title: Off-label use of cetuximab plus sorafenib and panitumumab plus regorafenib to personalize therapy for a patient with V600E BRAF-mutant metastatic colon cancer.
abstract: Sorafenib, the first agent developed to target BRAF mutant melanoma, is a multi-kinase inhibitor that was approved by the FDA for therapy of kidney and subsequently liver cancer, and is currently in clinical trials for thyroid, lung and brain cancer. Colorectal cancer with V600E BRAF mutation has shown relative resistance to standard chemotherapy regimens, as well as lack of efficacy to vemurafenib in clinical trials. New treatments are needed for BRAF-mutant colorectal cancer. We report a case of a patient with BRAF-mutant metastatic colon cancer whose disease had progressed on FOLFOX plus bevacizumab and subsequent FOLFIRI plus cetuximab. Based on preclinical data published in Nature in 2012 suggesting that successful therapeutic targeting of BRAF in colorectal cancer may require concomitant targeting of the EGFR, we offered this patient without other attractive options the combination of sorafenib plus cetuximab, in off-label use with informed consent. Sorafenib and cetuximab therapy led to a mixed radiographic response with some areas showing dramatic improvement and other areas showing stable disease over a 7-month period which is a notably long period of progression-free survival for V600E BRAF mutated colon cancer. The cetuximab plus sorafenib therapy was very well-tolerated by the patient who remained on it long enough until another therapy option, regorafenib, was approved in September 2012. The patient was offered single agent regorafenib at the time of progression. At the time of progression on single agent regorafenib, panitumumab was combined with regorafenib and this was also well-tolerated and appeared to slow disease progression. Further study of these approaches in the clinic as personalized treatment of BRAF-mutant advanced colorectal cancer is warranted.
authors.affiliation: Division of Hematology/Oncology, Penn State Hershey Cancer Institute, Hershey, PA USA. malmarrawi@hmc.psu.edu
authors.forename: Mhd Yaser
authors.initials: MY
authors.lastname: Al-Marrawi
authors.forename: Bikramajit Singh
authors.initials: BS
authors.lastname: Saroya
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Brennan
authors.forename: Zhaohai
authors.initials: Z
authors.lastname: Yang
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Dykes
authors.forename: Wafik S
authors.initials: WS
authors.lastname: El-Deiry
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D056687:Off-Label Use; D000077544:Panitumumab; D010671:Phenylurea Compounds / Q000008:administration & dosage; D057285:Precision Medicine / Q000379:methods*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000627:therapeutic use; D011725:Pyridines / Q000008:administration & dosage; D000077157:Sorafenib
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D010671:Phenylurea Compounds; D011725:Pyridines; C559147:regorafenib; D009536:Niacinamide; D000077544:Panitumumab; D000077157:Sorafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000068818:Cetuximab
keywords: BAY43-9006; RAF inhibitor; cetuximab; colorectal cancer therapy; combined therapy; sorafenib; sorafenib and cetuximab