Prof. Cho, head of the lung cancer center at Yonsei Cancer Hospital, "J INTS BIO’s new oral administration 4th generation EGFR TKI ‘JIN-A02' expected to be a game changer”

Prof. Cho Byoung-chul at Yonsei University College of Medicine (Director, Lung Cancer Center, Yonsei Cancer Hospital) is one of the most influential researchers in the lung cancer field and is involved in the development of innovative new drugs globally. Although the survival rate of patients with EGFR mutation positive NSCLC has improved significantly with the discovery of TKI (tyrosine kinase inhibitor), the continuous occurrence of resistant mutations as the result of the use of these TKI is leading to cancer recurrence and relapse. Accordingly, our Journal met with Prof. Cho to seek his opinion and assessment on the standard of care for EGFR positive NSCLC, its treatment limitations and how he views the new 4th Generation oral TKI, ‘JIN-A02’, which is currently in development.   1) What is the standard of care patients with EGFR positive NSCLC? EGFR mutant lung cancer accounts for the largest proportion of all lung cancers. 30-40% of NSCLC patients worldwide are EGFR-positive lung cancer patients. The most important treatment for EGFR mutant lung cancer is EGFR-targeted therapeutics. Currently approved EGFR-targeted therapeutics include Iressa and Tarceva in the 1st generation, Giotrif in the 2nd generation, and Tagrisso and Leclaza in the 3rd generation. These targeted therapeutics have been approved and are being used in patients.   2) What is your experience with the use of 3rd Generation EGFR TKI and what are your concerns? Drugs such as 3rd-generation EGFR-TKIs, such as Leclaza and Tagrisso, are targeted therapeutics that are prioritized as first-line or second-line agents for stage IV EGFR mutant lung cancer. These drugs show better anticancer effects compared to the existing 1st and 2nd generation TKIs and have brain permeability, for brain metastasis.  But these 3rd generation TKIs also have limitations, and resistance develops in most patients leading to cancer recurrence and relapse. On average, after 16 to 18 months with the use of 3rd generation TKIs, most patients develop resistance.   3) What are the attributes of the 4th generation EGFR TKI that you are looking for? The most important attribute is effectiveness against EGFR C797S mutation, which occurs when the cysteine at codon 797 is substituted with serine and is known to occur in up to 20% of all resistant patients.  Secondly, it must have good brain penetrance to act against brain metastasis. Finally, the toxicity seen in patients should be low. If it has all these attributes, it is the 4th generation TKI that is urgently needed in clinical practice.   4) Having participated in J INTS BIO’s Advisory Board meetings and reviewing the data of their novel oral 4th generation EGFR TKI ‘JIN-A02’, what is your assessment? For more than 15 years, I have had numerous cancer translational and clinical research experiences with domestic and global companies. J INTS BIO's 'JIN-A02' compound is among the best I have seen so far. First, it showed excellent antitumor effect in both in-vitro and in-vivo studies against C797S mutation, which is an important resistance mechanism which I mentioned earlier. This is especially so with the increasing global use of 3rd generations TKIs as first line treatment, which will lead to more patients with C797S mutations. Second, ‘JIN-A02’ is also effective again primary EGFR mutations such as Exon 19 deletion, L858R mutation, and T790M mutations which arose from the use of first- and second-generation TKIs. These resistant mutations tend to coexist leading to tumor heterogeneity. 'JIN-A02' is different from other drug substances under development because it is effective against all these EGFR mutations, primary or acquired. Finally, animal study results confirmed that 'JIN-A02' showed high brain penetrance with excellent antitumor effect on brain metastasis. Considering these excellent antitumor effect and safety of 'JIN-A02', I have no doubt that 'JIN-A02' will bring hope to many patients with EGFR mutation lung cancer who are resistant to 3rd generation EGFR TKIs in the upcoming Phase 1 clinical trial.   박원중 기자 (park.wonjun.ja@gmail.com)cancer administration lung cancers cancer hospital generation oral