Key Clinical Summary: BRAF-driven treatment decisions - Biomarker testing in practice

This is a micro-learning module summary of Dr. Zev Wainberg’s session which you can find here. Before participating, please read our CME and disclosure information which can be found here.

Acknowledgment: This program is supported by an educational grant from Pfizer. It is designed only for healthcare professionals in the United States.

Introduction

This summary reviews the evolution of targeted therapy strategies in BRAF V600E–mutated metastatic colorectal cancer (mCRC) and non–small cell lung cancer (NSCLC), focusing on evidence supporting dual and triplet targeted regimens, biomarker-driven patient selection, and emerging questions regarding sequencing with immunotherapy. In addition, key efficacy and safety outcomes from pivotal trials supporting regulatory approvals and guideline recommendations are highlighted.

Second-line BRAF-targeted Therapy in mCRC: The BEACON Trial

• In the phase 3, multicenter BEACON trial, dual and triplet regimens were evaluated in patients who had progressed on frontline chemotherapy (ChT)
• A safety lead-in first tested the combination of encorafenib (a BRAF inhibitor), cetuximab (an EGFR inhibitor), and binimetinib (a MEK inhibitor)
• The study subsequently compared encorafenib plus cetuximab ± binimetinib with standard ChT (FOLFIRI/cetuximab or irinotecan/cetuximab)
• The primary endpoint of overall survival was met for the encorafenib–cetuximab doublet compared with the control arm (9.3 versus 5.9 months; hazard ratio [HR] 0.61; 95% confidence interval [CI]: 0.48–0.77)
• Improvements in progression-free survival (PFS) were also observed (4.3 versus 1.5 months; HR 0.44; 95% CI: 0.35–0.55)
• Adverse events in BEACON were consistent with the class effects of BRAF and EGFR inhibition:
• Rash and dermatologic toxicities occurred more frequently with encorafenib–cetuximab than in the control arm, and cytopenias were modestly increased
• Quality-of-life assessments favored the targeted combination over ChT, further supporting its use in the second-line setting
• Although the addition of binimetinib increased biochemical pathway suppression, the dual regimen ultimately served as the basis for regulatory approval due to similar efficacy with a more favorable toxicity profile
• The BEACON findings resulted in endorsement from major guideline organizations (ASCO, ESMO and NCCN) and led to the approval of encorafenib plus cetuximab for mCRC previously treated with ChT

Biomarkers and Combination Strategies with Immunotherapy in mCRC

• Approximately 15–20% of BRAF V600E mCRC tumors exhibit microsatellite instability (MSI-high status). Because immune checkpoint inhibitors are highly active in MSI-high disease, interest has grown in combining or sequencing immunotherapy with BRAF-targeted therapy
• Early exploratory biomarker work has examined potential predictors such as MSI status and the RNF43 gene signature, but these remain investigational
• Emerging small studies have tested triplet combinations of BRAF + MEK + EGFR inhibition alongside PD-1 blockade
• One such study evaluated encorafenib, cetuximab, and nivolumab in refractory BRAF-mutant mCRC, reporting response rates of 50% among 22 evaluable patients and a median overall survival of 15 months
• A similar trial combining dabrafenib, trametinib, and an anti–PD-1 antibody produced response rates of ~25%
• The optimal treatment sequence remains under investigation:
• Checkpoint inhibitors show activity in MSI-high, BRAF-mutated mCRC based on subgroup analyses of KEYNOTE-177, but the population was small
• The ongoing SEAMARK trial is testing pembrolizumab alone versus pembrolizumab + encorafenib + cetuximab in the first line in patients with concurrent MSI-high and BRAF V600E mutations. Its results will inform whether upfront triplet targeted-immunotherapy combinations can outperform immunotherapy alone.

BRAF-targeted Therapy in NSCLC

• BRAF mutations also occur in NSCLC, although less frequently than in CRC
• Approximately 2–4% of metastatic NSCLC tumors harbor a BRAF alteration, and only about half of these are V600E.
• As in mCRC, V600E is the principal actionable subtype, whereas non-V600E variants exhibit variable biology
• Dual BRAF and MEK inhibition has become the backbone of therapy in this population. The earliest data came from studies of dabrafenib plus trametinib, demonstrating response rates of ~40–50% in previously treated patients and leading to its approval in 2017
• More recently, encorafenib plus binimetinib has been evaluated in the PHAROS trial V600E-mutated NSCLC across treatment-naïve and previously treated cohorts:
• Among 59 treatment-naïve individuals, overall response rate (ORR) reached 75% , with a median duration of response (DOR) of 40 months and median PFS of 30 months; remarkably durable outcomes for this molecular subgroup
• In 39 previously treated patients, the ORR was 46%, median DOR was almost 17 months and median PFS was 9 months
• Toxicities included rash, gastrointestinal adverse events, and cytopenias, consistent with experiences in other tumor types
• These results led to approval of encorafenib plus binimetinib in 2023, expanding the therapeutic landscape for BRAF-mutant NSCLC

Conclusion

BRAF V600E mutations define aggressive, biologically distinct subsets of mCRC and NSCLC. Advances in targeted therapy, particularly combinations inhibiting BRAF, MEK, and EGFR, have significantly improved outcomes, establishing new standards of care in both the frontline and refractory settings. Universal molecular testing is essential to identify candidates for these therapies. Ongoing research is exploring integration with immunotherapy and strategies to optimize sequencing and patient selection, promising further refinement of precision treatment approaches for this challenging molecular subgroup.

Content is accurate as of the date of release on 6 January 2026.