433P - Preclinical study of olmutinib (HM61713) with optimal dosing in ectopic and metastatic mouse model of EGFR-mutant (T790M-positive) non-small cell l...

Date 18 November 2017
Event ESMO Asia 2017 Congress
Session Poster lunch
Topics Basic Science
Non-Small-Cell Lung Cancer, Metastatic
Lung and other Thoracic Tumours
Presenter HO JEONG LEE
Citation Annals of Oncology (2017) 28 (suppl_10): x124-x143. 10.1093/annonc/mdx671
Authors H.J. LEE1, H. Yu1, Y. Ha1, J. Byun1, J. Oh1, T. Song1, S. Hong1, E.Y. Kim2, S. Jang3, G.Y. Kim4, Y.H. Kim4, K.H. Suh5, S.C. Kwon6, S. Kim6
  • 1Pharmacology, Hanmi Research Center, 18469 - Hwaseong-si/KR
  • 2Analysis Research Team Ii, Hanmi Research Center, 18469 - Hwaseong-si/KR
  • 3Nce Team, Hanmi Research Center, 18469 - Hwaseong-si/KR
  • 4Toxicology Team, Hanmi Research Center, 18469 - Hwaseong-si/KR
  • 5Nce Drug Discovery And Early Development, Hanmi Research Center, 18469 - Hwaseong-si/KR
  • 6R&d Center, Hanmi Research Center, 18469 - Hwaseong-si/KR

Abstract

Background

Olmutinib (HM61713) is the 3rd generation oral EGFR mutant specific tyrosine kinase inhibitor (TKI). In previous phase 1 and 2 studies, olmutinib has shown modest clinical activity and tolerability in NSCLC patients pre-exposed to EGFR TKI, harboring a T790M mutation. To improve clinical tolerability and specify the clinical indication, we further optimized the dose and regimens using the ectopic and brain metastasis mouse model of T790M+ NSCLC.

Methods

We assessed the PK/PD profile and in vivo efficacy of olmutinib at the various doses (from 40 to 160 mg/kg) in T790M+ NSCLC ectopic and brain metastasis mouse models. H1975 cells were subcutaneously implanted to nude mice or luciferase labeled H1975 cells were injected into the internal carotid artery of nude mice for the establishment of each model. Therapeutic efficacy of olmutinib was evaluated by tumor growth curve and apoptosis/proliferation indexes and PD markers were analyzed by immuno-histochemical staining of tumor tissues. The effect of olmutinib treatment on T790M+ NSCLC brain metastasis was evaluated by bioluminescence imaging and survival analysis of mice.

Results

Olmutinib treatment showed therapeutic efficacy by decreasing the tumor volumes in T790M+ NSCLC ectopic model. PK/PD analysis revealed that olmutinib treatment inhibited EGFR, Akt and MAPK phosphorylation up to 24 hours after administration. According to the immuno-histochemical analysis, proliferating cells were significantly decreased but apoptotic cells were dramatically increased in tumor tissues treated with olmutinib. Expression of activated Akt and MAPK in tumor tissues was decreased with olmutinib treatment even with low dose. Olmutinib treatment induced tumor shrinkage of brain metastasis and prolonged survival of mice harboring brain metastasis of T790M+ NSCLC.

Conclusions

Olmutinib treatment effectively inhibited EGFR pathway related factors in tumor tissues, which induced tumor regression in T790M+ NSCLC model. Optimal dosing of olmutinib may improve the clinical outcomes by maximizing therapeutic efficacy and minimizing toxicity in patients with EGFR-mutant NSCLC including brain metastasis.

Clinical trial identification

Legal entity responsible for the study

Hanmi Pharm. Co., Ltd.

Funding

Hanmi Pharm. Co., Ltd.

Disclosure

H.J. Lee, H. Yu, Y. Ha, J.-Y. Byun, J. Oh, T. Song, S. Hong, E.Y. Kim, S.-Y. Jang, G.Y. Kim, Y.H. Kim, K.H. Suh, S.-J. Kim: I am an employee of Hanmi Pharm. Co. Ltd.

All other authors have declared no conflicts of interest.