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VEGF and dual-EGFR inhibition in colorectal cancer

Epidermal growth factor receptor (EGFR), which plays an important role in tumorigenesis, is overexpressed in a high percentage of patients with late-stage colorectal cancer.1 EGFR can maintain cancer cell survival independent of its kinase activity,2 and preclinical studies have demonstrated that combining anti-EGFR antibodies and kinase inhibitors was synergistic in colon cancer cell lines.3 
 
Angiogenesis, which plays an important role in tumor development and metastasis, is partly mediated by vascular endothelial growth factor (VEGF) and its receptor VEGFR.4 Resistance to EGFR inhibitors may be mediated, at least partly, by activating VEGF-dependent signaling, and strategies that combine anti-EGFR and anti-VEGF agents appear promising in preclinical and clinical studies.5 
 
Preclinical studies demonstrate that EGFR signals through both kinase-dependent and independent pathways and that combining a small-molecule EGFR inhibitor, EGFR antibody, and/or anti-angiogenic agent may be synergistic.2,5 Supporting these preclinical observations, our recent report in Oncoscience demonstrates antitumor activity for the combination of cetuximab, erlotinib, and bevacizumab in heavily pretreated patients with metastatic colorectal cancer entered on a phase I trial of this triple-drug regimen.6 This is the first description of dual EGFR inhibition (erlotinib plus cetuximab) together with an anti-angiogenic agent (bevacizumab) in patients with advanced colorectal cancer. Cetuximab is a monoclonal antibody against EGFR that is approved by the Food and Drug Administration (FDA) for KRAS wild-type metastatic colorectal cancer. Erlotinib, an EGFR tyrosine kinase, is FDA-approved for non-small cell lung cancer and pancreatic adenocarcinoma. Bevacizumab, a monoclonal antibody to VEGF, is FDA-approved for metastatic colorectal cancer. 
 
The key findings of the report include description of the preliminary anti-tumor activity and safety profile of this 3-drug combination in patients with metastatic colorectal cancer. Forty-one patients were enrolled, and the study population had advanced disease, with a median of 5 prior systemic therapies. Almost all of the patients (n = 38, 93%) had previously received bevacizumab, and 33 patients (80%) had received prior cetuximab. 
 
In spite of the extensive prior treatment of the enrolled patients, stable disease (SD) of at least 6 months (n = 11) or partial response (PR) (n = 3) was achieved in 14 patients (34%), and was observed even in patients who had received prior bevacizumab and/or cetuximab or who had been treated at doses below the recommended phase 2 dose. Among the 31 patients who had received prior sequential cetuximab and bevacizumab, 10 (32%) achieved SD ≥ 6 months/PR. Of the 4 patients who had received prior concurrent bevacizumab and cetuximab, 2 achieved SD ≥ 6 months/PR. 
 
Recent investigations suggest that combining EGFR kinase inhibitors and anti-EGFR antibodies could be more effective than either alone, possibly because EGFR has the ability to maintain cancer cell survival independent of its kinase activity.1,2 A prior preclinical study combining erlotinib and cetuximab demonstrated synergistic antitumor activity in colorectal cancer, and a phase 2 trial of this combination achieved an overall response rate of 31%,3 which is similar to the rate of SD ≥ 6 months/PR observed in the present study. 
 
Prior clinical trials that combined cetuximab and bevacizumab with cytotoxic chemotherapy in patients with colorectal cancer had disappointing results, including shorter overall survival, shorter time to progression, and lower quality of life.7 It is conceivable that the chemotherapy included in such regimens may be the variable contributing to the negative outcomes in such trials, in contrast to regimens that combine anti-EGFR and anti-VEGF agents without cytotoxic chemotherapy, which may be promising and may deserve further investigation. 
 
Analysis of the side effects observed reveals that this 3-drug combination was well-tolerated in patients with metastatic colorectal cancer. The recommended phase 2 dose (RP2D) was determined to be the full FDA-approved doses of cetuximab, erlotinib, and bevacizumab. Among the 34 patients treated at the RP2D, 31 patients (91%) tolerated the treatment without drug-related dose-limiting effects. The most common treatment-related adverse events of grade 2 or higher occurring in at least 15% of patients included rash (68%) and hypomagnesemia (44%). Only two patients (5%) withdrew from the study because of toxicity, including one patient with grade 2 skin rash and another individual with grade 2 diarrhea and fatigue. Although previous studies have demonstrated correlation between rash and response to EGFR inhibitors, no such correlation or trend was observed in the current study. 
 
Overall, the findings of this study have demonstrated that dual inhibition of EGFR with erlotinib and cetuximab, combined with the VEGF antibody bevacizumab, was well-tolerated and was associated with significant antitumor activity in heavily pretreated patients with metastatic colorectal cancer. These results are promising and merit further investigation in future, larger studies.