Abstract 5283
Background
ABN401 is a highly selective best-in-class Met inhibitor that is targeting MET-driven cancers. Met which is also known as a hepatocyte growth factor (HGF) receptor is encoded by the MET gene. MET alterations, including amplification and mutation, and Met overexpression are well known for tumorigenic transformation, tumor growth, angiogenesis, invasion, and metastasis in several cancer types, including gastric and non-small-cell lung cancer (NSCLC). ABN401 shows significant MET signaling inhibition in in vitro and in vivo preclinical studies, especially for cell lines, xenograft, and PDx models which have high MET amplification and/or MET exon 14 deletion.
Methods
In this study, to confirm the pharmacokinetic and pharmocodynamic correlation of ABN401, gastric cancer and NSCLC xenograft models were used. SNU-5, a gastric cancer cell line and EBC-1, a NSCLC cell line both of which has high MET amplification, were used for the xenograft model and dosed at 10 mg/kg and 30 mg/kg of ABN401 by oral administration. Pharmacokinetic parameters were analyzed in both plasma and tumor tissue samples. Pharmacodynamic biomarkers including Met and phospho-Met (T1234/1235) and downstream signaling were analyzed by immunoblotting. In addition, an expression of Met and phospho-Met were analyzed by immunohistochemistry.
Results
The PK results demonstrated that in both gastric and NSCLC xenograft models ABN401 drug was readily distributed to tumor tissues. According to both PD studies, ABN401 showed inhibitory effects of Met and downstream signaling in a time dependent manner for both cancer types. There was also correlated between the PK parameters in plasma and tumor samples and pharmacodynamics studies.
Conclusions
This preclinical PK/PD correlation study of ABN401 provides evidence for human dose predictions and dosing strategy for clinical studies.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Abion Inc.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
3887 - First Real Life Data on Durvalumab after definitive concomitant ChemoRadiotherapy (cCRT) in unresectable Stage (St) III Non-Small Cell Lung Cancer (NSCLC) in France: Analysis of 591 patients (pts) enrolled in the French cohort (c) Temporary Authorization of Use (ATU)
Presenter: Virginie Avrillon
Session: Poster Display session 1
Resources:
Abstract
682 - EGFR Inhibitor Versus Chemotherapy as Adjuvant Treatment for Locally-advanced EGFR-mutant Non-Small Cell Lung Cancer
Presenter: Peng Xie
Session: Poster Display session 1
Resources:
Abstract
2509 - Afatinib in EGFR TKI-naïve patients with EGFR mutation-positive (EGFRm+) NSCLC: interim analysis of a Phase IIIb, multi-national, open-label study
Presenter: Filippo de Marinis
Session: Poster Display session 1
Resources:
Abstract
3300 - First-line ceritinib versus chemotherapy in patients (pts) with advanced ALK rearranged (ALK+) non-small cell lung cancer (NSCLC): ASCEND-4 Asian subgroup analysis
Presenter: Daniel SW Tan
Session: Poster Display session 1
Resources:
Abstract
2653 - A combined analysis of two Phase IIIb studies of afatinib in EGFR TKI-naïve patients (pts) with EGFR mutation-positive (EGFRm+) NSCLC
Presenter: Filippo de Marinis
Session: Poster Display session 1
Resources:
Abstract
3663 - Impact of plasma EGFR mutation fractions on response to first generation tyrosine-kinase inhibitor in treatment of naïve non-small cell lung cancer patients
Presenter: Xiaohong Wang
Session: Poster Display session 1
Resources:
Abstract
5921 - Definition of an afatinib trough concentration threshold in the treatment of NSCLC
Presenter: Stephane Bouchet
Session: Poster Display session 1
Resources:
Abstract
2852 - A Phase Ib Trial of Neoadjuvant Chemoradiotherapy and Durvalumab(MEDI4736) for Potentially Resectable stage III Non-Small Cell Lung Cancer (NSCLC)
Presenter: Beung chul AHN
Session: Poster Display session 1
Resources:
Abstract
3273 - Low expression of Notch1 and combined Notch1/HES1 are associated with adverse survival factor for limited stage small cell lung cancer
Presenter: Jinsoo Lee
Session: Poster Display session 1
Resources:
Abstract
5141 - Mutational profiling of tumor tissue and sequential plasma illustrates emergent clones during treatment in late stage small cell lung cancer (SCLC)
Presenter: Stephanie Yaung
Session: Poster Display session 1
Resources:
Abstract