Dr. Khanal and Dr. Upadhyay are third year internal medicine residents, both in the Department of Internal Medicine, and Dr. Silberstein is the division chief of hematology/oncology and professor of internal medicine, all at Creighton University in Omaha, Nebraska. Dr. Silberstein is also the chief of oncology at the VA Nebraska-Western Iowa Health Care System in Omaha, Nebraska.
References
portions from the extracellular domains of human VEGF receptors 1 and 2, fused to the Fc portion of human immunoglobulin IgG1 that blocks the activity of VEGF-A, VEGF-B, and placental growth factor by acting as a high-affinity ligand trap to prevent these ligands from binding to their endogenous receptors. 22 It was approved by the FDA in August 2012 for use in combination with FOLFIRI (5-FU, leucovorin, irinotecan) for the treatment of patients with mCRC that is resistant to or has progressed following an oxaliplatin‑containing regimen. 23
Cetuximab (a chimeric IgG1 anti-EGFR monoclonal antibody) and panitumumab (a human IgG2 anti-EGFR monoclonal antibody) have been shown to improve OS and progression-free survival (PFS) in up to 20% of cases, either alone or in combination with chemotherapy. 24,25 The FDA approved cetuximab in July 2012 for use in combination with FOLFIRI for first-line treatment of patients with K-ras mutation-negative (wild-type), EGFRexpressing mCRC. 26 The FDA approved panitumumab in September 2006 for the treatment of patients with EGFRexpressing metastatic colorectal carcinoma with disease progression on or following FOLFOX (5-FU, leucovorin, oxaliplatin)/FOLFIRI.27 (See Table 3.)
KRAS, a member of the rat sarcoma virus (ras) gene family of oncogenes, encodes for a small G protein downstream of EGFR. KRAS is mutated in CRC in up to 37% cases, resulting in activation of the different downstream signaling pathways. 15,28 Therefore, KRAS mutations predict resistance to anti-EGFR therapy. 28,29 Testing for KRAS mutation prior to treatment with cetuximab or panitumumab leads to targeted us of the very costly monoclonal antibodies and hence is considered a cost-effective practice. 30
Even in cases with wild-type KRAS mutation, response to anti-EGFR therapies is seen in only less than half of patients. 31 Up to 17% of tumors with wild-type for KRAS exon 2 at codons 12 and 13 can have a mutation in another of the ras pathway genes (eg, KRAS exon 3, 4 and NRAS exon 2, 3, 4). 25 Mutations in the BRAF oncogene have been described in up to 13% of colorectal carcinoma cases. 15 The data to suggest a lack of antitumor activity from anti-EGFR therapies in the presence of BRAF V600E mutation are still limited, but BRAF mutation is considered a poor prognostic factor.
A recent trial involving 1,137 patients with KRAS exon 2 wild-type mCRC randomly assigned to cetuximab or bevacizumab with standard chemotherapy (FOLFOX or FOLFIRI) found OS of 29.9 vs 29.0 months and median PFS 10.4 vs 10.8 months for cetuximab and bevacizumab, respectively.32 The OS for 5-FU–based therapies was about 11 months. 33
Regorafenib is an oral multikinase inhibitor of angiogenic, stromal, and oncogenic receptor protein kinases, including those involved in the regulation of tumor angiogenesis (eg, VEGFR1-3 and TIE2 [tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2]), tumor microenvironment (plateletderived growth factor receptor-β and fibroblast growth factor receptor 1), as
