84IN - Breakthroughs in basic research

Date 01 October 2012
Event ESMO Congress 2012
Session Latest innovations in NSCLC management
Topics Basic Science
Non-Small-Cell Lung Cancer, Metastatic
Presenter Pasi Janne
Authors P.A. Janne
  • Lowe Center For Thoracic Oncology, Dana Farber Cancer Institute, Boston/US

Abstract

Over the last few years several basic research studies have led to new therapeutic insights into the treatment of patients with advanced non-small cell lung cancer (NSCLC). These include genomic studies of lung cancers which have revealed novel potential therapeutic targets. One such target is fibroblast growth factor receptor (FGFR) 1 which has been found to be amplified in a subset of squamous cell lung cancers. Preclinical studies have further demonstrated that inhibition of FGFR1 kinase activity using FGFR tyrosine kinase inhibitors (TKIs) may be clinically effective in this subset of NSCLC. Clinical trials are now underway using FGFR TKIs in this subset of NSCLC. A second example is the identification of novel genomic rearrangements of the RET oncogene in NSCLC. These rearrangements lead to a fusion gene (KIF5B-RET) which is transforming in vitro and in vivo. Several already approved kinase inhibitors, including vandetinib, sorafenib and sunitinib, also inhibit RET and may be effective as clinical therapies in this subset of NSCLC. In addition, several more potent RET TKIs are under preclinical development and undergoing validation in model systems. A second recent basic science advance is the use of mouse models of lung cancer to mirror ongoing or planned clinical trials. These “co-clinical” trials aim to use the murine models to determine if they can predict the outcome of human trials and/or be used to further understand the success and limitations of the therapeutic approach. A recent example evaluated docetaxel and the MEK inhibitor selumetinib compared to docetaxel alone in a genetically engineered mouse model of Kras mutant NSCLC. In this mouse model the combination led to a greater response rate and progression free survival compared to docetaxel alone. The result was similar in a recent clinical trial of the same therapeutic design in KRAS mutant NSCLC. Interestingly, in the mouse model, those tumors with concurrent Lkb1 loss (occurs in about 30% of KRAS mutant NSCLC in humans), the combination of docetaxel/selumetinib was significantly less effective. These findings open the possibility of evaluating the impact of LKB1 loss in KRAS mutant NSCLC patients treated with selumentib/docetaxel and more broadly underscore the potential utility of animal models in informing the design of human clinical trials.

Disclosure

P.A. Janne: I have acted as a consultant to Pfizer, Boehringer Ingelheim, Astra-Zeneca, Roche, Genentech and Sanofi