receptor formation, and activates the cytoplasmic kinase domain, which phosphorylates the receptor tail region of tyrosine. Dysregulation of HER2 signaling is associated with HER2 amplification, overexpression, or mutation, and is a common oncogenic driver in a variety of tumors.

In non-small cell lung cancer (NSCLC), HER2 protein overexpression and gene amplification respectively account for 6-35 % and 10-20 %. Although HER2 mutations account for only 2-4% of cases, they may be more associated with lung cancer. HER2 mutations usually do not co-occur with other driver gene variants (such as EGFR/ALK), and the mutation rate is as high as 6.7% in EGFR/ALK/ROS1-negative NSCLC. Patients with HER2 mutations have characteristics similar to those with EGFR mutations, and they are more common in women, nonsmokers, and adenocarcinoma patients ^[6].

Fig3. ErB family and downstream signal pathways

References

[1] OXNARD G R, et al. Natural history and molecular characteristics of lung cancers harboring EGFR exon 20 insertions. J Thorac Oncol, 2013. 8: 179-184.

[2] ARCILA M E, et al. EGFR exon 20 insertion mutations in lung adenocarcinomas: prevalence, molecular heterogeneity, and clinicopathologic characteristics. Mol Cancer Ther, 2013. 12: 220-229.

[3] ROBICHAUX J P, et al. Mechanisms and clinical activity of an EGFR and HER2 exon 20-selective kinase inhibitor in non-small cell lung cancer. Nature, 2018. 24: 638-646.

[4] YASUDA H, et al. Structural, biochemical, and clinical characterization of epidermal growth factor receptor (EGFR) exon 20 insertion mutations in lung cancer. Sci Transl Med, 2013. 5: 216ra177.

[5] Vyse S, Huang PH: Targeting EGFR exon 20 insertion mutations in non-small cell lung cancer. Signal Transduct Target Ther 4:5, 2019

[6] HYNES N E, MACDONALD G. ErbB receptors and signaling pathways in cancer. Curr Opin Cell Biol, 2009. 21: 177-184.