A Phase II Study of Sorafenib in Patients with Platinum-Pretreated, Advanced (Stage IIIb or IV) Non–Small Cell Lung Cancer with a KRAS Mutation
- 31 January 2013
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 19 (3), 743-751
- https://doi.org/10.1158/1078-0432.ccr-12-1779
Abstract
Purpose: Sorafenib inhibits the Ras/Raf pathway, which is overactive in cancer patients with a KRAS mutation. We hypothesized that patients with non–small cell lung cancer (NSCLC) with KRAS mutation will benefit from treatment with sorafenib. Experimental Design: In this phase II study, patients with KRAS-mutated, stage IIIb or IV NSCLC that progressed after at least one platinum-containing regimen were treated with sorafenib. Treatment consisted of sorafenib 400 mg twice daily until disease progression or unacceptable toxicity. Pretreatment serum from each patient was obtained to predict outcome using a proteomic assay (VeriStrat). Primary endpoint was disease control rate (DCR) at 6 weeks. Results: Fifty-nine patients were entered between May 2010 and February 2011. Fifty-seven patients started sorafenib. Mean age was 58.5 (SD = ±8.1) years, 16 male/41 female, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0/1/2 24/30/3. At 6 weeks, 5 partial response, 25 stable disease, and 27 progressive disease were observed; DCR was 52.6%. Median duration of treatment was 9 weeks. The median progression-free survival (PFS) was 2.3 months and median overall survival (OS) was 5.3 months. Patients with a prediction of good prognosis according to VeriStrat serum proteomics assay showed a significantly superior PFS [HR, 1.4; 95% confidence interval (CI), 1.0–1.9] but not OS (HR, 1.3; 95% CI, 0.9–1.7). Sorafenib-related grade III/IV toxicity was reported in 10 patients (17.5%); all but one patient experienced grade III skin toxicity (14.0%) or grade III gastrointestinal toxicity (8.8%). Conclusion: Treatment with sorafenib has relevant clinical activity in patients with NSCLC harboring KRAS mutations. Further randomized study with this agent is warranted as single-agent or combination therapy. Clin Cancer Res; 19(3); 743–51. ©2012 AACR.Keywords
This publication has 41 references indexed in Scilit:
- Effect of KRAS Oncogene Substitutions on Protein Behavior: Implications for Signaling and Clinical OutcomeJNCI Journal of the National Cancer Institute, 2012
- Targeting renal cell carcinoma with NVP-BEZ235, a dual PI3K/mTOR inhibitor, in combination with sorafenibMolecular Cancer, 2011
- The Ras-ERK and PI3K-mTOR pathways: cross-talk and compensationTrends in Biochemical Sciences, 2011
- Therapeutic Strategies for Targeting Ras ProteinsGenes & Cancer, 2011
- Evaluation of KRAS Mutations, Angiogenic Biomarkers, and DCE-MRI in Patients with Advanced Non–Small-Cell Lung Cancer Receiving SorafenibClinical Cancer Research, 2011
- Knockdown of Oncogenic KRAS in Non–Small Cell Lung Cancers Suppresses Tumor Growth and Sensitizes Tumor Cells to Targeted TherapyMolecular Cancer Therapeutics, 2011
- VeriStrat® classifier for survival and time to progression in non-small cell lung cancer (NSCLC) patients treated with erlotinib and bevacizumabLung Cancer, 2010
- Detection of Tumor Epidermal Growth Factor Receptor Pathway Dependence by Serum Mass Spectrometry in Cancer PatientsCancer Epidemiology, Biomarkers & Prevention, 2010
- Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancersNature Medicine, 2008
- Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancerThe Lancet Oncology, 2008