BRAF V600E-mutant colorectal cancer
BRAF V600E bowel cancer carries the same mutation as many melanomas, but BRAF drugs alone did nothing here because the tumour re-routes its growth signal through EGFR. Blocking both with encorafenib and cetuximab, now given with chemotherapy from the start, has doubled survival in a subtype that used to be the worst.
Overview
BRAF V600E locks the RAS-MAPK pathway on, and in colorectal cancer it arises in the serrated pathway with CpG island methylation; about a third of localised BRAF-mutant tumours are also mismatch-repair deficient, in which case the immunotherapy of that subtype applies and the outlook is good. Microsatellite-stable BRAF V600E disease is different: it is often right-sided, presents with peritoneal and nodal spread, responds poorly to chemotherapy, and anti-EGFR antibodies alone do not work. Non-V600 BRAF mutations, about 2 percent of cancers, behave as a separate and less aggressive group.
Single-agent vemurafenib failed in 2011 because inhibiting BRAF in bowel cells releases feedback activation of EGFR; blocking both proved the answer. BEACON CRC (2019) randomised 665 previously treated patients to encorafenib and cetuximab with or without binimetinib against chemotherapy plus cetuximab: median survival was 9.3 months with either targeted regimen against 5.9 months, response rates were 20 to 27 percent against 2 percent, and the FDA approved encorafenib with cetuximab in April 2020. BREAKWATER (2024 to 2025) then moved the doublet into first line with mFOLFOX6: the response rate was 61 percent against 40 percent for chemotherapy and median survival 30.3 months against 15.1 months, which brought accelerated approval in December 2024 and full approval in 2026.
The next questions are whether to add a PD-1 antibody (SEAMARK, encorafenib-cetuximab-pembrolizumab in mismatch-repair deficient BRAF disease), how to treat after progression on the targeted doublet, when MAPK reactivation and MET amplification drive resistance, and whether the triplet should be given in the adjuvant setting for stage III disease.
State of the art
- The EGFR-feedback mechanism explained a decade of failed BRAF monotherapy and is the template for vertical pathway blockade.
- Mismatch-repair deficient BRAF tumours get immunotherapy, not targeted therapy, first.
Show survival figures (1)
Averages across everyone diagnosed, often years ago. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.
- Encorafenib plus cetuximab with FOLFOX in first line (BREAKWATER) doubles survival against chemotherapy.
Red cards
From the labels and guidelines behind the standard of care. Your team's thresholds win.- Emergency services nowBleeding or bruising
Bleeding that will not stop, black or bloody stools, or unexplained bruising when platelets are expected to be low.
- Emergency services nowFainting or palpitations
Fainting, near-fainting, or an irregular or racing heartbeat; several kinase inhibitors prolong the QT interval and the labels require ECG and electrolyte monitoring.
- Emergency services nowHypophysitis or adrenal crisis
Persistent headache with extreme tiredness, nausea, dizziness on standing or low blood pressure. Vomiting, severe weakness or collapse is adrenal crisis.
- Emergency services nowBowel perforation
Sudden severe abdominal pain, a hard or very tender abdomen, or abdominal pain with vomiting and fever. Boxed warning for gastrointestinal perforation on bevacizumab.
- Check before combiningFood and drink: Oxaliplatin
Cold-triggered acute neuropathy: avoid cold drinks and air for days after infusion.
- Check before combiningFood and drink: Pembrolizumab
No pharmacokinetic interactions expected (antibody). See the irAE guide for toxicity management.
See all on the product pages:CAPOX (capecitabine, oxaliplatin)EncorafenibFOLFOX (5-FU, leucovorin, oxaliplatin)FruquintinibIpilimumabNivolumabOxaliplatinPembrolizumabRegorafenibTrifluridine/tipiracil·Printable cards in the navigator
Anatomy and lymph node drainage
- Right colon (MSI-high, BRAF commoner)
- Left colon and sigmoid
- Rectum
- Anal canal (HPV squamous)
- Appendix
- Peritoneum and omentum (mesothelioma, peritoneal spread)
- Nodes: pericolic
- Nodes: mesenteric root
- Nodes: para-aortic
- Nodes: mesorectal
- Nodes: lateral pelvic and inguinal (anal)
Right-sided tumours behave differently from left-sided and rectal ones; the colon drains along its mesenteric vessels, the rectum into the mesorectum and pelvic side wall.
- Right colon (MSI-high, BRAF commoner)BRAF V600E, microsatellite-stable (the aggressive majority; targeted therapy with encorafenib and cetuximab) · BRAF V600E with mismatch-repair deficiency (right-sided; immunotherapy first) · BRAF non-V600 (class 2 and 3) mutations, a distinct and less aggressive group · Right-sided serrated-pathway tumours with CpG island methylation
- Left colon and sigmoid
- Rectum
- Anal canal (HPV squamous)
- Appendix
- Peritoneum and omentum (mesothelioma, peritoneal spread)
- pericolic
- mesenteric root
- para-aortic
- mesorectal
- lateral pelvic and inguinal (anal)
Same organ: Peritoneal mesothelioma, Colorectal cancer, Rectal cancer, Mismatch-repair deficient (MSI-high) colorectal cancer, HER2-amplified colorectal cancer, KRAS G12C-mutant colorectal cancer, Early-onset colorectal cancer (under 50), Anal cancer (squamous cell carcinoma), Appendiceal cancer and pseudomyxoma peritonei, Small intestine cancer (small bowel adenocarcinoma)
Show survival figures (1)
Averages across everyone diagnosed, often years ago. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.
- About 8 to 10 percent of colorectal cancers carry BRAF V600E; they are commoner in older women and right-sided tumours, are often mismatch-repair deficient when localised, and when metastatic and microsatellite-stable have had among the shortest survival of any colorectal subtype.
- Liquid biopsy (ctDNA)Standard of care
Nothing recorded yet.
Nothing recorded yet.
Also on OnCo: Symptoms and red flags · Early detection roadmap.
Cases by country
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.
Encorafenib plus cetuximab plus mFOLFOX6 (BREAKWATER); encorafenib plus cetuximab alone for patients unfit for chemotherapy.
Encorafenib plus cetuximab (BEACON CRC) if not already given; then trifluridine-tipiracil with bevacizumab, fruquintinib or regorafenib.
Checkpoint blockade first (pembrolizumab, or nivolumab plus ipilimumab); BRAF-targeted therapy at progression.
Surgery and stage-based adjuvant FOLFOX or CAPOX as for colorectal cancer; BRAF status does not yet change adjuvant treatment outside trials.
Subtypes & biomarkers
top- BRAF V600E, microsatellite-stable (the aggressive majority; targeted therapy with encorafenib and cetuximab)
- BRAF V600E with mismatch-repair deficiency (right-sided; immunotherapy first)
- BRAF non-V600 (class 2 and 3) mutations, a distinct and less aggressive group
- Right-sided serrated-pathway tumours with CpG island methylation
- BRAF V600E by sequencing or VE1 immunohistochemistry
- Mismatch repair status (immunotherapy if deficient)
- RAS wild-type by definition; co-mutations rare
- Consensus molecular subtype 1 enrichment
- Circulating tumour DNA to track MAPK reactivation on treatment
How often this target appears
- 2002BRAF mutations discovered in human cancer (Davies, Nature)
- 2011Vemurafenib alone fails in BRAF-mutant colorectal cancer; EGFR feedback identified the next year
- 2019BEACON CRC: encorafenib plus cetuximab improves survival after prior therapy
- 2020FDA approves encorafenib with cetuximab, the first targeted therapy for the subtype
- 2024BREAKWATER: encorafenib-cetuximab-FOLFOX first line; accelerated approval in December
- 2025BREAKWATER overall survival 30.3 versus 15.1 months
- 2026Full approval of the first-line triplet
Dated changes read from the records linked to this cancer: approvals, regulatory steps, reported trials, guideline versions and milestones. Newest first; no date is inferred.
All 12 changes by month →- 2026-09-17This recordBRAF V600E-mutant colorectal cancerFacts on this page last checked
When this page itself was last checked or edited.
- 2026MilestoneEncorafenibFull approval of the first-line triplet
A milestone in how this cancer is treated.
- 2025Trial resultBREAKWATERBREAKWATER reported
OS 30.
- 2025MilestoneBREAKWATERBREAKWATER overall survival 30.3 versus 15.1 months
A milestone in how this cancer is treated.
- 2024Trial resultCheckMate 8HWCheckMate 8HW reported
First-line PFS 54.
- 2024MilestoneBREAKWATERBREAKWATER: encorafenib-cetuximab-FOLFOX first line; accelerated approval in December
A milestone in how this cancer is treated.
What is in development for BRAF V600E-mutant colorectal cancer, drawn from the whole corpus: 4 items. Drugs are grouped by the most advanced trial phase they have reached anywhere; approved treatments sit under standard of care. Technologies are the methods being tested for this cancer, trials are the studies recorded here, and ideas are proposals not yet in a trial.
Trials under way · 2
- A Study of Encorafenib Plus Cetuximab Taken Together With Pembrolizumab Compared to Pembrolizumab Alone in People With Previously Untreated Metastatic · phase 2 · Pfizer
- Efficacy and Safety of Tunlametinib Plus Vemurafenib in Patients With BRAF V600E-mutant Metastatic Colorectal Cancer · phase 3 · Shanghai Kechow Pharma, Inc.
Trials reported · 2
- BREAKWATER · phase 3 · 2025 · positive
- BEACON CRC · phase 3 · 2019 · positive
Open problems and what is being done
No standard therapy after progression on encorafenib and cetuximab.
and how the field plans to fix it →What is being done about thisResistance to treatmentAvailable now- Liquid biopsy (ctDNA)Standard of care
- Small-molecule kinase inhibitorsStandard of care
In trials- BEACON CRCPositive
Ideas and roadmapsNothing recorded yet.
Background: Circulating tumour DNA (ctDNA). Also on OnCo: Resistance atlas · Lines of therapy.
Resistance through MAPK reactivation and MET amplification is common and untargeted.
and how the field plans to fix it →What is being done about thisResistance to treatmentAvailable now- Liquid biopsy (ctDNA)Standard of care
- Small-molecule kinase inhibitorsStandard of care
In trials- BEACON CRCPositive
Ideas and roadmapsNothing recorded yet.
Background: Circulating tumour DNA (ctDNA). Also on OnCo: Resistance atlas · Lines of therapy.
Adjuvant use of the targeted doublet in stage III disease is untested.
Non-V600 BRAF mutations have no approved targeted option.
Trials
topTrials recruiting now
Country and place are remembered in this browser only. A postcode is sent to OpenStreetMap's Nominatim service to find coordinates when you press the button; nothing else leaves your device.
Landmark trials
Expert centres
topExpert centres
Houston · cancer center | United States | 0 | 6,724 | 95,007 | #2 | ||
Baltimore · cancer center | United States | 0 | 2,955 | 41,449 | #10 | ||
Boston · hospital | United States | 0 | 3,582 | 54,857 | #16 | ||
| Spain | none recorded | 0 | 966 | 23,221 | none recorded | #28 | |
Barcelona · hospital | Spain | none recorded | 0 | 1,265 | 15,631 | - | |
Pittsburgh, PA · cancer center | United States | 0 | 1,078 | 21,539 | - | ||
Lyon · cancer center | France | none recorded | 0 | 1,071 | 14,301 | - | |
Naples · cancer center | Italy | none recorded | 0 | 961 | 15,028 | - | |
Changsha · cancer center | China | none recorded | 0 | 930 | 14,477 | - | |
Taipei · hospital | Taiwan | none recorded | 0 | 746 | 8,966 | - | |
Guangzhou · hospital | China | none recorded | 0 | 704 | 7,832 | - | |
Nagoya · cancer center | Japan | none recorded | 0 | 657 | 8,832 | - | |
Shanghai · hospital | China | none recorded | 0 | 539 | 6,491 | - | |
Lausanne · hospital | Switzerland | none recorded | 0 | 509 | 9,176 | - | |
Ghent · hospital | Belgium | none recorded | 0 | 495 | 5,334 | - |
These are the things we can measure; they are not a ranking of quality. Each column is a field on the institution record or a count over what OnCo has linked; a centre that treats many patients with BRAF V600E-mutant colorectal cancer but is thinly recorded here will look small.
Not known: OnCo holds no case-volume or outcome figures for centres, so none are shown. Where a national audit or registry publishes them, the centre's page links to it. Default order: Newsweek rank, then trials for this cancer, then research output.
Questions to ask
topQuestions to ask your oncologist about BRAF V600E-mutant colorectal cancer
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Why: Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example BRAF V600E by sequencing or VE1 immunohistochemistry, Mismatch repair status, RAS wild-type by definition; co-mutations rare, Consensus molecular subtype 1 enrichment, Circulating tumour DNA to track MAPK reactivation on treatment), and what were the results?Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Why: Recognised subtypes for this cancer include BRAF V600E, microsatellite-stable, BRAF V600E with mismatch-repair deficiency, BRAF non-V600mutations, a distinct and less aggressive group.
- Is germline (inherited) genetic testing recommended for me or my family?Why: Inherited variants can change treatment and matter for relatives.
Metastatic, microsatellite-stable, first line
- For my situation (metastatic, microsatellite-stable, first line), which of the standard options do you recommend and why?Why: Guideline options include: Encorafenib plus cetuximab plus mFOLFOX6 (BREAKWATER); encorafenib plus cetuximab alone for patients unfit for chemotherapy.
- Am I a candidate for Encorafenib, Cetuximab, FOLFOX (5-FU, leucovorin, oxaliplatin), and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of BREAKWATER apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Metastatic, previously treated
- For my situation (metastatic, previously treated), which of the standard options do you recommend and why?Why: Guideline options include: Encorafenib plus cetuximab (BEACON CRC) if not already given; then trifluridine-tipiracil with bevacizumab, fruquintinib or regorafenib.
- Am I a candidate for Encorafenib, Cetuximab, Trifluridine/tipiracil or related drugs, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of BEACON CRC apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Metastatic, mismatch-repair deficient
- For my situation (metastatic, mismatch-repair deficient), which of the standard options do you recommend and why?Why: Guideline options include: Checkpoint blockade first (pembrolizumab, or nivolumab plus ipilimumab); BRAF-targeted therapy at progression.
- Am I a candidate for Pembrolizumab, Nivolumab, Ipilimumab, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of KEYNOTE-177 and CheckMate 8HW apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Localised
- For my situation (localised), which of the standard options do you recommend and why?Why: Guideline options include: Surgery and stage-based adjuvant FOLFOX or CAPOX as for colorectal cancer; BRAF status does not yet change adjuvant treatment outside trials.
- Am I a candidate for FOLFOX (5-FU, leucovorin, oxaliplatin), CAPOX (capecitabine, oxaliplatin), Oxaliplatin, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Any stage
- Are there clinical trials I could join, for example of A Study of Encorafenib Plus Cetuximab Taken Together With Pembrolizumab Compared to Pembrolizumab Alone in People With Previously Untreated Metastatic, Efficacy and Safety of Tunlametinib Plus Vemurafenib in Patients With BRAF V600E-mutant Metastatic Colorectal Cancer, BREAKWATER, Encorafenib?Why: Trials are how the next standard of care is set; asking early keeps options open.
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Why: Supportive care improves quality of life and helps patients complete treatment.
- I read that “No standard therapy after progression on encorafenib and cetuximab”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “Resistance through MAPK reactivation and MET amplification is common and untargeted”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
Newly diagnosed? Read the first 60 days with BRAF V600E-mutant colorectal cancer, then print the one-page appointment sheet with room for the answers.
Print this page for your appointment (your browser's print command). These prompts are for discussion; your clinical team knows your case.
Direct links plus the targets, companies, and technologies of this cancer's products.
technologies
7targets
8drugs
12companies
8pathways
2terms
4trials
6people
3Latest papers
topQuery for this cancer: (TITLE:"BRAF V600E-mutant colorectal cancer" OR ABSTRACT:"BRAF V600E-mutant colorectal cancer" OR TITLE:"BRAF-mutant colorectal cancer" OR ABSTRACT:"BRAF-mutant colorectal cancer" OR TITLE:"BRAF V600E metastatic colorectal cancer" OR ABSTRACT:"BRAF V600E metastatic colorectal cancer" OR TITLE:"BRAF-mutated bowel cancer" OR ABSTRACT:"BRAF-mutated bowel cancer") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about BRAF V600E-mutant colorectal cancer, not a curated reading list.
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