FOLFOXIRI plus bevacizumab as first-line treatment in BRAF mutant metastatic colorectal cancer☆
Introduction
BRAF mutant metastatic colorectal cancers (mCRC) represent one of the most difficult and intriguing challenges for colorectal oncologists. In the last years a number of reports have consistently evidenced the negative impact of BRAF V600E mutation on mCRC patients’ prognosis, with median overall survival (OS) ranging from 9 to 14 months [1], [2], [3], [4], [5], [6]. In an attempt to better characterise this molecularly-defined subset, it has been noticed that BRAF mutant tumours also share peculiar histopathologic and clinical characteristics. They are enriched in right-sided tumours, with mucinous histology, microsatellite instability and a distinct pattern of metastatic spread, consisting of a high rate of peritoneal and node metastases [7], [8], [9], [10].
Moreover, in vitro experiences have highlighted that some genes are differently expressed in BRAF mutant and wild-type CRC cell lines [11], [12] and, even more interestingly, a characteristic gene expression signature associated with BRAF mutation has been identified [13].
Despite the clear improvement in biologic insights, no effective strategies to counteract BRAF mutant tumours’ aggressiveness have been developed. Data from retrospective series and post hoc analyses of randomised trials reveal that standard first-line regimens, including a chemo-doublet and a biologic, lead to poor results in terms of Progression Free Survival (PFS), ranging from 4 to 6 months [1], [3], [4], [5].
We previously published a phase II trial evaluating the safety and activity of FOLFOXIRI (5-FU/LV+Oxaliplatin+Irinotecan) plus bevacizumab regimen as first-line treatment in 57 mCRC patients. Such treatment was highly active with a response rate (RR) of 77% that translated into median PFS and OS of 13.1 and 30.9 months, respectively [14]. At an exploratory post hoc analysis, the subgroup of 10 patients with BRAF mutant tumours reported remarkable results in terms of RR (90%), median PFS (12.8 months) and median OS (23.8 months), with no significant differences compared to the BRAF wild-type subgroup.
These preliminary results suggested that such an intensive up-front treatment might be a promising strategy to contrast the aggressiveness of BRAF mutant mCRC. Drawing from these remarks, we designed a prospective trial, with the aim to validate those retrospective findings and to better estimate the potential impact of FOLFOXIRI plus bevacizumab as initial treatment for BRAF mutant mCRC patients. Here we present results from the prospective validation cohort and a secondary analysis of the pooled population of retrospectively and prospectively treated patients.
Section snippets
Study population
From 19th September 2008 to 12th October 2010, patients were enrolled in two Italian Oncology Units. Patients were eligible for mutational screening if the following criteria were met: histological diagnosis of colorectal adenocarcinoma; metastatic disease deemed initially unresectable; age 18–75 years; Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–2 if patients were aged (70 years, or 0 if they were aged 71–75 years); measurable disease according to Response Evaluation
Study population
Two-hundred-fourteen mCRC patients were centrally screened for BRAF mutational status. Fifteen BRAF mutant patients (7%) were included in the validation cohort. Main characteristics of both the validation cohort and the pooled population are summarised in Table 1. Only 1 (4%) out of 23 analysed samples was MSI-high.
Treatment duration and safety
In the validation cohort all patients were assessed for safety. A total of 145 cycles of FOLFOXIRI plus bevacizumab were administered, with a median of 10 cycles (range 2–21) per
Discussion
In the last years, notable advances in targeted treatments have roused oncologists’ interest in mCRC’s molecular characterisation. The predictive role of KRAS mutations as predictors of resistance to anti-EGFR monoclonal antibodies sanctioned the entrance of KRAS assessment in the clinical practice. At the same time BRAF V600E mutation has been recognised as a strong prognostic factor, with an impressive negative impact on mCRC patients’ survival. Nevertheless, up today, there are no clear and
Conflict of interest statement
None declared.
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Acknowledgement of funding: Partially supported by A.R.C.O. Foundation.
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These authors contributed equally.