Targeted therapy in advanced BRAF-mutated colorectal cancer: systematic review and network meta-analysis
Bao-Dong Qin1, Xiao-Dong Jiao1, Zhan Wang1
1Department of Medical Oncology, Changzheng Hospital, Naval Medical University, Shanghai 200003, China.
Objective:
To investigate the individual and comparative efficacy and safety of targeted therapy based strategies in advanced BRAF-mutated colorectal cancer.
Design:
Systematic review and network meta-analysis.
Data Sources:
PubMed, Embase, Cochrane Library, and ClinicalTrials.gov from inception to 31 May 2025, and international conference proceedings.
Eligibility Criteria For Selecting Studies:
Clinical trials and multicentre, real world studies investigating the efficacy and safety of targeted therapies for advanced BRAF-mutated colorectal cancer with at least one of the clinical outcomes of interest.
Data Synthesis:
The primary endpoint was overall survival in the first line and second or later line settings. Secondary endpoints included progression-free survival, objective response rate, disease control rate, and grade ≥3 adverse events. Single arm meta-analysis, pairwise meta-analysis, and network meta-analysis were performed to pool hazard ratios with 95% credible intervals (CrIs) for overall survival and progression-free survival, and odds ratios with 95% CrIs for objective response rate, disease control rate, and adverse events. The rankogram and surface under the cumulative ranking curve (SUCRA) evaluated the relative superiority of regimens in the network meta-analysis.
Results:
60 studies involving 4633 patients with advanced BRAF-mutated colorectal cancer were included. Pooled estimates indicated that patients could benefit from an anti-EGFR (epidermal growth factor receptor)/BRAF based regimen. Doublet chemotherapy (DCT)-anti-EGFR/BRAF was associated with the best overall survival, providing significant benefits compared with DCT-anti-VEGF (vascular endothelial growth factor) (hazard ratio 0.49, 95% CrI 0.36 to 0.66), triplet chemotherapy-anti-VEGF (0.51, 0.33 to 0.80), and anti-EGFR/BRAF (0.70, 0.51 to 0.96) regimens in the first line setting. Chemotherapy-anti-EGFR/BRAF showed significant superiority in overall survival (SUCRA=0.94 for DCT-anti-EGFR/BRAF, 0.90 for single agent chemotherapy (SCT)-anti-EGFR/BRAF) and progression-free survival (0.93 for DCT-anti-EGFR/BRAF and 0.92 for SCT-anti-EGFR/BRAF) among all first line targeted therapy strategies. In the second or later line setting, anti-EGFR/BRAF with or without an additional inhibitor (anti-MEK (mitogen-activated protein kinase kinase) or anti-PI3K (phosphoinositide 3-kinase)), exhibited better efficacy compared with other alternative strategies, ranking highest across study endpoints based on rank probability and SUCRA.
Conclusions:
For initial treatment of advanced BRAF-mutated colorectal cancer, combining doublet chemotherapy with anti-EGFR/BRAF therapy offers the best survival benefit. For patients who have had previous treatment, anti-EGFR/BRAF regimens (with or without a MEK inhibitor) are the most effective and tolerable options.
Systematic Review Registration:
PROSPERO CRD420250653959.
Insights
Targeted therapy combining doublet chemotherapy with anti-EGFR/BRAF agents offers the best survival for advanced BRAF-mutated colorectal cancer. For later lines of treatment, anti-EGFR/BRAF regimens are most effective and tolerable.
Area of Science:
- Oncology
- Genetics
- Pharmacology
Background:
- Colorectal cancer (CRC) with BRAF mutations presents a therapeutic challenge.
- Targeted therapies are emerging as crucial treatment modalities.
- Understanding optimal treatment strategies is vital for improving patient outcomes.
Purpose of the Study:
- To evaluate the efficacy and safety of targeted therapy strategies for advanced BRAF-mutated colorectal cancer.
- To compare different targeted therapy regimens using network meta-analysis.
Main Methods:
- Systematic review and network meta-analysis of clinical trials and real-world studies.
- Inclusion of studies reporting on targeted therapies for advanced BRAF-mutated CRC.
- Primary endpoint: overall survival; secondary endpoints: progression-free survival, objective response rate, disease control rate, and adverse events.
Main Results:
- Doublet chemotherapy (DCT) with anti-EGFR/BRAF demonstrated superior overall survival in the first-line setting compared to other regimens.
- Chemotherapy combined with anti-EGFR/BRAF showed significant benefits in overall and progression-free survival.
- In later lines of treatment, anti-EGFR/BRAF regimens, with or without MEK inhibitors, exhibited the best efficacy.
Conclusions:
- Combining doublet chemotherapy with anti-EGFR/BRAF therapy is the optimal first-line treatment for advanced BRAF-mutated colorectal cancer.
- For previously treated patients, anti-EGFR/BRAF-based regimens are the most effective and tolerable options.
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