Trial Outcomes & Findings for MEK162 for Patients With RAS/RAF/MEK Activated Tumors (NCT NCT01885195)

NCT ID: NCT01885195

Last Updated: 2021-02-21

Results Overview

CBR: participants with complete response (CR), partial response (PR) or stable disease (SD) for at least 16 weeks. As per RECIST 1.1, CR: disappearance of all target and non-target lesions, normalization of tumor marker level, pathological lymph nodes assigned as target or non-target lesions must have a reduction in short axis to less than (\<) 10 millimeter (mm); PR: at least a 30 percent (%) decrease in sum of diameter of all target lesions, taking as reference the baseline sum of diameters; SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters; PD: at least a 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 was also an absolute increase of at least 5 mm. Unequivocal progression of existing non-target lesions. Appearance of \>=1 new target or non-target lesions.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 110 participants
• Primary outcome timeframe: Week 16
• Results posted on: 2021-02-21

Participant Flow

Participants diagnosed with select solid tumors or hematological malignancies pre-identified (prior to study consent) and had an activation of the v-raf murine sarcoma viral oncogene (RAF)/ RAS oncogene [rat sarcoma viral oncogene homologue] (RAS)/mitogen-activated erk kinase (MEK) pathway and whose disease had progressed on or after standard treatment.

Participant milestones

Measure	Binimetinib (MEK162) Participants received an oral dose of 45 milligram (mg) of binimetinib tablets (3 tablets of 15 mg) twice daily in each cycle starting from Cycle 1 Day 1 (1 cycle =28 days) until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment due to any other reason. Maximum treatment exposure was approximately of 19.4 months.
Overall Study STARTED	110
Overall Study COMPLETED	0
Overall Study NOT COMPLETED	110

Reasons for withdrawal

Measure	Binimetinib (MEK162) Participants received an oral dose of 45 milligram (mg) of binimetinib tablets (3 tablets of 15 mg) twice daily in each cycle starting from Cycle 1 Day 1 (1 cycle =28 days) until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment due to any other reason. Maximum treatment exposure was approximately of 19.4 months.
Overall Study Adverse Event	29
Overall Study Death	1
Overall Study Disease Progression	67
Overall Study Protocol Deviation	2
Overall Study Physician Decision	3
Overall Study Patient/guardian decision	8

Baseline Characteristics

MEK162 for Patients With RAS/RAF/MEK Activated Tumors

Baseline characteristics by cohort

Measure	Binimetinib (MEK162) n=110 Participants Participants received an oral dose of 45 mg of binimetinib tablets (3 tablets of 15 mg) twice daily in each cycle starting from Cycle 1 Day 1 (1 cycle =28 days) until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment due to any other reason. Maximum treatment exposure was approximately of 19.4 months.
Age, Continuous	60.4 Years STANDARD_DEVIATION 12.29 • n=5 Participants
Sex: Female, Male Female	68 Participants n=5 Participants
Sex: Female, Male Male	42 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week 16

Population: Full analysis set included all the participants who had received at least 1 dose of study drug. Here, "Overall Number of Participants Analyzed" signifies participants evaluable for this outcome measure.

CBR: participants with complete response (CR), partial response (PR) or stable disease (SD) for at least 16 weeks. As per RECIST 1.1, CR: disappearance of all target and non-target lesions, normalization of tumor marker level, pathological lymph nodes assigned as target or non-target lesions must have a reduction in short axis to less than (<) 10 millimeter (mm); PR: at least a 30 percent (%) decrease in sum of diameter of all target lesions, taking as reference the baseline sum of diameters; SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters; PD: at least a 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 was also an absolute increase of at least 5 mm. Unequivocal progression of existing non-target lesions. Appearance of >=1 new target or non-target lesions.

Outcome measures

Measure	Binimetinib (MEK162) n=104 Participants Participants received an oral dose of 45 mg of binimetinib tablets (3 tablets of 15 mg) twice daily in each cycle starting from Cycle 1 Day 1 (1 cycle =28 days) until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment due to any other reason. Maximum treatment exposure was approximately of 19.4 months.
Clinical Benefit Rate (CBR) for Solid Tumors at Week 16 as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1	23.1 Percentage of participants Interval 15.4 to 32.4

PRIMARY outcome

Timeframe: Week 16

Population: Full analysis set included all the participants who had received at least 1 dose of study drug. Here, "Overall Number of Participants Analyzed" signifies participants evaluable for this outcome measure.

CBR: participants with stringent complete response(sCR), CR, very good partial response(VGPR), PR/SD for at least 16 weeks. For hematologic tumors (multiple myeloma), sCR: negative immunofixation on serum, urine, disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow plus normal free light chain(FLC) ratio and absence of clonal cells in bone marrow by immunohistochemistry/immunofluorescence; CR: negative immunofixation on the serum, urine, disappearance of any soft tissue, plasmacytomas and <5% plasma cells in bone marrow; VGPR: serum,urine M-component detectable by immunofixation but not on electrophoresis or>=90% reduction in serum M-component plus urine M-component <100 mg/24 hr; PR: >50% reduction of serum M-protein and reduction in 24hr urinary M-protein by >90%/to <200 mg/24 hr; SD: not meeting criteria for CR, VGPR, PRor PD; PD: increase of >25% from lowest response value in serum M-component, urine M-component and bone marrow plasma cell percentage.

Outcome measures

Measure	Binimetinib (MEK162) n=3 Participants Participants received an oral dose of 45 mg of binimetinib tablets (3 tablets of 15 mg) twice daily in each cycle starting from Cycle 1 Day 1 (1 cycle =28 days) until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment due to any other reason. Maximum treatment exposure was approximately of 19.4 months.
CBR for Hematologic Tumors at Week 16: Multiple Myeloma	0.0 Percentage of participants Interval 0.0 to 70.8

PRIMARY outcome

Timeframe: Week 16

Population: Full analysis set included all the participants who had received at least 1 dose of study drug. Here, "Overall Number of Participants Analyzed" signifies participants evaluable for this outcome measure.

CBR: participants with complete remission (CR), CR with incomplete blood count recovery (CRi), partial remission (PR) and no resposne for at least 16 weeks. For hematologic tumors (acute myeloid leukemia); CR: as bone marrow- < 5% blasts, no blasts with auer rods, peripheral blood- neutrophils ≥1.0*10^9/L and/or platelets ≥100*10^9/L, ≤1% blasts, no evidence of extramedullary disease (such as CNS or soft tissue involvement), transfusion independent; CRi: all the CR criteria were involved but platelet and neutrophil transfusions were also allowed; PR: bone marrow- 50% or greater decrease (absolute range 5-25% blasts), < 5% of blasts contain auer rods, peripheral blood- neutrophils <1.0*10^9/L and/or platelets <100*10^9/L, no evidence of extramedullary disease; no response: in case a patient did not achieve CR, CRi, PR or relapse for an individual response assessment.

Outcome measures

Measure	Binimetinib (MEK162) n=3 Participants Participants received an oral dose of 45 mg of binimetinib tablets (3 tablets of 15 mg) twice daily in each cycle starting from Cycle 1 Day 1 (1 cycle =28 days) until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment due to any other reason. Maximum treatment exposure was approximately of 19.4 months.
CBR for Hematologic Tumors at Week 16: Acute Myeloid Leukemia	33.3 Percentage of participants Interval 0.8 to 90.6

SECONDARY outcome

Timeframe: From the start of the treatment until disease progression (maximum up to 19.4 months)

Population: Full analysis set included all the participants who had received at least 1 dose of study drug. Here, "Overall Number of Participants Analyzed" signifies participants evaluable for this outcome measure.

ORR: percentage of participants with a best overall response (BOR) of CR or PR as assessed per RECIST version 1.1. BOR: the best response recorded from the start of the treatment until disease progression (PD). CR: disappearance of all target and non-target lesions, normalization of tumor marker level, pathological lymph nodes assigned as target or non-target lesions must have a reduction in short axis to less than <10 mm; PR: at least a 30 % decrease in sum of diameter of all target lesions, taking as reference the baseline sum of diameters; PD: at least a 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 was also an absolute increase of at least 5 mm. Unequivocal progression of existing non-target lesions. Appearance of >=1 new target or non-target lesions.

Outcome measures

Measure	Binimetinib (MEK162) n=104 Participants Participants received an oral dose of 45 mg of binimetinib tablets (3 tablets of 15 mg) twice daily in each cycle starting from Cycle 1 Day 1 (1 cycle =28 days) until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment due to any other reason. Maximum treatment exposure was approximately of 19.4 months.
Overall Response Rate (ORR) as Per RECIST Version 1.1	2.9 Percentage of participants Interval 0.6 to 8.2

SECONDARY outcome

Timeframe: From the start of the treatment until disease progression (maximum up to 19.4 months)

Population: Full analysis set included all the participants who had received at least 1 dose of study drug. Here, "Overall Number of Participants Analyzed" signifies participants evaluable for this outcome measure.

ORR: percentage of participants with sCR, CR, VGPR or PR. For hematologic tumors (multiple myeloma), sCR: negative immunofixation on the serum, urine, disappearance of any soft tissue plasmacytomas and <5% plasma cells in bone marrow plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence; CR: CR: negative immunofixation on the serum, urine, disappearance of any soft tissue, plasmacytomas and <5% plasma cells in bone marrow; VGPR: serum and urine M-component detectable by immunofixation but not on electrophoresis or greater than equal to >=90% reduction in serum M-component plus urine M-component <100 mg per 24hour (hr); PR: >50% reduction of serum M-protein and reduction in 24 hr urinary M-protein by >90% or to <200 mg/24 hr.

Outcome measures

Measure	Binimetinib (MEK162) n=3 Participants Participants received an oral dose of 45 mg of binimetinib tablets (3 tablets of 15 mg) twice daily in each cycle starting from Cycle 1 Day 1 (1 cycle =28 days) until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment due to any other reason. Maximum treatment exposure was approximately of 19.4 months.
ORR for Hematologic Tumors: Multiple Myeloma	33.3 Percentage of participants Interval 0.8 to 90.6

SECONDARY outcome

Timeframe: From the start of the treatment until disease progression (maximum up to 19.4 months)

Population: Full analysis set included all the participants who had received at least 1 dose of study drug. Here, "Overall Number of Participants Analyzed" signifies participants evaluable for this outcome measure.

ORR: participants with complete remission (CR), CR with incomplete blood count recovery (CRi), partial remission (PR) and no resposne for at least 16 weeks. For hematologic tumors (acute myeloid leukemia); CR: as bone marrow- < 5% blasts, no blasts with auer rods, peripheral blood- neutrophils ≥1.0*10^9/L and/or platelets ≥100*10^9/L, ≤1% blasts, no evidence of extramedullary disease (such as CNS or soft tissue involvement), transfusion independent; CRi: all the CR criteria were involved but platelet and neutrophil transfusions were also allowed; PR: bone marrow- 50% or greater decrease (absolute range 5-25% blasts), < 5% of blasts contain auer rods, peripheral blood- neutrophils <1.0*10^9/L and/or platelets <100*10^9/L, no evidence of extramedullary disease.

Outcome measures

Measure	Binimetinib (MEK162) n=3 Participants Participants received an oral dose of 45 mg of binimetinib tablets (3 tablets of 15 mg) twice daily in each cycle starting from Cycle 1 Day 1 (1 cycle =28 days) until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment due to any other reason. Maximum treatment exposure was approximately of 19.4 months.
ORR for Hematologic Tumors: Acute Myeloid Leukemia	33.3 Percentage of participants Interval 0.8 to 90.6

SECONDARY outcome

Timeframe: From the date of first dose to the date of the first documented PD, censored date or death (maximum up to 19.4 months)

Population: Full analysis set included all the participants who had received at least 1 dose of study drug.

PFS was defined as the time from the date of first dose to the date of first documented PD or relapse or death due to any cause. PD: at least a 20% increase in the 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. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Unequivocal progression of existing non-target lesions. Appearance of >=1 new target or non-target lesions was also considered progression. PFS data was censored at date of last adequate tumor assessment.

Outcome measures

Measure	Binimetinib (MEK162) n=110 Participants Participants received an oral dose of 45 mg of binimetinib tablets (3 tablets of 15 mg) twice daily in each cycle starting from Cycle 1 Day 1 (1 cycle =28 days) until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment due to any other reason. Maximum treatment exposure was approximately of 19.4 months.
Progression-free Survival (PFS) as Per RECIST Version 1.1	2.6 Months Interval 1.9 to 3.5

SECONDARY outcome

Timeframe: From the date of first dose to the date of death due to any cause (maximum up to 19.4 months)

Population: Full analysis set included all the participants who had received at least 1 dose of study drug.

OS was defined as the time from the date of first dose to the date of death due to any cause. If a participant was not known to have died, survival time was censored at the date of last contact.

Outcome measures

Measure	Binimetinib (MEK162) n=110 Participants Participants received an oral dose of 45 mg of binimetinib tablets (3 tablets of 15 mg) twice daily in each cycle starting from Cycle 1 Day 1 (1 cycle =28 days) until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment due to any other reason. Maximum treatment exposure was approximately of 19.4 months.
Overall Survival (OS)	8.5 Months Interval 6.6 to 11.8

SECONDARY outcome

Timeframe: From the first documented response (CR or PR) to the date of the first documented PD or death (maximum up to 19.4 months)

Population: Full analysis set included all the participants who had received at least 1 dose of study drug. Here, "Overall Number of Participants Analyzed" signifies participants evaluable for this outcome measure.

DOR was defined as the time from the first documented response (CR or PR) to the date of first documented disease progression, relapse or death due to any cause. As per RECIST 1.1, CR: disappearance of all target and non-target lesions, normalization of tumor marker level, pathological lymph nodes assigned as target or non-target lesions must have a reduction in short axis to <10 mm; PR: at least a 30% decrease in sum of diameter of all target lesions, taking as reference the baseline sum of diameters; PD: at least a 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 was also an absolute increase of at least 5 mm. Unequivocal progression of existing non-target lesions. Appearance of >=1 new target or non-target lesions. The DOR was determined only in participants whose best response was PR or greater.

Outcome measures

Measure	Binimetinib (MEK162) n=3 Participants Participants received an oral dose of 45 mg of binimetinib tablets (3 tablets of 15 mg) twice daily in each cycle starting from Cycle 1 Day 1 (1 cycle =28 days) until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment due to any other reason. Maximum treatment exposure was approximately of 19.4 months.
Duration of Response (DOR) as Per RECIST Version 1.1	NA Months Median and 95% CI were not estimable due to low number of participants who had an event.

SECONDARY outcome

Timeframe: From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months)

Population: Safety analysis set included all participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.

Adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. As per NCI-CTCAE version 4.03, severity was graded as Grade 1: asymptomatic/mild symptoms, clinical/diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local/noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe/medically significant but not immediately life-threatening, hospitalization/prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated. Treatment-emergent adverse events were defined as new or worsening events that were collected from first study treatment date to last treatment date +30 days. AEs of all grades were reported.

Outcome measures

Measure	Binimetinib (MEK162) n=110 Participants Participants received an oral dose of 45 mg of binimetinib tablets (3 tablets of 15 mg) twice daily in each cycle starting from Cycle 1 Day 1 (1 cycle =28 days) until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment due to any other reason. Maximum treatment exposure was approximately of 19.4 months.
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Graded According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 Grade 1	2 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Graded According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 Grade 2	27 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Graded According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 Grade 3	64 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs) Graded According to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03 Grade 4	17 Participants

SECONDARY outcome

Timeframe: From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months)

Population: Safety analysis set included all participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.

Vital signs included hypertension, hypotension and weight decreased were reported. As per NCI-CTCAE version 4.03, severity was graded as Grade 1: asymptomatic/mild symptoms, clinical/diagnostic observations only, intervention not indicated; Grade 2: moderate, minimal, local/noninvasive intervention indicated, limiting age-appropriate instrumental activities of daily life (ADL); Grade 3: severe/medically significant but not immediately life-threatening, hospitalization/prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated. Participants with grade 3 or higher vital sign abnormality are reported.

Outcome measures

Measure	Binimetinib (MEK162) n=110 Participants Participants received an oral dose of 45 mg of binimetinib tablets (3 tablets of 15 mg) twice daily in each cycle starting from Cycle 1 Day 1 (1 cycle =28 days) until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment due to any other reason. Maximum treatment exposure was approximately of 19.4 months.
Number of Participants With Vital Sign Abnormality of Greater Than or Equal to (>=) Grade 3 as Per CTCAE v4.03 Hypertension	15 Participants
Number of Participants With Vital Sign Abnormality of Greater Than or Equal to (>=) Grade 3 as Per CTCAE v4.03 Hypotension	6 Participants
Number of Participants With Vital Sign Abnormality of Greater Than or Equal to (>=) Grade 3 as Per CTCAE v4.03 Weight Decreased	11 Participants

SECONDARY outcome

Timeframe: From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months)

Population: Safety analysis set included all participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.

ECG abnormalities criteria included: 1) QTc interval adjusted according to Bazett formula (QTcF) in millisecond (msec): greater than equal to (>=) 450 to less than (<) 480, >=480 to <500, >=500, increase from baseline >=30, increase from baseline >=60; 2) QTc interval adjusted according to Fridericia formula (QTcB) (msec): >=450 to <480, >=480 to <500, >=500, increase from baseline >=30, increase from baseline >=60. 3) QT (msec): >=450 to <480, >=480 to <500, >=500, increase from baseline >=30, increase from baseline >=60.

Outcome measures

Measure	Binimetinib (MEK162) n=110 Participants Participants received an oral dose of 45 mg of binimetinib tablets (3 tablets of 15 mg) twice daily in each cycle starting from Cycle 1 Day 1 (1 cycle =28 days) until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment due to any other reason. Maximum treatment exposure was approximately of 19.4 months.
Number of Participants With Electrocardiogram (ECG) Abnormalities QTcF: >=450 to <480 msec	15 Participants
Number of Participants With Electrocardiogram (ECG) Abnormalities QTcF: >=480 to <500 msec	4 Participants
Number of Participants With Electrocardiogram (ECG) Abnormalities QTcF: >=500 msec	1 Participants
Number of Participants With Electrocardiogram (ECG) Abnormalities QTcF: Increase from baseline >=30 msec	20 Participants
Number of Participants With Electrocardiogram (ECG) Abnormalities QTcF: Increase from baseline >=60 msec	3 Participants
Number of Participants With Electrocardiogram (ECG) Abnormalities QTcB: >=450 to <480 msec	13 Participants
Number of Participants With Electrocardiogram (ECG) Abnormalities QTcB: >=480 to <500 msec	5 Participants
Number of Participants With Electrocardiogram (ECG) Abnormalities QTcB: >=500 msec	8 Participants
Number of Participants With Electrocardiogram (ECG) Abnormalities QTcB: Increase from baseline >=30 msec	53 Participants
Number of Participants With Electrocardiogram (ECG) Abnormalities QTcB: Increase from baseline >=60 msec	29 Participants
Number of Participants With Electrocardiogram (ECG) Abnormalities QT: >=450 to <480 msec	13 Participants
Number of Participants With Electrocardiogram (ECG) Abnormalities QT: >=480 to <500 msec	2 Participants
Number of Participants With Electrocardiogram (ECG) Abnormalities QT: >=500 msec	2 Participants
Number of Participants With Electrocardiogram (ECG) Abnormalities QT: Increase from baseline >=30 msec	39 Participants
Number of Participants With Electrocardiogram (ECG) Abnormalities QT: Increase from baseline >=60 msec	7 Participants

SECONDARY outcome

Timeframe: From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months)

Population: Safety analysis set included all participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment. Here, "Number Analyzed" signifies number of participants evaluable for specified rows.

Laboratory parameters included hematological and biochemistry parameters. Hematological parameters included neutrophils, platelets, prothrombin time, activated partial thromboplastin time, INR, fibrinogen. Number of participants with hematological abnormalities by grades (as per Common Terminology Criteria for Adverse Events (CTCAE version 4.03) were reported. Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Participants with a grade shift of 3 or more from baseline are reported in this outcome measure.

Outcome measures

Measure	Binimetinib (MEK162) n=110 Participants Participants received an oral dose of 45 mg of binimetinib tablets (3 tablets of 15 mg) twice daily in each cycle starting from Cycle 1 Day 1 (1 cycle =28 days) until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment due to any other reason. Maximum treatment exposure was approximately of 19.4 months.
Number of Participants With Shift From Baseline in Clinical Laboratory - Hematology Parameters Neutrophils	6 Participants
Number of Participants With Shift From Baseline in Clinical Laboratory - Hematology Parameters Platelets	3 Participants
Number of Participants With Shift From Baseline in Clinical Laboratory - Hematology Parameters Prothrombin Time	2 Participants
Number of Participants With Shift From Baseline in Clinical Laboratory - Hematology Parameters Activated Partial Thromboplastin Time	2 Participants
Number of Participants With Shift From Baseline in Clinical Laboratory - Hematology Parameters INR	2 Participants
Number of Participants With Shift From Baseline in Clinical Laboratory - Hematology Parameters Fibrinogen	0 Participants

SECONDARY outcome

Timeframe: From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months)

Population: Safety analysis set included all participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment. Here, "Number Analyzed" signifies number of participants evaluable for specified rows.

Laboratory parameters included hematological and biochemistry parameters. Biochemistry parameters included: creatinine, phosphorus, albumin, gamma-glutamyl transferase, aspartate transaminase, alanine aminotransferase, alkaline phosphatase, total bilirubin, uric acid, amylase, lipase, creatine kinase, total cholesterol and triglycerides. Number of participants with biochemistry test abnormalities by grades (CTCAE version 4.03) were reported. Grade 1= mild; Grade 2= moderate; Grade 3= severe and Grade 4= life-threatening or disabling. Participants with a grade shift of 3 or more from baseline are reported in this outcome measure.

Outcome measures

Measure	Binimetinib (MEK162) n=110 Participants Participants received an oral dose of 45 mg of binimetinib tablets (3 tablets of 15 mg) twice daily in each cycle starting from Cycle 1 Day 1 (1 cycle =28 days) until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment due to any other reason. Maximum treatment exposure was approximately of 19.4 months.
Number of Participants With Shift From Baseline in Clinical Laboratory - Biochemistry Parameters Creatinine	0 Participants
Number of Participants With Shift From Baseline in Clinical Laboratory - Biochemistry Parameters Phosphorus	1 Participants
Number of Participants With Shift From Baseline in Clinical Laboratory - Biochemistry Parameters Albumin	5 Participants
Number of Participants With Shift From Baseline in Clinical Laboratory - Biochemistry Parameters Gamma-Glutamyl Transferase	1 Participants
Number of Participants With Shift From Baseline in Clinical Laboratory - Biochemistry Parameters Aspartate Transaminase	2 Participants
Number of Participants With Shift From Baseline in Clinical Laboratory - Biochemistry Parameters Alanine Aminotransferase	2 Participants
Number of Participants With Shift From Baseline in Clinical Laboratory - Biochemistry Parameters Alkaline Phosphatase	0 Participants
Number of Participants With Shift From Baseline in Clinical Laboratory - Biochemistry Parameters Total Bilirubin	0 Participants
Number of Participants With Shift From Baseline in Clinical Laboratory - Biochemistry Parameters Uric Acid	0 Participants
Number of Participants With Shift From Baseline in Clinical Laboratory - Biochemistry Parameters Amylase	2 Participants
Number of Participants With Shift From Baseline in Clinical Laboratory - Biochemistry Parameters Lipase	5 Participants
Number of Participants With Shift From Baseline in Clinical Laboratory - Biochemistry Parameters Creatine Kinase	18 Participants
Number of Participants With Shift From Baseline in Clinical Laboratory - Biochemistry Parameters Total Cholesterol	0 Participants
Number of Participants With Shift From Baseline in Clinical Laboratory - Biochemistry Parameters Triglycerides	1 Participants

SECONDARY outcome

Timeframe: From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months)

Population: Safety analysis set included all participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.

Number of Participants With Shift From Baseline in Cardiac Imaging were reported.

Outcome measures

Measure	Binimetinib (MEK162) n=110 Participants Participants received an oral dose of 45 mg of binimetinib tablets (3 tablets of 15 mg) twice daily in each cycle starting from Cycle 1 Day 1 (1 cycle =28 days) until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment due to any other reason. Maximum treatment exposure was approximately of 19.4 months.
Number of Participants With Shift From Baseline in Cardiac Imaging	10 Participants

Adverse Events

Binimetinib (MEK162)

Serious events: 50 serious events

Other events: 110 other events

Deaths: 0 deaths

Serious adverse events

Measure	Binimetinib (MEK162) n=110 participants at risk Participants received an oral dose of 45 mg of binimetinib tablets (3 tablets of 15 mg) twice daily in each cycle starting from Cycle 1 Day 1 (1 cycle =28 days) until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment due to any other reason. Maximum treatment exposure was approximately of 19.4 months.
Blood and lymphatic system disorders Coagulopathy	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Blood and lymphatic system disorders Febrile neutropenia	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Cardiac disorders Dilatation ventricular	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Eye disorders Cataract	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Eye disorders Retinal artery occlusion	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Eye disorders Retinal detachment	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Eye disorders Retinal tear	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Eye disorders Vitreous haemorrhage	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Gastrointestinal disorders Abdominal pain	3.6% 4/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Gastrointestinal disorders Small intestinal obstruction	3.6% 4/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Gastrointestinal disorders Vomiting	1.8% 2/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Gastrointestinal disorders Ascites	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Gastrointestinal disorders Diarrhoea	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Gastrointestinal disorders Gastric ulcer	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Gastrointestinal disorders Haematemesis	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Gastrointestinal disorders Intestinal obstruction	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Gastrointestinal disorders Mesenteric vein thrombosis	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Gastrointestinal disorders Nausea	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Gastrointestinal disorders Oesophageal haemorrhage	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Gastrointestinal disorders Oesophageal obstruction	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Gastrointestinal disorders Oesophageal perforation	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Gastrointestinal disorders Pancreatitis	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
General disorders Oedema peripheral	1.8% 2/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
General disorders Asthenia	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
General disorders Chest pain	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
General disorders Fatigue	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
General disorders Oedema	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
General disorders Pain	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
General disorders Pyrexia	1.8% 2/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Hepatobiliary disorders Bile duct obstruction	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Infections and infestations Pneumonia	2.7% 3/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Infections and infestations Urinary tract infection	2.7% 3/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Infections and infestations Cellulitis	1.8% 2/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Infections and infestations Sepsis	1.8% 2/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Infections and infestations Cystitis	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Infections and infestations Influenza	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Infections and infestations Lung abscess	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Infections and infestations Post procedural infection	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Infections and infestations Streptococcal bacteraemia	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Infections and infestations Upper respiratory tract infection	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Injury, poisoning and procedural complications Femur fracture	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Injury, poisoning and procedural complications Hip fracture	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Investigations Blood creatine phosphokinase increased	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Investigations Troponin I increased	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Investigations Troponin T increased	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Metabolism and nutrition disorders Dehydration	3.6% 4/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Metabolism and nutrition disorders Decreased appetite	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Metabolism and nutrition disorders Hypercalcaemia	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Musculoskeletal and connective tissue disorders Back pain	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Musculoskeletal and connective tissue disorders Musculoskeletal chest pain	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Musculoskeletal and connective tissue disorders Myositis	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Musculoskeletal and connective tissue disorders Pain in extremity	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Nervous system disorders Haemorrhage intracranial	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Nervous system disorders Peripheral motor neuropathy	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Nervous system disorders Peripheral sensory neuropathy	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Psychiatric disorders Confusional state	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Renal and urinary disorders Urinary retention	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Respiratory, thoracic and mediastinal disorders Dyspnoea	10.9% 12/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Respiratory, thoracic and mediastinal disorders Hypoxia	2.7% 3/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Respiratory, thoracic and mediastinal disorders Haemoptysis	1.8% 2/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Respiratory, thoracic and mediastinal disorders Pleural effusion	1.8% 2/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	1.8% 2/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Respiratory, thoracic and mediastinal disorders Cough	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Respiratory, thoracic and mediastinal disorders Pharyngeal oedema	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Respiratory, thoracic and mediastinal disorders Pulmonary hypertension	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Respiratory, thoracic and mediastinal disorders Respiratory distress	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Respiratory, thoracic and mediastinal disorders Sleep apnoea syndrome	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Respiratory, thoracic and mediastinal disorders Upper airway obstruction	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Vascular disorders Embolism	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Vascular disorders Haemorrhage	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Vascular disorders Hypotension	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Vascular disorders Lymphoedema	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Vascular disorders Lymphorrhoea	0.91% 1/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.

Other adverse events

Measure	Binimetinib (MEK162) n=110 participants at risk Participants received an oral dose of 45 mg of binimetinib tablets (3 tablets of 15 mg) twice daily in each cycle starting from Cycle 1 Day 1 (1 cycle =28 days) until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment due to any other reason. Maximum treatment exposure was approximately of 19.4 months.
Blood and lymphatic system disorders Anaemia	26.4% 29/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Blood and lymphatic system disorders Neutropenia	6.4% 7/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Eye disorders Vision blurred	16.4% 18/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Eye disorders Chorioretinopathy	7.3% 8/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Eye disorders Periorbital oedema	6.4% 7/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Eye disorders Visual impairment	5.5% 6/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Gastrointestinal disorders Diarrhoea	47.3% 52/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Gastrointestinal disorders Nausea	43.6% 48/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Gastrointestinal disorders Vomiting	38.2% 42/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Gastrointestinal disorders Constipation	22.7% 25/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Gastrointestinal disorders Dry mouth	10.0% 11/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Gastrointestinal disorders Dyspepsia	10.0% 11/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Gastrointestinal disorders Abdominal pain	9.1% 10/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Gastrointestinal disorders Stomatitis	8.2% 9/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Gastrointestinal disorders Ascites	5.5% 6/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Gastrointestinal disorders Dysphagia	5.5% 6/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
General disorders Fatigue	50.0% 55/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
General disorders Oedema peripheral	40.0% 44/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
General disorders Mucosal inflammation	11.8% 13/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
General disorders Pyrexia	11.8% 13/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
General disorders Asthenia	10.0% 11/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
General disorders Face oedema	9.1% 10/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
General disorders Chills	6.4% 7/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
General disorders Oedema	6.4% 7/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Infections and infestations Urinary tract infection	17.3% 19/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Investigations Blood creatine phosphokinase increased	34.5% 38/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Investigations Aspartate aminotransferase increased	20.0% 22/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Investigations Alanine aminotransferase increased	13.6% 15/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Investigations Lipase increased	11.8% 13/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Investigations Amylase increased	10.0% 11/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Investigations Blood lactate dehydrogenase increased	10.0% 11/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Investigations Ejection fraction decreased	10.0% 11/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Investigations Weight decreased	10.0% 11/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Investigations Blood alkaline phosphatase increased	8.2% 9/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Investigations Blood phosphorus increased	7.3% 8/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Investigations Blood creatinine increased	5.5% 6/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Investigations Gamma-glutamyltransferase increased	5.5% 6/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Investigations Intraocular pressure increased	5.5% 6/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Investigations Troponin T increased	5.5% 6/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Investigations White blood cell count decreased	5.5% 6/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Metabolism and nutrition disorders Decreased appetite	21.8% 24/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Metabolism and nutrition disorders Hypomagnesaemia	15.5% 17/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Metabolism and nutrition disorders Hyperglycaemia	12.7% 14/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Metabolism and nutrition disorders Dehydration	10.0% 11/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Metabolism and nutrition disorders Hypokalaemia	10.0% 11/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Metabolism and nutrition disorders Hypoalbuminaemia	9.1% 10/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Metabolism and nutrition disorders Hyponatraemia	6.4% 7/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Metabolism and nutrition disorders Hyperkalaemia	5.5% 6/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Musculoskeletal and connective tissue disorders Muscular weakness	12.7% 14/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Musculoskeletal and connective tissue disorders Back pain	9.1% 10/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Musculoskeletal and connective tissue disorders Pain in extremity	7.3% 8/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Musculoskeletal and connective tissue disorders Myalgia	6.4% 7/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Musculoskeletal and connective tissue disorders Arthralgia	5.5% 6/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Nervous system disorders Dizziness	11.8% 13/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Nervous system disorders Headache	6.4% 7/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Nervous system disorders Neuropathy peripheral	5.5% 6/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Psychiatric disorders Insomnia	9.1% 10/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Psychiatric disorders Anxiety	8.2% 9/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Respiratory, thoracic and mediastinal disorders Dyspnoea	26.4% 29/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Respiratory, thoracic and mediastinal disorders Cough	13.6% 15/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Respiratory, thoracic and mediastinal disorders Epistaxis	5.5% 6/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Skin and subcutaneous tissue disorders Rash	43.6% 48/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Skin and subcutaneous tissue disorders Dermatitis acneiform	19.1% 21/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Skin and subcutaneous tissue disorders Dry skin	13.6% 15/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Skin and subcutaneous tissue disorders Pruritus	8.2% 9/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Skin and subcutaneous tissue disorders Rash maculo-papular	7.3% 8/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Vascular disorders Hypertension	13.6% 15/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.
Respiratory, thoracic and mediastinal disorders Pleural effusion	5.5% 6/110 • From Baseline up to 30 days following the last dose of study treatment (maximum up to 21 months) Same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 participant and as non-serious in another, or a participant may have experienced both a serious and non-serious event. Safety analysis set included all the participants who received at least 1 dose of study treatment and had at least 1 post-baseline safety assessment.

Additional Information

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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