A PHASE II STUDY OF SORAFENIB IN PATIENTS WITH LOCALLY ADVANCED AND/OR METASTATIC (STAGE IIIB OR IV) NON-SMALL CELL LUNG CANCER (NSCLC) WITH A K-RAS MUTATION

Lung cancer is the major cause of cancer related death in the Western World. In
the year 2006 10357 cases of lung cancer were diagnosed in The Netherlands,
6667 in men and 3690 in women while 9889 patients died of lung cancer1.
Non-small cell lung cancer (NSCLC) constitutes about 85% of all lung cancer and
more than 50% of patients are not curable at presentation. The current standard
of therapy for patients with advanced non small cell lung cancer is platinum
based doublet chemotherapy. Therapeutic results are far from satisfactory:
survival has reached a plateau at a median of 9-11 months in the recently
published phase III trials. Therefore, clinical research of new treatment
strategies is warranted. One way to improve on these results is to personalize
treatment, amongst others based on tumor molecular characteristics. In NSCLC
the most frequent occurring somatic mutations are located in 3 codons of the
K-Ras gene. Constitutional activation of K-Ras, leads to signaling through the
Raf-Mek-Erk pathway which is implicated in cellular growth and survival
pathways. Treatment options for patients that have K-Ras mutated tumors are
limited as these are believed to be poor responders to cytotoxic chemotherapy
and refractory to EGFR TKI*s. Sorafenib, a multitargeted tyrosine kinase
inhibitor, inhibits amongst others the Ras-Raf pathway. Sorafenib has been
evaluated in unselected advanced NSCLC patients both as a single agent and in
conjuncture with platinum doublet chemotherapy as first line treatment. The
results of these studies are not equivocal: while the single agent studies
showed some activity of sorafenib in all lines of treatment, the ESCAPE phase
III trial failed to improve survival when sorafenib was added to the commonly
used paclitaxel-carboplatin doublet. Sorafenib is orally available and is
labeled for all histologies of NSCLC. We hypothesized that selecting NSCLC
patients with K-Ras mutated tumors will enhance the clinical efficacy of
sorafenib

Efficacy of sorafenib in NSCLC with a K-RAS mutation as determined by the
Disease Control Rate at 6 weeks

Single arm open label phase II study.

Sorafenib 400 mg td po

Usual risk associated with treatment with chemotherapy. Extra burden associated
with participation is one additional tumor biopsy after 3 weeks of treatment
(optional) and two additional venapunctures before and after 3 weeks of
treatment.