Phase 3 Study of Encorafenib, Cetuximab and mFOLFOX6 in BRAF-Mutant Metastatic Colorectal Cancer (BREAKWATER): Progression-Free Survival and Updated Overall Survival

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
  • BREAKWATER (NCT04607421) is a phase 3 study evaluating encorafenib plus cetuximab (EC) with or without chemotherapy (oxaliplatin, leucovorin, and 5-FU [mFOLFOX6]) vs. standard care, investigator's choice of chemotherapy ± bevacizumab
  • BREAKWATER previously met one of the dual primary endpoints, objective response by blinded independent central review, demonstrating clinically meaningful and statistically significant improvement in confirmed objective response rate by blinded independent central review in the EC+mFOLFOX6 vs the standard care groups (60.9% vs 40.0%, odds ratio=2.443, one-sided P-value=0.0008), with a rapid and durable response8
  • Following these positive results, the US Food and Drug Administration granted accelerated approval under Project FrontRunner for EC+mFOLFOX6 in patients with BRAF V600E-mutant mCRC, including in the first-line setting9
  • EC+mFOLFOX6 is practice changing as a new standard of care for BRAF V600E-mutant mCRC

The full publication is available at this link:

https://www.nejm.org/doi/full/10.1056/NEJMoa2501912

Methods

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Study Design

An open-label, multicenter, randomized, phase 3 study of first-line EC ± chemotherapy vs. standard care 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

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

The key secondary endpoint is overall survival between the EC+mFOLFOX6 and standard care groups

Other secondary endpoints include time to response, response duration, 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 Endpoints

Progression-Free Survival by BICR (EC+mFOLFOX6 vs standard care)

Key Secondary Endpoint

Overall Survival (EC+mFOLFOX6 vs standard care)

Other Secondary Endpoints

Progression-Free Survival by BICR (All groups)

Overall Survival (All groups)

Objective Response Rate, Duration of Response, and Time to Response by BICR in all Randomized Patients

Most Common All-Causality TEAEs
(≥20% of Patients in the EC+mFOLFOX6 group) by Preferred Term

Most Common Serious All-Causality TEAEs
(≥1% of Patients in the EC+mFOLFOX6 group) by Preferred Term

Summary

  • BREAKWATER has now met both of its dual primary endpoints and key secondary endpoint
    • Progression-free survival by blinded independent central review data demonstrated statistically significant and clinically meaningful improvement with EC+mFOLFOX6 vs standard care
    • This updated interim analysis of overall survival also demonstrated statistically significant and clinically meaningful improvement with EC+mFOLFOX6 vs standard care
  • The safety data continued to show that EC+mFOLFOX6 was generally tolerable, with a safety profile consistent with that known for each agent and no substantial increase in chemotherapy dose reduction or discontinuation vs standard care
  • EC+mFOLFOX6 is practice changing as a new standard of care for BRAF V600E-mutant mCRC, including in the first line setting
  • EC showed a numerically higher objective response rate, comparable progression-free survival, longer median overall survival, and early separation of overall survival Kaplan-Meier curves vs standard care, and EC has a more tolerable safety profile than standard care
    • EC may be considered for patients in the first line setting who are unable to tolerate chemotherapy

References

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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
Baseline Demographics and Disease Characteristics

Characteristic

EC N = 158

EC+mFOLFOX6 N = 236

Standard Care N = 243

Age - yr
Median
59.0
60.0
62.0
Range
26.0-84.0
24.0-81.0
28.0-84.0
Sex - no. (%)
Male
79 (50.0)
123 (52.1)
119 (49.0)
Female
79 (50.0)
113 (47.9)
124 (51.0)
Race - no. (%)
White
88 (55.7)
141 (59.7)
144 (59.3)
Asian
64 (40.5)
88 (37.3)
91 (37.4)
Multiracial
0
0
2 (0.8)
Black or African American
1 (0.6)
0
1 (0.4)
American Indian or Alaska Native
1 (0.6)
0
0
Not reported
4 (2.5)
7 (3.0)
5 (2.1)
Side of tumor - no. (%)
Left
69 (43.7)
90 (38.1)
98 (40.3)
Right
89 (56.3)
146 (61.9)
145 (59.7)
Stage at initial diagnosis - no. (%)
Stage I
4 (2.5)
3 (1.3)
2 (0.8)
Stage II
7 (4.4)
13 (5.5)
10 (4.1)
Stage III
24 (15.2)
38 (16.1)
45 (18.5)
Stage IV
123 (77.8)
182 (77.1)
186 (76.5)
Primary tumor resection - no. (%)
Complete
81 (51.3)
116 (49.2)
110 (45.3)
Partial
9 (5.7)
14 (5.9)
11 (4.5)
None
68 (43.0)
106 (44.9)
122 (50.2)
No. of organs involved - no. (%)†
≤2
86 (54.4)
119 (50.4)
127 (52.3)
≥3
72 (45.6)
117 (49.6)
116 (47.7)
Liver metastases - no. (%)†
Yes
94 (59.5)
147 (62.3)
160 (65.8)
No
64 (40.5)
89 (37.7)
83 (34.2)
Eastern Cooperative Oncology Group performance status - no. (%)
0
79 (50.0)
128 (54.2)
131 (53.9)
1
74 (46.8)
104 (44.1)
98 (40.3)
Missing
5 (3.2)
4 (1.7)
14 (5.8)
Central BRAF V600E status (tumor tissue) - no. (%)‡
Detected
150 (94.9)
226 (95.8)
224 (92.2)
Indeterminate
1 (0.6)
0
1 (0.4)
Not detected
0
4 (1.7)
2 (0.8)
Not available
7 (4.4)
6 (2.5)
16 (6.6)
Local microsatellite instability/mismatch repair deficiency status - no. (%)§
High microsatellite instability/ mismatch repair deficiency
0
1 (0.4)
0
Microsatellite stable/proficient mismatch repair
152 (96.2)
229 (97.0)
227 (93.4)
Not available
6 (3.8)
6 (2.5)
16 (6.6)
Carcinoembryonic antigen at baseline - no. (%)
≤5 µg/L
50 (31.6)
64 (27.1)
63 (25.9)
>5 µg/L
102 (64.6)
167 (70.8)
163 (67.1)
Missing
6 (3.8)
5 (2.1)
17 (7.0)
C-reactive protein at baseline - no. (%)
≤10 mg/L
91 (57.6)
125 (53.0)
118 (48.6)
>10 mg/L
61 (38.6)
105 (44.5)
108 (44.4)
Missing
6 (3.8)
6 (2.5)
17 (7.0)

*The last assessment prior to the date of first dose of study intervention for ECOG and biomarker endpoints was used as baseline.

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

†Local testing could be performed by tumor or blood-based assays.

§Local microsatellite instability status of microsatellite stable/proficient mismatch repair includes low microsatellite instability.

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 group (encorafenib 300 mg orally once daily; cetuximab 500 mg/m2 intravenously once every 2 weeks)
  • The EC+mFOLFOX6 group (encorafenib 300 mg orally once daily; cetuximab 500 mg/m2 intravenously once every 2 weeks; oxaliplatin 85 mg/m2 intravenously, leucovorin 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 standard care group (mFOLFOX6 with or without bevacizumab [per prescribing instructions]; irinotecan 165 mg/m2 intravenously, oxaliplatin 85 mg/m2 intravenously, leucovorin 400 mg/m2 intravenously, and 5-FU 2400 or 3200 mg/m2 continuous intravenously infusion over 46-48h 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 group was stopped and patients were randomized 1:1 to the EC+mFOLFOX6 group or investigator's choice standard care group.

Patient Disposition

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

†Following closure of the EC group, randomization was 1:1 to the EC+mFOLFOX6 and standard-care groups.

Endpoints
  • Objective response rate is defined as confirmed complete response or partial response according to RECIST 1.1 from the date of randomization until the date of the first documentation of progression of disease by BICR; 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. This was analyzed in the first 110 patients randomized in the EC+mFOLFOX6 group and the standard care group respectively
  • Progression-free survival is defined as the time from the date of randomization to the 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
  • Safety
  • Biomarkers (correlation with clinical outcomes)
Progression-Free Survival by BICR (EC+mFOLFOX6 vs standard care)
Overall Survival (All groups)

CI, confidence interval; HR, hazard ratio.

*Analyses of EC versus standard care and EC versus EC+mFOLFOX6 are descriptive. CIs are not adjusted for multiplicity and should not be mistaken for hypothesis tests. Following a protocol amendment, enrolment into the EC group was discontinued prematurely.

Progression-Free Survival by BICR (All groups)

CI, confidence interval; HR, hazard ratio.

*Analyses of EC versus standard care and EC versus EC+mFOLFOX6 are descriptive. CIs are not adjusted for multiplicity and should not be mistaken for hypothesis tests. Following a protocol amendment, enrollment into the EC group was discontinued prematurely.

Objective Response Rate, Duration of Response, and Time to Response by BICR in all Randomized Patients

Characteristic

EC N = 72

EC+mFOLFOX6 N = 155

Standard Care N = 91

Median time to response (range), weeks
6.6 (4.3 to 86.4)
7.0 (5.1 to 103.6)
7.3 (5.4 to 48.0)
Median duration of response (95% CI), months
7.0 (4.2, 11.6)
13.9 (10.9, 18.5)
10.8 (7.6, 13.4)
Patients with a duration of response of ≥6 months, n (%)
29 (40.3)
110 (71.0)
38 (41.8)
Patients with a duration of response of ≥12 months, n (%)
15 (20.8)
54 (34.8)
16 (17.6)
Most Common All-Causality TEAEs(≥20% of Patients in the EC+mFOLFOX6 group) by Preferred Term

Adverse Event

EC N = 153

EC+mFOLFOX6 N = 232

Standard Care N = 229

Treatment-emergent adverse events — no. (%)
Any grade
Grade 3-4
Any grade
Grade 3-4
Any grade
Grade 3-4
Nausea
31 (20.3)
2 (1.3)
125 (53.9)
7 (3.0)
114 (49.8)
9 (3.9)
Anemia
32 (20.9)
10 (6.5)
107 (46.1)
35 (15.1)
58 (25.3)
9 (3.9)
Diarrhea
28 (18.3)
2 (1.3)
97 (41.8)
3 (1.3)
115 (50.2)
11 (4.8)
Decreased appetite
25 (16.3)
1 (0.7)
87 (37.5)
5 (2.2)
62 (27.1)
3 (1.3)
Vomiting
22 (14.4)
2 (1.3)
84 (36.2)
9 (3.9)
51 (22.3)
5 (2.2)
Neutrophil count decrease
2 (1.3)
1 (0.7)
79 (34.1)
44 (19.0)
67 (29.3)
39 (17.0)
Arthralgia
53 (34.6)
1 (0.7)
73 (31.5)
6 (2.6)
12 (5.2)
1 (0.4)
Rash
27 (17.6)
1 (0.7)
70 (30.2)
3 (1.3)
9 (3.9)
0
Asthenia
28 (18.3)
1 (0.7)
68 (29.3)
12 (5.2)
34 (14.8)
3 (1.3)
Pyrexia
26 (17.0)
2 (1.3)
67 (28.9)
5 (2.2)
36 (15.7)
1 (0.4)
Neuropathy peripheral
2 (1.3)
0
64 (27.6)
18 (7.8)
54 (23.6)
8 (3.5)
Constipation
22 (14.4)
1 (0.7)
63 (27.2)
1 (0.4)
52 (22.7)
1 (0.4)
Peripheral sensory neuropathy
3 (2.0)
0
62 (26.7)
16 (6.9)
54 (23.6)
8 (3.5)
Fatigue
33 (21.6)
2 (1.3)
61 (26.3)
6 (2.6)
64 (27.9)
8 (3.5)
Neutropenia
3 (2.0)
2 (1.3)
56 (24.1)
35 (15.1)
57 (24.9)
23 (10.0)
Alopecia
13 (8.5)
0
53 (22.8)
0
26 (11.4)
0
Platelet count decreased
3 (2.0)
0
53 (22.8)
3 (1.3)
32 (14.0)
4 (1.7)
Lipase increased
10 (6.5)
5 (3.3)
52 (22.4)
40 (17.2)
27 (11.8)
14 (6.1)
Abdominal pain
25 (16.3)
5 (3.3)
47 (20.3)
11 (4.7)
53 (23.1)
3 (1.3)
Most Common Serious All-Causality TEAEs(≥1% of Patients in the EC+mFOLFOX6 group) by Preferred Term

Adverse Event

EC N = 153

EC+mFOLFOX6 N = 232

Standard Care N = 229

Treatment-emergent adverse events — no. (%)
Intestinal obstruction
6 (3.9)
11 (4.7)
5 (2.2)
Pyrexia
0
9 (3.9)
3 (1.3)
Anemia
0
8 (3.4)
1 (0.4)
Disease progression
4 (2.6)
8 (3.4)
1 (0.4)
Abdominal pain
3 (2.0)
6 (2.6)
7 (3.1)
Vomiting
1 (0.7)
6 (2.6)
1 (0.4)
Sepsis
1 (0.7)
4 (1.7)
1 (0.4)
ALT increased
0
3 (1.3)
1 (0.4)
Ascites
0
3 (1.3)
0
Ileus
2 (1.3)
3 (1.3)
4 (1.7)
Pneumonia
0
3 (1.3)
5 (2.2)
Pulmonary embolism
0
3 (1.3)
1 (0.4)
Small intestinal obstruction
1 (0.7)
3 (1.3)
1 (0.4)
Urinary tract infection
6 (3.9)
3 (1.3)
2 (0.9)

ALT, Alanine aminotransferase.

Study Sites
Overall Survival (EC+mFOLFOX6 vs standard care)