Trial Outcomes & Findings for Study Comparing the Efficacy of MEK162 Versus Dacarbazine in Unresectable or Metastatic NRAS Mutation-positive Melanoma (NCT NCT01763164)

Last Updated: 2021-03-22

Results Overview

PFS: time from randomization to first documented PD or death due to any cause, whichever occurred first. RECIST 1.1, PD: \>=20% increase in sum of diameter of target lesions (TLs) taking as reference the smallest sum on study (including baseline sum), sum must also be an absolute increase of \>=5 mm; unequivocal progression of existing non-TLs; appearance of \>=1 lesion. Complete response (CR): disappearance of all lesions; any pathological lymph nodes (TLs) or non-pathological (non-TLs) must have reduction in short axis to \<10 mm; normalization of tumor marker level for non-TLs. Partial response (PR): \>=30% decrease in sum of diameter of all TLs, referring baseline sum of diameters. Stable disease (SD): neither sufficient shrinkage to qualify for PR nor increase in lesions qualified for PD referring smallest sum diameter. With no event at time of analysis cut-off or at start of any new anti-neoplastic therapy, PFS censored at date of last adequate tumor assessment of CR, PR or SD.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

402 participants

Primary outcome timeframe

From the date of randomization to the date of the first documented PD or death, whichever occurred first (maximum up to 77 weeks for binimetinib arm; maximum up to 61 weeks for dacarbazine arm)

Results posted on

2021-03-22

Participant Flow

Participants randomized were with previously untreated, advanced unresectable or metastatic Neuroblastoma RAS viral oncogene homolog (NRAS) mutation-positive melanoma as confirmed by central assessment.

Participant milestones

Participant milestones
Measure	Binimetinib (MEK162) Participants received oral binimetinib 45 milligram (mg) (3\*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.	Dacarbazine Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m\^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Treatment Phase STARTED	269	133
Treatment Phase Treated/Safety Set	269	114
Treatment Phase Full Analysis Set	269	133
Treatment Phase COMPLETED	0	0
Treatment Phase NOT COMPLETED	269	133
Follow up Phase STARTED	200	78
Follow up Phase COMPLETED	3	3
Follow up Phase NOT COMPLETED	197	75

Reasons for withdrawal

Reasons for withdrawal
Measure	Binimetinib (MEK162) Participants received oral binimetinib 45 milligram (mg) (3\*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.	Dacarbazine Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m\^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Treatment Phase Participant/Guardian decision	26	14
Treatment Phase Protocol Violation	1	1
Treatment Phase Progressive Disease	142	76
Treatment Phase Physician Decision	24	13
Treatment Phase Death	10	1
Treatment Phase Adverse Event	66	8
Treatment Phase Randomized but not Treated	0	19
Treatment Phase Other	0	1
Follow up Phase New therapy for study indication	12	3
Follow up Phase Death	21	4
Follow up Phase Subject/guardian decision	9	2
Follow up Phase Progressive disease	127	62
Follow up Phase Physician Decision	10	3
Follow up Phase Lost to Follow-up	1	0
Follow up Phase Adverse Event	17	1

Baseline Characteristics

Study Comparing the Efficacy of MEK162 Versus Dacarbazine in Unresectable or Metastatic NRAS Mutation-positive Melanoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Binimetinib (MEK162) n=269 Participants Participants received oral binimetinib 45 milligram (mg) (3\*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.	Dacarbazine n=133 Participants Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m\^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.	Total n=402 Participants Total of all reporting groups
Age, Continuous	63.6 years STANDARD_DEVIATION 12.28 • n=93 Participants	60.6 years STANDARD_DEVIATION 13.35 • n=4 Participants	62.6 years STANDARD_DEVIATION 12.71 • n=27 Participants
Sex: Female, Male Female	103 Participants n=93 Participants	48 Participants n=4 Participants	151 Participants n=27 Participants
Sex: Female, Male Male	166 Participants n=93 Participants	85 Participants n=4 Participants	251 Participants n=27 Participants

PRIMARY outcome

Timeframe: From the date of randomization to the date of the first documented PD or death, whichever occurred first (maximum up to 77 weeks for binimetinib arm; maximum up to 61 weeks for dacarbazine arm)

Population: FAS consisted of all randomized participants.

Outcome measures

Outcome measures
Measure	Binimetinib (MEK162) n=269 Participants Participants received oral binimetinib 45 milligram (mg) (3\*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.	Dacarbazine n=133 Participants Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m\^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Progression-Free Survival (PFS) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1	2.83 Months Interval 2.76 to 3.55	1.51 Months Interval 1.48 to 1.71

SECONDARY outcome

Timeframe: From the date of randomization to the date of death (maximum up to 107 weeks for binimetinib arm; maximum up to 88 weeks for dacarbazine arm)

Population: FAS consisted of all randomized participants.

Overall survival was defined as the time from the date of randomization to the date of death due to any cause. If a participant was not known to have died, overall survival was censored at the date of last known date participant alive.

Outcome measures

Outcome measures
Measure	Binimetinib (MEK162) n=269 Participants Participants received oral binimetinib 45 milligram (mg) (3\*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.	Dacarbazine n=133 Participants Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m\^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Overall Survival (OS)	10.97 Months Interval 8.94 to 13.6	10.09 Months Interval 7.03 to 16.46

SECONDARY outcome

Timeframe: From date of randomization until first documented response of CR or PR (maximum up to 77 weeks for binimetinib arm; maximum up to 61 weeks for dacarbazine arm)

Population: FAS consisted of all randomized participants.

ORR: percentage of participants with best overall response (BOR) of CR or PR. BOR: best response recorded from start of treatment until CR or PR. RECIST V1.1, a) CR: disappearance of all lesions; any pathological lymph nodes (TLs) or non-pathological (non-TLs) must have reduction in short axis to \<10 mm; normalization of tumor marker level for non-TLs; b) PR: \>=30% decrease in sum of diameter of all TLs, taking as reference baseline sum of diameters. ORR is reported for confirmed and unconfirmed responses. Confirmed CR or PR = at least 2 determinations of CR or PR at least 4 weeks apart before PD. PD: \>=20% increase in sum of diameter of all measured target lesions, taking as reference smallest sum of diameter of all TLs recorded at or after baseline, sum must also be absolute increase of \>=5 mm. Unequivocal progression of existing non TLs. Appearance of at least 1 new lesion.

Outcome measures

Outcome measures
Measure	Binimetinib (MEK162) n=269 Participants Participants received oral binimetinib 45 milligram (mg) (3\*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.	Dacarbazine n=133 Participants Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m\^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Overall Response Rate (ORR) Confirmed + Unconfirmed: ORR	22.7 Percentage of Participants Interval 17.8 to 28.2	9.8 Percentage of Participants Interval 5.3 to 16.1
Overall Response Rate (ORR) Confirmed ORR	15.2 Percentage of Participants Interval 11.2 to 20.1	6.8 Percentage of Participants Interval 3.1 to 12.5

SECONDARY outcome

Timeframe: From date of randomization until first documented response of CR or PR (maximum up to 77 weeks for binimetinib arm; maximum up to 61 weeks for dacarbazine arm)

Population: Analysis population consisted of all randomized participants and who had at least once CR or PR.

TTR: time between date of randomization until first documented response of CR or PR. RECIST V1.1, a) CR: disappearance of all lesions; any pathological lymph nodes (TLs) or non-pathological (non-TLs) must have reduction in short axis to \<10 mm; normalization of tumor marker level for non-TLs; b) PR: \>=30% decrease in sum of diameter (dia) of all TLs, referring baseline sum of dia; c) PD: \>=20% increase in sum of diameter of all measured TLs taking as reference smallest sum of diameter of all TLs recorded at or after baseline, sum must also be absolute increase of \>=5 mm. Unequivocal progression of existing non-TLs. Appearance of \>=1 new lesion. Participants who did not achieve PR or CR censored at last adequate tumor assessment date when they did not have PFS event (time from date of randomization to date of first documented PD or death due to any cause, whichever occur first) or at maximum follow-up when they had PFS event.

Outcome measures

Outcome measures
Measure	Binimetinib (MEK162) n=61 Participants Participants received oral binimetinib 45 milligram (mg) (3\*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.	Dacarbazine n=13 Participants Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m\^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Time to Response (TTR)	1.45 Months Interval 1.45 to 1.48	2.79 Months Interval 1.22 to 3.38

SECONDARY outcome

Timeframe: From the date of first documented response (CR or PR) to the first documented progression or death (maximum up to 77 weeks for binimetinib arm; maximum up to 61 weeks for dacarbazine arm)

Population: Analysis population consisted of all randomized participants and who had confirmed responses (CR or PR).

DOR: time from date of first documented response (CR or PR) to first documented progression or death due to underlying cancer. RECIST V1.1, a) CR: disappearance of all lesions; any pathological lymph nodes (TLs) or non-pathological (non-TLs) must have reduction in short axis to \<10 mm; normalization of tumor marker level for non-TLs; b) PR: \>=30% decrease in sum of diameter (dia) of all TLs, referring baseline sum of dia; c) PD: \>=20% increase in sum of diameter of all measured target lesions taking as reference smallest sum of diameter of all target lesions recorded at or after baseline, sum must also be absolute increase of \>=5 mm. Unequivocal progression of existing non-target lesions. Appearance of at least 1 new lesion. If a participant with a CR or PR had no PD or death due to underlying cancer, participants was censored at date of last adequate tumor assessment.

Outcome measures

Outcome measures
Measure	Binimetinib (MEK162) n=41 Participants Participants received oral binimetinib 45 milligram (mg) (3\*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.	Dacarbazine n=9 Participants Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m\^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Duration of Objective Response (DOR)	6.87 Months Interval 4.21 to 11.07	NA Months Interval 4.14 to Median and 95% CI upper limit was not estimable due to very less number of participants with event.

SECONDARY outcome

Timeframe: From date of randomization until first documented response of CR, PR, SD or non-CR/non-PD (maximum up to 77 weeks for binimetinib arm; maximum up to 61 weeks for dacarbazine arm)

Population: FAS consisted of all randomized participants.

DCR was calculated as the percentage of participants with a BOR of CR, PR, SD RECIST V1.1, a) CR: disappearance of all lesions; any pathological lymph nodes (TLs) or non-pathological (non-TLs) must have reduction in short axis to \<10 mm; normalization of tumor marker level for non-TLs; b) PR: \>=30% decrease in sum of diameter of all target lesions, taking as reference the baseline sum of diameters; c) SD: neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD taking as reference the smallest sum diameters; d) PD: \>=20% increase in sum of diameter of all measured target lesions, taking as reference the smallest sum of diameter of all target lesions recorded at or after baseline, sum must also be absolute increase of \>=5 mm. Unequivocal progression of existing non-target lesions. Appearance of at least 1 new lesion.

Outcome measures

Outcome measures
Measure	Binimetinib (MEK162) n=269 Participants Participants received oral binimetinib 45 milligram (mg) (3\*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.	Dacarbazine n=133 Participants Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m\^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Disease Control Rate (DCR)	58.4 Percentage of participants Interval 52.2 to 64.3	24.8 Percentage of participants Interval 17.7 to 33.0

SECONDARY outcome

Timeframe: From baseline up to 219.4 weeks for binimetinib arm; From baseline up to 123.9 weeks for dacarbazine arm

Population: The safety set consisted all participants who received at least one dose of the study drug and had at least one valid post-baseline safety evaluation.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study treatment. SAE was defined as one of the following: was fatal or life-threatening; resulted in persistent or significant disability/incapacity; constituted a congenital anomaly/birth defect; was medically significant; required inpatient hospitalization or prolongation of existing hospitalization. Treatment-emergent AE was defined as an AE with onset date occurring during the on-treatment period. AEs included all SAEs and non-SAEs.

Outcome measures

Outcome measures
Measure	Binimetinib (MEK162) n=269 Participants Participants received oral binimetinib 45 milligram (mg) (3\*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.	Dacarbazine n=114 Participants Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m\^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) AEs	269 Participants	104 Participants
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) SAEs	95 Participants	26 Participants

SECONDARY outcome

Timeframe: From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm

Population: The safety set consisted all participants who received at least one dose of the study drug and had at least one valid post-baseline safety evaluation.

Clinically notable shifts are defined as worsening by at least 2 grades or to \>= grade 3. Severity was graded as Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE.

Outcome measures

Outcome measures
Measure	Binimetinib (MEK162) n=269 Participants Participants received oral binimetinib 45 milligram (mg) (3\*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.	Dacarbazine n=114 Participants Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m\^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Number of Participants With Clinically Notable Hematology Shifts Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.03 Activated partial thromboplastin time prolonged	7 Participants	2 Participants
Number of Participants With Clinically Notable Hematology Shifts Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.03 Hemoglobin decreased	17 Participants	13 Participants
Number of Participants With Clinically Notable Hematology Shifts Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.03 Prothrombin international normalized ratio increased	9 Participants	0 Participants
Number of Participants With Clinically Notable Hematology Shifts Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.03 Lymphocytes increased	20 Participants	0 Participants
Number of Participants With Clinically Notable Hematology Shifts Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.03 Lymphocytes decreased	35 Participants	19 Participants
Number of Participants With Clinically Notable Hematology Shifts Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.03 Neutrophils decreased	8 Participants	21 Participants
Number of Participants With Clinically Notable Hematology Shifts Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.03 Platelets decreased	3 Participants	17 Participants
Number of Participants With Clinically Notable Hematology Shifts Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.03 Leukocytes increased	0 Participants	0 Participants
Number of Participants With Clinically Notable Hematology Shifts Based on National Cancer Institute Common Terminology Criteria (NCI-CTCAE) Grade, Version 4.03 Leukocytes decreased	6 Participants	26 Participants

SECONDARY outcome

Timeframe: From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm

Population: The safety set consisted all participants who received at least one dose of the study drug and had at least one valid post-baseline safety evaluation.

Clinically notable shifts are defined as worsening by at least 2 grades or to \>= grade 3. Severity was graded as Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental ADL; Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE.

Outcome measures

Outcome measures
Measure	Binimetinib (MEK162) n=269 Participants Participants received oral binimetinib 45 milligram (mg) (3\*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.	Dacarbazine n=114 Participants Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m\^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Number of Participants With Clinically Notable Clinical Chemistry/Biochemistry Shifts Based on NCI-CTCAE Grade, Version 4.03 Albumin decreased	27 Participants	5 Participants
Number of Participants With Clinically Notable Clinical Chemistry/Biochemistry Shifts Based on NCI-CTCAE Grade, Version 4.03 Alkaline phosphatase	8 Participants	2 Participants
Number of Participants With Clinically Notable Clinical Chemistry/Biochemistry Shifts Based on NCI-CTCAE Grade, Version 4.03 Alanine aminotransferase	14 Participants	4 Participants
Number of Participants With Clinically Notable Clinical Chemistry/Biochemistry Shifts Based on NCI-CTCAE Grade, Version 4.03 Aspartate aminotransferase	20 Participants	1 Participants
Number of Participants With Clinically Notable Clinical Chemistry/Biochemistry Shifts Based on NCI-CTCAE Grade, Version 4.03 Bilirubin	1 Participants	1 Participants
Number of Participants With Clinically Notable Clinical Chemistry/Biochemistry Shifts Based on NCI-CTCAE Grade, Version 4.03 Corrected Calcium increased	2 Participants	4 Participants
Number of Participants With Clinically Notable Clinical Chemistry/Biochemistry Shifts Based on NCI-CTCAE Grade, Version 4.03 Corrected Calcium decreased	2 Participants	0 Participants
Number of Participants With Clinically Notable Clinical Chemistry/Biochemistry Shifts Based on NCI-CTCAE Grade, Version 4.03 Creatinine	9 Participants	2 Participants
Number of Participants With Clinically Notable Clinical Chemistry/Biochemistry Shifts Based on NCI-CTCAE Grade, Version 4.03 Gamma-glutamyl transferase	9 Participants	7 Participants
Number of Participants With Clinically Notable Clinical Chemistry/Biochemistry Shifts Based on NCI-CTCAE Grade, Version 4.03 Glucose serum fasting increased	13 Participants	5 Participants
Number of Participants With Clinically Notable Clinical Chemistry/Biochemistry Shifts Based on NCI-CTCAE Grade, Version 4.03 Glucose serum fasting decreased	6 Participants	0 Participants
Number of Participants With Clinically Notable Clinical Chemistry/Biochemistry Shifts Based on NCI-CTCAE Grade, Version 4.03 Potassium increased	13 Participants	3 Participants
Number of Participants With Clinically Notable Clinical Chemistry/Biochemistry Shifts Based on NCI-CTCAE Grade, Version 4.03 Potassium decreased	14 Participants	1 Participants
Number of Participants With Clinically Notable Clinical Chemistry/Biochemistry Shifts Based on NCI-CTCAE Grade, Version 4.03 Magnesium increased	1 Participants	0 Participants
Number of Participants With Clinically Notable Clinical Chemistry/Biochemistry Shifts Based on NCI-CTCAE Grade, Version 4.03 Magnesium decreased	1 Participants	0 Participants
Number of Participants With Clinically Notable Clinical Chemistry/Biochemistry Shifts Based on NCI-CTCAE Grade, Version 4.03 Phosphate decreased	17 Participants	5 Participants
Number of Participants With Clinically Notable Clinical Chemistry/Biochemistry Shifts Based on NCI-CTCAE Grade, Version 4.03 Sodium increased	23 Participants	4 Participants
Number of Participants With Clinically Notable Clinical Chemistry/Biochemistry Shifts Based on NCI-CTCAE Grade, Version 4.03 Sodium decreased	4 Participants	0 Participants

SECONDARY outcome

Timeframe: From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm

Population: The safety set consisted all participants who received at least one dose of the study drug and had at least one valid post-baseline safety evaluation. Here, "number analyzed" signifies participants evaluable for this outcome measure for specified rows.

Abnormalities criteria included: low/high pulse rate (beats per minute \[bpm\]):\<=50bpm with decrease from baseline \>=15bpm/\>=120bpm with increase from baseline \>=15bpm; Low/high systolic blood pressure (millimeters of mercury \[mmHg\]): \<=90mmHg with decrease from baseline \>=20mmHg/\>=160mmHg with increase from baseline \>=20mmHg; Low/high diastolic blood pressure \[mmHg\]: \<=50mmHg with decrease from baseline \>=15mmHg/\>=100mmHg with increase from baseline \>=15mmHg; Low/high body weight (kilogram \[kg\]): \>=20% decrease from baseline / \>=10% increase from baseline; Low/high body temperature (degree Celsius \[°C\]): \<=36°C / \>= 37.5°C

Outcome measures

Outcome measures
Measure	Binimetinib (MEK162) n=269 Participants Participants received oral binimetinib 45 milligram (mg) (3\*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.	Dacarbazine n=114 Participants Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m\^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Number of Participants With Clinically Notable Vital Signs Sitting Pulse Rate - High	4 Participants	1 Participants
Number of Participants With Clinically Notable Vital Signs Sitting Pulse Rate - Low	3 Participants	1 Participants
Number of Participants With Clinically Notable Vital Signs Sitting systolic blood pressure - High	43 Participants	8 Participants
Number of Participants With Clinically Notable Vital Signs Sitting systolic blood pressure -Low	2 Participants	4 Participants
Number of Participants With Clinically Notable Vital Signs Sitting diastolic blood pressure - High	28 Participants	4 Participants
Number of Participants With Clinically Notable Vital Signs Sitting diastolic blood pressure - Low	2 Participants	1 Participants
Number of Participants With Clinically Notable Vital Signs Weight - High	16 Participants	1 Participants
Number of Participants With Clinically Notable Vital Signs Weight - Low	0 Participants	0 Participants
Number of Participants With Clinically Notable Vital Signs Body temperature - High	15 Participants	6 Participants
Number of Participants With Clinically Notable Vital Signs Body temperature - Low	90 Participants	24 Participants

SECONDARY outcome

Timeframe: From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm

Criteria for notable ECG values were as follow: QT interval (in millisecond \[msec\]) new (newly occurring post-baseline value) greater than (\>) 450, 480, 500, increase from baseline \>30, increase from baseline \>60; corrected QT interval by Fredericia formula (QTcF) in msec new (newly occurring post-baseline value) \> 450, 480, 500, increase from baseline \>30, increase from baseline \>60; corrected QT interval by Bazett's formula (QTcB) in msec new (newly occurring post-baseline value) \> 450, 480, 500, increase from baseline \>30, increase from baseline \>60; heart rate in bpm new (newly occurring post-baseline value) \<60 and \>100.

Outcome measures

Outcome measures
Measure	Binimetinib (MEK162) n=269 Participants Participants received oral binimetinib 45 milligram (mg) (3\*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.	Dacarbazine n=114 Participants Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m\^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Number of Participants With Notable Electrocardiogram (ECG) Values QT - Increase from baseline > 60 msec	28 Participants	5 Participants
Number of Participants With Notable Electrocardiogram (ECG) Values QTcF - Increase from baseline > 60 msec	9 Participants	5 Participants
Number of Participants With Notable Electrocardiogram (ECG) Values QTcF - Increase from baseline > 30 msec	52 Participants	25 Participants
Number of Participants With Notable Electrocardiogram (ECG) Values QTcB - New > 450 msec	65 Participants	26 Participants
Number of Participants With Notable Electrocardiogram (ECG) Values QTcB - New > 480 msec	24 Participants	8 Participants
Number of Participants With Notable Electrocardiogram (ECG) Values QT - New > 450 msec	32 Participants	8 Participants
Number of Participants With Notable Electrocardiogram (ECG) Values QT - New > 480 msec	7 Participants	1 Participants
Number of Participants With Notable Electrocardiogram (ECG) Values QT - New > 500 msec	5 Participants	0 Participants
Number of Participants With Notable Electrocardiogram (ECG) Values QT - Increase from baseline > 30 msec	109 Participants	33 Participants
Number of Participants With Notable Electrocardiogram (ECG) Values QTcF - New > 450 msec	29 Participants	15 Participants
Number of Participants With Notable Electrocardiogram (ECG) Values QTcF - New > 480 msec	10 Participants	1 Participants
Number of Participants With Notable Electrocardiogram (ECG) Values QTcF - New > 500 msec	5 Participants	1 Participants
Number of Participants With Notable Electrocardiogram (ECG) Values QTcB - New > 500 msec	6 Participants	6 Participants
Number of Participants With Notable Electrocardiogram (ECG) Values QTcB - Increase from baseline > 30 msec	76 Participants	36 Participants
Number of Participants With Notable Electrocardiogram (ECG) Values QTcB - Increase from baseline > 60 msec	11 Participants	9 Participants
Number of Participants With Notable Electrocardiogram (ECG) Values Heart rate - New < 60 bpm	85 Participants	13 Participants
Number of Participants With Notable Electrocardiogram (ECG) Values Heart rate - New > 100 bpm	18 Participants	16 Participants

SECONDARY outcome

Timeframe: From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm

Population: The safety set consisted all participants who received at least one dose of the study drug and had at least one valid post-baseline safety evaluation.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study treatment. Grade 1: asymptomatic or mild symptoms, clinical or diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local or noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE. Here, in this outcome measure data is reported for events falling in any of the grades.

Outcome measures

Outcome measures
Measure	Binimetinib (MEK162) n=269 Participants Participants received oral binimetinib 45 milligram (mg) (3\*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.	Dacarbazine n=114 Participants Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m\^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Number of Participants With Adverse Events of Special Interest: Cardiac Events	35 Participants	2 Participants

SECONDARY outcome

Timeframe: From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm

Population: No data was collected and analyzed for this outcome measure, any clinically significant physical examination findings were counted as adverse events and reported in safety section.

A complete physical examination included the examination of general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular and neurological systems. If indicated based on medical history and/or symptoms, rectal, external genitalia, breast, and pelvic examinations were performed. Clinical significance in physical examination was reported as adverse events.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm

Population: The safety set consisted all participants who received at least one dose of the study drug and had at least one valid post-baseline safety evaluation.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with the study treatment. Grade 1: Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated; Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate instrumental ADL; Grade 3: Severe or medically significant but not immediately sight threatening; Hospitalization or prolongation of existing hospitalization indicated; disabling; limiting self-care ADL; Grade 4: Sight-threatening consequences; urgent intervention indicated; blindness (20/200 or worse) in the affected eye. Here, in this outcome measure data is reported for events falling in any of the grades.

Outcome measures

Outcome measures
Measure	Binimetinib (MEK162) n=269 Participants Participants received oral binimetinib 45 milligram (mg) (3\*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.	Dacarbazine n=114 Participants Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m\^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Number of Participants With Adverse Events of Special Interest: Ocular Events	6 Participants	0 Participants

SECONDARY outcome

Timeframe: Day 1 of Week 1: Pre-dose, 1, 1.5, 2, 10 hours post-dose; Day 1 of Weeks 4, 7: Pre-dose, 1.5 hours post-dose; Day 1 of Weeks 10, 13: Pre-dose

Population: The pharmacokinetic analysis set (PAS) consisted of all participants who received at least one dose of binimetinib and had at least one evaluable post-baseline binimetinib concentration measurement. Here, "Overall Number of Participants Analyzed" = number of participants evaluable for this outcome measure. This outcome was planned to be evaluated only for binimetinib arm. Here, "number analyzed" signifies participants evaluable for this outcome measure for specified timeframes.

Outcome measures

Outcome measures
Measure	Binimetinib (MEK162) n=264 Participants Participants received oral binimetinib 45 milligram (mg) (3\*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.	Dacarbazine Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m\^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Plasma Concentration of Binimetinib Week 4 Day 1, 1.5 hr Post-dose	418 Nanogram per milliliter Geometric Coefficient of Variation 51.9	—
Plasma Concentration of Binimetinib Week 7 Day 1, Pre-dose	101 Nanogram per milliliter Geometric Coefficient of Variation 97.7	—
Plasma Concentration of Binimetinib Week 7 Day 1, 1.5 hr Post-dose	372 Nanogram per milliliter Geometric Coefficient of Variation 63.4	—
Plasma Concentration of Binimetinib Week 1 Day 1, Pre-dose	64.4 Nanogram per milliliter Geometric Coefficient of Variation 1132.3	—
Plasma Concentration of Binimetinib Week 1 Day 1, 1 hour (hr) Post-dose	182 Nanogram per milliliter Geometric Coefficient of Variation 237.6	—
Plasma Concentration of Binimetinib Week 1 Day 1, 1.5 hr Post-dose	313 Nanogram per milliliter Geometric Coefficient of Variation 71.6	—
Plasma Concentration of Binimetinib Week 1 Day 1, 2 hr Post-dose	321 Nanogram per milliliter Geometric Coefficient of Variation 64.4	—
Plasma Concentration of Binimetinib Week 1 Day 1, 10 hr Post-dose	153 Nanogram per milliliter Geometric Coefficient of Variation 52.6	—
Plasma Concentration of Binimetinib Week 4 Day 1, Pre-dose	101 Nanogram per milliliter Geometric Coefficient of Variation 100.8	—
Plasma Concentration of Binimetinib Week 10 Day 1, Pre-dose	92.9 Nanogram per milliliter Geometric Coefficient of Variation 60.6	—
Plasma Concentration of Binimetinib Week 13 Day 1, Pre-dose	93.9 Nanogram per milliliter Geometric Coefficient of Variation 89.8	—

SECONDARY outcome

Timeframe: From baseline up to 77 weeks in binimetinib arm; From baseline up to 61 weeks for dacarbazine arm

Population: FAS consisted of all randomized participants.

The time to definitive 10% deterioration was defined as the time from the date of randomization to the date of event, which was defined as death due to any cause or at least 10% worsening of the corresponding scale score, relative to baseline, with no later improvement above this threshold observed during the course of the study or death due to any cause. If a participant had no event prior to analysis cut-off or start of another anticancer therapy, time to deterioration was censored at the date of the last adequate health related quality of life (HRQoL) evaluation. EORTC QLQ-C30: 5 functional scales (physical, role, cognitive, emotional, and social), a global health status scale, 3 symptom scales (nausea/vomiting, pain, fatigue) and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties). All scales and single-item measures range =0 to 100. High score for global health status = high quality of life.

Outcome measures

Outcome measures
Measure	Binimetinib (MEK162) n=269 Participants Participants received oral binimetinib 45 milligram (mg) (3\*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.	Dacarbazine n=133 Participants Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m\^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Time to Definitive 10% Deterioration in Global Health Status Score of European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30)	2.79 Months Interval 1.64 to 4.24	4.27 Months Interval 2.86 to 95% CI upper limit was not estimable due to very less number of participants with event.

SECONDARY outcome

Timeframe: Both arms: Baseline, Day 1 Treatment Week (TW) 4,7,13,19,25,34,43,52; Post-treatment follow-up Visit (FUV) 1 to 6; Binimetinib: Day 1 TW61,70; End of treatment (EOT= TW73); Safety FUV=30 days post TW73; Dacarbazine: EOT=TW 57;Safety FUV=30 days post TW57

Population: FAS consisted of all randomized participants. Here, "Number analyzed" signifies number of participants evaluable at specified time points.

EORTC QLQ-C30: 5 functional scales (physical, role, cognitive, emotional, and social), a h global health status scale, 3 symptom scales (nausea/vomiting, pain, fatigue) and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties). All scales and single-item measures range =0 to 100. High score for global health status = high quality of life. Post-treatment tumor assessments follow up visits occurred at every 9 weeks if participants started new anticancer therapy.

Outcome measures

Outcome measures
Measure	Binimetinib (MEK162) n=269 Participants Participants received oral binimetinib 45 milligram (mg) (3\*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.	Dacarbazine n=133 Participants Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m\^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-Treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 30-day safety follow-up	-8.10 Units on a scale Standard Deviation 21.361	-9.62 Units on a scale Standard Deviation 14.372
Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-Treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Post treatment follow-up 2	0.00 Units on a scale Standard Deviation NA SD was not estimable due to very less number of participants with event.	—
Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-Treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Baseline	68.35 Units on a scale Standard Deviation 23.463	70.50 Units on a scale Standard Deviation 21.823
Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-Treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Week 4 Day 1	-5.75 Units on a scale Standard Deviation 22.285	-1.81 Units on a scale Standard Deviation 17.512
Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-Treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Week 7 Day 1	-8.63 Units on a scale Standard Deviation 22.562	0.00 Units on a scale Standard Deviation 15.691
Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-Treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Week 13 Day 1	-8.28 Units on a scale Standard Deviation 19.659	-1.34 Units on a scale Standard Deviation 16.955
Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-Treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Week 19 Day 1	-8.05 Units on a scale Standard Deviation 21.053	-3.26 Units on a scale Standard Deviation 22.296
Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-Treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Week 25 Day 1	-10.58 Units on a scale Standard Deviation 21.775	-3.47 Units on a scale Standard Deviation 13.036
Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-Treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Week 34 Day 1	-6.25 Units on a scale Standard Deviation 18.755	3.57 Units on a scale Standard Deviation 20.893
Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-Treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Week 43 Day 1	-11.36 Units on a scale Standard Deviation 20.841	-6.94 Units on a scale Standard Deviation 23.224
Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-Treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Week 52 Day 1	-1.52 Units on a scale Standard Deviation 20.006	-8.33 Units on a scale Standard Deviation 11.785
Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-Treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Week 61 Day 1	-10.00 Units on a scale Standard Deviation 18.066	—
Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-Treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Week 70 Day 1	-20.83 Units on a scale Standard Deviation 5.893	—
Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-Treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 End of Treatment	-12.20 Units on a scale Standard Deviation 22.512	-6.74 Units on a scale Standard Deviation 21.536
Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-Treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Post treatment follow-up 1	-5.95 Units on a scale Standard Deviation 19.211	-8.59 Units on a scale Standard Deviation 21.218
Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-Treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Post treatment follow-up 3	16.67 Units on a scale Standard Deviation NA SD was not estimable due to very less number of participants with event.	—
Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-Treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Post treatment follow-up 4	25.00 Units on a scale Standard Deviation 11.785	—
Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-Treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Post treatment follow-up 5	25.00 Units on a scale Standard Deviation 11.785	—
Change From Baseline in Global Health Status Score of EORTC QLQ-C30 at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-Treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Post treatment follow-up 6	33.33 Units on a scale Standard Deviation NA SD was not estimable due to very less number of participants with event.	—

SECONDARY outcome

Population: FAS consisted of all randomized participants. Here, "Number analyzed" signifies number of participants evaluable at specified time points.

EQ-5D-5L, is a standardized measure of health utility that provides a single index value for one's health status. EQ-5D-5L contained 1 item for each of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each dimension has 5 levels: 1= no problems, 2= slight problems, 3= moderate problems, 4= severe problems, and 5= extreme problems. Index score: participant responses to the 5 dimensions reflected a specific health state that corresponded to a population preference weight for that state on a continuous scale of 0 (death) to 1 (perfect health). Higher index scores = better health state. Post-treatment tumor assessments follow up visits occurred at every 9 weeks if participants started new anticancer therapy.

Outcome measures

Outcome measures
Measure	Binimetinib (MEK162) n=269 Participants Participants received oral binimetinib 45 milligram (mg) (3\*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.	Dacarbazine n=133 Participants Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m\^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Change From Baseline in EuroQoL-5 Dimensions- 5 Levels (EQ-5D-5L) Index Score at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Week 34 Day 1	-0.0801 Units on a scale Standard Deviation 0.11141	0.0617 Units on a scale Standard Deviation 0.15254
Change From Baseline in EuroQoL-5 Dimensions- 5 Levels (EQ-5D-5L) Index Score at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Week 61 Day 1	0.0690 Units on a scale Standard Deviation 0.21080	—
Change From Baseline in EuroQoL-5 Dimensions- 5 Levels (EQ-5D-5L) Index Score at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Post treatment follow-up 4	0.1115 Units on a scale Standard Deviation 0.15768	—
Change From Baseline in EuroQoL-5 Dimensions- 5 Levels (EQ-5D-5L) Index Score at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Post treatment follow-up 5	0.1730 Units on a scale Standard Deviation 0.24466	—
Change From Baseline in EuroQoL-5 Dimensions- 5 Levels (EQ-5D-5L) Index Score at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Baseline	0.7780 Units on a scale Standard Deviation 0.22464	0.7657 Units on a scale Standard Deviation 0.23003
Change From Baseline in EuroQoL-5 Dimensions- 5 Levels (EQ-5D-5L) Index Score at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Week 4 Day 1	-0.0422 Units on a scale Standard Deviation 0.18291	0.0110 Units on a scale Standard Deviation 0.12135
Change From Baseline in EuroQoL-5 Dimensions- 5 Levels (EQ-5D-5L) Index Score at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Week 7 Day 1	-0.0397 Units on a scale Standard Deviation 0.19154	0.0132 Units on a scale Standard Deviation 0.14084
Change From Baseline in EuroQoL-5 Dimensions- 5 Levels (EQ-5D-5L) Index Score at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Week 13 Day 1	-0.0773 Units on a scale Standard Deviation 0.17543	0.0198 Units on a scale Standard Deviation 0.15236
Change From Baseline in EuroQoL-5 Dimensions- 5 Levels (EQ-5D-5L) Index Score at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Week 19 Day 1	-0.0576 Units on a scale Standard Deviation 0.22503	0.0257 Units on a scale Standard Deviation 0.18052
Change From Baseline in EuroQoL-5 Dimensions- 5 Levels (EQ-5D-5L) Index Score at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Week 25 Day 1	-0.1563 Units on a scale Standard Deviation 0.32142	0.0657 Units on a scale Standard Deviation 0.16052
Change From Baseline in EuroQoL-5 Dimensions- 5 Levels (EQ-5D-5L) Index Score at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Week 43 Day 1	-0.0170 Units on a scale Standard Deviation 0.22978	0.1060 Units on a scale Standard Deviation 0.15033
Change From Baseline in EuroQoL-5 Dimensions- 5 Levels (EQ-5D-5L) Index Score at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Week 52 Day 1	-0.0389 Units on a scale Standard Deviation 0.24609	0.0000 Units on a scale Standard Deviation 0.00000
Change From Baseline in EuroQoL-5 Dimensions- 5 Levels (EQ-5D-5L) Index Score at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Week 70 Day 1	0.0120 Units on a scale Standard Deviation 0.14001	—
Change From Baseline in EuroQoL-5 Dimensions- 5 Levels (EQ-5D-5L) Index Score at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 End of Treatment	-0.0978 Units on a scale Standard Deviation 0.23931	-0.0540 Units on a scale Standard Deviation 0.19164
Change From Baseline in EuroQoL-5 Dimensions- 5 Levels (EQ-5D-5L) Index Score at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 30-day safety follow-up	-0.1165 Units on a scale Standard Deviation 0.24410	-0.0740 Units on a scale Standard Deviation 0.17682
Change From Baseline in EuroQoL-5 Dimensions- 5 Levels (EQ-5D-5L) Index Score at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Post treatment follow-up 1	-0.0820 Units on a scale Standard Deviation 0.11993	-0.0438 Units on a scale Standard Deviation 0.25374
Change From Baseline in EuroQoL-5 Dimensions- 5 Levels (EQ-5D-5L) Index Score at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Post treatment follow-up 2	-0.2480 Units on a scale Standard Deviation NA SD was not estimable due to very less number of participants with event.	—
Change From Baseline in EuroQoL-5 Dimensions- 5 Levels (EQ-5D-5L) Index Score at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Post treatment follow-up 3	-0.1210 Units on a scale Standard Deviation NA SD was not estimable due to very less number of participants with event.	—
Change From Baseline in EuroQoL-5 Dimensions- 5 Levels (EQ-5D-5L) Index Score at Weeks 4, 7, 13, 19, 25, 34, 43, 52, 61, 70, End of Treatment, Safety Follow-up Visit, Post-treatment Follow-up Visit 1, 2, 3, 4, 5 and 6 Post treatment follow-up 6	0.2230 Units on a scale Standard Deviation NA SD was not estimable due to very less number of participants with event.	—

SECONDARY outcome

Timeframe: From baseline up to 73 weeks 3 days for binimetinib arm; From baseline up to 57 weeks 3 days for dacarbazine arm

Population: The safety set consisted all participants who received at least one dose of the study drug and had at least one valid post-baseline safety evaluation. Here, "Overall Number of Participants Analyzed" = number of participants evaluable for this outcome measure.

ECOG PS was used to assess the physical health of participants, and ranged from 0 (most active) to 5 (dead). ECOG PS grades: 0= fully active, able to carry on all pre-disease performance without restriction, 1= restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work, 2= ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours, 3= capable of only limited self-care, confined to bed or chair more than 50% of waking hours, 4=completely disabled. cannot carry on any selfcare. Totally confined to bed or chair and 5= dead. Definitive deterioration is defined as on treatment death due to any cause or decrease in ECOG PS by at least one category from baseline score.

Outcome measures

Outcome measures
Measure	Binimetinib (MEK162) n=262 Participants Participants received oral binimetinib 45 milligram (mg) (3\*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.	Dacarbazine n=105 Participants Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m\^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Time to Definitive 1 Point Deterioration in Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)	NA Months Interval 5.62 to Median and upper limit of 95% CI, was not estimable due to very less number of participants with event.	NA Months Data was not estimable due to very less number of participants with event.

SECONDARY outcome

Timeframe: For both arms: Baseline, Weeks 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55 and 30-day Follow-up For binimetinib only: Weeks 58, 61, 64, 67, 70, 73

Population: The safety set consisted all participants who received at least one dose of the study drug and had at least one valid post-baseline safety evaluation. Here, "Number Analyzed" signifies number of participants evaluable for specified rows.

ECOG PS was used to assess the physical health of participants, and ranged from 0 (most active) to 5 (dead). ECOG PS grades: 0= fully active, able to carry on all pre-disease performance without restriction, 1= restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work, 2= ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours, 3= capable of only limited self-care, 4=completely disabled. cannot carry on any selfcare. Totally confined to bed or chair confined to bed or chair more than 50% of waking hours and 5= dead. Post-treatment tumor assessments follow up visits occurred at every 9 weeks if participants started new anticancer therapy.

Outcome measures

Outcome measures
Measure	Binimetinib (MEK162) n=269 Participants Participants received oral binimetinib 45 milligram (mg) (3\*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.	Dacarbazine n=114 Participants Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m\^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 7 Day 1: Grade 0	138 Participants	51 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 13 Day 1: Grade 3	1 Participants	0 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 25 Day 1: Grade 0	37 Participants	13 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 40 Day 1: Grade 0	15 Participants	6 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 43 Day 1: Grade 2	1 Participants	0 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 49 Day 1: Grade 0	9 Participants	1 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Baseline : Grade 0	193 Participants	82 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Baseline: Grade 1	76 Participants	31 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Baseline : Grade 2	0 Participants	1 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 4 Day 1: Grade 0	146 Participants	66 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 4 Day 1: Grade 1	101 Participants	27 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 4 Day 1: Grade 2	6 Participants	4 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 4 Day 1: Grade 3	3 Participants	0 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 7 Day 1: Grade 1	84 Participants	26 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 7 Day 1: Grade 2	10 Participants	3 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 7 Day 1: Grade 3	3 Participants	0 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 7 Day 1: Grade 4	1 Participants	0 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 10 Day 1: Grade 0	118 Participants	34 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 10 Day 1: Grade 1	72 Participants	15 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 10 Day 1: Grade 2	8 Participants	2 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 10 Day 1: Grade 3	3 Participants	0 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 13 Day 1: Grade 0	93 Participants	29 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 13 Day 1: Grade 1	62 Participants	14 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 13 Day 1: Grade 2	11 Participants	0 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 16 Day 1: Grade 0	70 Participants	24 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 16 Day 1: Grade 1	48 Participants	5 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 16 Day 1: Grade 2	5 Participants	1 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 16 Day 1: Grade 4	1 Participants	0 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 19 Day 1: Grade 0	53 Participants	19 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 19 Day 1: Grade 1	43 Participants	7 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 19 Day 1:Grade 2	4 Participants	2 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 22 Day 1: Grade 0	42 Participants	17 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 22 Day 1: Grade 1	26 Participants	5 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 22 Day 1: Grade 2	3 Participants	0 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 22 Day 1: Grade 3	1 Participants	0 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 25 Day 1: Grade 1	19 Participants	6 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 25 Day 1: Grade 2	1 Participants	0 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 25 Day 1: Grade 3	1 Participants	0 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 28 Day 1: Grade 0	28 Participants	9 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 28 Day 1: Grade 1	15 Participants	2 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 28 Day 1: Grade 2	2 Participants	0 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 28 Day 1: Grade 5	1 Participants	0 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 31 Day 1: Grade 0	22 Participants	7 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 31 Day 1: Grade 1	11 Participants	2 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 31 Day 1: Grade 2	1 Participants	0 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 34 Day 1: Grade 0	20 Participants	9 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 34 Day 1: Grade 1	7 Participants	1 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 34 Day 1: Grade 2	2 Participants	0 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 37 Day 1: Grade 0	16 Participants	7 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 37 Day 1: Grade 1	4 Participants	1 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 40 Day 1: Grade 1	0 Participants	1 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 43 Day 1: Grade 0	12 Participants	5 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 43 Day 1: Grade 1	1 Participants	0 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 46 Day 1: Grade 0	11 Participants	4 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 46 Day 1: Grade 1	2 Participants	0 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 46 Day 1: Grade 2	1 Participants	0 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 49 Day 1: Grade 1	2 Participants	0 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 52 Day 1: Grade 0	10 Participants	2 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 52 Day 1: Grade 1	1 Participants	1 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 55 Day 1: Grade 0	9 Participants	1 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 55 Day 1: Grade 1	1 Participants	1 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 58 Day 1: Grade 0	7 Participants	—
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 58 Day 1: Grade 1	1 Participants	—
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 61 Day 1: Grade 0	5 Participants	—
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 64 Day 1: Grade 0	4 Participants	—
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 67 Day 1: Grade 0	3 Participants	—
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 70 Day 1: Grade 0	2 Participants	—
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Week 73 Day 1: Grade 0	1 Participants	—
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Safety Follow up Visit: Grade 0	42 Participants	24 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Safety Follow up Visit: Grade 1	41 Participants	16 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Safety Follow up Visit: Grade 2	14 Participants	4 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Safety Follow up Visit: Grade 3	4 Participants	0 Participants
Number of Participants With Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) Safety Follow up Visit: Grade 4	4 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline

Population: FAS consisted of all randomized participants. Here, "number analyzed" signifies participants evaluable for this outcome measure for specified rows.

Number of participants with NRAS mutation status at baseline were reported.

Outcome measures

Outcome measures
Measure	Binimetinib (MEK162) n=269 Participants Participants received oral binimetinib 45 milligram (mg) (3\*15 mg tablets) twice daily, until disease progression (PD), unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of binimetinib treatment exposure in the study was 215.4 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per Blinded Independent Review Committee (BIRC), withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.	Dacarbazine n=133 Participants Participants received intravenous (IV) dacarbazine 1000 mg per square meter (mg/m\^2) once every 3 weeks until PD, unacceptable toxicity, death, physician decision, study termination or discontinuation due to any other reason (e.g., withdrawal of consent, lost to follow-up, start of a new anti-cancer therapy). Maximum duration of dacarbazine treatment exposure in the study was 119.9 weeks and participants were followed up to 30 days after last dose of study treatment. Participants who discontinued study treatment due to start of a new anti-cancer therapy, were followed up at every 9 weeks until documented progression per BIRC, withdrawal of consent, lost to follow-up, study closure or death whichever occurred first.
Number of Participants With Neuroblastoma RAS Viral (V-ras) Oncogene Homolog (NRAS) Mutation Status at Baseline Mutant: Q61R	137 Participants	64 Participants
Number of Participants With Neuroblastoma RAS Viral (V-ras) Oncogene Homolog (NRAS) Mutation Status at Baseline Wild Type	0 Participants	1 Participants
Number of Participants With Neuroblastoma RAS Viral (V-ras) Oncogene Homolog (NRAS) Mutation Status at Baseline Mutant: Q61K	100 Participants	51 Participants
Number of Participants With Neuroblastoma RAS Viral (V-ras) Oncogene Homolog (NRAS) Mutation Status at Baseline Mutant: Q61L	32 Participants	17 Participants

Adverse Events

Binimetinib (MEK162)

Serious events: 95 serious events

Other events: 266 other events

Deaths: 0 deaths

Dacarbazine

Serious events: 26 serious events

Other events: 100 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Pfizer ClinicalTrials.gov Call Center

Pfizer Inc.

Phone: 1-800-718-1021

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.
Publication restrictions are in place

Restriction type: OTHER