TY - JOUR
T1 - A Phase II Study of Sorafenib Combined With Cetuximab in EGFR-Expressing, KRAS-Mutated Metastatic Colorectal Cancer
AU - Do, Khanh
AU - Cao, Liang
AU - Kang, Zhigang
AU - Turkbey, Baris
AU - Lindenberg, Maria L.
AU - Larkins, Erin
AU - Holkova, Beata
AU - Steinberg, Seth M.
AU - Raffeld, Mark
AU - Peer, Cody J.
AU - Figg, William D.
AU - Eugeni, Michelle
AU - Jacobs, Paula
AU - Choyke, Peter
AU - Wright, John J.
AU - Doroshow, James H.
AU - Kummar, Shivaani
N1 - Funding Information:
This project has been funded in whole or part with federal funds from the National Cancer Institute , National Institutes of Health . The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organizations imply endorsement by the US Government.
PY - 2015/9/1
Y1 - 2015/9/1
N2 - Background Mutations in the KRAS gene predict for resistance to anti-epidermal growth factor receptor (EGFR) therapies, including cetuximab. Upregulation of vascular endothelial growth factor (VEGF)-A has been implicated in resistance to anti-EGFR treatment. Abrogation of the VEGF and RAS/RAF/MEK/ERK pathways has the potential to restore cetuximab sensitivity. Patients and Methods Adult patients with histologically documented, measurable, EGFR-expressing, KRAS-mutated metastatic colorectal cancer (mCRC) that had progressed after 5-fluorouracil-based regimens were treated with sorafenib 400 mg orally twice daily and intravenous cetuximab weekly in 28-day cycles. The primary endpoint was the response rate (complete response, partial response, and stable disease at 4 cycles). The secondary endpoints included plasma biomarker analysis of angiogenic cytokines and correlative imaging studies with dynamic contrast-enhanced magnetic resonance imaging and zirconium 89-panitumumab. Results Of the 30 patients enrolled, 26 were evaluable for response. Of the 26 patients evaluated, 4 had stable disease at 4 cycles and 1 had stable disease at 8 cycles. The median progression-free survival was 1.84 months. The common toxicities were rash, diarrhea, and liver enzyme elevations. Of the angiogenic cytokines evaluated, only the placental growth factor increased significantly with treatment (P <.0001). No pharmacodynamic parameters were associated with the treatment response. Conclusion We report the results of a trial that combined cetuximab and sorafenib for the treatment of KRAS-mutated mCRC, with correlative imaging studies and pharmacodynamic angiogenic cytokine profiling as downstream markers of EGFR and VEGF receptor (VEGFR) signaling. No objective responses were observed. Additional development of biomarkers for patient selection is needed to evaluate combined EGFR and VEGFR blockade as a therapeutic option in KRAS-mutated CRC.
AB - Background Mutations in the KRAS gene predict for resistance to anti-epidermal growth factor receptor (EGFR) therapies, including cetuximab. Upregulation of vascular endothelial growth factor (VEGF)-A has been implicated in resistance to anti-EGFR treatment. Abrogation of the VEGF and RAS/RAF/MEK/ERK pathways has the potential to restore cetuximab sensitivity. Patients and Methods Adult patients with histologically documented, measurable, EGFR-expressing, KRAS-mutated metastatic colorectal cancer (mCRC) that had progressed after 5-fluorouracil-based regimens were treated with sorafenib 400 mg orally twice daily and intravenous cetuximab weekly in 28-day cycles. The primary endpoint was the response rate (complete response, partial response, and stable disease at 4 cycles). The secondary endpoints included plasma biomarker analysis of angiogenic cytokines and correlative imaging studies with dynamic contrast-enhanced magnetic resonance imaging and zirconium 89-panitumumab. Results Of the 30 patients enrolled, 26 were evaluable for response. Of the 26 patients evaluated, 4 had stable disease at 4 cycles and 1 had stable disease at 8 cycles. The median progression-free survival was 1.84 months. The common toxicities were rash, diarrhea, and liver enzyme elevations. Of the angiogenic cytokines evaluated, only the placental growth factor increased significantly with treatment (P <.0001). No pharmacodynamic parameters were associated with the treatment response. Conclusion We report the results of a trial that combined cetuximab and sorafenib for the treatment of KRAS-mutated mCRC, with correlative imaging studies and pharmacodynamic angiogenic cytokine profiling as downstream markers of EGFR and VEGF receptor (VEGFR) signaling. No objective responses were observed. Additional development of biomarkers for patient selection is needed to evaluate combined EGFR and VEGFR blockade as a therapeutic option in KRAS-mutated CRC.
KW - Antiangiogenic therapy
KW - Biomarkers
KW - Combination Therapy
KW - Panitumumab imaging
KW - Pharmacodynamics
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U2 - 10.1016/j.clcc.2015.02.007
DO - 10.1016/j.clcc.2015.02.007
M3 - Article
C2 - 25861837
AN - SCOPUS:84938963326
SN - 1533-0028
VL - 14
SP - 154
EP - 161
JO - Clinical Colorectal Cancer
JF - Clinical Colorectal Cancer
IS - 3
M1 - 198
ER -