Abstract 2298: A potent and selective EGFR/HER2 exon 20 mutations inhibitor NIP142 induced tumor regression

Objective: Approximately 1.6-3.4% and 2-4% of NSCLC patients harbor EGFR or HER2 exon20 insertion mutations, respectively. No targeted therapy has been approved for these patients yet. NIP142 is a novel EGFR/HER2 inhibitor with potent inhibitory activities against above mentioned mutations. Purpose of this study is to provide evidence to support NIP142 as a clinical candidate for treatment of NSCLC driven by EGFR or HER2 exon20 insertion mutations. Method: Enzymatic activities of NIP142 were evaluated in EGFR/HER2 exon20 insertion mutants, including EGFR (D770_N771insNPG) and HER2 (V777_G778ins>CG). Anti-proliferative activities of NIP142 were evaluated in Ba/F3 cell lines with exon20 mutants (such as EGFR(D770_N771insSVD), EGFR(H773_V774insNPH), EGFR(V769_D770insASV), HER2(A775_G776insYVMA)), LU0387(EGFR-H773_V774insNPH), NCI-H1975 (EGFRL858R/T790M) and A431 (EGFRWT) cell lines. In vivo efficacy was evaluated in genetically engineered Ba/F3 (EGFR-D770_N771insSVD) mouse model, and LU0387 (EGFR-H773_V774insNPH) PDX model. Result: NIP142 displayed potent enzymatic inhibition activities in exon20 mutants, such as EGFR (D770_N771insNPG) (IC50 = 0.5 nM), HER2 (V777_G778ins>CG) (IC50 = 0.67 nM) and potent anti-proliferative activities in Ba/F3 cell lines with exon20 mutants, EGFR-D770_N771insSVD (IC50 = 32 nM), EGFR-H773_V774insNPH (IC50 = 32 nM), EGFR-V769_D770insASV (IC50 = 22 nM), HER2 A775_G776insYVMA (IC50 = 30 nM) respectively. NIP142 also exhibited potent anti-proliferative activities in NCI-H1975 (EGFRT790M\L858R) (IC50 = 9.4 nM), LU0387 (EGFR-H773_V774insNPH) (IC50 = 25 nM), and moderate anti-proliferation activity in EGFRWT A431cell line (IC50 = 37 nM). NIP142 was investigated in various CDX models. In particular, NIP142 significantly inhibited tumor growth in the LU0387 (EGFR-H773_V774insNPH) PDX tumor model of NSCLC, and tumor regression was achieved at 15 mg/kg. Conclusion: NIP142 is a potent EGFR/HER2 exon20 insertions inhibitor and showed excellent activities in preclinical in vitro assays and relevant tumor models. These results together with its preclinical safety data (not shown) support NIP142 to enter the clinical research to explore its potential for treating NSCLC with EGFR/HER2 exon20 insertions. Citation Format: Huijun Yin, Xu Yan, Weixue Tian, Guobiao Chu, Zhuo Wang, Xin Zhao, lu zhang, Xile Liu, Charles Z. Ding, Lihong Hu, Chengyuan Li, Gang Bai, Yuanfeng Xia, Chi-Chung Chan, Shuhui Chen. A potent and selective EGFR/HER2 exon 20 mutations inhibitor NIP142 induced tumor regression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2298.