Abstract: |
Background: Sorafenib,
an oral multi-kinase inhibitor, targets the Raf/MEK/ERK pathway at the
level of Raf kinase and receptor tyrosine kinases, and has shown
efficacy against several tumor types in phase I/II trials.
Non-small-cell lung cancer (NSCLC) is associated with mutations in k-ras, upstream of Raf/MEK/ERK. Methods: This
multi-center, uncontrolled, phase II trial evaluated efficacy (every 8
weeks using RECIST) and safety of sorafenib (400 mg bid, continuous) in
patients with relapsed or refractory advanced NSCLC. Plasma for
proteomic biomarker analysis (ELISA [n=44]; mass-spectrometry [n=43])
was taken at screening, Day 21 of Cycle 1, and Day 1 of Cycle 3. Results: Fifty-two
of 54 patients enrolled received sorafenib. Most (49/52) patients who
received sorafenib had stage IV NSCLC. Thirty patients (59%) out of 51
evaluable for efficacy had SD. Although there were no confirmed PRs,
tumor shrinkage was observed in 15 (29%) patients (four had >30%
shrinkage). Patients with SD had a median progression-free survival
(PFS) of 23.7 weeks, while all evaluable patients (n=51) had a median
PFS of 11.9 weeks and median overall survival of 29.3 weeks. The most
frequent drug-related adverse events observed in 52 patients were
diarrhea (21 [40%] patients), hand-foot skin reaction (HFS; 19 [37%]),
fatigue (14 [27%]), and nausea (13 [25%]). Frequent drug-related
adverse events > grade 3 included HFS (n=5 [10%]) and
hypertension (n=2 [4%]). Three patients discontinued due to adverse
events (HFS, elevated lipase, and myocardial infarction). There were
nine deaths within 30 days of discontinuation of sorafenib (n=5 PD; n=2
cardiopulmonary arrest; n=1 hemoptysis; and n=1 unknown cause). The
levels of five proteins measured by ELISA, either at screening or
change over treatment duration, correlated significantly with time to
progression (TTP) or maximum tumor shrinkage. Levels of five additional
proteins, identified by mass-spectrometry, also correlated with TTP. Conclusions: Identified
biomarkers may help assess efficacy of sorafenib in NSCLC patients.
Sorafenib 400 mg bid is generally well tolerated and shows promising
efficacy in patients with advanced, progressive NSCLC, with
approximately 60% of pts achieving disease stabilization. |