Ask AI
Back Back
BRAF V600E mCRC and mNSCLC
Experts Discuss Key Questions Surrounding Treatment of BRAF V600E–Mutated Metastatic CRC and NSCLC

Released: June 30, 2026

Christopher Lieu
Christopher Lieu, MD, FASCO
Gregory J. Riely
Gregory J. Riely, MD, PhD
Activity Information

Activity

Progress
1
Course Completed
Continue
Key Takeaways
  • Rapid, comprehensive biomarker testing with tissue NGS supplemented by plasma ctDNA can accelerate identification of BRAF V600E mutations and other actionable biomarkers, enabling timely first-line treatment decisions.
  • Molecular test results should be acted on as soon as they become available, as earlier incorporation of BRAF-directed therapy in eligible patients with mCRC is associated with better outcomes than delaying targeted treatment until later lines of therapy.
  • Targeted therapy is the preferred initial strategy for most patients with BRAF V600E-mutated metastatic cancers, including encorafenib plus cetuximab plus chemotherapy for mCRC and dual BRAF/MEK inhibition for metastatic NSCLC.

In this commentary, Christopher Lieu, MD, FASCO, and Gregory J. Riely, MD, PhD, discuss questions from healthcare professionals (HCPs) participating in a local live meeting series on the management of BRAF V600E–mutated metastatic colorectal cancer (mCRC) and non-small-cell lung cancer (NSCLC), including best practices in testing and targeted therapy.

How do you manage BRAF V600E–mutant mCRC?
Christopher Lieu, MD, FASCO: Patients with newly diagnosed BRAF V600E–mutant mCRC should receive BRAF-targeted therapy as early as possible if they are eligible. The BREAKWATER trial has fundamentally changed the treatment paradigm by demonstrating that first-line encorafenib plus cetuximab combined with chemotherapy significantly improves patient outcomes compared with standard chemotherapy alone. Median progression-free survival with encorafenib plus cetuximab plus mFOLFOX6 nearly doubled to approximately 13 months vs standard chemotherapy (12.8 vs 7.1 months), objective response rates (ORRs) increased to 65.7% from 37.4, and median overall survival improved from 15.1 months to 30.3 months. Of importance, this survival advantage was observed despite crossover to targeted therapy in some patients assigned to the control arm, emphasizing the importance of introducing BRAF-directed therapy upfront rather than sequentially.

This benefit was consistent across clinically relevant subgroups, including patients with right-sided primary tumors, liver metastases, and multiorgan disease. More recently, BREAKWATER cohort 3 demonstrated similarly encouraging activity with encorafenib plus cetuximab combined with FOLFIRI, providing additional flexibility for patients in whom oxaliplatin-based therapy may not be ideal.

A common clinical dilemma arises when molecular results become available after treatment has already begun. If a patient starts FOLFOX-bevacizumab and next-generation sequencing subsequently identifies a BRAF V600E mutation, I strongly encourage making the switch to encorafenib plus cetuximab with chemotherapy. Data have consistently demonstrated that simply sequencing therapies is not equivalent to targeting biology aggressively from the beginning. Acting on newly available molecular information can have a meaningful impact on survival.

The one important exception is patients with microsatellite instability–high mCRC. Those patients should continue to receive first-line immunotherapy because of the profound benefit observed in that population. If the disease progresses following immunotherapy, incorporating chemotherapy with BRAF-targeted therapy becomes an appropriate next step.

How do you manage BRAF V600E–mutant metastatic NSCLC?
Gregory J. Riely, MD, PhD: For patients with metastatic NSCLC harboring a BRAF V600E mutation, dual BRAF and MEK inhibition remains the standard initial treatment approach. Currently, HCPs can choose between dabrafenib plus trametinib or encorafenib plus binimetinib. Although no randomized trial has directly compared these regimens, both have demonstrated substantial and durable clinical activity.

The rationale for dual inhibition is straightforward. Combining BRAF and MEK inhibition provides more complete suppression of MAPK signaling, delays resistance mechanisms, and improves tolerability compared with BRAF inhibition alone. A phase II study with dabrafenib plus trametinib produced ORRs approaching 65% in both treatment-naive and previously treated patients. More recently, the phase II PHAROS study reported an ORR of 75% in untreated patients receiving encorafenib plus binimetinib, with durable responses lasting more than 40 months in many individuals. Median progression-free survival approached 30 months in treatment-naive patients.

One challenge is that, unlike with EGFR- or ALK-positive mNSCLC, we still lack randomized studies comparing targeted therapy directly with chemoimmunotherapy. Of consequence, treatment decisions often rely on clinical judgment. In my own practice, I generally favor encorafenib plus binimetinib because my experience has been that patients experience potentially less pyrexia than with dabrafenib plus trametinib.

There are exceptions. In patients with a substantial smoking history and very high PD-L1 expression, I discuss both targeted therapy and chemoimmunotherapy as reasonable first-line options. However, I generally need compelling clinical reasons before moving away from targeted therapy because of the robust activity observed with dual BRAF/MEK inhibition.

What are best practices in obtaining biomarker test results in an efficient manner?
Gregory J. Riely, MD, PhD: Rapid molecular testing has become one of the most important components of precision oncology. The challenge is no longer deciding whether to test; it is obtaining results quickly enough to influence first-line treatment decisions. In lung cancer, comprehensive tissue-based NGS should be initiated immediately after diagnosis. However, tissue testing can require several weeks, and many patients should not wait that long before beginning treatment.

For that reason, I routinely obtain plasma ctDNA testing whenever tissue results are not immediately available. Plasma testing is not a replacement for tissue NGS because of its false-negative rate, but it serves as an excellent complementary strategy. A positive plasma result is actionable, allowing HCPs to begin targeted therapy immediately while comprehensive tissue sequencing continues. If plasma testing is negative, I simply wait for the tissue results before making definitive molecular treatment decisions.

When treatment cannot be delayed, my preference is to begin chemotherapy alone while intentionally avoiding immune checkpoint inhibitors until driver mutations have been excluded. This preserves future targeted therapy options and minimizes the potential complications associated with sequencing immunotherapy before targeted agents. In both metastatic and early-stage NSCLC, broad NGS panels have become standard because multiple actionable biomarkers now influence treatment decisions.

Christopher Lieu, MD, FASCO: Many of the same principles apply in mCRC. Fortunately, concordance between primary tumors and metastatic lesions is very high, allowing molecular testing from either specimen when sufficient tissue is available. Although metastatic tissue is ideal when obtainable, testing the primary tumor remains highly informative.

My own practice has evolved considerably regarding plasma ctDNA. I now routinely obtain both tissue NGS and plasma testing at diagnosis. Plasma testing can rapidly identify clinically actionable findings such as BRAF V600E mutations or microsatellite instability–high disease, allowing treatment decisions to proceed while tissue testing is pending. However, HCPs must remember that a negative plasma result does not exclude an actionable alteration. Tissue-based sequencing remains essential.

Perhaps the most important point is that obtaining molecular results is only valuable if HCPs act on them. Patients may appear to be doing well after starting standard chemotherapy, but the BREAKWATER data clearly demonstrate that earlier implementation of BRAF-directed therapy produces better long-term outcomes than waiting until later lines of treatment to use targeted therapy. Molecular testing should therefore be viewed as a dynamic process that continues to influence management even after therapy has begun.

Do you repeat molecular testing at progression to reassess BRAF or other mutations?
Christopher Lieu, MD, FASCO: In mCRC, I do repeat ctDNA testing after progression on BRAF-targeted therapy because it often reveals acquired resistance mechanisms. It is common to identify newly emerging KRAS or NRAS mutations alongside the original BRAF mutation, providing insight into why treatment stopped working. Unfortunately, these resistance alterations are not yet clinically actionable in most cases. For now, repeat testing is primarily educational rather than practice changing, although I anticipate that future targeted therapies will make serial ctDNA monitoring increasingly valuable.

How do you manage patients with BRAF-mutant NSCLC and brain metastases at diagnosis?
Gregory J. Riely, MD, PhD: Management depends largely on the size, location, and symptoms associated with the brain metastases. Patients with large or symptomatic lesions, or lesions in particularly high-risk locations, should generally undergo local therapy with surgery or radiation before considering systemic treatment.

Conversely, patients with small, asymptomatic brain metastases can often begin targeted therapy first with careful surveillance. I typically obtain a repeat brain MRI at approximately 6 weeks, coinciding with systemic imaging, to ensure that intracranial disease is responding appropriately. Close collaboration with radiation oncology is essential so that local therapy can be initiated promptly if central nervous system progression occurs. Although central nervous system–specific data remain limited, available evidence suggests that BRAF-targeted therapy has meaningful intracranial activity.

In BRAF V600E–mutant mCRC, when might you omit chemotherapy?
Christopher Lieu, MD, FASCO: Whenever possible, I favor combining chemotherapy with encorafenib and cetuximab because the BREAKWATER trial clearly demonstrated impressive efficacy with the triplet approach. Nevertheless, not every patient is an appropriate candidate for combination chemotherapy. Older adults, patients with significant comorbidities, or those with preexisting neuropathy may not tolerate oxaliplatin- or irinotecan-based regimens.

In those situations, targeted therapy alone becomes an attractive option. Encorafenib plus cetuximab produces response rates approaching 45%, which compares favorably with historical outcomes achieved using chemotherapy alone. BREAKWATER has also expanded flexibility by demonstrating that both FOLFOX- and FOLFIRI-based combinations can be paired successfully with BRAF-targeted therapy, allowing HCPs to individualize treatment according to patient characteristics while maintaining a biology-driven treatment strategy.

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 or answering the polling question.

Continue

Poll

1.

On which of the following topics in the use of BRAF-targeted agents would you most like additional education?

Submit