Abstract 1875A: Preclinical proof of concept for the first Nanocyclix TKI-PET radiotracer targeting activated EGFR positive lung tumors
Authors: Genne Philippe , Berthet Cyril , Raguin Olivier , Chalon Sylvie , Tizon Xavier , Serriere Sophie , Provent Peggy , Boisferon Marc Hillairet de , Vercouillie Johnny , Mothes Céline , Gourand Fabienne , BARRE Louisa , Guilloteau Denis , Blom Pétra , Hoflack Jan 
Published: July 2017

Background: IMAkinib® program is an innovative approach, based on Nanocyclix® chemistry technology, which aims to develop new Tyrosine Kinase Inhibitors (TKIs) radiotracers used for Positron Emission Tomography (PET). The epidermal growth factor receptor (EGFR) is an established target for the treatment of advanced non-small cell lung cancer (NSCLC). Gefitinib (Iressa®), erlotinib (Tarceva®) and afatinib (Giotrif®), TKIs targeting EGFR have already been approved for treatment of advanced non-small cell lung cancer (NSCLC). Unfortunately, the majority of patients develop a resistance to the TKI, which is for most of them (&gt; 50%) related to an acquired T790M mutation of EGFR. TKI PET-imaging can provide a tool to determine and predict the activity of EGFR and the responsiveness to EGFR TKI.

Methods: New compound ODS2004436 was characterized in vitro for its activity and metabolism. After radiolabeling with [18F], the compound was evaluated in vivo in three clinically relevant lung cancer cell lines (NCI-H441 – EGFR_wild-type (WT); NCI-H3255 - EGFR_L858R; NCI-H1975 – EGFR_L858R/T790M) xenografted in nude rats.

Results: The biochemical and cellular profiles were comparable to gefitinib on EGFR_WT and activated EGFR_L858R mutant. The cellular activity was in the nanomolar range (5 ± 2 nM) on NCI-H3255 and weak on NCI-H441 (42 ± 27 µM) suggesting that our compound might inhibit to a lesser extent non activated WT-EGFR. We observed a better biochemical inhibition (254 nM vs 1350 nM) and cellular activity on NCI-H1975, the EGFR double mutant (4.8 ± 0.7 µM vs 18 ± 8.7 µM) of ODS2004436 compared to gefitinib. These data suggest that our compound is suitable to bind in vivo activated EGFR. In vitro binding experiments showed that [18F]-ODS2004436 specifically bound to patient tumor samples expressing EGFR. The in vivo experiments in rats showed that [18F]-ODS2004436 was rapidly cleared from the blood. Nevertheless the tumor uptake is stable overtime (up to 180 min) with a mean tumor/muscle ratio &gt; 4 in NCI-H3255 and &gt; 2 in NCI-H1975 at 90 min instead no specific binding was observed in the WT tumor, NCI-H441. Moreover, we observed a good correlation between the radiotracer uptake in the tumors and pEGFR immunostaining, suggesting that [18F]-ODS2004436 is a good biomarker of activated EGFR, regardless of the mutation.

Conclusions: Based on this study, we proved in vivo that [18F]-ODS2004436 binds selectively to activated EGFR, and is a good candidate to evaluate the EGFR activity in NLCSC using PET imaging. Clinical evaluation of this novel radiotracer is ongoing (first in-man phase 0/I clinical trial NCT02847377).

Citation Format: Philippe Genne, Cyril Berthet, Olivier Raguin, Sylvie Chalon, Xavier Tizon, Sophie Serriere, Peggy Provent, Marc Hillairet de Boisferon, Johnny Vercouillie, Céline Mothes, Fabienne Gourand, Louisa BARRE, Denis Guilloteau, Pétra Blom, Jan Hoflack. Preclinical proof of concept for the first Nanocyclix TKI-PET radiotracer targeting activated EGFR positive lung tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1875A. doi:10.1158/1538-7445.AM2017-1875A