Ultra-deep sequencing of circulating free DNA to identify predictive, mutated HSP90 clients in GALAXY-1 (NCT01348126), a randomized phase 2b study o...

Date 27 March 2014
Event ELCC 2014
Session Poster Discussion 1
Topics Non-Small-Cell Lung Cancer, Metastatic
Translational Research
Presenter Dean Fennell
Citation Journal of Thoracic Oncology (2014) 9 (Supplement 9): S7-S52. 10.1097/JTO.0000000000000131
Authors D. Fennell1, J. Shaw2, I. El-Hariry3, V.M. Vukovic3, V. Reichert4, L.M. Martins5
  • 1Thoracic Medical Oncology, University Hospitals of Leicester Leicester Royal Infirmary, LE1 9HN - Leicester/UK
  • 2Cancer Studies And Molecular Medicine, University of Leicester, LE2 7 LX - Leicester/UK
  • 3Clinical, Synta Pharmaceuticals, 02421 - Lexington/US
  • 4Translational Research, Synta Pharmaceuticals, 02421 - Lexington/US
  • 5Cell Death Regulation Laboratory, MRC Toxicology Unit, Leicester/UK

Abstract

Aim

Inhibition of Hsp90, a key molecular chaperone required for activation of many oncoproteins critical to NSCLC growth and aggressiveness, can lead to cancer cell death. Ganetespib (G) is a 2nd generation Hsp90 inhibitor (Hsp90i) that has shown single agent clinical activity in patients with tumors harboring ALK, KRAS, HER2, and BRAF mutations. Circulating free DNA (cfDNA) is present at low levels in plasma of healthy individuals allowing detection of somatic mutations by deep sequencing. The aim of this work was to determine the mutational spectrum of patients enrolled into the GALAXY-1 trial using this liquid biopsy strategy.

Methods

Prospective exploratory analysis was performed to identify plasma-borne somatic mutations as predictors of clinical outcome with G in GALAXY-1. Plasma samples were collected from approximately 318 patients with adenocarcinoma at baseline prior to initiation of treatment, during cycles 1 and 2, and end of treatment. cfDNA samples were evaluated using the Ion AmpliSeq™ Cancer Panel on the Ion Torrent |PGM platform to survey 739 amplicons in 46 cancer genes at up to 6000x depth.

Results

CfDNA targeted sequence analysis reached the quality control (QC) threshold in 94% of samples. Analysis of the first 105 patients revealed multiple concurrent mutations in HSP90 client proteins. Sequencing of DNA from a larger cohort is underway. Longitudinal sampling of plasma has been conducted to monitor temporal evolution of the penetrance of mutations.

Conclusions

Ultra-deep re-sequencing of multiple somatic mutations in circulating cfDNA is feasible, and can be used to identify biomarkers of response to G. This represents a new approach to biomarker discovery in the context of phase 2 trials. Results of analysis of cfDNA from the large cohort enrolled in GALAXY-1 will be presented.

Disclosure

I. El-Hariry: Full-time employee of Synta Pharmaceuticals and stock ownership in this company V.M. Vukovic: Synta pharmaceuticals: stock ownership and full-time employee V. Reichert: Synta Pharmaceuticals: full-time employee, stock ownership All other authors have declared no conflicts of interest.