Chemo plus targeted therapy extends survival in advanced BRAF-mutated CRC

The combination of chemotherapy and anti-EGFR/BRAF therapy provides optimal survival benefits to patients with advanced BRAF-mutated colorectal cancer (CRC), according to a study.

“For pretreated patients, anti-EGFR/BRAF therapy without chemotherapy is the preferred strategy, balancing efficacy with reduced toxicity,” the researchers said.

In this systematic review and network meta-analysis, the research team accessed the databases of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov from inception to 31 May 2025, as well as international conference proceedings. They identified clinical trials and real-world studies examining the efficacy and safety of targeted therapies for advanced BRAF-mutated CRC.

Overall survival (OS) in the first- and second- or later-line settings was the primary endpoint. Other endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and grade ≥3 adverse events.

Sixty studies, including a total of 4,633 patients with advanced BRAF-mutated CRC, met the eligibility criteria. Pooled estimates suggested survival benefits with an anti-EGFR/BRAF-based regimen. [BMJ 2025;391:e086026]

Treatment with doublet chemotherapy (DCT) combined with anti-EGFR/BRAF therapy resulted in the best OS, providing significant benefits relative to DCT-anti-VEGF therapy (hazard ratio [HR], 0.49, 95 percent credible interval [CrI], 0.36–0.66), triplet chemotherapy-anti-VEGF (HR, 0.51, 95 percent CrI, 0.33–0.80), and anti-EGFR/BRAF regimens (HR, 0.70, 95 percent CrI, 0.51–0.96) in the first-line setting.

Chemotherapy plus anti-EGFR/BRAF was superior to all first-line targeted therapy strategies in terms of OS (surface under the cumulative ranking curve [SUCRA], 0.94 for DCT-anti-EGFR/BRAF, 0.90 for single agent chemotherapy [SCT]-anti-EGFR/BRAF) and PFS (SUCRA, 0.93 for DCT-anti-EGFR/BRAF and 0.92 for SCT-anti-EGFR/BRAF).

In the second- or later-line setting, anti-EGFR/BRAF with or without an additional anti-MEK inhibitor or anti-PI3K performed better than other strategies, with highest ranking across endpoints based on rank probability and SUCRA, according to the researchers.

“Using multiple meta-analysis approaches, we found that anti-EGFR/BRAF-based regimens represent an optimal therapeutic strategy for patients with advanced BRAF-mutated CRC,” the researchers said. “The integration of chemotherapy with EGFR/BRAF targeted therapies is essential to maximize therapeutic efficacy in chemotherapy-naïve patients, albeit at the cost of increased toxicity.”

Safety profile

In safety analyses, anti-EGFR/BRAF combinations with chemotherapy in the first-line setting resulted in higher rates of grade ≥3 adverse events, but these were not significantly different from traditional anti-VEGF regimens, according to the researchers.

“Anti-EGFR/BRAF showed a favourable safety profile, with adverse event rates significantly lower than those of chemotherapy containing regimens,” they said. 

However, adding another targeted agent, such as PI3K inhibitors, elevated the toxicity risk. This highlighted the need to balance efficacy with tolerability.

“For instance, frontline strategies may prioritize intensive chemotherapy regimens, whereas later-line therapy may favour low toxicity anti-BRAF/EGFR alone, as reflected in recent guideline updates,” the researchers said. 

“These findings highlight the necessity of line-specific therapeutic decision making and clarify the roles of anti-EGFR/BRAF-based treatment strategies in patients with advanced BRAF-mutated CRC, potentially complementing the current guidelines,” they added.