Anticancer activity of combination targeted therapy using cetuximab plus vemurafenib for refractory BRAFV600E-mutant metastatic colorectal carcinoma

Abstract

colorectal cancers have responded to braf kinase inhibitor monotherapy in early-phase trials 14 , raising the possibility that effective treatment may require blockade of one or more additional pathways 15 . Conversely, the clinical response of colorectal cancers to regimens including epidermal growth factor receptor (egfr) inhibitors appears to require both wild-type BRAF and KRAS status [16][17][18] .Because recent laboratory studies have confirmed that de novo resistance to braf inhibitors in BRAF V600E -mutated colorectal cancer is caused by egfr signalling 19,20 , we hypothesised that dual blockade of the braf and egfr pathways might be therapeutically useful, as has been suggested by preclinical data 15 . Moreover, a previous randomized trial of cetuximab combined with the nonspecific Raf inhibitor sorafenib indicated a doubling of the response rate in patients with metastatic colon cancer 21 . Here, we report an end-stage colorectal cancer patient benefiting from combination noncytotoxic drug therapy simultaneously targeting the egfr and braf signalling pathways. CASE REPORTA 78-year-old man presented in 2006 with anemia caused by an obstructive mucinous colorectal cancer of the hepatic flexure. The 75-mm tumour was resected en bloc. Vascular invasion and perineural infiltration were present, and 9 of 21 nodes contained metastases. The mismatch repair proteins mlh1 and pms2 were not detectable by immunohistochemistry.After surgery and biweekly oxaliplatin-based (folfox) adjuvant chemotherapy, our patient remained well until 2010, when rising serum carcinoembryonic antigen (cea) and fluorodeoxyglucose positron-emission tomography heralded recurrence in the right external iliac and inguinal nodes, with involvement of the anterior abdominal wall. Palliative use of oral capecitabine was poorly tolerated because of severe diarrhea and hand-foot syndrome, and it failed to stem the rising cea. Treatment was ABSTRACT Mismatch-repair-deficient colorectal cancers often contain kinase-activating V600E BRAF mutations, but no clinical utility has yet been demonstrated in this setting for monotherapy using oral braf kinase inhibitors such as vemurafenib or dabrafenib. Recent studies have indicated that tumour resistance to braf inhibition is mediated by upregulated epidermal growth factor receptor (egfr) signalling, disruption of which is a routine treatment strategy in KRAS wildtype colorectal cancer. In this report, we describe the clinical course of a heavily pretreated patient who elected to receive off-label dual-targeted braf-and egfr-inhibitory therapy with good tolerance and apparent clinical benefit.

Homologous Mutation to Human BRAF V600E Is Common in Naturally Occurring Canine Bladder Cancer—Evidence for a Relevant Model System and Urine-Based Diagnostic Test

“…In a phase III trial of 675 melanoma patients, the vemurafenib response rate was 57%, compared to 9% with standard dacarbazine treatment, and progression-free survival was significantly longer in patients receiving vemurafenib (6.9 months vs 1.6 months in the control arm) (50). However, some BRAF(V600E) positive cancers, including colorectal cancer, are inherently resistant to BRAF inhibitors (51), and even initially sensitive tumors adeptly develop vemurafenib resistance. Ongoing trials seek to delay resistance via co-administration with other drugs, including other MAPK pathway inhibitors(29,52).…”

B-Raf Inhibitors Induce Epithelial Differentiation inBRAF-Mutant Colorectal Cancer Cells

“…These approaches prevent compensatory feedback loops and crosstalk, which currently limit the use of B-Raf inhibitors as single agents (4,(19)(20)(21). These preclinical drug combinations initiated several clinical trials that are currently ongoing (www.clinicaltrials.gov) and a first case report further demonstrates the utility of such combinations (22). However, to interpret the effect of such combinatorial approaches, it is necessary to obtain a more comprehensive understanding of their effects as monosubstances.…”

Role and mechanisms of resistance of epidermal growth factor receptor antagonists in the treatment of colorectal cancer

“…This lack of efficacy seems to suggest that the biology of BRAF activation in patients with CRC is more heterogeneous than that in melanoma. As a matter of fact, a feedback activation of EGFR on BRAF inhibition, leading to EGFR-dependent compensatory signals, has been indicated as one of the main mechanisms of vemurafenib failure [43][44][45].…”