A randomised study of encorafenib, cetuximab, and FOLFIRI versus FOLFIRI with or without bevacizumab in BRAF V600E-mutant colorectal cancer: BREAKWATER Cohort 3

Background

BRAF V600E mutations occur in 8-12% of metastatic colorectal cancers (mCRC)^1,2
BREAKWATER (NCT04607421) is a Phase III trial that demonstrated clinically meaningful and statistically significant objective response rate by blinded independent central review (ORR by BICR), progression-free survival (PFS) by BICR, and overall survival (OS) with EC+mFOLFOX6 (oxaliplatin, leucovorin, and fluorouracil [5-FU]) versus chemotherapy^a with or without bevacizumab in patients with BRAF V600E-mutant mCRC^3,4

Additional data from the safety lead-in (SLI) portion of the trial showed encouraging response rates and PFS with EC+mFOLFOX6 or EC+FOLFIRI (irinotecan, leucovorin, and 5-FU) in patients with BRAF V600E-mutant mCRC^5,6
Here we report results from the Cohort 3 portion of BREAKWATER that evaluated EC+FOLFIRI versus FOLFIRI with or without bevacizumab (control) in the first-line setting in patients with BRAF V600E-mutant mCRC

^amFOLFOX6; irinotecan, oxaliplatin, leucovorin, and 5-FU (FOLFOXIRI); or oxaliplatin and capecitabine (CAPOX).

The full publication is available at this link:
https://www.annalsofoncology.org/article/S0923-7534(26)00179-1/fulltext

Methods

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Study Design

An open-label, multicenter, randomised study of first-line encorafenib + cetuximab ± chemotherapy vs. chemotherapy ± bevacizumab for BRAF V600E-mutant mCRC

Inclusion and Exclusion Criteria

Patients who were at least 16 years of age (where permitted locally), with histologically or cytologically confirmed colorectal adenocarcinoma that had evidence of Stage IV metastatic disease

Endpoints

Study sites

Results

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Patient Disposition

Baseline Demographics and Disease Characteristics

Primary Endpoint

Objective Response Rate by Blinded Independent Central Review

Key Secondary Endpoint

Progression-Free Survival by Blinded Independent Central Review

Other Secondary Endpoints

Overall Survival

Time to Response and Duration of Response

Most Common Serious Treatment-Emergent Adverse Events by Preferred Term (≥2% of Patients in Either Arm)

Most Common Treatment-Emergent Adverse Events by Preferred Term (≥15% of Patients in the EC+FOLFIRI Arm)

Summary

BREAKWATER Cohort 3 met its primary endpoint and key secondary endpoint by demonstrating a clinically meaningful and statistically significant benefit in ORR and PFS by BICR for EC+FOLFIRI versus control
OS was prolonged with EC+FOLFIRI versus control
Other secondary endpoints showed that the response with EC+FOLFIRI was rapid and durable

The safety profiles of the study treatments were consistent with that known for each agent, with no new safety signals observed. Furthermore, no substantial increase in treatment discontinuations was observed with the addition of EC to FOLFIRI
These data support that EC can also be combined with FOLFIRI as a standard of care for patients with BRAF V600E-mutant mCRC⁷

References

Tabernero J, Ros J, Élez E. The evolving treatment landscape in BRAF-V600E–mutated metastatic colorectal cancer. Am Soc Clin Oncol Educ Book. 2022;42:254-263.
Tran B, Kopetz S, Tie J, et al. Impact of BRAF mutation and microsatellite instability on the pattern of metastatic spread and prognosis in metastatic colorectal cancer. Cancer. 2011;117:4623-4632.
Kopetz S, Yoshino T, Van Cutsem E, et al. Encorafenib, cetuximab and chemotherapy in BRAF-mutant colorectal cancer: a randomized phase 3 trial. Nat Med. 2025;31(3):901-908. https://www.breakwaterphase3-infographic.com/
Elez E, Yoshino T, Shen L, et al. Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer. N Engl J Med. 2025. https://www.breakwaterphase3-pfs-and-os-infographic.com/
Kopetz S, Yoshino T, Kim TW, et al. BREAKWATER safety lead-in (SLI): encorafenib (E) + cetuximab (C) + chemotherapy for BRAF V600E metastatic colorectal cancer (mCRC). J Clin Oncol. 2023;41(4_suppl):Abstract 119.
Tabernero J, Yoshino T, Kim TW, et al. 515MO Encorafenib + cetuximab (EC) + FOLFIRI for BRAF V600E-mutant metastatic colorectal cancer (mCRC): Updated results from the BREAKWATER safety lead-in (SLI). Annals of Oncology. 2024;35:S435-S436.
US Food and Drug Administration. BRAFTOVI® (encorafenib) Prescribing information. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/210496s021lbl.pdf. Accessed March 03, 2026.

Study Design

EC+FOLFIRI (encorafenib 300 mg orally once daily; cetuximab 500 mg/m² intravenously once every 2 weeks; irinotecan 180 mg/m² intravenously once every 2 weeks; leucovorin 400 mg/m² intravenously once every 2 weeks; and 5-FU 400 mg/m² intravenous bolus, then 5-FU 2400 mg/m² continuous intravenous infusion over 46-48 hours, once every 2 weeks). FOLFIRI (irinotecan 180 mg/m² intravenously once every 2 weeks; leucovorin 400 mg/m² intravenously once every 2 weeks; and 5-FU 400 mg/m² intravenous bolus, then 5-FU 2400 mg/m² continuous intravenous infusion over 46-48 hours, once every 2 weeks) with or without bevacizumab (per local prescribing instructions) (control).

R, randomisation; ECOG PS, Eastern Cooperative Oncology Group performance status; FOLFIRI, irinotecan, leucovorin, and fluorouracil.

Inclusion and Exclusion Criteria

Measurable disease (RECIST 1.1)
Presence of a BRAF V600E mutation

BRAF V600E mutation status was confirmed by the central laboratory using tumour tissue collected within two years prior to study enrolment

No prior systemic treatment for metastatic disease
ECOG PS of 0 or 1
Adequate bone marrow, hepatic, and renal function

Previously received any selective BRAF inhibitor or any EGFR inhibitor
Patients with symptomatic brain metastases (unless stable for ≥4 weeks prior to randomisation)
Patients with MSI-H/dMMR unless ineligible to receive immune checkpoint inhibitors due to a pre-existing medical condition
Patients with a RAS mutation

ECOG PS, Eastern Cooperative Oncology Group performance status; MSI-H/dMMR, microsatellite instability-high/mismatch repair deficient tumours; RECIST, Response Evaluation Criteria in Solid Tumors.

Endpoints

ORR by BICR in all randomised patients. Defined as the proportion of patients who have achieved a best overall response of complete response or partial response per RECIST 1.1

PFS by BICR in all randomised patients. Defined as the time from the date of randomisation to the earliest documented disease progression per RECIST 1.1, or death due to any cause

Investigator-assessed ORR and PFS
OS
DOR
TTR
Safety

BICR, blinded independent central review; DOR, duration of response; OS, overall survival; ORR, objective response rate; PFS, progression-free survival; RECIST, Response Evaluation Criteria in Solid Tumors; TTR, time to response.

Study Sites

Patient Disposition (January 06, 2026)

Cohort 3 patient disposition flow diagram

EC, encorafenib + cetuximab; FOLFIRI, irinotecan, leucovorin, and fluorouracil.

Baseline Demographics and Disease Characteristics

Characteristic

EC+FOLFIRI n=73

Control n=74

Age, years

Median

Range

28.0–81.0

29.0–84.0

Sex, n (%)

Male

33 (45.2)

35 (47.3)

Female

40 (54.8)

39 (52.7)

Race, n (%)

White

41 (56.2)

49 (66.2)

Asian

29 (39.7)

20 (27.0)

Native Hawaiian or other Pacific Islander

1 (1.4)

Multiracial

1 (1.4)

Black or African American

American Indian or Alaska Native

Not reported

2 (2.7)

3 (4.1)

Side of tumour, n (%)

Left

31 (42.5)

36 (48.6)

Right

41 (56.2)

38 (51.4)

Missing

1 (0.7)

Stage at initial diagnosis, n (%)

Stage I

3 (4.1)

Stage II

6 (8.2)

1 (1.4)

Stage III

10 (13.7)

26 (35.1)

Stage IV

54 (74.0)

47 (63.5)

Primary tumour resection, n (%)

Complete

36 (49.3)

34 (45.9)

Partial

4 (5.5)

2 (2.7)

None

33 (45.2)

38 (51.4)

Number of organs involved, n (%)

≤2

38 (52.1)

34 (45.9)

≥3

35 (47.9)

40 (54.1)

Liver metastases, n (%)

Yes

43 (58.9)

46 (62.2)

30 (41.1)

28 (37.8)

ECOG PS, n (%)

47 (64.4)

41 (55.4)

24 (32.9)

27 (36.5)

Missing

2 (2.7)

6 (8.1)

Central BRAF V600E status (tumour tissue), n (%)

Detected

67 (91.8)

62 (83.8)

Indeterminate

1 (1.4)

Not detected

2 (2.7)

1 (1.4)

Not available

4 (5.5)

10 (13.5)

Local microsatellite instability/mismatch repair deficiency status, n (%)

High microsatellite instability/mismatch repair deficiency

Microsatellite stable/proficient mismatch repair

70 (95.9)

68 (91.9)

Not available

3 (4.1)

6 (8.1)

Carcinoembryonic antigen at baseline, n (%)

≤5 µg/L

25 (34.2)

19 (25.7)

>5 µg/L

45 (61.6)

49 (66.2)

Missing

3 (4.1)

6 (8.1)

C-reactive protein at baseline, n (%)

≤10 mg/L

45 (61.6)

40 (54.1)

>10 mg/L

26 (35.6)

28 (37.8)

Missing

2 (2.7)

6 (8.1)

EC, encorafenib + cetuximab; ECOG PS, Eastern Cooperative Oncology Group performance status; FOLFIRI, irinotecan, leucovorin, and fluorouracil.

The last assessment prior to date of the first dose of study intervention was used as baseline for Eastern Cooperative Oncology Group performance status and biomarkers.

Primary Endpoint: Objective Response Rate by Blinded Independent Central Review

CI, confidence interval; CR, complete response; EC, encorafenib + cetuximab; FOLFIRI, irinotecan, leucovorin, and fluorouracil; PR, partial response.

Key Secondary Endpoint: Progression-Free Survival by Blinded Independent Central Review (January 06, 2026)

Progression-free survival Kaplan-Meier curve, EC+FOLFIRI vs control

CI, confidence interval; EC, encorafenib + cetuximab; FOLFIRI, irinotecan, leucovorin, and fluorouracil; NE, not estimable.

Secondary Endpoint: Overall Survival (January 06, 2026)

Overall survival Kaplan-Meier curve, EC+FOLFIRI vs control

CI, confidence interval; EC, encorafenib + cetuximab; FOLFIRI, irinotecan, leucovorin, and fluorouracil; NE, not estimable.

Secondary Endpoints: Duration of Response, and Time to Response by Blinded Independent Central Review

EC+FOLFIRI n=73

Control n=74

Responders

n=47

n=29

Median time to response (range), weeks

6.9 (5.4–36.1)

7.1 (5.9–25.3)

Estimated median duration of response (95% CI), months

NE (NE–NE)

NE (7.0–NE)

Patients with a duration of response of ≥6 months, n (%)

27 (57.4)

10 (34.5)

EC+FOLFIRI n=73

Control n=74

Responders

n=48

n=30

Median time to response (range), weeks

6.9 (5.4–49.4)

7.6 (5.9–54.3)

Estimated median duration of response (95% CI), months

13.6 (11.1–NE)

12.4 (8.2–NE)

Patients with a duration of response of ≥6 months, n (%)

35 (72.9)

16 (53.3)

CI, confidence interval; EC, encorafenib + cetuximab; FOLFIRI, irinotecan, leucovorin, and fluorouracil; NE, not estimable.

Most Common Treatment-Emergent Adverse Events by Preferred Term (≥15% of Patients in the EC+FOLFIRI Arm) (January 06, 2026)

Patients, n (%)

EC+FOLFIRI n=71

Control n=68

Any grade

Grade ≥3

Any grade

Grade ≥3

Nausea

46 (64.8)

2 (2.8)

40 (58.8)

1 (1.5)

Diarrhoea

42 (59.2)

9 (12.7)

34 (50.0)

6 (8.8)

Vomiting

36 (50.7)

2 (2.8)

22 (32.4)

Anaemia

32 (45.1)

10 (14.1)

18 (26.5)

1 (1.5)

Alopecia

25 (35.2)

1 (1.4)

15 (22.1)

Fatigue

25 (35.2)

2 (2.8)

27 (39.7)

2 (2.9)

Neutrophil count decreased

25 (35.2)

13 (18.3)

20 (29.4)

14 (20.6)

Constipation

23 (32.4)

1 (1.4)

20 (29.4)

1 (1.5)

Decreased appetite

23 (32.4)

4 (5.6)

23 (33.8)

2 (2.9)

Neutropenia

21 (29.6)

9 (12.7)

18 (26.5)

8 (11.8)

Arthralgia

20 (28.2)

3 (4.4)

Asthenia

19 (26.8)

4 (5.6)

8 (11.8)

3 (4.4)

Abdominal pain

18 (25.4)

2 (2.8)

15 (22.1)

1 (1.5)

Skin hyperpigmentation

17 (23.9)

3 (4.4)

Pyrexia

16 (22.5)

6 (8.8)

1 (1.5)

Rash

16 (22.5)

1 (1.5)

Weight decreased

16 (22.5)

2 (2.8)

9 (13.2)

1 (1.5)

Dry skin

15 (21.1)

5 (7.4)

Insomnia

15 (21.1)

10 (14.7)

Lipase increased

14 (19.7)

8 (11.3)

4 (5.9)

Palmar-plantar erythrodysaesthesia syndrome

14 (19.7)

5 (7.4)

White blood cell count decreased

14 (19.7)

5 (7.0)

14 (20.6)

2 (2.9)

Alanine aminotransferase increased

12 (16.9)

2 (2.8)

8 (11.8)

3 (4.4)

Hypokalaemia

12 (16.9)

3 (4.2)

11 (16.2)

3 (4.4)

Stomatitis

12 (16.9)

10 (14.7)

2 (2.9)

Haemorrhoids

11 (15.5)

3 (4.4)

Mucosal inflammation

11 (15.5)

9 (13.2)

2 (2.9)

EC, encorafenib + cetuximab; FOLFIRI, irinotecan, leucovorin, and fluorouracil.

Most Common Serious Treatment-Emergent Adverse Events by Preferred Term (≥2% of Patients in Either Arm) (January 06, 2026)

Patients, n (%)

EC+FOLFIRI n=71

Control n=68

Febrile neutropenia

4 (5.6)

Infusion related reaction

3 (4.2)

Abdominal infection

2 (2.8)

1 (1.5)

Appendicitis

2 (2.8)

Diarrhoea

2 (2.8)

4 (5.9)

Ileus

2 (2.8)

3 (4.4)

Intestinal perforation

2 (2.8)

Pulmonary embolism

2 (2.8)

3 (4.4)

Pyrexia

2 (2.8)

Vomiting

2 (2.8)

Intestinal obstruction

1 (1.4)

5 (7.4)

Pyelonephritis

1 (1.4)

2 (2.9)

Urinary tract infection

1 (1.4)

2 (2.9)

Large intestine perforation

3 (4.4)

EC, encorafenib + cetuximab; FOLFIRI, irinotecan, leucovorin, and fluorouracil.