Trial Outcomes & Findings for Encorafenib and Binimetinib Before Local Treatment in Patients With BRAF Mutant Melanoma Metastatic to the Brain (NCT NCT03898908)
NCT ID: NCT03898908
Last Updated: 2025-05-21
Results Overview
iORR calculated as the proportion of patient with a best overall intracranial response of complete response (CR) or partial response (PR) before local treatment according to modified RECIST 1.1. Modified RECIST 1.1 consists of: Up to 5 intracranial lesions could be selected as target lesions Target lesions might have a longest diameter ≥ 5 mm when evaluated by contrast-enhanced MRI This endpoint was also independently reported in patients with symptomatic and asymptomatic brain metastasis.
Recruitment status
COMPLETED
Study phase
PHASE2
Target enrollment
48 participants
Primary outcome timeframe
24 months after start of treatment
Results posted on
2025-05-21
Participant Flow
the initial sample size was set at 48 patients, to ensure obtaining 38 evaluable patients. The cohort of symptomatic patients was exploratory and no formal sample calculation was performed, anticipating the inclusion of up to 15 patients.The trial was amended and patients were included irrespective of symptomatology.
Participant milestones
| Measure |
COMBO450
Encorafenib - Orally, 75 mg and 50 mg capsules Binimetinib - Orally, 15 mg tablets
In each cohort, patients will be treated with encorafenib 450 mg once daily and binimetinib 45 mg twice daily until PD or death.
encorafenib: Encorafenib 75mg and 50mg (capsules) for a 450mg daily for oral administration during 56 days and after local radiation treatment.
If no progression of disease progression (PD) is reported, treatment will continue until PD, unacceptable toxicity or death.
binimetinib: Binimetinib 15mg (tablets) for a 45mg/12 hours for oral administration during 56 days and after local radiation treatment.
Whole brain radiation therapy: The whole brain planning target volume (PTV) will receive 30 Gy in 10 fractions.
Treatment will be delivered once daily, 5 fractions per week, over 2 to 2.5 weeks.
Radiosurgery/stereotactic radiosurgery: Dose selection must be based on previously published Radiation Therapy Oncology Group (RTOG) data, with dose modification left up to the treating physician. The total dose will depend on the size of the metastatic lesion(s) and proximity to critical structures.
Suggested doses are as follow: 1 fraction x 15-25 Gy; 3 fractions x 9-11 Gy; 5 fractions x 6-7 Gy; or 6 fractions x 5-6 Gy.
For GTV \> 20 mm hypofractionated stereotactic radiotherapy could be preferred. Treatment will be delivered once daily, alternate-day, 3 fractions per week.
|
|---|---|
|
Overall Study
STARTED
|
48
|
|
Overall Study
COMPLETED
|
48
|
|
Overall Study
NOT COMPLETED
|
0
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
Race and Ethnicity were not collected from any participant.
Baseline characteristics by cohort
| Measure |
COMBO450
n=48 Participants
Encorafenib - Orally, 75 mg and 50 mg capsules Binimetinib - Orally, 15 mg tablets
In each cohort, patients will be treated with encorafenib 450 mg once daily and binimetinib 45 mg twice daily until PD or death.
encorafenib: Encorafenib 75mg and 50mg (capsules) for a 450mg daily for oral administration during 56 days and after local radiation treatment.
If no progression of disease progression (PD) is reported, treatment will continue until PD, unacceptable toxicity or death.
binimetinib: Binimetinib 15mg (tablets) for a 45mg/12 hours for oral administration during 56 days and after local radiation treatment.
Whole brain radiation therapy: The whole brain planning target volume (PTV) will receive 30 Gy in 10 fractions.
Treatment will be delivered once daily, 5 fractions per week, over 2 to 2.5 weeks.
Radiosurgery/stereotactic radiosurgery: Dose selection must be based on previously published Radiation Therapy Oncology Group (RTOG) data, with dose modification left up to the treating physician. The total dose will depend on the size of the metastatic lesion(s) and proximity to critical structures.
Suggested doses are as follow: 1 fraction x 15-25 Gy; 3 fractions x 9-11 Gy; 5 fractions x 6-7 Gy; or 6 fractions x 5-6 Gy.
For GTV \> 20 mm hypofractionated stereotactic radiotherapy could be preferred. Treatment will be delivered once daily, alternate-day, 3 fractions per week.
|
|---|---|
|
Age, Continuous
|
54 years
n=48 Participants
|
|
Sex: Female, Male
Female
|
24 Participants
n=48 Participants
|
|
Sex: Female, Male
Male
|
24 Participants
n=48 Participants
|
|
Region of Enrollment
Spain
|
48 participants
n=48 Participants
|
|
Eastern cooperative oncology group (ECOG) performance status (PS) at baseline
Score 0
|
26 Participants
n=48 Participants
|
|
Eastern cooperative oncology group (ECOG) performance status (PS) at baseline
Score 1
|
20 Participants
n=48 Participants
|
|
Eastern cooperative oncology group (ECOG) performance status (PS) at baseline
Score 2
|
2 Participants
n=48 Participants
|
|
Barthel Index
Total dependent (0-4)
|
3 Participants
n=48 Participants
|
|
Barthel Index
Severe dependent (5-12)
|
4 Participants
n=48 Participants
|
|
Barthel Index
Moderate dependent (13-18)
|
6 Participants
n=48 Participants
|
|
Barthel Index
Slight dependent (19-20)
|
33 Participants
n=48 Participants
|
|
Barthel Index
NA
|
2 Participants
n=48 Participants
|
|
BRAF genotype
V600E · Mutated
|
41 Participants
n=48 Participants
|
|
BRAF genotype
V600E · Not mutated
|
7 Participants
n=48 Participants
|
|
BRAF genotype
V600K · Mutated
|
11 Participants
n=48 Participants
|
|
BRAF genotype
V600K · Not mutated
|
37 Participants
n=48 Participants
|
|
BRAF genotype
V600R · Mutated
|
6 Participants
n=48 Participants
|
|
BRAF genotype
V600R · Not mutated
|
42 Participants
n=48 Participants
|
|
BRAF genotype
V600 other · Mutated
|
25 Participants
n=48 Participants
|
|
BRAF genotype
V600 other · Not mutated
|
23 Participants
n=48 Participants
|
|
Brain symptoms
Asymptomatic
|
25 Participants
n=48 Participants
|
|
Brain symptoms
Symptomatic
|
23 Participants
n=48 Participants
|
|
Sum of longest diameters of intracranial target lesions
|
26.5 millimeters
n=48 Participants
|
|
Number of brain target lesion
1 intracranial lesion
|
21 Participants
n=48 Participants
|
|
Number of brain target lesion
2 intracranial lesions
|
15 Participants
n=48 Participants
|
|
Number of brain target lesion
3 or more intracranial lesions
|
12 Participants
n=48 Participants
|
|
Extracranial metastases
Yes
|
41 Participants
n=48 Participants
|
|
Extracranial metastases
No
|
7 Participants
n=48 Participants
|
|
Lactate dehydrogenase (LDH) levels
≤ upper limit normal (ULN)
|
26 Participants
n=48 Participants
|
|
Lactate dehydrogenase (LDH) levels
> ULN
|
21 Participants
n=48 Participants
|
|
Lactate dehydrogenase (LDH) levels
Unknown
|
1 Participants
n=48 Participants
|
|
Corticosteroids use at baseline
Yes
|
33 Participants
n=48 Participants
|
|
Corticosteroids use at baseline
No
|
15 Participants
n=48 Participants
|
|
Corticosteroid dose
|
8 milligram per day
n=33 Participants • The dose of corticosteroids is only reported in patients receiving corticosteroids.
|
|
Previous anti-PD-1 based immunotherapy
Anti PD-1
|
11 Participants
n=48 Participants
|
|
Previous anti-PD-1 based immunotherapy
Anti PD-1 / anti CTLA-4
|
5 Participants
n=48 Participants
|
|
Previous anti-PD-1 based immunotherapy
No previous PD-L1
|
32 Participants
n=48 Participants
|
|
Radiotherapy received in the EBRAIN trial
Radiosurgery (RS)
|
10 Participants
n=48 Participants
|
|
Radiotherapy received in the EBRAIN trial
Fractioned stereotactic radiotherapy (FSRT)
|
6 Participants
n=48 Participants
|
|
Radiotherapy received in the EBRAIN trial
Whole brain radiotherapy (WBRT)
|
15 Participants
n=48 Participants
|
|
Radiotherapy received in the EBRAIN trial
None
|
17 Participants
n=48 Participants
|
PRIMARY outcome
Timeframe: 24 months after start of treatmentPopulation: The endpoint is calculated for the full dataset and also in two subgroups with symptomatic or asymptomatic brain metastasis, respectively.
iORR calculated as the proportion of patient with a best overall intracranial response of complete response (CR) or partial response (PR) before local treatment according to modified RECIST 1.1. Modified RECIST 1.1 consists of: Up to 5 intracranial lesions could be selected as target lesions Target lesions might have a longest diameter ≥ 5 mm when evaluated by contrast-enhanced MRI This endpoint was also independently reported in patients with symptomatic and asymptomatic brain metastasis.
Outcome measures
| Measure |
COMBO450
n=48 Participants
Encorafenib - Orally, 75 mg and 50 mg capsules Binimetinib - Orally, 15 mg tablets
In each cohort, patients will be treated with encorafenib 450 mg once daily and binimetinib 45 mg twice daily until PD or death.
encorafenib: Encorafenib 75mg and 50mg (capsules) for a 450mg daily for oral administration during 56 days and after local radiation treatment.
If no progression of disease progression (PD) is reported, treatment will continue until PD, unacceptable toxicity or death.
binimetinib: Binimetinib 15mg (tablets) for a 45mg/12 hours for oral administration during 56 days and after local radiation treatment.
Whole brain radiation therapy: The whole brain planning target volume (PTV) will receive 30 Gy in 10 fractions.
Treatment will be delivered once daily, 5 fractions per week, over 2 to 2.5 weeks.
Radiosurgery/stereotactic radiosurgery: Dose selection must be based on previously published Radiation Therapy Oncology Group (RTOG) data, with dose modification left up to the treating physician. The total dose will depend on the size of the metastatic lesion(s) and proximity to critical structures.
Suggested doses are as follow: 1 fraction x 15-25 Gy; 3 fractions x 9-11 Gy; 5 fractions x 6-7 Gy; or 6 fractions x 5-6 Gy.
For GTV \> 20 mm hypofractionated stereotactic radiotherapy could be preferred. Treatment will be delivered once daily, alternate-day, 3 fractions per week.
|
|---|---|
|
Intracranial Objective Response (iORR) by Modified RECIST 1.1 Before Local Radiotherapy Treatment in Full Dataset
Full analysis set · Patients with intracranial response
|
34 Participants
|
|
Intracranial Objective Response (iORR) by Modified RECIST 1.1 Before Local Radiotherapy Treatment in Full Dataset
Full analysis set · Patients with NO intracranial response
|
13 Participants
|
|
Intracranial Objective Response (iORR) by Modified RECIST 1.1 Before Local Radiotherapy Treatment in Full Dataset
Full analysis set · Not evaluable
|
1 Participants
|
|
Intracranial Objective Response (iORR) by Modified RECIST 1.1 Before Local Radiotherapy Treatment in Full Dataset
Asymptomatic brain metastasis · Patients with intracranial response
|
20 Participants
|
|
Intracranial Objective Response (iORR) by Modified RECIST 1.1 Before Local Radiotherapy Treatment in Full Dataset
Asymptomatic brain metastasis · Patients with NO intracranial response
|
5 Participants
|
|
Intracranial Objective Response (iORR) by Modified RECIST 1.1 Before Local Radiotherapy Treatment in Full Dataset
Asymptomatic brain metastasis · Not evaluable
|
0 Participants
|
|
Intracranial Objective Response (iORR) by Modified RECIST 1.1 Before Local Radiotherapy Treatment in Full Dataset
Symptomatic brain metastasis · Patients with intracranial response
|
14 Participants
|
|
Intracranial Objective Response (iORR) by Modified RECIST 1.1 Before Local Radiotherapy Treatment in Full Dataset
Symptomatic brain metastasis · Patients with NO intracranial response
|
8 Participants
|
|
Intracranial Objective Response (iORR) by Modified RECIST 1.1 Before Local Radiotherapy Treatment in Full Dataset
Symptomatic brain metastasis · Not evaluable
|
1 Participants
|
SECONDARY outcome
Timeframe: Throughout the study period, up to approximately 24 monthsPopulation: Only patients who have an intracranial responses were analyzed for its duration.
Calculated as the time from the date of first documented CR or PR to the first documented intracranial progression or death due to underlying cancer accoridng to modified RECIST 1.1, in patients with documented intracranial CR or PR before local treatment.
Outcome measures
| Measure |
COMBO450
n=34 Participants
Encorafenib - Orally, 75 mg and 50 mg capsules Binimetinib - Orally, 15 mg tablets
In each cohort, patients will be treated with encorafenib 450 mg once daily and binimetinib 45 mg twice daily until PD or death.
encorafenib: Encorafenib 75mg and 50mg (capsules) for a 450mg daily for oral administration during 56 days and after local radiation treatment.
If no progression of disease progression (PD) is reported, treatment will continue until PD, unacceptable toxicity or death.
binimetinib: Binimetinib 15mg (tablets) for a 45mg/12 hours for oral administration during 56 days and after local radiation treatment.
Whole brain radiation therapy: The whole brain planning target volume (PTV) will receive 30 Gy in 10 fractions.
Treatment will be delivered once daily, 5 fractions per week, over 2 to 2.5 weeks.
Radiosurgery/stereotactic radiosurgery: Dose selection must be based on previously published Radiation Therapy Oncology Group (RTOG) data, with dose modification left up to the treating physician. The total dose will depend on the size of the metastatic lesion(s) and proximity to critical structures.
Suggested doses are as follow: 1 fraction x 15-25 Gy; 3 fractions x 9-11 Gy; 5 fractions x 6-7 Gy; or 6 fractions x 5-6 Gy.
For GTV \> 20 mm hypofractionated stereotactic radiotherapy could be preferred. Treatment will be delivered once daily, alternate-day, 3 fractions per week.
|
|---|---|
|
Duration of Intracranial Response
|
5.6 months
Interval 3.6 to 7.5
|
SECONDARY outcome
Timeframe: Throughout the study period, up to approximately 24 monthsDefined as the time from the date of inclusion to the date of the first documented intracranial disease progression or death due to any cause, whichever occurs first. PFS was determined based on tumor assessment (modified RECIST version 1.1 criteria). The local Investigator's assessments was used for analyses. Those patients who were alive and had not progressed at the last follow-up, date of progression was censored at the date of the last follow-up. Patients with no additional image test other than baseline were censored the day after inclusion.
Outcome measures
| Measure |
COMBO450
n=48 Participants
Encorafenib - Orally, 75 mg and 50 mg capsules Binimetinib - Orally, 15 mg tablets
In each cohort, patients will be treated with encorafenib 450 mg once daily and binimetinib 45 mg twice daily until PD or death.
encorafenib: Encorafenib 75mg and 50mg (capsules) for a 450mg daily for oral administration during 56 days and after local radiation treatment.
If no progression of disease progression (PD) is reported, treatment will continue until PD, unacceptable toxicity or death.
binimetinib: Binimetinib 15mg (tablets) for a 45mg/12 hours for oral administration during 56 days and after local radiation treatment.
Whole brain radiation therapy: The whole brain planning target volume (PTV) will receive 30 Gy in 10 fractions.
Treatment will be delivered once daily, 5 fractions per week, over 2 to 2.5 weeks.
Radiosurgery/stereotactic radiosurgery: Dose selection must be based on previously published Radiation Therapy Oncology Group (RTOG) data, with dose modification left up to the treating physician. The total dose will depend on the size of the metastatic lesion(s) and proximity to critical structures.
Suggested doses are as follow: 1 fraction x 15-25 Gy; 3 fractions x 9-11 Gy; 5 fractions x 6-7 Gy; or 6 fractions x 5-6 Gy.
For GTV \> 20 mm hypofractionated stereotactic radiotherapy could be preferred. Treatment will be delivered once daily, alternate-day, 3 fractions per week.
|
|---|---|
|
Intracranial Progression-free Survival (iPFS) by RECIST 1.1
|
8.5 months
Interval 6.4 to 11.8
|
SECONDARY outcome
Timeframe: Throughout the study period, up to approximately 24 monthsDefined as the time from the date of inclusion to the date of the first documented extracranial disease progression or death due to any cause, whichever occurs first. PFS was determined based on tumor assessment (RECIST version 1.1 criteria). The local Investigator's assessments was used for analyses. Those patients who were alive and had not progressed at the last follow-up, date of progression was censored at the date of the last follow-up. Patients with no additional image test other than baseline were censored the day after inclusion.
Outcome measures
| Measure |
COMBO450
n=48 Participants
Encorafenib - Orally, 75 mg and 50 mg capsules Binimetinib - Orally, 15 mg tablets
In each cohort, patients will be treated with encorafenib 450 mg once daily and binimetinib 45 mg twice daily until PD or death.
encorafenib: Encorafenib 75mg and 50mg (capsules) for a 450mg daily for oral administration during 56 days and after local radiation treatment.
If no progression of disease progression (PD) is reported, treatment will continue until PD, unacceptable toxicity or death.
binimetinib: Binimetinib 15mg (tablets) for a 45mg/12 hours for oral administration during 56 days and after local radiation treatment.
Whole brain radiation therapy: The whole brain planning target volume (PTV) will receive 30 Gy in 10 fractions.
Treatment will be delivered once daily, 5 fractions per week, over 2 to 2.5 weeks.
Radiosurgery/stereotactic radiosurgery: Dose selection must be based on previously published Radiation Therapy Oncology Group (RTOG) data, with dose modification left up to the treating physician. The total dose will depend on the size of the metastatic lesion(s) and proximity to critical structures.
Suggested doses are as follow: 1 fraction x 15-25 Gy; 3 fractions x 9-11 Gy; 5 fractions x 6-7 Gy; or 6 fractions x 5-6 Gy.
For GTV \> 20 mm hypofractionated stereotactic radiotherapy could be preferred. Treatment will be delivered once daily, alternate-day, 3 fractions per week.
|
|---|---|
|
Extracranial Progression-free Survival (ePFS) in Both Cohorts
|
7.7 months
Interval 6.1 to 11.8
|
SECONDARY outcome
Timeframe: at 6 months (week 24), 12 months (week 48) and 24-month (week 96)Proportion of patients free of intracranial progression assessed by modified RECIST at 6 months (week 24), 12 months (week 48) and 24-month (week 96) considering date of inclusion estimated through Kaplan-Meier method
Outcome measures
| Measure |
COMBO450
n=48 Participants
Encorafenib - Orally, 75 mg and 50 mg capsules Binimetinib - Orally, 15 mg tablets
In each cohort, patients will be treated with encorafenib 450 mg once daily and binimetinib 45 mg twice daily until PD or death.
encorafenib: Encorafenib 75mg and 50mg (capsules) for a 450mg daily for oral administration during 56 days and after local radiation treatment.
If no progression of disease progression (PD) is reported, treatment will continue until PD, unacceptable toxicity or death.
binimetinib: Binimetinib 15mg (tablets) for a 45mg/12 hours for oral administration during 56 days and after local radiation treatment.
Whole brain radiation therapy: The whole brain planning target volume (PTV) will receive 30 Gy in 10 fractions.
Treatment will be delivered once daily, 5 fractions per week, over 2 to 2.5 weeks.
Radiosurgery/stereotactic radiosurgery: Dose selection must be based on previously published Radiation Therapy Oncology Group (RTOG) data, with dose modification left up to the treating physician. The total dose will depend on the size of the metastatic lesion(s) and proximity to critical structures.
Suggested doses are as follow: 1 fraction x 15-25 Gy; 3 fractions x 9-11 Gy; 5 fractions x 6-7 Gy; or 6 fractions x 5-6 Gy.
For GTV \> 20 mm hypofractionated stereotactic radiotherapy could be preferred. Treatment will be delivered once daily, alternate-day, 3 fractions per week.
|
|---|---|
|
Intracranial Progression-free Rates
24 months
|
5.5 Percentage of patients free of PD
Interval 0.9 to 32.0
|
|
Intracranial Progression-free Rates
6 months
|
66.8 Percentage of patients free of PD
Interval 54.4 to 82.1
|
|
Intracranial Progression-free Rates
12 months
|
29.5 Percentage of patients free of PD
Interval 18.2 to 47.6
|
SECONDARY outcome
Timeframe: Throughout the study period, up to approximately 24 monthsCalculated as the time from date of inclusion to date of death due to any cause.
Outcome measures
| Measure |
COMBO450
n=48 Participants
Encorafenib - Orally, 75 mg and 50 mg capsules Binimetinib - Orally, 15 mg tablets
In each cohort, patients will be treated with encorafenib 450 mg once daily and binimetinib 45 mg twice daily until PD or death.
encorafenib: Encorafenib 75mg and 50mg (capsules) for a 450mg daily for oral administration during 56 days and after local radiation treatment.
If no progression of disease progression (PD) is reported, treatment will continue until PD, unacceptable toxicity or death.
binimetinib: Binimetinib 15mg (tablets) for a 45mg/12 hours for oral administration during 56 days and after local radiation treatment.
Whole brain radiation therapy: The whole brain planning target volume (PTV) will receive 30 Gy in 10 fractions.
Treatment will be delivered once daily, 5 fractions per week, over 2 to 2.5 weeks.
Radiosurgery/stereotactic radiosurgery: Dose selection must be based on previously published Radiation Therapy Oncology Group (RTOG) data, with dose modification left up to the treating physician. The total dose will depend on the size of the metastatic lesion(s) and proximity to critical structures.
Suggested doses are as follow: 1 fraction x 15-25 Gy; 3 fractions x 9-11 Gy; 5 fractions x 6-7 Gy; or 6 fractions x 5-6 Gy.
For GTV \> 20 mm hypofractionated stereotactic radiotherapy could be preferred. Treatment will be delivered once daily, alternate-day, 3 fractions per week.
|
|---|---|
|
Overall Survival
|
15.9 months
Interval 10.7 to 21.4
|
SECONDARY outcome
Timeframe: at 6 months, 12 month and 24-monthProportion of of patients alive at 6 months, 12 month and 24-month considering date of inclusion estimated using Kaplan-Meier. Patients alive at the moment of the analysis were censored on the date of their last follow-up.
Outcome measures
| Measure |
COMBO450
n=48 Participants
Encorafenib - Orally, 75 mg and 50 mg capsules Binimetinib - Orally, 15 mg tablets
In each cohort, patients will be treated with encorafenib 450 mg once daily and binimetinib 45 mg twice daily until PD or death.
encorafenib: Encorafenib 75mg and 50mg (capsules) for a 450mg daily for oral administration during 56 days and after local radiation treatment.
If no progression of disease progression (PD) is reported, treatment will continue until PD, unacceptable toxicity or death.
binimetinib: Binimetinib 15mg (tablets) for a 45mg/12 hours for oral administration during 56 days and after local radiation treatment.
Whole brain radiation therapy: The whole brain planning target volume (PTV) will receive 30 Gy in 10 fractions.
Treatment will be delivered once daily, 5 fractions per week, over 2 to 2.5 weeks.
Radiosurgery/stereotactic radiosurgery: Dose selection must be based on previously published Radiation Therapy Oncology Group (RTOG) data, with dose modification left up to the treating physician. The total dose will depend on the size of the metastatic lesion(s) and proximity to critical structures.
Suggested doses are as follow: 1 fraction x 15-25 Gy; 3 fractions x 9-11 Gy; 5 fractions x 6-7 Gy; or 6 fractions x 5-6 Gy.
For GTV \> 20 mm hypofractionated stereotactic radiotherapy could be preferred. Treatment will be delivered once daily, alternate-day, 3 fractions per week.
|
|---|---|
|
Overall Survival Rates
6 months
|
91.6 Percentage of patients alive
Interval 84.1 to 99.8
|
|
Overall Survival Rates
12 months
|
59.2 Percentage of patients alive
Interval 46.2 to 76.0
|
|
Overall Survival Rates
24 months
|
15.5 Percentage of patients alive
Interval 6.7 to 35.8
|
SECONDARY outcome
Timeframe: Throughout the study period, up to approximately 24 monthsNumber of patients experiencing treatment related adverse events. These events were graded accrding to CTCAE, a scale that ranges from 0 (less intense; no event) to 5 (death) . Here we report the number of patients experiencing any grade toxicities and the number of patients experiencing high grade (grade 3-5) toxicities.
Outcome measures
| Measure |
COMBO450
n=48 Participants
Encorafenib - Orally, 75 mg and 50 mg capsules Binimetinib - Orally, 15 mg tablets
In each cohort, patients will be treated with encorafenib 450 mg once daily and binimetinib 45 mg twice daily until PD or death.
encorafenib: Encorafenib 75mg and 50mg (capsules) for a 450mg daily for oral administration during 56 days and after local radiation treatment.
If no progression of disease progression (PD) is reported, treatment will continue until PD, unacceptable toxicity or death.
binimetinib: Binimetinib 15mg (tablets) for a 45mg/12 hours for oral administration during 56 days and after local radiation treatment.
Whole brain radiation therapy: The whole brain planning target volume (PTV) will receive 30 Gy in 10 fractions.
Treatment will be delivered once daily, 5 fractions per week, over 2 to 2.5 weeks.
Radiosurgery/stereotactic radiosurgery: Dose selection must be based on previously published Radiation Therapy Oncology Group (RTOG) data, with dose modification left up to the treating physician. The total dose will depend on the size of the metastatic lesion(s) and proximity to critical structures.
Suggested doses are as follow: 1 fraction x 15-25 Gy; 3 fractions x 9-11 Gy; 5 fractions x 6-7 Gy; or 6 fractions x 5-6 Gy.
For GTV \> 20 mm hypofractionated stereotactic radiotherapy could be preferred. Treatment will be delivered once daily, alternate-day, 3 fractions per week.
|
|---|---|
|
Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0
Any grade toxicities · Experienced Toxicity
|
40 Participants
|
|
Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0
Any grade toxicities · Do NOT experienced toxicity
|
8 Participants
|
|
Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0
Grade 3-5 toxicities · Experienced Toxicity
|
12 Participants
|
|
Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v4.0
Grade 3-5 toxicities · Do NOT experienced toxicity
|
36 Participants
|
SECONDARY outcome
Timeframe: 8 weeksPopulation: Only patients who completed the quality of life questionnaires
The EORTC QLQ-C30 questionnaire is validated for cancer. It is composed of 30 questions or items that assess QoL. The questionnaire is structured in 5 functional scales physical functioning, daily activities, emotional functioning, cognitive functioning and social functioning), 3 symptom scales (fatigue, pain and nausea, vomiting), 1 global health status scale, and 6 independent items (dyspnea, insomnia, anorexia, constipation, diarrhea and economic impact). Values between 1 and 4 (1: not at all, 2: a little, 3: quite, 4: a lot) are assigned according to the patient's responses to the item, only in items 29 and 30 are they evaluated with a score of 1 to 7 (1: dreadful, 7: excellent). The scores obtained are standardized and a score between 0 and 100 is obtained, which determines the level of impact of the cancer on the patient on each of the scales. Higher values indicate better performance
Outcome measures
| Measure |
COMBO450
n=36 Participants
Encorafenib - Orally, 75 mg and 50 mg capsules Binimetinib - Orally, 15 mg tablets
In each cohort, patients will be treated with encorafenib 450 mg once daily and binimetinib 45 mg twice daily until PD or death.
encorafenib: Encorafenib 75mg and 50mg (capsules) for a 450mg daily for oral administration during 56 days and after local radiation treatment.
If no progression of disease progression (PD) is reported, treatment will continue until PD, unacceptable toxicity or death.
binimetinib: Binimetinib 15mg (tablets) for a 45mg/12 hours for oral administration during 56 days and after local radiation treatment.
Whole brain radiation therapy: The whole brain planning target volume (PTV) will receive 30 Gy in 10 fractions.
Treatment will be delivered once daily, 5 fractions per week, over 2 to 2.5 weeks.
Radiosurgery/stereotactic radiosurgery: Dose selection must be based on previously published Radiation Therapy Oncology Group (RTOG) data, with dose modification left up to the treating physician. The total dose will depend on the size of the metastatic lesion(s) and proximity to critical structures.
Suggested doses are as follow: 1 fraction x 15-25 Gy; 3 fractions x 9-11 Gy; 5 fractions x 6-7 Gy; or 6 fractions x 5-6 Gy.
For GTV \> 20 mm hypofractionated stereotactic radiotherapy could be preferred. Treatment will be delivered once daily, alternate-day, 3 fractions per week.
|
|---|---|
|
Change on Quality of Life at Week 8 in Both Cohorts Based on the EORTC QLQ 30 Scale
Week 8
|
85.5 Score
Interval 48.6 to 99.4
|
|
Change on Quality of Life at Week 8 in Both Cohorts Based on the EORTC QLQ 30 Scale
Baseline
|
78.4 Score
Interval 29.3 to 98.7
|
SECONDARY outcome
Timeframe: 24 weeksPopulation: Only patients who completed the quality of life questionnaires
The EORTC QLQ-C30 questionnaire is validated for cancer. It is composed of 30 questions or items that assess QoL. The questionnaire is structured in 5 functional scales physical functioning, daily activities, emotional functioning, cognitive functioning and social functioning), 3 symptom scales (fatigue, pain and nausea, vomiting), 1 global health status scale, and 6 independent items (dyspnea, insomnia, anorexia, constipation, diarrhea and economic impact). Values between 1 and 4 (1: not at all, 2: a little, 3: quite, 4: a lot) are assigned according to the patient's responses to the item, only in items 29 and 30 are they evaluated with a score of 1 to 7 (1: dreadful, 7: excellent). The scores obtained are standardized and a score between 0 and 100 is obtained, which determines the level of impact of the cancer on the patient on each of the scales. Higher values indicate better performance
Outcome measures
| Measure |
COMBO450
n=26 Participants
Encorafenib - Orally, 75 mg and 50 mg capsules Binimetinib - Orally, 15 mg tablets
In each cohort, patients will be treated with encorafenib 450 mg once daily and binimetinib 45 mg twice daily until PD or death.
encorafenib: Encorafenib 75mg and 50mg (capsules) for a 450mg daily for oral administration during 56 days and after local radiation treatment.
If no progression of disease progression (PD) is reported, treatment will continue until PD, unacceptable toxicity or death.
binimetinib: Binimetinib 15mg (tablets) for a 45mg/12 hours for oral administration during 56 days and after local radiation treatment.
Whole brain radiation therapy: The whole brain planning target volume (PTV) will receive 30 Gy in 10 fractions.
Treatment will be delivered once daily, 5 fractions per week, over 2 to 2.5 weeks.
Radiosurgery/stereotactic radiosurgery: Dose selection must be based on previously published Radiation Therapy Oncology Group (RTOG) data, with dose modification left up to the treating physician. The total dose will depend on the size of the metastatic lesion(s) and proximity to critical structures.
Suggested doses are as follow: 1 fraction x 15-25 Gy; 3 fractions x 9-11 Gy; 5 fractions x 6-7 Gy; or 6 fractions x 5-6 Gy.
For GTV \> 20 mm hypofractionated stereotactic radiotherapy could be preferred. Treatment will be delivered once daily, alternate-day, 3 fractions per week.
|
|---|---|
|
Change on Quality of Life at Week 24 in Both Cohorts Based on the EORTC QLQ 30 Scale
Week 24
|
74.9 Score
Interval 47.3 to 97.9
|
|
Change on Quality of Life at Week 24 in Both Cohorts Based on the EORTC QLQ 30 Scale
Baseline
|
78.4 Score
Interval 29.3 to 98.7
|
SECONDARY outcome
Timeframe: at 6 months (week 24), 12 months (week 48) and 24-month (week 96)Proportion of patients free of extracranial progression assessed by modified RECIST at 6 months (week 24), 12 months (week 48) and 24-month (week 96) considering date of inclusion estimated through Kaplan-Meier method
Outcome measures
| Measure |
COMBO450
n=48 Participants
Encorafenib - Orally, 75 mg and 50 mg capsules Binimetinib - Orally, 15 mg tablets
In each cohort, patients will be treated with encorafenib 450 mg once daily and binimetinib 45 mg twice daily until PD or death.
encorafenib: Encorafenib 75mg and 50mg (capsules) for a 450mg daily for oral administration during 56 days and after local radiation treatment.
If no progression of disease progression (PD) is reported, treatment will continue until PD, unacceptable toxicity or death.
binimetinib: Binimetinib 15mg (tablets) for a 45mg/12 hours for oral administration during 56 days and after local radiation treatment.
Whole brain radiation therapy: The whole brain planning target volume (PTV) will receive 30 Gy in 10 fractions.
Treatment will be delivered once daily, 5 fractions per week, over 2 to 2.5 weeks.
Radiosurgery/stereotactic radiosurgery: Dose selection must be based on previously published Radiation Therapy Oncology Group (RTOG) data, with dose modification left up to the treating physician. The total dose will depend on the size of the metastatic lesion(s) and proximity to critical structures.
Suggested doses are as follow: 1 fraction x 15-25 Gy; 3 fractions x 9-11 Gy; 5 fractions x 6-7 Gy; or 6 fractions x 5-6 Gy.
For GTV \> 20 mm hypofractionated stereotactic radiotherapy could be preferred. Treatment will be delivered once daily, alternate-day, 3 fractions per week.
|
|---|---|
|
Extracranial Progression-free Rates
6 months
|
64.1 Percentage of patients free of PD
Interval 51.4 to 79.9
|
|
Extracranial Progression-free Rates
12 months
|
31.2 Percentage of patients free of PD
Interval 19.6 to 49.6
|
|
Extracranial Progression-free Rates
24 months
|
5.8 Percentage of patients free of PD
Interval 1.0 to 33.8
|
Adverse Events
COMBO450
Serious events: 22 serious events
Other events: 48 other events
Deaths: 33 deaths
Serious adverse events
| Measure |
COMBO450
n=48 participants at risk
Encorafenib - Orally, 75 mg and 50 mg capsules Binimetinib - Orally, 15 mg tablets
In each cohort, patients will be treated with encorafenib 450 mg once daily and binimetinib 45 mg twice daily until PD or death.
encorafenib: Encorafenib 75mg and 50mg (capsules) for a 450mg daily for oral administration during 56 days and after local radiation treatment.
If no progression of disease progression (PD) is reported, treatment will continue until PD, unacceptable toxicity or death.
binimetinib: Binimetinib 15mg (tablets) for a 45mg/12 hours for oral administration during 56 days and after local radiation treatment.
Whole brain radiation therapy: The whole brain planning target volume (PTV) will receive 30 Gy in 10 fractions.
Treatment will be delivered once daily, 5 fractions per week, over 2 to 2.5 weeks.
Radiosurgery/stereotactic radiosurgery: Dose selection must be based on previously published Radiation Therapy Oncology Group (RTOG) data, with dose modification left up to the treating physician. The total dose will depend on the size of the metastatic lesion(s) and proximity to critical structures.
Suggested doses are as follow: 1 fraction x 15-25 Gy; 3 fractions x 9-11 Gy; 5 fractions x 6-7 Gy; or 6 fractions x 5-6 Gy.
For GTV \> 20 mm hypofractionated stereotactic radiotherapy could be preferred. Treatment will be delivered once daily, alternate-day, 3 fractions per week.
|
|---|---|
|
Immune system disorders
Anaphylaxis
|
2.1%
1/48 • Number of events 1 • Throughout the study period, up to approximately 24 months
|
|
Blood and lymphatic system disorders
Anemia
|
4.2%
2/48 • Number of events 2 • Throughout the study period, up to approximately 24 months
|
|
Investigations
Creatinine increased
|
2.1%
1/48 • Number of events 1 • Throughout the study period, up to approximately 24 months
|
|
Gastrointestinal disorders
Diarrhea
|
4.2%
2/48 • Number of events 2 • Throughout the study period, up to approximately 24 months
|
|
Gastrointestinal disorders
Vomiting
|
2.1%
1/48 • Number of events 2 • Throughout the study period, up to approximately 24 months
|
|
Gastrointestinal disorders
Upper gastrointestinal hemorrhage
|
2.1%
1/48 • Number of events 1 • Throughout the study period, up to approximately 24 months
|
|
Nervous system disorders
Seizure
|
6.2%
3/48 • Number of events 3 • Throughout the study period, up to approximately 24 months
|
|
Respiratory, thoracic and mediastinal disorders
Pulmonary thromboembolism
|
2.1%
1/48 • Number of events 1 • Throughout the study period, up to approximately 24 months
|
|
Respiratory, thoracic and mediastinal disorders
Right pleural empyema by streptococcus constellatus
|
2.1%
1/48 • Number of events 1 • Throughout the study period, up to approximately 24 months
|
|
Respiratory, thoracic and mediastinal disorders
Respiratory sepsis
|
2.1%
1/48 • Number of events 1 • Throughout the study period, up to approximately 24 months
|
|
Respiratory, thoracic and mediastinal disorders
Amigdalitis
|
2.1%
1/48 • Number of events 1 • Throughout the study period, up to approximately 24 months
|
|
Renal and urinary disorders
Acute renal insufficiency
|
2.1%
1/48 • Number of events 1 • Throughout the study period, up to approximately 24 months
|
|
Respiratory, thoracic and mediastinal disorders
Pneumonitis
|
2.1%
1/48 • Number of events 1 • Throughout the study period, up to approximately 24 months
|
|
Gastrointestinal disorders
Pancreatitis
|
2.1%
1/48 • Number of events 1 • Throughout the study period, up to approximately 24 months
|
|
General disorders
Pain
|
2.1%
1/48 • Number of events 1 • Throughout the study period, up to approximately 24 months
|
|
Nervous system disorders
Instability
|
2.1%
1/48 • Number of events 1 • Throughout the study period, up to approximately 24 months
|
|
Nervous system disorders
Focal seizures
|
2.1%
1/48 • Number of events 1 • Throughout the study period, up to approximately 24 months
|
|
General disorders
Acute pain in rib zone irradiated to legs
|
2.1%
1/48 • Number of events 1 • Throughout the study period, up to approximately 24 months
|
|
Nervous system disorders
Epileptic status
|
2.1%
1/48 • Number of events 1 • Throughout the study period, up to approximately 24 months
|
|
Nervous system disorders
Eplectic seizures
|
2.1%
1/48 • Number of events 1 • Throughout the study period, up to approximately 24 months
|
|
Surgical and medical procedures
Brain metastasis surgery
|
2.1%
1/48 • Number of events 1 • Throughout the study period, up to approximately 24 months
|
|
Nervous system disorders
Movements involuntary
|
2.1%
1/48 • Number of events 1 • Throughout the study period, up to approximately 24 months
|
|
Nervous system disorders
Headache
|
4.2%
2/48 • Number of events 3 • Throughout the study period, up to approximately 24 months
|
|
General disorders
Left Hemiparesis
|
2.1%
1/48 • Number of events 1 • Throughout the study period, up to approximately 24 months
|
|
General disorders
Febrile syndrome of unknown origin
|
2.1%
1/48 • Number of events 1 • Throughout the study period, up to approximately 24 months
|
|
General disorders
Encorafenib overdose
|
2.1%
1/48 • Number of events 1 • Throughout the study period, up to approximately 24 months
|
|
Gastrointestinal disorders
Digestive bleeding
|
2.1%
1/48 • Number of events 1 • Throughout the study period, up to approximately 24 months
|
|
Gastrointestinal disorders
Clostridium Difficile infectious diarrhea
|
2.1%
1/48 • Number of events 1 • Throughout the study period, up to approximately 24 months
|
Other adverse events
| Measure |
COMBO450
n=48 participants at risk
Encorafenib - Orally, 75 mg and 50 mg capsules Binimetinib - Orally, 15 mg tablets
In each cohort, patients will be treated with encorafenib 450 mg once daily and binimetinib 45 mg twice daily until PD or death.
encorafenib: Encorafenib 75mg and 50mg (capsules) for a 450mg daily for oral administration during 56 days and after local radiation treatment.
If no progression of disease progression (PD) is reported, treatment will continue until PD, unacceptable toxicity or death.
binimetinib: Binimetinib 15mg (tablets) for a 45mg/12 hours for oral administration during 56 days and after local radiation treatment.
Whole brain radiation therapy: The whole brain planning target volume (PTV) will receive 30 Gy in 10 fractions.
Treatment will be delivered once daily, 5 fractions per week, over 2 to 2.5 weeks.
Radiosurgery/stereotactic radiosurgery: Dose selection must be based on previously published Radiation Therapy Oncology Group (RTOG) data, with dose modification left up to the treating physician. The total dose will depend on the size of the metastatic lesion(s) and proximity to critical structures.
Suggested doses are as follow: 1 fraction x 15-25 Gy; 3 fractions x 9-11 Gy; 5 fractions x 6-7 Gy; or 6 fractions x 5-6 Gy.
For GTV \> 20 mm hypofractionated stereotactic radiotherapy could be preferred. Treatment will be delivered once daily, alternate-day, 3 fractions per week.
|
|---|---|
|
Gastrointestinal disorders
Nausea
|
22.9%
11/48 • Throughout the study period, up to approximately 24 months
|
|
Gastrointestinal disorders
Diarrhea
|
27.1%
13/48 • Throughout the study period, up to approximately 24 months
|
|
General disorders
Fatigue
|
25.0%
12/48 • Throughout the study period, up to approximately 24 months
|
|
General disorders
Fever
|
14.6%
7/48 • Throughout the study period, up to approximately 24 months
|
|
Blood and lymphatic system disorders
Anemia
|
16.7%
8/48 • Throughout the study period, up to approximately 24 months
|
|
Investigations
Alanine aminotransferase increased
|
18.8%
9/48 • Throughout the study period, up to approximately 24 months
|
|
Gastrointestinal disorders
Constipation
|
10.4%
5/48 • Throughout the study period, up to approximately 24 months
|
|
Gastrointestinal disorders
Vomiting
|
10.4%
5/48 • Throughout the study period, up to approximately 24 months
|
|
Investigations
Aspartate aminotransferase increased
|
16.7%
8/48 • Throughout the study period, up to approximately 24 months
|
|
Investigations
GGT increased
|
16.7%
8/48 • Throughout the study period, up to approximately 24 months
|
|
Skin and subcutaneous tissue disorders
Other not specified
|
14.6%
7/48 • Throughout the study period, up to approximately 24 months
|
|
Investigations
Other not specified
|
12.5%
6/48 • Throughout the study period, up to approximately 24 months
|
|
General disorders
Asthenia
|
10.4%
5/48 • Throughout the study period, up to approximately 24 months
|
|
Nervous system disorders
Dysgeusia
|
10.4%
5/48 • Throughout the study period, up to approximately 24 months
|
|
Gastrointestinal disorders
Other not specified
|
8.3%
4/48 • Throughout the study period, up to approximately 24 months
|
|
Musculoskeletal and connective tissue disorders
Arthralgia
|
8.3%
4/48 • Throughout the study period, up to approximately 24 months
|
|
Investigations
CPK increased
|
6.2%
3/48 • Throughout the study period, up to approximately 24 months
|
|
Eye disorders
Other not specified
|
6.2%
3/48 • Throughout the study period, up to approximately 24 months
|
|
Skin and subcutaneous tissue disorders
Pruritus
|
6.2%
3/48 • Throughout the study period, up to approximately 24 months
|
|
Gastrointestinal disorders
Abdominal pain
|
6.2%
3/48 • Throughout the study period, up to approximately 24 months
|
|
Investigations
Creatinine increased
|
6.2%
3/48 • Throughout the study period, up to approximately 24 months
|
|
Blood and lymphatic system disorders
Lymphocyte count decreased
|
6.2%
3/48 • Throughout the study period, up to approximately 24 months
|
Additional Information
GEM Technical Secretary
Grupo Español Multidisciplinar en Melanoma (GEM)
Phone: 0034934344412
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place