Real-World Outcomes of Patients With BRAF-Mutated Metastatic Colorectal Cancer Treated in the United States

Abstract

Background: BRAF mutations portend a poor prognosis in metastatic colorectal cancer (mCRC). Whether these patients may benefit from more aggressive frontline chemotherapy with a triplet regimen such as FOLFOXIRI remains unclear. We used real-world data from a cohort of patients in the United States to assess the BRAF testing rate, determine the prevalence of FOLFOXIRI use, and compare survival outcomes in mCRC, stratified by BRAF mutation status and first-line therapy. Methods: A nationwide electronic health record–derived deidentified database was reviewed for patients diagnosed with mCRC between 2013 and 2018. Those with documented BRAF mutation testing who received standard first-line therapy were included. Kaplan-Meier estimates with corresponding log-rank tests and Cox proportional hazards modeling compared survival outcomes stratified by BRAF status and first-line therapy. Results: Of 4,457 included patients, 3,991 (89.5%) had BRAF wild-type (BRAFwt) and 466 (10.5%) had BRAF-mutated (BRAFmt) mCRC. Median overall survival (OS) was 15.4 months in the BRAFmt group versus 28.1 months in the BRAFwt group (hazard ratio [HR], 0.48; 95% CI, 0.41–0.56; P<.001). Only 3% of patients with BRAF mutations received first-line FOLFOXIRI ± bevacizumab, with a median OS of 13.8 months compared with 15.5 months in those treated with doublet chemotherapy ± bevacizumab (P=.38). In patients with BRAF mutations, propensity-weighted analysis did not detect a significant improvement in OS with FOLFIRI + bevacizumab (HR, 0.90; 95% CI, 0.58–1.39; P=.63) or FOLFOX/CAPEOX + bevacizumab (HR, 0.81; 95% CI, 0.52–1.26; P=.35) versus doublet chemotherapy alone. In 2018, only 56% of patients diagnosed with mCRC had documented BRAF testing at any time. Conclusions: This real-world data analysis confirms the negative prognostic impact of BRAF mutations in mCRC and suggests that FOLFOXIRI has not been widely adopted in the United States. The proportion of patients with documented BRAF testing in this real-world population was low at 56%. We were unable to show any significant difference in OS of patients with BRAFmt mCRC based on the first-line therapy received.

Translational analysis and final efficacy of the AVETUX trial – Avelumab, cetuximab and FOLFOX in metastatic colorectal cancer

“…Identification of these markers may allow patient stratification to reduce toxicity, costs, and potentially allocate non-responder patients to other treatment approaches. In addition, the applicability of new and complex treatment regimens, as observed for e.g., FOLFOXIRI and VEGF- or anti-EGFR-antibodies ( 25 ), may be hampered in mCRC due to the high response rates of the backbone chemotherapy alone and response predicting markers may allow clinical stratification of patients. If asked to speculate, this may be especially important for patients who are in need of maximal response to treatment to achieve a potential secondary resection.…”

Resectability, conversion, metastasectomy and outcome according to RAS and BRAF status for metastatic colorectal cancer in the prospective RAXO study

“…Also, a meta-analysis of 11 prospective and retrospective studies of liver resection reported that KRAS mt and BRAF mt mutational status was negatively associated with OS and relapse-free survival (RFS) [ 9 ]. Also, a recent retrospective real-world study from US reported worse survival for BRAF mt mCRC patients compared to BRAF wt [ 34 ]. The worse outcome in RAS mt and BRAF mt is probably due to both the mutations and right-sided primary according to multivariable analysis.…”