Encorafenib, Binimetinib and Cetuximab in Subjects With Previously Untreated BRAF-mutant ColoRectal Cancer (ANCHOR-CRC)

• ClinicalTrials.gov Identifier: NCT03693170
• Recruitment Status: Completed
• First Posted: October 2, 2018
• Results First Posted: August 30, 2022
• Last Update Posted: February 2, 2024
• Sponsor: Pierre Fabre Medicament
• Collaborators: Pfizer; Merck KGaA, Darmstadt, Germany; Ono Pharmaceutical Co. Ltd
• Information provided by (Responsible Party): Pierre Fabre Medicament

• Study Type: Interventional
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: BRAF V600E-mutant Metastatic Colorectal Cancer
• Interventions: Drug: encorafenib; Drug: Binimetinib; Drug: Cetuximab
• Enrollment: 95

Participant Flow

Recruitment Details	95 subjects were enrolled in the study between 17 January 2019 and 27 December 2019 in 68 investigational centers : 45 in EU, 7 in UK, 10 in USA and 6 in Japan
Pre-assignment Details	125 subjects were screened for inclusion in the study. 30 subjects were excluded (29 due to eligibility criteria not met and 1 due to adverse event).

Arm/Group Title	Encorafenib Plus Binimetinib Plus Cetuximab
Arm/Group Description	Encorafenib: 300 mg QD. Binimetinib: 45 mg PO BID. Cetuximab: 400 mg/m2 intravenous (IV) at Cycle 1 day 1 then 250 mg/m2 (IV) every week (QW) for the first 28 weeks. Then, 500mg/m2 IV every two weeks (Q2W) from week 29 (Cycle 8 day 1)
Period Title: Overall Study
Started	95
Completed	20 [1]
Not Completed	75
Reason Not Completed
Disease Progression	48
Adverse Event	16
Physician Decision	6
Protocol Violation	2
Death	1
Non compliance with study drug	1
Withdrawal by Subject	1
[1] Participants with study treatment ongoing at the time of cut off date (29JUN2020)

Baseline Characteristics

Arm/Group Title		1 Arm
Arm/Group Description		encorafenib plus binimetinib plus cetuximab encorafenib: Once daily, orally Binimetinib: Twice daily, orally Cetuximab: Standard of care for the 28 first weeks and then every 2 weeks
Overall Number of Baseline Participants		95
Baseline Analysis Population Description		[Not Specified]
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	95 participants
	<=18 years	0 0.0%
	Between 18 and 65 years	43 45.3%
	>=65 years	52 54.7%
Age, Continuous; Median (Inter-Quartile Range); Unit of measure: Years
	Number Analyzed	95 participants
		65; (57 to 70)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	95 participants
	Female	51 53.7%
	Male	44 46.3%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	95 participants
	Hispanic or Latino	8 8.4%
	Not Hispanic or Latino	73 76.8%
	Unknown or Not Reported	14 14.7%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	95 participants
	American Indian or Alaska Native	0 0.0%
	Asian	11 11.6%
	Native Hawaiian or Other Pacific Islander	0 0.0%
	Black or African American	0 0.0%
	White	71 74.7%
	More than one race	0 0.0%
	Unknown or Not Reported	13 13.7%
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	95 participants
Austria		1 1.1%
Netherlands		1 1.1%
Belgium		9 9.5%
United States		3 3.2%
Japan		11 11.6%
Italy		15 15.8%
United Kingdom		13 13.7%
France		13 13.7%
Spain		29 30.5%
Primary tumor location [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	95 participants
	Right-sided/transverse	57 60.0%
	Left-sided/rectum	37 38.9%
	Other	1 1.1%
		[1] Measure Description: The category right-sided/transverse includes "Colon, Right " and "Colon, Transverse" tumor locations". The category left-sided includes "Colon, Left " and "Rectum" tumor locations".
Number of metastatic organs; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	95 participants
	1	23 24.2%
	2	33 34.7%
	>2	39 41.1%
ECOG Performance Status [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	95 participants
	0	43 45.3%
	1	52 54.7%
		[1] Measure Description: Eastern Cooperative Oncology Group (ECOG) Scale describes a patient's level of functioning in terms of their ability to care for themself, daily activity, and physical ability. Scale is ranged from 0 to 5 with lower score meaning a lower functional impairment (0 corresponding to "fully active", 5 corresponding to death).
Local BRAFV600E mutation result; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	95 participants
	Positive	95 100.0%
	Negative	0 0.0%
Central BRAFV600E mutation result; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	95 participants
	Positive	92 96.8%
	Negative	2 2.1%
	Indeterminate	1 1.1%
Metastatic organs; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	95 participants
Adrenal gland		3 3.2%
Bone		4 4.2%
Liver		52 54.7%
Lung		35 36.8%
Lymph node		49 51.6%
Mediastinum		4 4.2%
Ovary		3 3.2%
Peritoneum/Omentum		46 48.4%
Pleural cavity		3 3.2%
Rectum		1 1.1%
Skin		1 1.1%
Stomach		2 2.1%
Other		11 11.6%
Prior antineoplastic therapy setting; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	95 participants
Adjuvant		17 17.9%
Neo-adjuvant		3 3.2%
Locally advanced		2 2.1%
Prior antineoplastic monotherapy / combination; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	95 participants
5-Fluorouracil + Folinic Acid		4 4.2%
5-Fluorouracil + Folinic Acid + Oxaliplatin		9 9.5%
Oxaliplatin + Capecitabine		5 5.3%
Capecitabine		6 6.3%

Outcome Measures

1. Primary Outcome

Title	Confirmed Overall Response Rate (cORR) Based on Local Tumor Assessments
Description	The confirmed overall response rate (cORR) is the percentage of confirmed responses, defined as complete response (CR) or partial response (PR), as assessed by local radiologist/investigator review based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR): Disappearance of all target lesions; Partiel response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Overall Response (OR) = CR + PR.
Time Frame	From initiation of treatment to disease progression up to a maximum of 17.6 months.

Outcome Measure Data

Analysis Population Description

The Efficacy Set (ES) is composed of all included subjects having received at least one dose of study treatment (partial or full) with a centrally confirmed BRAFV600E mutation.

Arm/Group Title	1 Arm
Arm/Group Description:	encorafenib plus binimetinib plus cetuximab encorafenib: Once daily, orally Binimetinib: Twice daily, orally Cetuximab: Standard of care for the 28 first weeks and then every 2 weeks
Overall Number of Participants Analyzed	92
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of confirmed responses
	47.8; (37.3 to 58.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	1 Arm
	Comments	The null hypothesis that the true response rate is 30% will be tested against a one-sided alternative. The cORR will be provided with a corresponding Clopper-Pearson (exact) binomial 95% CI for the Efficacy Set. This design yields a 1-sided type I error rate equal to 1.6% and power of 80% when the true response rate is 45%.
	Type of Statistical Test	Other
	Comments	[Not Specified]
Other Statistical Analysis		If 37 or more confirmed responses were observed in the 90 treated subjects with a centrally confirmed BRAFV600E mutation, corresponding to a lower limit of Clopper-Pearson (exact) binomial 95% CI exceeding 30%, the study was considered to have met its primary endpoint. If more than 90 subjects were enrolled, the lower limit of Clopper-Pearson was to be used for decision.

2. Secondary Outcome

Title	Confirmed Overall Response Rate (cORR) Based on Central Tumor Assessment
Description	The confirmed overall response rate (cORR) is the percentage of confirmed responses, defined as complete response (CR) or partial response (PR), as assessed by central radiologist review based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR): Disappearance of all target lesions; Partiel response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Overall Response (OR) = CR + PR.
Time Frame	From initiation of treatment to disease progression up to a maximum of 17.6 months

Outcome Measure Data

Analysis Population Description

The Efficacy Set (ES) is composed of all included subjects having received at least one dose of study treatment (partial or full) with a centrally confirmed BRAFV600E mutation.

Arm/Group Title	1 Arm
Arm/Group Description:	encorafenib plus binimetinib plus cetuximab encorafenib: 300 mg administered orally once daily (QD) Binimetinib: Binimetinib 45 mg administered orally twice daily (BID) Cetuximab: Standard of care for the 28 first weeks(*) and then every 2 weeks (**) : (*) 400 mg/m2 administered as a 120-min infusion on Cycle 1 Day 1, followed by 250 mg/m2 administered as a 60-min infusion once weekly (QW) for the first 28 weeks. (**) 500 mg/m2 administered as a 120-min infusion twice weekly (Q2W) from Week 29 (Cycle 8 Day 1) onward. Following implementation of an Urgent Safety Measure on 26 Mar 2020 due to the outbreak of COVID-19 pandemic, cetuximab infusions could be administered Q2W regardless of the cycle number, after investigator's evaluation of the benefit/risk ratio for the subject, with regards to COVID-19 pandemic.
Overall Number of Participants Analyzed	92
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of confirmed responses
	45.7; (35.2 to 56.4)

3. Secondary Outcome

Title	Overall Response Rate (ORR) Based on Local Tumor Assessments
Description	The overall response rate (ORR) is the percentage of responses, defined as complete response (CR) or partial response (PR), as assessed by local radiologist/investigator review based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR): Disappearance of all target lesions; Partiel response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Overall Response (OR) = CR + PR.
Time Frame	From initiation of treatment to disease progression up to a maximum of 17.6 months

Outcome Measure Data

Analysis Population Description

The Efficacy Set (ES) is composed of all included subjects having received at least one dose of study treatment (partial or full) with a centrally confirmed BRAFV600E mutation.

Arm/Group Title	1 Arm
Arm/Group Description:	encorafenib plus binimetinib plus cetuximab encorafenib: Once daily, orally Binimetinib: Twice daily, orally Cetuximab: Standard of care for the 28 first weeks and then every 2 weeks
Overall Number of Participants Analyzed	92
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of responses
	62; (51.2 to 71.9)

4. Secondary Outcome

Title	Overall Response Rate (ORR) Based on Central Tumor Assessments
Description	The overall response rate (ORR) is the percentage of responses, defined as complete response (CR) or partial response (PR), as assessed by central radiologist review based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR): Disappearance of all target lesions; Partiel response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Overall Response (OR) = CR + PR.
Time Frame	From initiation of treatment to disease progression up to a maximum of 17.6 months

Outcome Measure Data

Analysis Population Description

The Efficacy Set (ES) is composed of all included subjects having received at least one dose of study treatment (partial or full) with a centrally confirmed BRAFV600E mutation.

Arm/Group Title	1 Arm
Arm/Group Description:	encorafenib plus binimetinib plus cetuximab encorafenib: Once daily, orally Binimetinib: Twice daily, orally Cetuximab: Standard of care for the 28 first weeks and then every 2 weeks
Overall Number of Participants Analyzed	92
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of responses
	60.9; (50.1 to 70.9)

5. Secondary Outcome

Title	Duration of Response (DOR) Per Local Assessment
Description	Time from first radiographic evidence of response based on local radiologist/investigator review to the earliest documented PD or death due to underlying disease
Time Frame	From first radiographic evidence of response to disease progression up to a maximum of 17.6 months

Outcome Measure Data

Analysis Population Description

Confirmed responders per local radiologist/investigator assessment

Arm/Group Title	1 Arm
Arm/Group Description:	encorafenib plus binimetinib plus cetuximab encorafenib: Once daily, orally Binimetinib: Twice daily, orally Cetuximab: Standard of care for the 28 first weeks and then every 2 weeks
Overall Number of Participants Analyzed	45
Median (95% Confidence Interval); Unit of Measure: months
	5.1; (3.7 to 6.9)

6. Secondary Outcome

Title	Duration of Response (DOR) Per Central Assessment
Description	Time from first radiographic evidence of response based on central review to the earliest documented PD or death due to underlying disease
Time Frame	From first radiographic evidence of response to disease progression up to a maximum of 17.6 months

Outcome Measure Data

Analysis Population Description

Confirmed responders per central assessment

Arm/Group Title	1 Arm
Arm/Group Description:	encorafenib plus binimetinib plus cetuximab encorafenib: Once daily, orally Binimetinib: Twice daily, orally Cetuximab: Standard of care for the 28 first weeks and then every 2 weeks
Overall Number of Participants Analyzed	42
Median (95% Confidence Interval); Unit of Measure: months
	5.1; (3.4 to 5.5)

7. Secondary Outcome

Title	Time to Response (TTR) Per Local Review
Description	The TTR is defined as the time from the first dose until the first documented radiographic evidence of response of CR or PR per local review
Time Frame	From initiation of treatment to the first radiographic evidence of response up to a maximum of 17.6 months

Outcome Measure Data

Analysis Population Description

Confirmed responders per local radiologist/investigator assessment

Arm/Group Title	1 Arm
Arm/Group Description:	encorafenib plus binimetinib plus cetuximab encorafenib: Once daily, orally Binimetinib: Twice daily, orally Cetuximab: Standard of care for the 28 first weeks and then every 2 weeks
Overall Number of Participants Analyzed	45
Median (95% Confidence Interval); Unit of Measure: months
	1.4; (1.4 to 1.5)

8. Secondary Outcome

Title	Time to Response (TTR) Per Central Review
Description	The TTR is defined as the time from the first dose until the first documented radiographic evidence of response of CR or PR per central review
Time Frame	From initiation of treatment to the first radiographic evidence of response up to a maximum of 17.6 months

Outcome Measure Data

Analysis Population Description

Confirmed responders per central assessment

Arm/Group Title	1 Arm
Arm/Group Description:	encorafenib plus binimetinib plus cetuximab encorafenib: Once daily, orally Binimetinib: Twice daily, orally Cetuximab: Standard of care for the 28 first weeks and then every 2 weeks
Overall Number of Participants Analyzed	42
Median (95% Confidence Interval); Unit of Measure: months
	1.4; (1.3 to 1.4)

9. Secondary Outcome

Title	Progression-Free Survival (PFS) Per Local Review
Description	Time from first dose to the earliest documented date of disease progression based on local radiologist/investigator review or death due to any cause
Time Frame	From initiation of treatment to disease progression or death up to a maximum of 17.6 months

Outcome Measure Data

Analysis Population Description

The Efficacy Set (ES) is composed of all included subjects having received at least one dose of study treatment (partial or full) with a centrally confirmed BRAFV600E mutation.

Arm/Group Title	1 Arm
Arm/Group Description:	encorafenib plus binimetinib plus cetuximab encorafenib: Once daily, orally Binimetinib: Twice daily, orally Cetuximab: Standard of care for the 28 first weeks and then every 2 weeks
Overall Number of Participants Analyzed	92
Median (95% Confidence Interval); Unit of Measure: months
	5.8; (4.6 to 6.4)

10. Secondary Outcome

Title	Progression of Free Survival (PFS) Per Central Review
Description	Time from first dose to the earliest documented date of disease progression based on central review or death due to any cause
Time Frame	From initiation of treatment to disease progression or death up to a maximum of 17.6 months

Outcome Measure Data

Analysis Population Description

The Efficacy Set (ES) is composed of all included subjects having received at least one dose of study treatment (partial or full) with a centrally confirmed BRAFV600E mutation.

Arm/Group Title	1 Arm
Arm/Group Description:	encorafenib plus binimetinib plus cetuximab encorafenib: Once daily, orally Binimetinib: Twice daily, orally Cetuximab: Standard of care for the 28 first weeks and then every 2 weeks
Overall Number of Participants Analyzed	92
Median (95% Confidence Interval); Unit of Measure: months
	5.0; (4.6 to 6.4)

11. Secondary Outcome

Title	Overall Survival (OS)
Description	Time from first dose to death due to any cause
Time Frame	From initiation of treatment to death up to a maximum of 17.6 months

Outcome Measure Data

Analysis Population Description

The Full Analysis Set (FAS) is composed of all subjects having received at least one dose of study treatment (partial or full)

Arm/Group Title	1 Arm
Arm/Group Description:	encorafenib plus binimetinib plus cetuximab encorafenib: Once daily, orally Binimetinib: Twice daily, orally Cetuximab: Standard of care for the 28 first weeks and then every 2 weeks
Overall Number of Participants Analyzed	95
Median (95% Confidence Interval); Unit of Measure: months
	17.2 [1]; (14.1 to NA)

[1]

Insufficient data maturity

12. Secondary Outcome

Title	Plasma Concentration of Encorafenib
Description	Plasma concentration of encorafenib
Time Frame	2 hours and 6 hours after dose on Day 1 cycle 1; Predose and 2 hours post dose on Day 1 cycle 2 (cycle length = 28 days)

Outcome Measure Data Not Reported

13. Secondary Outcome

Title	Plasma Concentration of Binimetinib
Description	Plasma concentration of binimetinib
Time Frame	2 hours and 6 hours after dose on Day 1 cycle 1; Predose and 2 hours post dose on Day 1 cycle 2 (cycle length = 28 days)

Outcome Measure Data Not Reported

14. Secondary Outcome

Title	Plasma Concentration of Cetuximab
Description	Plasma concentration of cetuximab
Time Frame	2 hours and 6 hours after dose on Day 1 cycle 1; Predose and 2 hours post dose on Day 1 cycle 2 (cycle length = 28 days)

Outcome Measure Data Not Reported

15. Secondary Outcome

Title	Change From Baseline in EORTC QLQ-C30 Over Time
Description	The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire for cancer subjects (EORTC QLQ-C30) includes a global health status/QoL. The scale ranges in score from 0 to 100, higher score on the global health status/QoL scale indicate higher QoL. Changes from baseline in EORTC QLQ-C30 global health status/quality of life (QoL) over time are presented in this record.
Time Frame	From Cycle 1 Day 1 (C1D1) Visit to the 30-day Safety Follow-up Visit up to a maximum of 17.6 months

Outcome Measure Data

Analysis Population Description

Changes from baseline are shown up to Cycle 10 Day 1 (C10D1) and for the 30-day safety follow-up period. Beyond C10D1, less than 10 subjects filled the questionnaire. Participants analyzed corresponds to the number of participant who completed the questionnaire the at the respective time point.

Arm/Group Title		1 Arm
Arm/Group Description:		encorafenib plus binimetinib plus cetuximab encorafenib: Once daily, orally Binimetinib: Twice daily, orally Cetuximab: Standard of care for the 28 first weeks and then every 2 weeks
Overall Number of Participants Analyzed		95
Mean (Standard Deviation); Unit of Measure: units on a scale
C2D1	Number Analyzed	79 participants
		-2.64 (19.270)
C3D1	Number Analyzed	71 participants
		-0.35 (20.866)
C4D1	Number Analyzed	69 participants
		0.97 (20.238)
C5D1	Number Analyzed	56 participants
		-0.89 (18.026)
C6D1	Number Analyzed	52 participants
		-1.92 (22.544)
C7D1	Number Analyzed	34 participants
		-5.39 (22.834)
C8D1	Number Analyzed	27 participants
		-4.63 (21.225)
C9D1	Number Analyzed	18 participants
		-1.85 (15.274)
C10D1	Number Analyzed	13 participants
		-7.69 (17.167)
30 days safety Follow up	Number Analyzed	40 participants
		-15.42 (25.775)

16. Secondary Outcome

Title	Change From Baseline in EQ-5D-5L Over Time
Description	The EQ-5D-5L consists of the EQ-5D descriptive system and the EQ visual analogue scale (EQ VAS). The EQ-5D-5L VAS records the patient's self-rated health on a vertical visual analogue scale numbered from 0 ("The worst health you can imagine") to 100 ("The best health you can imagine"). Changes from baseline in EQ-5D-5L VAS over time are presented in this record.
Time Frame	From Cycle 1 Day 1 (C1D1) Visit to the 30-day Safety Follow-up Visit up to a maximum of 17.6 months

Outcome Measure Data

Analysis Population Description

Changes from baseline are shown up to Cycle 10 Day 1 (C10D1) and for the 30-day safety follow-up period. Beyond C10D1, less than 10 subjects filled the questionnaire. Participants analyzed corresponds to the number of participant who completed the questionnaire the at the respective time point.

Arm/Group Title		1 Arm
Arm/Group Description:		encorafenib plus binimetinib plus cetuximab encorafenib: Once daily, orally Binimetinib: Twice daily, orally Cetuximab: Standard of care for the 28 first weeks and then every 2 weeks
Overall Number of Participants Analyzed		95
Mean (Standard Deviation); Unit of Measure: units on a scale
C2D1	Number Analyzed	78 participants
		0.04 (19.707)
C3D1	Number Analyzed	71 participants
		0.35 (21.668)
C4D1	Number Analyzed	68 participants
		2.66 (19.400)
C5D1	Number Analyzed	55 participants
		3.73 (17.052)
C6D1	Number Analyzed	52 participants
		1.69 (18.421)
C7D1	Number Analyzed	35 participants
		1.31 (18.903)
C8D1	Number Analyzed	28 participants
		2.89 (15.882)
C9D1	Number Analyzed	19 participants
		-2.32 (21.945)
C10D1	Number Analyzed	13 participants
		-4.00 (12.503)
30 days safety Follow up	Number Analyzed	40 participants
		-9.35 (23.585)

17. Secondary Outcome

Title	PGIC Scores Over Time
Description	The Patient Global Impression of Change (PGIC) is a measure of patients' perceptions of change in their symptoms over time. For this assessment, subjects answered the following question: "Since starting treatment, my colorectal cancer symptoms are: (1) very much improved, (2) much improved, (3) minimally improved, (4) no change, (5) minimally worse, (6) much worse or (7) very much worse."
Time Frame	From Cycle 1 Day 1 (C1D1) Visit to the 30-day Safety Follow-up Visit up to a maximum of 17.6 months

Outcome Measure Data

Analysis Population Description

PGIC scores are shown up to Cycle 10 Day 1 (C10D1) and for the 30-day safety follow-up period. Beyond C10D1, less than 10 subjects filled the questionnaire. Participants analyzed corresponds to the number of participant who completed the questionnaire the at the respective time point.

Arm/Group Title		1 Arm
Arm/Group Description:		encorafenib plus binimetinib plus cetuximab encorafenib: Once daily, orally Binimetinib: Twice daily, orally Cetuximab: Standard of care for the 28 first weeks and then every 2 weeks
Overall Number of Participants Analyzed		95
Measure Type: Count of Participants; Unit of Measure: Participants
C2D1	Number Analyzed	91 participants
	Very much improved	5 5.5%
	Much improved	15 16.5%
	Minimally improved	17 18.7%
	No change	29 31.9%
	Minimally worse	3 3.3%
	Much worse	0 0.0%
	Very much worse	0 0.0%
	Missing, not done	22 24.2%
C3D1	Number Analyzed	81 participants
	Very much improved	10 12.3%
	Much improved	28 34.6%
	Minimally improved	11 13.6%
	No change	20 24.7%
	Minimally worse	0 0.0%
	Much worse	0 0.0%
	Very much worse	0 0.0%
	Missing, not done	12 14.8%
C4D1	Number Analyzed	77 participants
	Very much improved	9 11.7%
	Much improved	31 40.3%
	Minimally improved	12 15.6%
	No change	16 20.8%
	Minimally worse	0 0.0%
	Much worse	0 0.0%
	Very much worse	0 0.0%
	Missing, not done	9 11.7%
C5D1	Number Analyzed	65 participants
	Very much improved	10 15.4%
	Much improved	19 29.2%
	Minimally improved	11 16.9%
	No change	13 20.0%
	Minimally worse	2 3.1%
	Much worse	0 0.0%
	Very much worse	0 0.0%
	Missing, not done	10 15.4%
C6D1	Number Analyzed	57 participants
	Very much improved	7 12.3%
	Much improved	18 31.6%
	Minimally improved	13 22.8%
	No change	13 22.8%
	Minimally worse	0 0.0%
	Much worse	0 0.0%
	Very much worse	0 0.0%
	Missing, not done	6 10.5%
C7D1	Number Analyzed	43 participants
	Very much improved	4 9.3%
	Much improved	13 30.2%
	Minimally improved	7 16.3%
	No change	11 25.6%
	Minimally worse	0 0.0%
	Much worse	0 0.0%
	Very much worse	0 0.0%
	Missing, not done	8 18.6%
C8D1	Number Analyzed	33 participants
	Very much improved	4 12.1%
	Much improved	11 33.3%
	Minimally improved	5 15.2%
	No change	5 15.2%
	Minimally worse	2 6.1%
	Much worse	0 0.0%
	Very much worse	0 0.0%
	Missing, not done	6 18.2%
C9D1	Number Analyzed	20 participants
	Very much improved	1 5.0%
	Much improved	9 45.0%
	Minimally improved	2 10.0%
	No change	5 25.0%
	Minimally worse	0 0.0%
	Much worse	0 0.0%
	Very much worse	0 0.0%
	Missing, not done	3 15.0%
C10D1	Number Analyzed	14 participants
	Very much improved	2 14.3%
	Much improved	4 28.6%
	Minimally improved	4 28.6%
	No change	4 28.6%
	Minimally worse	0 0.0%
	Much worse	0 0.0%
	Very much worse	0 0.0%
	Missing, not done	0 0.0%
30 days safety Follow-up	Number Analyzed	72 participants
	Very much improved	3 4.2%
	Much improved	12 16.7%
	Minimally improved	5 6.9%
	No change	9 12.5%
	Minimally worse	6 8.3%
	Much worse	6 8.3%
	Very much worse	0 0.0%
	Missing, not done	31 43.1%

Adverse Events

Time Frame	From patient enrolment date to 30 days after the last dose of study drug up to a maximum of 17.6 months
Adverse Event Reporting Description	Only treatment emergent Adverse Events are provided in summary tables. A treatment emergent adverse event (TEAE) is defined as any event that first occurred during the treatment period (i.e. from first treatment administration date up to last administration date + 30 days) or that worsened during that study period.
Arm/Group Title	1 Arm
Arm/Group Description	encorafenib plus binimetinib plus cetuximab encorafenib: Once daily, orally Binimetinib: Twice daily, orally Cetuximab: Standard of care for the 28 first weeks and then every 2 weeks
All-Cause Mortality
	1 Arm
	Affected / at Risk (%)
Total	27/95 (28.42%)
Serious Adverse Events
	1 Arm
	Affected / at Risk (%)	# Events
Total	49/95 (51.58%)
Blood and lymphatic system disorders
Anaemia † 1	2/95 (2.11%)	2
Cardiac disorders
Cardiac failure † 1	1/95 (1.05%)	1
Myocardial infarction † 1	1/95 (1.05%)	1
Myocarditis † 1	1/95 (1.05%)	1
Eye disorders
Detachment of retinal pigment epithelium † 1	1/95 (1.05%)	1
Gastrointestinal disorders
Abdominal pain † 1	4/95 (4.21%)	4
Abdominal pain upper † 1	1/95 (1.05%)	1
Diarrhoea † 1	4/95 (4.21%)	4
Diverticulum † 1	1/95 (1.05%)	1
Enteritis † 1	1/95 (1.05%)	1
Enterocolitis † 1	1/95 (1.05%)	2
Intestinal obstruction † 1	5/95 (5.26%)	5
Intra-abdominal fluid collection † 1	1/95 (1.05%)	1
Large intestinal obstruction † 1	6/95 (6.32%)	6
Large intestine perforation † 1	1/95 (1.05%)	1
Lower gastrointestinal haemorrhage † 1	1/95 (1.05%)	1
Nausea † 1	5/95 (5.26%)	5
Pancreatitis acute † 1	1/95 (1.05%)	2
Small intestinal obstruction † 1	4/95 (4.21%)	5
Subileus † 1	1/95 (1.05%)	1
Vomiting † 1	4/95 (4.21%)	4
General disorders
Asthenia † 1	1/95 (1.05%)	1
General physical health deterioration † 1	1/95 (1.05%)	1
Pyrexia † 1	2/95 (2.11%)	2
Hepatobiliary disorders
Bile duct stenosis † 1	1/95 (1.05%)	1
Cholangitis † 1	1/95 (1.05%)	1
Cholecystitis † 1	1/95 (1.05%)	1
Hepatic function abnormal † 1	1/95 (1.05%)	1
Infections and infestations
Appendicitis † 1	1/95 (1.05%)	1
Bacteraemia † 1	1/95 (1.05%)	1
Biliary tract infection † 1	1/95 (1.05%)	1
Cellulitis † 1	1/95 (1.05%)	1
Escherichia sepsis † 1	1/95 (1.05%)	1
Lymph node tuberculosis † 1	1/95 (1.05%)	1
Respiratory tract infection † 1	1/95 (1.05%)	1
Sepsis † 1	1/95 (1.05%)	1
Streptococcal bacteraemia † 1	1/95 (1.05%)	1
Tuberculosis † 1	1/95 (1.05%)	1
Urinary tract infection † 1	1/95 (1.05%)	1
Injury, poisoning and procedural complications
Diversion colitis † 1	1/95 (1.05%)	3
Femoral neck fracture † 1	1/95 (1.05%)	1
Infusion related reaction † 1	1/95 (1.05%)	1
Lumbar vertebral fracture † 1	1/95 (1.05%)	1
Investigations
Alanine aminotransferase increased † 1	1/95 (1.05%)	1
Aspartate aminotransferase increased † 1	1/95 (1.05%)	1
Blood bilirubin increased † 1	1/95 (1.05%)	1
Blood creatine phosphokinase increased † 1	1/95 (1.05%)	1
Gamma-glutamyltransferase increased † 1	1/95 (1.05%)	1
Metabolism and nutrition disorders
Decreased appetite † 1	1/95 (1.05%)	1
Hypokalaemia † 1	1/95 (1.05%)	2
Musculoskeletal and connective tissue disorders
Back pain † 1	1/95 (1.05%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour associated fever † 1	1/95 (1.05%)	1
Nervous system disorders
Dizziness † 1	1/95 (1.05%)	1
Renal and urinary disorders
Acute kidney injury † 1	6/95 (6.32%)	8
Haematuria † 1	1/95 (1.05%)	1
Nephritis † 1	1/95 (1.05%)	1
Nephrolithiasis † 1	1/95 (1.05%)	1
Renal failure † 1	2/95 (2.11%)	2
Respiratory, thoracic and mediastinal disorders
Pleural effusion † 1	1/95 (1.05%)	1
Pneumonia aspiration † 1	1/95 (1.05%)	1
Pneumonitis † 1	1/95 (1.05%)	1
Respiratory failure † 1	1/95 (1.05%)	1
1 Term from vocabulary, MedDRA 23.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	1 Arm
	Affected / at Risk (%)	# Events
Total	93/95 (97.89%)
Blood and lymphatic system disorders
Anaemia † 1	23/95 (24.21%)	60
Eye disorders
Vision blurred † 1	13/95 (13.68%)	17
Gastrointestinal disorders
Abdominal discomfort † 1	6/95 (6.32%)	6
Abdominal pain † 1	31/95 (32.63%)	43
Abdominal pain upper † 1	7/95 (7.37%)	11
Constipation † 1	25/95 (26.32%)	26
Diarrhoea † 1	64/95 (67.37%)	145
Dyspepsia † 1	8/95 (8.42%)	8
Flatulence † 1	5/95 (5.26%)	5
Nausea † 1	42/95 (44.21%)	83
Rectal haemorrhage † 1	6/95 (6.32%)	8
Stomatitis † 1	8/95 (8.42%)	16
Vomiting † 1	34/95 (35.79%)	59
General disorders
Asthenia † 1	30/95 (31.58%)	67
Fatigue † 1	18/95 (18.95%)	38
Mucosal inflammation † 1	6/95 (6.32%)	6
Pyrexia † 1	12/95 (12.63%)	19
Infections and infestations
Paronychia † 1	11/95 (11.58%)	11
Investigations
Amylase increased † 1	10/95 (10.53%)	17
Blood creatine phosphokinase increased † 1	5/95 (5.26%)	7
Blood creatinine increased † 1	9/95 (9.47%)	11
Lipase increased † 1	12/95 (12.63%)	24
Weight decreased † 1	6/95 (6.32%)	8
Metabolism and nutrition disorders
Decreased appetite † 1	22/95 (23.16%)	36
Hyperkalaemia † 1	5/95 (5.26%)	6
Hypoalbuminaemia † 1	7/95 (7.37%)	13
Hypomagnesaemia † 1	6/95 (6.32%)	9
Musculoskeletal and connective tissue disorders
Arthralgia † 1	8/95 (8.42%)	14
Back pain † 1	9/95 (9.47%)	9
Muscle spasms † 1	5/95 (5.26%)	5
Myalgia † 1	6/95 (6.32%)	8
Nervous system disorders
Dysgeusia † 1	12/95 (12.63%)	13
Headache † 1	10/95 (10.53%)	11
Psychiatric disorders
Insomnia † 1	5/95 (5.26%)	6
Respiratory, thoracic and mediastinal disorders
Cough † 1	8/95 (8.42%)	9
Dysphonia † 1	6/95 (6.32%)	8
Dyspnoea † 1	15/95 (15.79%)	23
Skin and subcutaneous tissue disorders
Dermatitis acneiform † 1	38/95 (40.00%)	77
Dry skin † 1	30/95 (31.58%)	35
Erythema † 1	5/95 (5.26%)	5
Hypertrichosis † 1	6/95 (6.32%)	6
Palmar-plantar erythrodysaesthesia syndrome † 1	5/95 (5.26%)	6
Pruritus † 1	12/95 (12.63%)	16
Rash † 1	38/95 (40.00%)	56
Skin fissures † 1	11/95 (11.58%)	17
1 Term from vocabulary, MedDRA 23.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

The absence of a comparator arm should be noted as a limitation. In addition, the short duration of the follow-up at the data cut-off date does not allow a robust estimate of OS results.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Isabelle Klauck, MD
• Organization: Pierre Fabre Medicament
• Phone: +33149108018
• EMail: isabelle.klauck@pierre-fabre.com

• Responsible Party: Pierre Fabre Medicament
• ClinicalTrials.gov Identifier: NCT03693170
• Other Study ID Numbers: W00090 GE 2 01
• First Submitted: September 17, 2018
• First Posted: October 2, 2018
• Results First Submitted: January 13, 2022
• Results First Posted: August 30, 2022
• Last Update Posted: February 2, 2024