A Phase II Study of Sorafenib Combined With Cetuximab in EGFR-Expressing, KRAS-Mutated Metastatic Colorectal Cancer

Abstract

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.

Keywords: Antiangiogenic therapy; Biomarkers; Combination Therapy; Panitumumab imaging; Pharmacodynamics.

Conflict of interest statement

Conflict of Interest:

The authors have no conflict of interest to disclose.

Published by Elsevier Inc.

Figures

Figure 1.. DCE-MRI image of a target metastatic liver lesion consistent with stable disease

Sample DCE-MRI images of a 58 year-old man with mCRC to the liver having had progressive disease through prior combination therapies containing oxaliplatin, irinotecan, or capecitabine with bevacizumab. The patient had progression of his disease on study after 2 cycles. Target lesion indicated by arrow. Baseline axial (A) raw DCE-MRI and (B) kep (wash out) map derived from DCE-MRI showing a large lesion in the right lobe (mean and median kep values 0.228 and 0.202 min−1, respectively). Post-dose (completion of cycle 2) axial (C) raw DCE-MRI and (D) kep derived from DCE-MRI again localizes the right lobe lesion (mean and median kep values of 0.322 and 0.208 min−1, respectively).

Figure 2.. Progression-free survival probability as a function of time

Median progression-free survival was 1.84 months (n=30).

Figure 3.. 89Zr-panitumumab biodistribution images for a patient

Sample 89Zr-panitumumab PET scans from a patient on study with metastatic lesions in the liver performed to study the dosimetry of this agent in humans. Preliminary biodistribution findings demonstrate increased physiologic activity in the liver, spleen, and large bowel detectable 24 and 170 hours after radiotracer injection. (A) Whole-body image of a patient taken 24 hours after injection of 89Zr-panitumumab. (B) Whole-body image of the same patient taken 170 hours after injection.