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BRAF mCRC and mNSCLC
Advancing Care for BRAF V600E-Mutated Metastatic CRC and NSCLC: Insights Into Targeted Therapies and Real-World Challenges

Released: January 22, 2026

Christopher Lieu
Christopher Lieu, MD, FASCO
Gregory J. Riely
Gregory J. Riely, MD, PhD
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Key Takeaways
  • Early and comprehensive biomarker testing is essential for guiding first-line therapy in both mCRC and mNSCLC, including for patients with BRAF V600E-mutated cancers.
  • Targeted therapy combinations have demonstrated significant efficacy for BRAF V600E-mutated mCRC and mNSCLC and are central to modern treatment paradigms.
  • Real-world barriers, including delayed testing and insufficient tissue, highlight the need for streamlined approaches such as liquid biopsy and timely NGS to ensure optimal patient care.

The management of BRAF V600E-mutated cancers has evolved rapidly as targeted therapies have demonstrated meaningful improvements in outcomes across multiple tumor types. In this commentary, experts discuss the latest strategies for first-line treatment of BRAF V600E-mutated metastatic colorectal cancer (mCRC) and metastatic non-small-cell lung cancer (mNSCLC) as well as barriers to implementation.

Contemporary Management of BRAF V600E-Mutated mCRC

Christopher Lieu, MD, FASCO:
Recent advances in targeted therapy have dramatically reshaped the treatment landscape for patients with BRAF V600E-mutated mCRC, leading to significant improvements in clinical outcomes in this population with an overall poor prognosis. Before effective targeted treatment approaches, BRAF V600E-mutated mCRC was managed with standard chemotherapy in the frontline setting, which typically included FOLFOX combined with bevacizumab.

BRAF V600E inhibitors first showed remarkable efficacy in metastatic melanoma. The phase III BEACON trial in patients with previously treated mCRC showed that the combination of encorafenib plus binimetinib and cetuximab led to a significant improvement in overall survival (OS) vs investigator’s choice chemotherapy plus cetuximab. 

More recently, the phase III BREAKWATER study showed that the combination of mFOLFOX6 with encorafenib and cetuximab led to a nearly doubling of median progression-free survival (PFS; 12.8 vs 7.1 months; P <.001) and median OS (30.3 vs 15.1 months; P <.001) vs investigator's choice of standard chemotherapy for patients with BRAF V600E-mutated mCRC with no prior treatment in the metastatic setting. This study taught us that with respect to both short-term outcomes like response and PFS as well as long-term outcomes like OS, when the most effective regimen is given first, the benefits are magnified. Of note, BREAKWATER also included an arm in which patients received encorafenib and cetuximab without chemotherapy. Numerically, the confirmed objective response rate (ORR) by BICR was higher in the encorafenib plus cetuximab arm (45.6%) compared to the SoC arm (37.4%), with the chemotherapy plus encorafenib/cetuximab arm demonstrating the highest ORR (65.7%). I think it has become clear that the first-line SoC therapy for patients with BRAF V600E-mutated mCRC should be chemotherapy combined with encorafenib and cetuximab, as this leads to significant survival benefits.  

Contemporary Management of BRAF V600E-Mutated mNSCLC

Gregory J. Riely, MD, PhD:
The foundation of choosing first-line therapy for NSCLC after having determined disease stage and tumor histology (ie, adenocarcinoma, squamous cell) is the presence or absence of actionable biomarkers. Key biomarkers include PD-L1, which is assessed through immunohistochemistry, and other common molecular markers like EGFR, KRAS G12C, ALK, ROS1, RET, ERBB2, MET, and BRAF. Every patient with NSCLC should be tested for all these alterations prior to the start of therapy.

BRAF mutations are present in approximately 2% of patients with NSCLC. The BRAF V600E mutation, which is reported in around 1% of patients with NSCLC, is readily targetable. Standard initial treatment for BRAF V600E-mutant NSCLC is now a combination of BRAF and MEK inhibitors. The first drugs approved in this context were dabrafenib and trametinib. In single-arm phase II trials, these agents demonstrated efficacy in both untreated and previously treated patients. The response rates were markedly higher with the combination vs monotherapy with BRAF inhibitors like dabrafenib or vemurafenib. Consequently, the combination of dabrafenib and trametinib was the first targeted therapy approved for BRAF V600E-mutant NSCLC.   

However, toxicity and tolerability are major limitations with dabrafenib plus trametinib. One of the more common adverse events seen with these agents is pyrexia, with nausea, diarrhea, fatigue, and edema also reported. These toxicities need to be addressed when caring for patients receiving these drugs.  

More recently, data with a different BRAF and MEK inhibitor combination were reported. The combination of encorafenib and binimetinib was first studied in patients with BRAF-mutant melanoma but was more recently investigated in patients with advanced BRAF V600E-mutated NSCLC in the single-arm phase II PHAROS trial. Treatment-naive or previously treated patients received the combination of encorafenib plus binimetinib. Response rates were 75% in treatment-naive patients and 46% in previously treated patients. While acknowledging that cross-trial comparisons can be problematic, median PFS in treatment-naive patients was 30.2 months with encorafenib and binimetinib in the PHAROS trial vs 10.8 months with dabrafenib and trametinib in a phase II trial. Thus, in the first-line setting, encorafenib and binimetinib is an efficacious combination, and recent clinical trial data emphasize that targeted therapy remains the standard first-line therapy for BRAF V600E-mutated NSCLC.   

One challenge for this patient population is that all of the approvals of BRAF plus MEK inhibitor combinations were based on single-arm trials—there has been no randomized trial to compare targeted therapy to either chemotherapy or chemotherapy plus immunotherapy in the context of newly diagnosed BRAF V600E-mutated NSCLC. Recently, there was a retrospective exploration of patients with BRAF V600E-mutated NSCLC who were treated with either standard therapy (ie, an immune checkpoint inhibitor [ICI] and/or chemotherapy) vs targeted therapy. It was not clear that targeted therapies were associated with better outcomes than standard therapies, although the analysis was limited by its retrospective nature. Traditionally, targeted therapies have been the standard, but recent evidence suggests that ICIs with or without chemotherapy may play a role in initial therapy for some patients.   

Barriers to Use of Targeted Therapy for BRAF V600E-Mutated NSCLC and CRC in Real-world Practice

Christopher Lieu, MD, FASCO:
Despite clear evidence supporting biomarker-driven treatment strategies in mCRC, several logistical and clinical barriers continue to impede the timely implementation of these approaches in routine practice. Barriers to incorporating this regimen are highly dependent on how early biomarker testing results are obtained. Since patients with newly diagnosed mCRC should start treatment right away, a biomarker test should be ordered immediately after diagnosis, as the results can take several weeks. Strategies to address these barriers include starting with a chemotherapy-only approach. In the United States, this approach typically includes FOLFOX, although FOLFIRI and FOLFOXIRI can also be used. After 1 or 2 cycles, and after obtaining information from the biomarker test, treatment can be tailored to patient needs. For instance, if treatment is started with FOLFOX and biomarker test results show a BRAF V600E mutation, encorafenib and cetuximab can be incorporated into treatment. Another approach is to send off a liquid biopsy in conjunction with the biomarker test. By testing for circulating tumor DNA (ctDNA) at the initial patient visit, results may be accessible within 1 week. At the ESMO 2025 Congress, data showed that the concordance rates between ctDNA and tumor tissue were very high for BRAF V600E mutations, and there did not appear to be any false positives from ctDNA. Therefore, if a ctDNA test shows a BRAF V600E mutation, healthcare professionals (HCPs) can act on results that are considered reliable. If the ctDNA assay does not show a BRAF mutation, HCPs can wait for the tumor tissue results.

I think the key here is that the BRAF V600E mutation is a critically important biomarker for patients with mCRC because the regimen of chemotherapy plus encorafenib and cetuximab can significantly improve OS over SoC first-line therapy. To provide the most effective therapies for our patients, it is critical to obtain biomarker information quickly and efficiently, which means ensuring that tumor tissue is sent for next-generation sequencing at presentation. In many cases, sending off liquid biopsies or performing ctDNA testing can be efficient ways to look for mutations to inform clinical practice while awaiting tumor tissue results.

Gregory J. Riely, MD, PhD:
Biomarker testing is critical when managing mNSCLC. Barriers to biomarker testing often include not having enough tissue at the time of diagnosis. Diagnostic biopsies in patients with metastatic disease are often based on bone biopsies or small biopsies of larger tumors, and the tumor tissue is exhausted prior to completion of all molecular tests. In this context, it is reasonable to explore repeat biopsy, but a “liquid biopsy,” a blood test that looks for circulating tumor DNA in plasma, can also be useful. ctDNA assays can be relatively sensitive in patients with metastatic disease, and BRAF V600E mutations are readily identified from plasma DNA.

Some patients in the community do not receive molecular testing upfront for various reasons—it’s possible that the treating HCP did not find it necessary, or perhaps there was insufficient tissue. In these patients, I generally push for repeat biopsy at some point during the treatment course. Clearly an opportunity for a biopsy exists between the first and second line. One benefit of identifying a BRAF V600E mutation is that targeted therapies are highly efficacious as either first- or second-line agents. Thus, if not identified prior to initial chemotherapy and immunotherapy, then using a BRAF inhibitor and MEK inhibitor combination in the second-line setting can be very effective. 

Your Thoughts
How are you currently integrating biomarker testing and targeted therapies into the management of patients with BRAF V600E-mutated metastatic cancers, and what challenges or gaps have you encountered in applying these strategies in real-world practice? Join the conversation by posting a comment below of answering the polling question.

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