This retrospective study consecutively collected patients diagnosed with BRAF V600E-mutated mCRC from the 3 July 2017 to 24 December 2022. All patients were collected from the database of three institutions, including West China Hospital of Sichuan University, Yunnan Cancer Hospital, and The First Affiliated Hospital of Chongqing Medical University. Patients were included if they met the following criteria: (1) pathologically confirmed metastatic colorectal adenocarcinoma with at least one measurable disease according to the Response Evaluation Criteria in Solid Tumors (v1.1); [14]; (2) BRAF V600E mutation confirmed by gene detection; (3) age older than 18 years; Patients were excluded if they lacked complete clinical information. Reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement [15].

The demographic features [including age, gender, Eastern Cooperative Oncology Group performance status (ECOG PS)], histological type, primary tumor location, metastatic pattern, and metastatic organ, treatment modalities (surgery, chemotherapy regimen, and targeted therapy), and survival data were obtained by medical record review. Age was dichotomized into two groups: ≤60 years and > 60 years according to the age segmentation between middle-aged people and elderly people in China. Primary tumor location was dichotomized into three groups: the right-sided colon (including the ileocecal junction, cecum, ascending colon, hepatic flexure, and transverse colon), left-sided colon (including the splenic flexure, descending colon, and sigmoid colon), and rectum.

The Doublet-drug arm received cytotoxic doublets, including XELOX (Oxaliplatin 130mg/m2, ivgtt, d1 + Capecitabine 1000mg/m2,po, bid, d1-14, q3w), mFOLFOX6 (Oxaliplatin 85mg/m2, ivgtt, d1 + leucovorin 400mg/m2, ivgtt, d1 + Fluorouracil 400mg/m2, ivgtt, d1 + Fluorouracil 1200mg/m2.d, ivgtt, d1-d2, q2w), or FOLFIRI (Irinotecan 180mg/m2, ivgtt, d1 + leucovorin 400mg/m2, ivgtt, d1 + Fluorouracil 400mg/m2, ivgtt, d1 + Fluorouracil 1200mg/m2.d, ivgtt, d1-d2, q2w) plus bevacizumab (5 mg/kg, ivgtt, d1, q2w), and triplet-drug group received a modified FOLFOXIRI regimen (Oxaliplatin 85mg/m2, ivgtt, d1 + Irinotecan 165mg/m2, ivgtt, d1 + leucovorin 400mg/m2, ivgtt, d1 + Fluorouracil 1200mg/m2.d, ivgtt, d1-d2, q2w) plus bevacizumab (5 mg/kg, ivgtt, d1, q2w). The chemotherapy alone group received chemotherapy without bevacizumab. Tumor assessment by computed tomography was performed based on the RECIST version 1.1.

The primary objective of the study was to evaluate OS according to the treatment regimen. The secondary endpoints were PFS, objective response rate (ORR), and disease control rate (DCR) in the first-line treatment and to estimate the difference in terms of efficacy between the doublet-drug and triplet-drug regimen as first-line therapy. OS was defined as the time from the diagnosis of metastatic disease to death from any cause. PFS was measured from the start of treatment to the date of disease progression or death from any cause. ORR was defined as complete response (CR) or partial response (PR), while DCR was defined as CR, PR, and stable disease (SD). Follows-up started when patients were diagnosed with mCRC and was conducted by telephone every 2 months.

We used a 1:1 propensity score matching (PSM) strategy to match different patients with doublet-drug group and triplet-drug group to create well-matched cohorts and reduce potential confounding effects. We included the variables with potential impact on prognosis, including age, sex, grade, primary tumor location, liver metastasis, peritoneal metastasis, distant lymph node metastasis, and number metastatic organs in this propensity score model. The nearest neighbor matching algorithm without replacement was applied to ensure adequate matches with a caliper of 0.02 standard deviation of the logit of the propensity score.

Statistical analysis was performed using SPSS version 25.0 and R version 4.2.2. Univariate and multivariate analysis was performed using a Cox proportional hazards model. Kaplan-Meier analyses were performed to analyze survival, including OS and PFS. The hazard ratio (HR) with 95% confidence intervals (CIs) was used to compare the risk of the two regimens. p-value less than 0.05 in a two-tailed test was used to define statistical significance.