BREAKWATER: Phase 3 Study of Encorafenib, Cetuximab and Chemotherapy in BRAF-Mutant Metastatic Colorectal Cancer

Background

  • BRAF V600E mutations occur in 8-12% of metastatic colorectal cancers (mCRC)1,2
  • Encorafenib is a highly selective, ATP-competitive, small molecule BRAF inhibitor with anti-proliferative and apoptotic activity in tumor cells expressing BRAF V600E and has prolonged pharmacodynamic activity compared with other approved BRAF inhibitors3,4
  • Encorafenib plus cetuximab, an anti-EGFR monoclonal antibody, is approved for previously treated BRAF V600E-mutant mCRC based on results from the BEACON study5,6
  • First-line chemotherapies with or without a biologic agent have had limited efficacy for BRAF V600E-mutant mCRC7
  • There are currently no first-line targeted treatments indicated for patients with BRAF V600E-mutant mCRC
  • BREAKWATER (NCT04607421) is a phase 3 study evaluating encorafenib plus cetuximab with or without chemotherapy (oxaliplatin, leucovorin, and 5-FU [mFOLFOX6]) (EC±mFOLFOX6) vs. standard of care (SOC), investigator's choice of chemotherapy8
  • Reported here are one of the dual primary endpoints, objective response rate by blinded independent central review (BICR; assessed in the first 110 patients randomized to each arm), the first interim analysis of overall survival, duration of response, time to response, and safety in the EC+mFOLFOX6 and SOC arms from the phase 3 portion

The full publication is available at this link:

https://www.nature.com/articles/s41591-024-03443-3

Methods

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Study Design

An open-label, multicenter, randomized, phase 3 study of first-line encorafenib + cetuximab ± chemotherapy vs. SOC chemotherapy 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

The dual primary endpoints are objective response rate and progression-free survival by BICR between the EC+mFOLFOX6 and SOC arms

The key secondary endpoint is overall survival between the EC+mFOLFOX6 and SOC arms

Other secondary endpoints include time to response, duration of response, progression after next line of therapy, patient-reported outcomes, pharmacokinetics, safety, and biomarker endpoints

Study Sites

BREAKWATER enrolled in 28 countries

Results

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Patient Disposition

Baseline Demographics and Disease Characteristics

Dual Primary Endpoint

Objective Response Rate by BICR

Key Secondary Endpoint

Overall Survival

Other Secondary Endpoints

Duration of Response and Time to Response by BICR

Most Common All-Causality TEAEs
(≥10% of Patients in Any Arm) by Preferred Term

Most Common Serious All-Causality TEAEs
(≥1% of Patients in Any Arm) by Preferred Term

Summary

  • BREAKWATER met one of its dual primary endpoints of objective response rate, demonstrating a significant and clinically relevant benefit in objective response rate by BICR with EC+mFOLFOX6 vs. SOC
  • At the time of this analysis, overall survival analysis showed a survival benefit trend with EC+mFOLFOX6 vs. SOC; 16.9% of patients in the EC+mFOLFOX6 arm and 29.6% of patients in the SOC arm had an event at data cutoff and data were not statistically significant at this first interim analysis
  • BREAKWATER is ongoing and once the required number of events specified in the protocol have occurred, the primary analysis of progression-free survival, the other dual primary endpoint, will be conducted
  • Secondary endpoints by BICR showed the response to EC+mFOLFOX6 was rapid and durable
  • The overall survival data showed a clear separation between the arms in the Kaplan-Meier curves, despite the number of deaths at data cutoff
  • Safety data showed that EC+mFOLFOX6 was generally tolerable, with a safety profile consistent with that known for each agent
  • The addition of EC to chemotherapy was generally tolerable without significant increase in chemotherapy dose reduction or discontinuation

References

©2025 Pfizer Inc. All rights reserved.

Study Design

Phase 3

Patients who have not received prior systemic treatment for mCRC

aRandomization stratification factors were Eastern Cooperative Oncology Group performance status (0 vs. 1) and region (US/Canada vs. Europe vs. Rest of World).

bPatients were randomized 1:1:1 to:

  • The EC arm (encorafenib 300 mg orally once daily; cetuximab 500 mg/m2 intravenously once every 2 weeks)
  • The EC+mFOLFOX6 arm (encorafenib 300 mg orally once daily; cetuximab 500 mg/m2 intravenously once every 2 weeks; oxaliplatin 85 mg/m2 intravenously, eucovorin 400 mg/m2 intravenously, and 5-FU 400 mg/m2 intravenous bolus, then 5-FU 2400 mg/m2 continuous intravenous infusion, all once every 2 weeks [mFOLFOX6; 28-day cycle])
  • Or investigator's choice SOC arm (mFOLFOX6 with or without bevacizumab [per prescribing instructions]; irinotecan 165 mg/m2 intravenously, oxaliplatin 85 mg/m2 intravenously, leucovorin 400 mg/m2 intravenously, and F-FU 2400 or 3200 mg/m2 intravenously all once every 2 weeks [FOLFOXIRI; 28-day cycle] with or without bevacizumab [per prescribing instructions]; oxaliplatin 130 mg/m2 intravenously once every 3 weeks [21-day cycle] and capecitabine 1000 mg/m2 orally twice daily [Days 1-14] [CAPOX] with or without bevacizumab [per prescribing instructions]).

cFollowing a protocol amendment, enrollment to the EC arm was stopped and patients were randomized 1:1 to the EC+mFOLFOX6 arm or investigator's choice SOC arm.

Inclusion and Exclusion Criteria
  • Measurable disease (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1)
  • Presence of a BRAF V600E mutation
  • No prior systemic treatment for metastatic disease
  • Eastern Cooperative Oncology Group performance status 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
  • Patients with microsatellite instability-high/mismatch repair deficient tumors (MSI-H/dMMR; unless ineligible to receive immune checkpoint inhibitors due to a pre-existing medical condition), or with a RAS mutation
Endpoints
  • Objective response rate is defined as confirmed complete response or partial response according to RECIST 1.1 recorded from randomization until the date of the first documentation of progression of disease, death, or start of subsequent anticancer therapy; both complete response and partial response must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met
  • Progression-free survival is defined as the time from the date of randomization to the earliest documented disease progression per RECIST 1.1 by BICR, or death due to any cause
  • Overall survival is defined as the time from the date of randomization to death due to any cause
  • Objective response rate and progression-free survival by investigator
  • Time to response and duration of response by BICR and investigator
  • Patient-reported outcomes
  • Biomarkers (correlation with clinical outcomes)
  • Safety
Study Sites
Patient Disposition

aOne participant who was randomized to the EC+mFOLFOX6 arm (but never treated) was inadvertently entered as withdrawal by patient on the screening case report form page.

Baseline Demographics and Disease Characteristics

EC+mFOLFOX6
n=236

SOC
n=243

Total
n=479

Median age (range), years
60.0 (24-81)
62.0 (28-84)
61.0 (24-84)
Male, n (%)
123 (52.1)
119 (49.0)
242 (50.5)
Female, n (%)
113 (47.9)
124 (51.0)
237 (49.5)
Race, n (%)
White
141 (59.7)
144 (59.3)
285 (59.5)
Asian
88 (37.3)
91 (37.4)
179 (37.4)
Multiracial
0
2 (0.8)
2 (0.4)
Black or African American
0
1 (0.4)
1 (0.2)
Not reported
7 (3.0)
5 (2.1)
12 (2.5)
Body site, n (%)
Colon
191 (80.9)
192 (79.0)
383 (80.0)
Rectum
24 (10.2)
27 (11.1)
51 (10.6)
Cecum
21 (8.9)
24 (9.9)
45 (9.4)
Side of tumor, n (%)
Left
89 (37.7)
98 (40.3)
187 (39.0)
Right
147 (62.3)
145 (59.7)
292 (61.0)
Stage at initial diagnosis, n (%)
Stage I
3 (1.3)
2 (0.8)
5 (1.0)
Stage II
13 (5.5)
10 (4.1)
23 (4.8)
Stage III
37 (15.7)
43 (17.7)
80 (16.7)
Stage IV
183 (77.5)
188 (77.4)
371 (77.5)
Primary tumor resection, n (%)
Complete
116 (49.2)
105 (43.2)
221 (46.1)
Partial
14 (5.9)
13 (5.3)
27 (5.6)
None
106 (44.9)
125 (51.4)
231 (48.2)
No. of organs involved, n (%)a
≤2
122 (51.7)
129 (53.1)
251 (52.4)
≥3
114 (48.3)
114 (46.9)
228 (47.6)
Liver metastases, n (%)a
144 (61.0)
156 (64.2)
300 (62.6)
Eastern Cooperative Oncology Group performance status, n (%)
0
129 (54.7)
131 (53.9)
260 (54.3)
1
103 (43.6)
98 (40.3)
201 (42.0)
Missing
4 (1.7)
14 (5.8)
18 (3.8)
Central BRAF V600E status (tumor tissue), n (%)
Detected
226 (95.8)
224 (92.2)
450 (93.9)
Indeterminate
0
1 (0.4)
1 (0.2)
Not detected
4 (1.7)
2 (0.8)
6 (1.3)
Not available
6 (2.5)
16 (6.6)
22 (4.6)
Local microsatellite instability/mismatch repair deficiency status, n (%)
High microsatellite instability/mismatch repair deficiency
1 (0.4)
0
1 (0.2)
Microsatellite stable/proficient mismatch repair
229 (97.0)
227 (93.4)
456 (95.2)
Not available
6 (2.5)
16 (6.6)
22 (4.6)
Carcinoembryonic antigen at baseline, n (%)
≤5 μg/L
65 (27.5)
63 (25.9)
128 (26.7)
>5 μg/L
166 (70.3)
163 (67.1)
329 (68.7)
Missing
5 (2.1)
17 (7.0)
22 (4.6)
C-reactive protein at baseline, n (%)
≤10 mg/L
125 (53.0)
119 (49.0)
244 (50.9)
>10 mg/L
105 (44.5)
107 (44.0)
212 (44.3)
Missing
6 (2.5)
17 (7.0)
23 (4.8)

aNumber of organs and presence of liver metastases are based on blinded independent central review data for the phase 3 portion of the study.

Objective Response Rate by BICR

Confirmed Objective Response Rate by BICR

Overall Survival
Duration of Response and Time to Response by BICR

EC+mFOLFOX6
n=67

SOC
n=44

Median time to response (range), weeks
7.1 (5.7-53.7)
7.3 (5.4-48.0)
Estimated median duration of response (range), months
13.9 (8.5-NE)
11.1 (6.7-12.7)
Patients with a duration of response of ≥6 months, n (%)
46 (68.7)
15 (34.1)
Patients with a duration of response of ≥12 months, n (%)
15 (22.4)
5 (11.4)
Most Common All-Causality TEAEs (≥10% of Patients in Any Arm) by Preferred Term

n (%)

EC+mFOLFOX6
n=231

SOC
n=228

Any grade
Grade ≥3
Any grade
Grade ≥3
Any adverse event
230 (99.6)
181 (78.4)
223 (97.8)
149 (65.4)
Nausea
118 (51.1)
6 (2.6)
110 (48.2)
7 (3.1)
Anemia
84 (36.4)
25 (10.8)
52 (22.8)
8 (3.5)
Diarrhea
79 (34.2)
3 (1.3)
107 (46.9)
8 (3.5)
Neutrophil count decreased
74 (32.0)
42 (18.2)
64 (28.1)
38 (16.7)
Decreased appetite
77 (33.3)
5 (2.2)
57 (25.0)
3 (1.3)
Vomiting
77 (33.3)
8 (3.5)
48 (21.1)
5 (2.2)
Asthenia
62 (26.8)
10 (4.3)
33 (14.5)
3 (1.3)
Pyrexia
60 (26.0)
4 (1.7)
31 (13.6)
1 (0.4)
Peripheral sensory neuropathy
57 (24.7)
13 (5.6)
49 (21.5)
5 (2.2)
Rash
57 (24.7)
2 (0.9)
6 (2.6)
0
Fatigue
56 (24.2)
6 (2.6)
57 (25.0)
6 (2.6)
Neuropathy peripheral
54 (23.4)
16 (6.9)
48 (21.1)
6 (2.6)
Arthralgia
51 (22.1)
2 (0.9)
8 (3.5)
0
Neutropenia
51 (22.1)
34 (14.7)
51 (22.4)
21 (9.2)
Alopecia
49 (21.2)
0
23 (10.1)
0
Constipation
47 (20.3)
1 (0.4)
44 (19.3)
1 (0.4)
Platelet count decreased
46 (19.9)
3 (1.3)
28 (12.3)
4 (1.8)
White blood cell count decreased
42 (18.2)
13 (5.6)
32 (14.0)
8 (3.5)
Lipase increased
46 (19.9)
34 (14.7)
22 (9.6)
12 (5.3)
Weight decreased
40 (17.3)
2 (0.9)
19 (8.3)
0
Skin hyperpigmentation
39 (16.9)
0
5 (2.2)
0
Abdominal pain
38 (16.5)
7 (3.0)
47 (20.6)
3 (1.3)
Dermatitis acneiform
35 (15.2)
2 (0.9)
1 (0.4)
0
Hypokalemia
30 (13.0)
4 (1.7)
22 (9.6)
7 (3.1)
Aspartate aminotransferase increased
29 (12.6)
2 (0.9)
25 (11.0)
3 (1.3)
Dry skin
29 (12.6)
0
8 (3.5)
0
Headache
29 (12.6)
1 (0.4)
17 (7.5)
0
Mucosal inflammation
29 (12.6)
4 (1.7)
22 (9.6)
1 (0.4)
Paresthesia
28 (12.1)
6 (2.6)
18 (7.9)
3 (1.3)
Dysgeusia
27 (11.7)
0
31 (13.6)
0
Epistaxis
27 (11.7)
0
28 (12.3)
0
Hypomagnesemia
27 (11.7)
2 (0.9)
9 (3.9)
1 (0.4)
Stomatitis
27 (11.7)
4 (1.7)
32 (14.0)
3 (1.3)
Alanine aminotransferase increased
26 (11.3)
3 (1.3)
22 (9.6)
3 (1.3)
Myalgia
26 (11.3)
0
9 (3.9)
0
Thrombocytopenia
26 (11.3)
0
18 (7.9)
0
Neurotoxicity
25 (10.8)
11 (4.8)
18 (7.9)
0
Palmar-plantar erythrodysesthesia syndrome
25 (10.8)
3 (1.3)
18 (7.9)
2 (0.9)
Pruritus
24 (10.4)
0
4 (1.8)
0
Hypoalbuminemia
23 (10.0)
1 (0.4)
13 (5.7)
0
Insomnia
23 (10.0)
0
13 (5.7)
0
Most Common Serious All-Causality TEAEs (≥1% of Patients in Any Arm) by Preferred Term

EC+mFOLFOX6
n=231

SOC
n=228

Any adverse event
87 (37.7)
79 (34.6)
Disease progression
8 (3.5)
0
Intestinal obstruction
8 (3.5)
5 (2.2)
Pyrexia
8 (3.5)
3 (1.3)
Anemia
6 (2.6)
1 (0.4)
Vomiting
6 (2.6)
1 (0.4)
Abdominal pain
4 (1.7)
7 (3.1)
Sepsis
4 (1.7)
1 (0.4)
Alanine aminotransferase increased
3 (1.3)
1 (0.4)
Febrile neutropenia
3 (1.3)
8 (3.5)
Ileus
2 (0.9)
3 (1.3)
Pneumonia
2 (0.9)
4 (1.8)
Acute kidney injury
1 (0.4)
3 (1.3)
Myocardial infarction
0
3 (1.3)