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Clinical Trial Results:
The LOGIC 2 Trial A Phase II, Multi-Center, Open-Label Study Of Sequential LGX818/MEK162 Combination Followed By A Rational Combination With Targeted Agents After Progression, To Overcome Resistance In Adult Patients With Locally Advanced Or Metastatic BRAF V600 Melanoma

Summary
EudraCT number	2013-004552-38
Trial protocol	NL GB ES IT
Global end of trial date	13 Jan 2023

Results information
Results version number	v1(current)
This version publication date	19 Jan 2024
First version publication date	19 Jan 2024
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

CLGX818X2109 (C4221013)

ISRCTN number

US NCT number

NCT02159066

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer Inc.

Sponsor organisation address

235 East 42nd Street, New York, United States, NY 10017

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

12 Jul 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

13 Jan 2023

Was the trial ended prematurely?

Main objective of the trial

To assess the anti-tumor activity of LGX818/MEK162 in combination with third targeted agents after progression on LGX818/MEK162 combination therapy.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

23 Jul 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 10

Country: Number of subjects enrolled

United States: 12

Country: Number of subjects enrolled

Germany: 37

Country: Number of subjects enrolled

Italy: 4

Country: Number of subjects enrolled

Netherlands: 7

Country: Number of subjects enrolled

Spain: 11

Country: Number of subjects enrolled

Switzerland: 38

Country: Number of subjects enrolled

Australia: 11

Country: Number of subjects enrolled

Canada: 28

Worldwide total number of subjects

158

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

118

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This study had 2 parts. In Part I, 158 subjects were enrolled and treated with encorafenib/ binimetinib (LGX818/MEK162) combination. In Part II, 58 subjects received tailored combination treatment.

Screening details

In Part I, subjects were treated until disease progression (PD). Based on the genetic assessment of a tumor biopsy obtained at PD, subjects from Part I entered Part II. Part II combination treatment were: encorafenib/ binimetinib + buparlisib (BKM120), infigratinib (BGJ398), capmatinib (INC280) or ribociclib (LEE011).

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Part I: Encorafenib + Binimetinib (naive)

Arm description

Subjects naive to selective V-raf murine sarcoma viral oncogene homolog B1 (BRAF) and mitogen-activated protein kinase (MEK) inhibitors, received encorafenib 450 milligram (mg) once a day and binimetinib 45 mg twice a day until disease progression or no clinical benefit. No dose reduction below 150 mg for encorafenib and 15 mg for binimetinib was permitted for this study. Treatment cycle for encorafenib and binimetinib was defined as 21 days of daily continuous treatment.

Arm type

Experimental

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

450 mg once a day. No dose reduction below 150 mg.

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

45 mg twice a day. No dose reduction below 15 mg.

Part I: Encorafenib + Binimetinib (non-naive)

Arm description

Subjects non-naive to selective BRAF and MEK inhibitors, received encorafenib 450 mg once a day and binimetinib 45 mg twice a day until disease progression or no clinical benefit. No dose reduction below 150 mg for encorafenib and 15 mg for binimetinib was permitted for this study. Treatment cycle for both drugs was defined as 21 days of daily continuous treatment.

Arm type

Experimental

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

45 mg twice a day. No dose reduction below 15 mg.

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

450 mg once a day. No dose reduction below 150 mg.

Part II: Encorafenib + Binimetinib + Ribociclib

Arm description

Subejcts received encorafenib 200 mg (starting dose) once a day, binimetinib 45 mg (starting dose) twice a day and ribociclib 100 mg (starting dose) once a day until disease progression or no clinical benefit. No dose reduction below 50 mg for encorafenib and 15 mg for binimetinib was permitted for this study. For ribociclib dose escalation was allowed till 600 mg and dose reduction was permitted till 50 mg. Ribociclib was taken for 21 consecutive days followed by a 7-day planned break.

Arm type

Experimental

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

200 mg (starting dose) once a day. No dose reduction below 50 mg.

Investigational medicinal product name

Ribociclib

Investigational medicinal product code

LEE011

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

100 mg (starting dose) once a day. Dose escalation was allowed till 600 mg and dose reduction was permitted till 50 mg.

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

45 mg twice a day. No dose reduction below 15 mg.

Part II: Encorafenib + Binimetinib + Infigratinib

Arm description

Subjects received encorafenib 450 mg (starting dose) once a day, binimetinib 45 mg (starting dose) twice a day and infigratinib 75 mg (starting dose) once a day until disease progression or no clinical benefit. No dose reduction below 150 mg for encorafenib and 15 mg for binimetinib was permitted for this study. For infigratinib dose escalation was allowed till 125 mg and dose reduction was permitted till 25 mg. Infigratinib was taken for 21 consecutive days followed by a 7-day planned break.

Arm type

Experimental

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

450 mg once a day. No dose reduction below 150 mg.

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

45 mg twice a day. No dose reduction below 15 mg.

Investigational medicinal product name

Infigratinib

Investigational medicinal product code

BGJ398

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

75 mg (starting dose) once a day. Dose escalation was allowed till 125 mg and dose reduction was permitted till 25 mg.

Part II: Encorafenib + Binimetinib + Capmatinib

Arm description

Subjects received encorafenib 200 mg (starting dose) once a day, binimetinib 45 mg (starting dose) twice a day and capmatinib 200 mg (starting dose) capsule or 400 mg (starting dose) tablet twice a day until disease progression or no clinical benefit. No dose reduction below 50 mg for encorafenib and 15 mg for binimetinib was permitted for this study. For capmatinib dose escalation was allowed till 600 mg and dose reduction was permitted till 50 mg. Treatment cycle for encorafenib, binimetinib and capmatinib was defined as 21 days of daily continuous treatment.

Arm type

Experimental

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

200 mg (starting dose) once a day. No dose reduction below 50 mg.

Investigational medicinal product name

Capmatinib

Investigational medicinal product code

INC280

Other name

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

200 mg (starting dose) capsule or 400 mg (starting dose) tablet twice a day. Dose escalation was allowed till 600 mg and dose reduction was permitted till 50 mg.

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

45 mg twice a day. No dose reduction below 15 mg.

Part II: Encorafenib + Binimetinib + Buparlisib

Arm description

Subjects received encorafenib 450 mg (starting dose) once a day, binimetinib 45 mg (starting dose) twice a day and buparlisib 60 mg (starting dose) once a day until disease progression or no clinical benefit. No dose reduction below 150 mg for encorafenib and 15 mg for binimetinib was permitted for this study. For buparlisib dose escalation was allowed till 100 mg and dose reduction was permitted till 30 mg. Treatment cycle for encorafenib, binimetinib and buparlisib was defined as 21 days of daily continuous treatment.

Arm type

Experimental

Investigational medicinal product name

Encorafenib

Investigational medicinal product code

LGX818

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

450 mg once a day. No dose reduction below 150 mg.

Investigational medicinal product name

Binimetinib

Investigational medicinal product code

MEK162

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

45 mg twice a day. No dose reduction below 15 mg.

Investigational medicinal product name

Buparlisib

Investigational medicinal product code

BKM120

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

60 mg (starting dose) once a day. Dose escalation was allowed till 100 mg and dose reduction was permitted till 30 mg.

Number of subjects in period 1	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Started	75	83	38	1	13	6
Completed	0	4	0	0	0	0
Not completed	75	79	38	1	13	6
Adverse event, serious fatal	11	9	1	-	2	1
Physician decision	2	9	1	-	-	-
Subjects/Guardian Decision	9	3	-	-	2	-
Adverse event, non-fatal	7	5	1	-	1	1
Progressive Disease	37	46	35	1	7	4
Missing Data	1	-	-	-	-	-
Study Terminated by Sponsor	3	3	-	-	-	-
New Therapy for Study Indication	5	4	-	-	1	-

Baseline characteristics

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Reporting group title

Part I: Encorafenib + Binimetinib (naive)

Reporting group description

Reporting group title

Part I: Encorafenib + Binimetinib (non-naive)

Reporting group description

Reporting group title

Part II: Encorafenib + Binimetinib + Ribociclib

Reporting group description

Reporting group title

Part II: Encorafenib + Binimetinib + Infigratinib

Reporting group description

Reporting group title

Part II: Encorafenib + Binimetinib + Capmatinib

Reporting group description

Reporting group title

Part II: Encorafenib + Binimetinib + Buparlisib

Reporting group description

Notes
[1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
Justification: In Part I, 158 subjects were enrolled and out of these, 58 subjects entered Part II of the study.

Reporting group values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib	Total
Number of subjects	75	83	38	1	13	6	216
Age categorical
Subject in Infigratinib arm has been reported under "Not disclosed" category to avoid risk of identification of the subject.
Units: Subjects
18-44 years	14	24	9	0	0	1	48
45-64 years	43	37	19	0	7	4	110
65 years and over	18	22	10	0	6	1	57
Not disclosed	0	0	0	1	0	0	1
Age Continuous
"0" suggests that age of subject has been masked in Infigratinib arm to avoid risk of identification of the subject. "99999" suggests no standard deviation estimated as there was only 1 evaluable subject.
Units: years
arithmetic mean (standard deviation)	55.3 ( 12.91 )	53.9 ( 13.81 )	54.6 ( 13.85 )	0 ( 99999 )	63.5 ( 8.84 )	50.5 ( 10.50 )	-
Sex: Female, Male
Subject in Infigratinib arm has been reported under "Not disclosed" category to avoid risk of identification of the subject.
Units: Subjects
Female	28	39	22	0	5	1	95
Male	47	44	16	0	8	5	120
Not disclosed	0	0	0	1	0	0	1
Ethnicity (NIH/OMB)
Subject in Infigratinib arm has been reported under "Not disclosed" category to avoid risk of identification of the subject.
Units: Subjects
Hispanic or Latino	3	7	1	0	0	0	11
Not Hispanic or Latino	72	76	37	0	13	6	204
Not disclosed	0	0	0	1	0	0	1
Race, Customized
Race is reported. Subject in Infigratinib arm has been reported under "Not disclosed" category to avoid risk of identification of the subject.
Units: Subjects
Caucasian	74	82	37	0	13	6	212
Asian	1	1	1	0	0	0	3
Not disclosed	0	0	0	1	0	0	1

End points

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Reporting group title

Part I: Encorafenib + Binimetinib (naive)

Reporting group description

Reporting group title

Part I: Encorafenib + Binimetinib (non-naive)

Reporting group description

Reporting group title

Part II: Encorafenib + Binimetinib + Ribociclib

Reporting group description

Reporting group title

Part II: Encorafenib + Binimetinib + Infigratinib

Reporting group description

Reporting group title

Part II: Encorafenib + Binimetinib + Capmatinib

Reporting group description

Reporting group title

Part II: Encorafenib + Binimetinib + Buparlisib

Reporting group description

Subject analysis set title

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 60mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 450 mg/ binimetinib 45 mg + buparlisib 60 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 90mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 450 mg/ binimetinib 45 mg + buparlisib 90 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 450mg/Binimetinib 45mg+Infigratinib 75mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 450 mg/ binimetinib 45 mg + infigratinib 75 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 200mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 200 mg/ binimetinib 45 mg + capmatinib 200 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 300mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 200 mg/ binimetinib 45 mg + capmatinib 300 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 400mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 200 mg/ binimetinib 45 mg + capmatinib 400 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 100mg/Binimetinib 30mg+Ribociclib 600mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects in received encorafenib 100 mg/ binimetinib 30 mg + ribociclib 600 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 400mg

Subject analysis set type

Per protocol

Subject analysis set description

Subejcts in received encorafenib 200 mg/ binimetinib 30 mg + ribociclib 400 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 600mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects in received encorafenib 200 mg/ binimetinib 30 mg + ribociclib 600 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 400mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects in received encorafenib 200 mg/ binimetinib 45 mg + ribociclib 400 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 600mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 200 mg/ binimetinib 45 mg + ribociclib 600 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 60mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 450 mg/ binimetinib 45 mg + buparlisib 60 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 90mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 450 mg/ binimetinib 45 mg + buparlisib 90 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 450mg/Binimetinib 45mg+Infigratinib 75mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 450 mg/ binimetinib 45 mg + infigratinib 75 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 100mg/Binimetinib 30mg+Ribociclib 600mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 100 mg/ binimetinib 30 mg + ribociclib 600 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 400mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 200 mg/ binimetinib 30 mg + ribociclib 400 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 600mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 200 mg/ binimetinib 30 mg + ribociclib 600 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 400mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 200 mg/ binimetinib 45 mg + ribociclib 400 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Encorafenib 300mg/Binimetinib 30mg+Ribociclib 600mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 300 mg/ binimetinib 30 mg + ribociclib 600 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 450mg/Binimetinib 45mg+Ribociclib 600mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 450 mg/ binimetinib 45 mg + ribociclib 600 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 300mg/Binimetinib 30mg+Ribociclib 600mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 300 mg/ binimetinib 30 mg + ribociclib 600 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 450mg/Binimetinib 45mg+Ribociclib 600mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 450 mg/ binimetinib 45 mg + ribociclib 600 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 300mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 450 mg/ binimetinib 45 mg + capmatinib 300 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 400mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 200 mg/ binimetinib 45 mg + capmatinib 400 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 90mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 450 mg/ binimetinib 45 mg + buparlisib 90 mg. This subject analysis set is for PK related endpoint.

Subject analysis set title

Part II:Encorafenib 300mg/Binimetinib 30mg+Ribociclib 600mg

Subject analysis set type

Per protocol

Subject analysis set description

Subjects received encorafenib 300 mg/binimetinib 30 mg + ribociclib 600 mg. This subject analysis set is for PK related endpoint.

Primary: Overall Response Rate (ORR): Part II

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End point title

Overall Response Rate (ORR): Part II ^[1] ^[2]

End point description

ORR: percentage of subjects with confirmed complete response (CR) and partial response (PR). Response evaluation criteria in solid tumors (RECIST) v1.1: a) CR: disappearance of all non-nodal target lesions. Any pathological lymph nodes assigned as target lesions that had a reduction in short axis to <10 mm. Disappearance of all non-target lesions. All lymph nodes assigned a non-target lesion must be non-pathological in size (<10 mm short axis); b) PR: at least a 30 percent (%) decrease in sum of diameter of all target lesions, taking as reference baseline sum of diameters. Any radiological assessments taken >30 days after last dose of study therapy or after antineoplastic agents other than study treatments taken by subjects was excluded from the best overall response derivation. Confirmation of CR or PR was to be at least 4 weeks apart from previous radiological assessment. Full analysis set (FAS) for Part II evaluated.

End point type

Primary

End point timeframe

From the start of the treatment until disease/clinical progression or death or early study discontinuation, whichever happened earlier (maximum treatment exposure for Part II was 97.0 weeks)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only descriptive data was planned to be evaluated.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	38	1	13	6
Units: Percentage of subjects
number (confidence interval 95%)	2.6 (0.1 to 13.8)	0 (0 to 0)	0 (0.0 to 24.7)	0 (0.0 to 45.9)

No statistical analyses for this end point

Secondary: Number of Subjects With Dose Limiting Toxicities (DLTs) in Cycle 1: Part II

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End point title

Number of Subjects With Dose Limiting Toxicities (DLTs) in Cycle 1: Part II ^[3]

End point description

DLT was defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurred within the first cycle (first 21 days for infigratinib and capmatinib; 28 days for ribociclib and buparlisib) of treatment initiation and met the defined criteria for study. Dose-determining analysis set (DDS) consisted of all subjects from the safety set for Part II who met the minimum requirements for safety evaluation and minimum exposure or experienced DLT during the first cycle of the assigned triple combination treatment. No subjects were included in the dose-determining analysis set in the encorafenib/binimetinib+ infigratinib or buparlisib arm, hence no subjects analyzed for these reporting arms for this endpoint.

End point type

Secondary

End point timeframe

Cycle 1 (21 days following the first dose of the combination treatment with infigratinib and capmatinib; 28 days for the combination with ribociclib and buparlisib)

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	34	0 ^[4]	12	0 ^[5]
Units: Subjects	1		0

Notes
[4] - No subjects were included in the dose-determining analysis set.
[5] - No subjects were included in the dose-determining analysis set.

No statistical analyses for this end point

Secondary: Number of Subjects With Adverse Events (AEs) and Serious AEs (SAEs): Part I

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End point title

Number of Subjects With Adverse Events (AEs) and Serious AEs (SAEs): Part I ^[6]

End point description

An AE was defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that occurred after subjects signed informed consent has been obtained. An SAE was an AE resulting in any of the following outcomes: was fatal or life-threatening; resulted in persistent or significant disability/incapacity; constituted a congenital anomaly/birth defect; was medically significant; required inpatient hospitalization or prolongation of existing hospitalization. Safety set included all subjects who received at least 1 dose of encorafenib or binimetinib for Part I and had at least 1 valid post-baseline safety assessment.

End point type

Secondary

End point timeframe

Day 1 up to 30 days after last dose (maximum treatment exposure for Part I was 403.7 weeks)

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	75	83
Units: Subjects
AEs	75	78
SAEs	47	37

No statistical analyses for this end point

Secondary: Number of Subjects With AEs and SAEs: Part II

Top of page

End point title

Number of Subjects With AEs and SAEs: Part II ^[7]

End point description

An AE was defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), symptom(s), or medical condition(s) that occurred after subjects signed informed consent has been obtained. An SAE was an AE resulting in any of the following outcomes: was fatal or life-threatening; resulted in persistent or significant disability/incapacity; constituted a congenital anomaly/birth defect; was medically significant; required inpatient hospitalization or prolongation of existing hospitalization. Safety set included all subjects who received at least 1 dose of 3rd combination agent for Part II and had at least 1 valid post-baseline safety assessment.

End point type

Secondary

End point timeframe

Day 1 up to 30 days after last dose (maximum treatment exposure for Part II was 97.0 weeks)

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	38	1	13	6
Units: Subjects
AEs	37	1	12	6
SAEs	19	0	6	4

No statistical analyses for this end point

Secondary: Number of Subjects With Worst Post-baseline Hematology Results Based on Common Terminology Criteria for Adverse Events (CTCAE) Grade: Part I

Top of page

End point title

Number of Subjects With Worst Post-baseline Hematology Results Based on Common Terminology Criteria for Adverse Events (CTCAE) Grade: Part I ^[8]

End point description

Parameters evaluated were: Activated partial thromboplastin time (APTT) (seconds [sec]) - CTCAE graded high, fibrinogen (gram per liter [g/L]) - CTCAE graded low, hemoglobin (g/L) - CTCAE graded low, hemoglobin (g/L) - CTCAE graded high, prothrombin international normalized ratio (PINR) - CTCAE graded high, lymphocytes (10^9/L) - CTCAE graded low, lymphocytes (10^9/L) - CTCAE graded high, neutrophils (10^9/L) - CTCAE graded low, platelets (10^9/L) - CTCAE graded low, leukocytes (10^9/L) - CTCAE graded low, leukocytes (10^9/L) - CTCAE graded high. CTCAE version 4.03 was used: grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life-threatening consequences; grade 0 = values not meeting any of the criteria for grade 1 or higher. Safety set for Part I evaluated. In results reported below: post-baseline has been abbreviated as PB, graded high as GH and graded low as GL.

End point type

Secondary

End point timeframe

Baseline up to last dose (maximum treatment exposure for Part I was 403.7 weeks)

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	75	83
Units: Subjects
APTT-CTCAE GH Worst PB value Grade 0	46	54
Fibrinogen-CTCAE GL Worst PB value Grade 0	28	36
Hemoglobin-CTCAE GL Worst PB value Grade 0	21	17
Hemoglobin-CTCAE GH Worst PB value Grade 0	70	80
PINR -CTCAE GH Worst PB value Grade 0	44	34
Lymphocytes-CTCAE GL Worst PB value Grade 0	23	27
Lymphocytes-CTCAE GH Worst PB value Grade 0	61	68
Neutrophils-CTCAE GL Worst PB value Grade 0	52	62
Platelets-CTCAE GL Worst PB value Grade 0	59	71
Leukocytes-CTCAE GL Worst PB value Grade 0	52	61
Leukocytes-CTCAE GH Worst PB value Grade 0	66	78
APTT-CTCAE GH Worst PB value Grade 1	1	4
Fibrinogen-CTCAE GL Worst PB value Grade 1	8	9
Hemoglobin-CTCAE GL Worst PB value Grade 1	28	39
Hemoglobin-CTCAE GH Worst PB value Grade 1	4	2
PINR -CTCAE GH Worst PB value Grade 1	0	2
Lymphocytes-CTCAE GL Worst PB value Grade 1	22	24
Lymphocytes-CTCAE GH Worst PB value Grade 1	0	0
Neutrophils-CTCAE GL Worst PB value Grade 1	4	6
Platelets-CTCAE GL Worst PB value Grade 1	14	11
Leukocytes-CTCAE GL Worst PB value Grade 1	11	14
Leukocytes-CTCAE GH Worst PB value Grade 1	0	0
APTT -CTCAE GH Worst PB value Grade 2	0	0
Fibrinogen-CTCAE GL Worst PB value Grade 2	5	7
Hemoglobin-CTCAE GL Worst PB value Grade 2	18	20
Hemoglobin-CTCAE GH Worst PB value Grade 2	0	0
PINR-CTCAE GH Worst PB value Grade 2	0	0
Lymphocytes-CTCAE GL Worst PB value Grade 2	13	12
Lymphocytes-CTCAE GH Worst PB value Grade 2	2	6
Neutrophils-CTCAE GL Worst PB value Grade 2	5	4
Platelets-CTCAE GL Worst PB value Grade 2	2	0
Leukocytes-CTCAE GL Worst PB value Grade 2	3	3
Leukocytes-CTCAE GH Worst PB value Grade 2	0	0
APTT-CTCAE GH Worst PB value Grade 3	0	0
Fibrinogen-CTCAE GL Worst PB value Grade 3	4	1
Hemoglobin-CTCAE GL Worst PB value Grade 3	8	6
Hemoglobin-CTCAE GH Worst PB value Grade 3	1	0
PINR -CTCAE GH Worst PB value Grade 3	0	0
Lymphocytes-CTCAE GL Worst PB value Grade 3	6	10
Lymphocytes-CTCAE GH Worst PB value Grade 3	1	0
Neutrophils-CTCAE GL Worst PB value Grade 3	3	1
Platelets-CTCAE GL Worst PB value Grade 3	0	0
Leukocytes-CTCAE GL Worst PB value Grade 3	0	0
Leukocytes-CTCAE GH Worst PB value Grade 3	0	0
APTT -CTCAE GH Worst PB value Grade 4	0	0
Fibrinogen-CTCAE GL Worst PB value Grade 4	0	0
Hemoglobin-CTCAE GL Worst PB value Grade 4	0	0
Hemoglobin-CTCAE GH Worst PB value Grade 4	0	0
PINR-CTCAE GH Worst PB value Grade 4	0	0
Lymphocytes-CTCAE GL Worst PB value Grade 4	0	1
Lymphocytes-CTCAE GH Worst PB value Grade 4	0	0
Neutrophils-CTCAE GL Worst PB value Grade 4	0	0
Platelets-CTCAE GL Worst PB value Grade 4	0	0
Leukocytes-CTCAE GL Worst PB value Grade 4	0	0
Leukocytes-CTCAE GH Worst PB value Grade 4	0	0
APTT -CTCAE GH Worst PB value Missing	28	25
Fibrinogen-CTCAE GL Worst PB value Missing	30	30
Hemoglobin-CTCAE GL Worst PB value Missing	0	1
Hemoglobin-CTCAE GH Worst PB value Missing	0	1
PINR -CTCAE GH Worst PB value Missing	31	47
Lymphocytes-CTCAE GL Worst PB value Missing	11	9
Lymphocytes-CTCAE GH Worst PB value Missing	11	9
Neutrophils-CTCAE GL Worst PB value Missing	11	10
Platelets-CTCAE GL Worst PB value Missing	0	1
Leukocytes-CTCAE GL Worst PB value Missing	9	5
Leukocytes-CTCAE GH Worst PB value Missing	9	5

No statistical analyses for this end point

Secondary: Number of Subjects With Worst Post-baseline Hematology Results Based on CTCAE Grade: Part II

Top of page

End point title

Number of Subjects With Worst Post-baseline Hematology Results Based on CTCAE Grade: Part II ^[9]

End point description

Parameters evaluated were: APTT (sec) - CTCAE graded high, fibrinogen (g/L) - CTCAE graded low, hemoglobin (g/L) - CTCAE graded low, hemoglobin (g/L) - CTCAE graded high, PINR - CTCAE graded high, lymphocytes (10^9/L) - CTCAE graded low, lymphocytes (10^9/L) - CTCAE graded high, neutrophils (10^9/L) - CTCAE graded low, platelets (10^9/L) - CTCAE graded low, leukocytes (10^9/L) - CTCAE graded low, leukocytes (10^9/L) - CTCAE graded high. CTCAE version 4.03 was used: grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life-threatening consequences; grade 0 = values not meeting any of the criteria for grade 1 or higher. Safety set included all subjects who received at least 1 dose of 3rd combination agent for Part II and had at least 1 valid post-baseline safety assessment. In results reported below: post-baseline has been abbreviated as PB, graded high as GH and graded low as GL

End point type

Secondary

End point timeframe

Baseline up to last dose (maximum treatment exposure for Part II was 97.0 weeks)

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	38	1	13	6
Units: Subjects
APTT-CTCAE GH Worst PB value Grade 0	27	1	9	4
Fibrinogen-CTCAE GL Worst PB value Grade 0	13	0	6	3
Hemoglobin-CTCAE GL Worst PB value Grade 0	4	0	4	2
Hemoglobin-CTCAE GH Worst PB value Grade 0	37	1	11	6
PINR-CTCAE GH Worst PB value Grade 0	14	1	8	1
Lymphocytes -CTCAE GL Worst PB value Grade 0	5	0	4	2
Lymphocytes-CTCAE GH Worst PB value Grade 0	29	0	11	6
Neutrophils-CTCAE GL Worst PB value Grade 0	10	0	11	6
Platelets-CTCAE GL Worst PB value Grade 0	33	1	11	6
Leukocytes-CTCAE GL Worst PB value Grade 0	8	0	11	6
Leukocytes-CTCAE GH Worst PB value Grade 0	31	0	11	6
APTT-CTCAE GH Worst PB value Grade 1	0	0	0	0
Fibrinogen-CTCAE GL Worst PB value Grade 1	3	1	1	0
Hemoglobin-CTCAE GL Worst PB value Grade 1	15	1	5	1
Hemoglobin-CTCAE GH Worst PB value Grade 1	0	0	1	0
PINR-CTCAE GH Worst PB value Grade 1	0	0	0	0
Lymphocytes -CTCAE GL Worst PB value Grade 1	7	0	4	3
Lymphocytes-CTCAE GH Worst PB value Grade 1	0	0	0	0
Neutrophils-CTCAE GL Worst PB value Grade 1	9	0	0	0
Platelets-CTCAE GL Worst PB value Grade 1	4	0	1	0
Leukocytes-CTCAE GL Worst PB value Grade 1	8	0	0	0
Leukocytes-CTCAE GH Worst PB value Grade 1	0	0	0	0
APTT-CTCAE GH Worst PB value Grade 2	0	0	0	0
Fibrinogen-CTCAE GL Worst PB value Grade 2	2	0	1	0
Hemoglobin-CTCAE GL Worst PB value Grade 2	14	0	2	1
Hemoglobin-CTCAE GH Worst PB value Grade 2	0	0	0	0
PINR-CTCAE GH Worst PB value Grade 2	0	0	0	0
Lymphocytes-CTCAE GL Worst PB value Grade 2	9	0	3	1
Lymphocytes-CTCAE GH Worst PB value Grade 2	0	0	0	0
Neutrophils-CTCAE GL Worst PB value Grade 2	6	0	0	0
Platelets-CTCAE GL Worst PB value Grade 2	0	0	0	0
Leukocytes-CTCAE GL Worst PB value Grade 2	12	0	0	0
Leukocytes-CTCAE GH Worst PB value Grade 2	0	0	0	0
APTT-CTCAE GH Worst PB value Grade 3	0	0	0	0
Fibrinogen-CTCAE GL Worst PB value Grade 3	1	0	0	0
Hemoglobin-CTCAE GL Worst PB value Grade 3	4	0	1	2
Hemoglobin-CTCAE GH Worst PB value Grade 3	0	0	0	0
PINR-CTCAE GH Worst PB value Grade 3	0	0	0	0
Lymphocytes-CTCAE GL Worst PB value Grade 3	7	0	0	0
Lymphocytes-CTCAE GH Worst PB value Grade 3	0	0	0	0
Neutrophils-CTCAE GL Worst PB value Grade 3	1	0	0	0
Platelets-CTCAE GL Worst PB value Grade 3	0	0	0	0
Leukocytes-CTCAE GL Worst PB value Grade 3	3	0	0	0
Leukocytes-CTCAE GH Worst PB value Grade 3	0	0	0	0
APTT-CTCAE GH Worst PB value Grade 4	0	0	0	0
Fibrinogen-CTCAE GL Worst PB value Grade 4	0	0	0	0
Hemoglobin-CTCAE GL Worst PB value Grade 4	0	0	0	0
Hemoglobin-CTCAE GH Worst PB value Grade 4	0	0	0	0
PINR-CTCAE GH Worst PB value Grade 4	0	0	0	0
Lymphocytes-CTCAE GL Worst PB value Grade 4	1	0	0	0
Lymphocytes-CTCAE GH Worst PB value Grade 4	0	0	0	0
Neutrophils-CTCAE GL Worst PB value Grade 4	1	0	0	0
Platelets-CTCAE GL Worst PB value Grade 4	0	0	0	0
Leukocytes-CTCAE GL Worst PB value Grade 4	0	0	0	0
Leukocytes-CTCAE GH Worst PB value Grade 4	0	0	0	0
APTT-CTCAE GH Worst PB value Missing	11	0	4	2
Fibrinogen-CTCAE GL Worst PB value Missing	19	0	5	3
Hemoglobin-CTCAE GL Worst PB value Missing	1	0	1	0
Hemoglobin-CTCAE GH Worst PB value Missing	1	0	1	0
PINR-CTCAE GH Worst PB value Missing	24	0	5	5
Lymphocytes-CTCAE GL Worst PB value Missing	9	1	2	0
Lymphocytes-CTCAE GH Worst PB value Missing	9	1	2	0
Neutrophils-CTCAE GL Worst PB value Missing	11	1	2	0
Platelets-CTCAE GL Worst PB value Missing	1	0	1	0
Leukocytes-CTCAE GL Worst PB value Missing	7	1	2	0
Leukocytes-CTCAE GH Worst PB value Missing	7	1	2	0

No statistical analyses for this end point

Secondary: Number of Subjects With Worst Post-baseline Serum Chemistry Results Based on CTCAE Grade: Part I

Top of page

End point title

Number of Subjects With Worst Post-baseline Serum Chemistry Results Based on CTCAE Grade: Part I ^[10]

End point description

Albumin (g/L)-CTCAE graded low, alkaline phosphatase (units per liter [U/L])-CTCAE graded high, alanine aminotransferase (AT) (U/L)-CTCAE graded high, amylase (U/L)-CTCAE graded high, aspartate AT (U/L)-CTCAE graded high, bilirubin (micromole per liter [umol/L])-CTCAE graded high, creatinine (umol/L)-CTCAE graded high, creatine kinase (U/L)-CTCAE graded high, gamma glutamyl transferase (GT) (U/L)-CTCAE graded high, glucose (millimole per liter [mmol/L])-CTCAE graded low, high, potassium (mmol/L)-CTCAE graded low, potassium (mmol/L)-CTCAE graded high, magnesium (mmol/L)-CTCAE graded low, high, phosphate (mmol/L)- CTCAE graded low, sodium (mmol/L)-CTCAE graded low, sodium (mmol/L)-CTCAE graded high, urate (umol/L)-CTCAE graded high. Grade 1=mild, grade 2=moderate, grade 3=severe, grade 4=life-threatening consequences; grade 0=values not meeting any of the criteria for >=grade 1. Safety set for Part I evaluated. In rows below, graded low=GL, graded high=GH, post-baseline value=PBV

End point type

Secondary

End point timeframe

Baseline up to last dose (maximum treatment exposure for Part I was 403.7 weeks)

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	75	83
Units: Subjects
Albumin-CTCAE GL Worst PBV Grade 0	32	40
Alkaline Phosphatase-CTCAE GH Worst PBV Grade 0	39	43
Alanine AT-CTCAE GH Worst PBV Grade 0	38	51
Amylase-CTCAE GH Worst PBV Grade 0	53	52
Aspartate AT-CTCAE GH Worst PBV Grade 0	38	50
Bilirubin-CTCAE GH Worst PBV Grade 0	73	81
Creatine Kinase-CTCAE GH Worst PBV Grade 0	22	56
Creatinine-CTCAE GH Worst PBV Grade 0	2	4
Gamma GT-CTCAE GH Worst PBV Grade 0	20	33
Glucose-CTCAE GL Worst PBV Grade 0	55	67
Glucose-CTCAE GH Worst PBV Grade 0	56	60
Potassium-CTCAE GL Worst PBV Grade 0	65	74
Potassium-CTCAE GH Worst PBV Grade 0	54	66
Magnesium-CTCAE GL Worst PBV Grade 0	66	68
Magnesium-CTCAE GH Worst PBV Grade 0	74	79
Phosphate-CTCAE GL Worst PBV Grade 0	40	62
Sodium-CTCAE GL Worst PBV Grade 0	54	53
Sodium-CTCAE GH Worst PBV Grade 0	66	75
Urate-CTCAE GH Worst PBV Grade 0	75	82
Albumin-CTCAE GL Worst PBV Grade 1	35	29
Alkaline Phosphatase-CTCAE GH Worst PBV Grade 1	28	31
Alanine AT-CTCAE GH Worst PBV Grade 1	27	28
Amylase-CTCAE GH Worst PBV Grade 1	14	6
Aspartate AT-CTCAE GH Worst PBV Grade 1	30	29
Bilirubin-CTCAE GH Worst PBV Grade 1	1	0
Creatine Kinase-CTCAE GH Worst PBV Grade 1	30	15
Creatinine-CTCAE GH Worst PBV Grade 1	57	56
Gamma GT-CTCAE GH Worst PBV Grade 1	19	18
Glucose-CTCAE GL Worst PBV Grade 1	15	7
Glucose-CTCAE GH Worst PBV Grade 1	4	10
Potassium-CTCAE GL Worst PBV Grade 1	7	5
Potassium-CTCAE GH Worst PBV Grade 1	18	15
Magnesium-CTCAE GL Worst PBV Grade 1	8	14
Magnesium-CTCAE GH Worst PBV Grade 1	1	3
Phosphate-CTCAE GL Worst PBV Grade 1	3	3
Sodium-CTCAE GL Worst PBV Grade 1	21	24
Sodium-CTCAE GH Worst PBV Grade 1	9	6
Urate-CTCAE GH Worst PBV Grade 1	0	0
Albumin-CTCAE GL Worst PBV Grade 2	8	12
Alkaline Phosphatase-CTCAE GH Worst PBV Grade 2	5	5
Alanine AT-CTCAE GH Worst PBV Grade 2	5	2
Amylase-CTCAE GH Worst PBV Grade 2	5	2
Aspartate AT-CTCAE GH Worst PBV Grade 2	4	2
Bilirubin-CTCAE GH Worst PBV Grade 2	1	0
Creatine Kinase-CTCAE GH Worst PBV Grade 2	18	8
Creatinine-CTCAE GH Worst PBV Grade 2	14	22
Gamma GT-CTCAE GH Worst PBV Grade 2	14	13
Glucose-CTCAE GL Worst PBV Grade 2	1	1
Glucose-CTCAE GH Worst PBV Grade 2	3	0
Potassium-CTCAE GL Worst PBV Grade 2	0	0
Potassium-CTCAE GH Worst PBV Grade 2	2	0
Magnesium-CTCAE GL Worst PBV Grade 2	0	0
Magnesium-CTCAE GH Worst PBV Grade 2	0	0
Phosphate-CTCAE GL Worst PBV Grade 2	24	12
Sodium-CTCAE GL Worst PBV Grade 2	0	0
Sodium-CTCAE GH Worst PBV Grade 2	0	1
Urate-CTCAE GH Worst PBV Grade 2	0	0
Albumin-CTCAE GL Worst PBV Grade 3	0	1
Alkaline Phosphatase-CTCAE GH Worst PBV Grade 3	3	3
Alanine AT-CTCAE GH Worst PBV Grade 3	5	0
Amylase-CTCAE GH Worst PBV Grade 3	2	2
Aspartate AT-CTCAE GH Worst PBV Grade 3	3	1
Bilirubin-CTCAE GH Worst PBV Grade 3	0	1
Creatine Kinase-CTCAE GH Worst PBV Grade 3	4	2
Creatinine-CTCAE GH Worst PBV Grade 3	2	0
Gamma GT-CTCAE GH Worst PBV Grade 3	20	15
Glucose-CTCAE GL Worst PBV Grade 3	0	0
Glucose-CTCAE GH Worst PBV Grade 3	7	5
Potassium-CTCAE GL Worst PBV Grade 3	3	3
Potassium-CTCAE GH Worst PBV Grade 3	1	0
Magnesium-CTCAE GL Worst PBV Grade 3	1	0
Magnesium-CTCAE GH Worst PBV Grade 3	0	0
Phosphate-CTCAE GL Worst PBV Grade 3	8	4
Sodium-CTCAE GL Worst PBV Grade 3	0	5
Sodium-CTCAE GH Worst PBV Grade 3	0	0
Urate-CTCAE GH Worst PBV Grade 3	0	0
Albumin-CTCAE GL Worst PBV Grade 4	0	0
Alkaline Phosphatase-CTCAE GH Worst PBV Grade 4	0	0
Alanine AT-CTCAE GH Worst PBV Grade 4	0	0
Amylase-CTCAE GH Worst PBV Grade 4	0	1
Aspartate AT-CTCAE GH Worst PBV Grade 4	0	0
Bilirubin-CTCAE GH Worst PBV Grade 4	0	0
Creatine Kinase-CTCAE GH Worst PBV Grade 4	1	1
Creatinine-CTCAE GH Worst PBV Grade 4	0	0
Gamma GT-CTCAE GH Worst PBV Grade 4	2	3
Glucose-CTCAE GL Worst PBV Grade 4	0	0
Glucose-CTCAE GH Worst PBV Grade 4	1	0
Potassium-CTCAE GL Worst PBV Grade 4	0	0
Potassium-CTCAE GH Worst PBV Grade 4	0	1
Magnesium-CTCAE GL Worst PBV Grade 4	0	0
Magnesium-CTCAE GH Worst PBV Grade 4	0	0
Phosphate-CTCAE GL Worst PBV Grade 4	0	1
Sodium-CTCAE GL Worst PBV Grade 4	0	0
Sodium-CTCAE GH Worst PBV Grade 4	0	0
Urate-CTCAE GH Worst PBV Grade 4	0	0
Albumin-CTCAE GL Worst PBV Missing	0	1
Alkaline Phosphatase-CTCAE GH Worst PBV Missing	0	1
Alanine AT-CTCAE GH Worst PBV Missing	0	2
Amylase-CTCAE GH Worst PBV Missing	1	20
Aspartate AT-CTCAE GH Worst PBV Missing	0	1
Bilirubin-CTCAE GH Worst PBV Missing	0	1
Creatine Kinase-CTCAE GH Worst PBV Missing	0	1
Creatinine-CTCAE GH Worst PBV Missing	0	1
Gamma GT-CTCAE GH Worst PBV Missing	0	1
Glucose-CTCAE GL Worst PBV Missing	4	8
Glucose-CTCAE GH Worst PBV Missing	4	8
Potassium-CTCAE GL Worst PBV Missing	0	1
Potassium-CTCAE GH Worst PBV Missing	0	1
Magnesium-CTCAE GL Worst PBV Missing	0	1
Magnesium-CTCAE GH Worst PBV Missing	0	1
Phosphate-CTCAE GL Worst PBV Missing	0	1
Sodium-CTCAE GL Worst PBV Missing	0	1
Sodium-CTCAE GH Worst PBV Missing	0	1
Urate-CTCAE GH Worst PBV Missing	0	1

No statistical analyses for this end point

Secondary: Number of Subjects With Worst Post-baseline Serum Chemistry Results Based on CTCAE Grade: Part II

Top of page

End point title

Number of Subjects With Worst Post-baseline Serum Chemistry Results Based on CTCAE Grade: Part II ^[11]

End point description

Albumin (g/L)- CTCAE graded low, alkaline phosphatase (U/L)- CTCAE graded high, alanine AT (U/L)- CTCAE graded high, amylase (U/L) - CTCAE graded high, aspartate AT (U/L)- CTCAE graded high, bilirubin (umol/L)- CTCAE graded high, creatinine (umol/L) - CTCAE graded high, creatine kinase (U/L)- CTCAE graded high, gamma GT (U/L)- CTCAE graded high, glucose (mmol/L)- CTCAE graded low, high, potassium (mmol/L)- CTCAE graded low, potassium (mmol/L)- CTCAE graded high, magnesium (mmol/L)- CTCAE graded low, high, phosphate (mmol/L)- CTCAE graded low, sodium (mmol/L)- CTCAE graded low, sodium (mmol/L)- CTCAE graded high, urate (umol/L)- CTCAE graded high. Grade 1= mild, Grade 2= moderate, Grade 3= severe, Grade 4= life-threatening consequences; Grade 0= values not meeting any of the criteria for >=grade 1. Safet set for Part II evaluated. In rows below, graded low=GL, graded high=GH, post-baseline value=PBV.

End point type

Secondary

End point timeframe

Baseline up to last dose (maximum treatment exposure for Part II was 97.0 weeks)

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	38	1	13	6
Units: Subjects
Albumin-CTCAE GL Worst PBV Grade 0	16	1	1	3
Alkaline Phosphatase-CTCAE GH Worst PBV Grade 0	22	1	7	1
Alanine AT-CTCAE GH Worst PBV Grade 0	27	1	9	4
Amylase-CTCAE GH Worst PBV Grade 0	27	1	9	1
Aspartate AT-CTCAE GH Worst PBV Grade 0	27	1	8	3
Bilirubin-CTCAE GH Worst PBV Grade 0	37	1	12	6
Creatine Kinase-CTCAE GH Worst PBV Grade 0	20	0	6	3
Creatinine-CTCAE GH Worst PBV Grade 0	1	0	0	1
Gamma GT-CTCAE GH Worst PBV Grade 0	20	1	5	0
Glucose -CTCAE GL Worst PBV Grade 0	24	0	11	5
Glucose-CTCAE GH Worst PBV Grade 0	26	1	10	4
Potassium -CTCAE GL Worst PBV Grade 0	34	1	11	5
Potassium-CTCAE GH Worst PBV Grade 0	32	1	9	3
Magnesium -CTCAE GL Worst PBV Grade 0	35	1	10	4
Magnesium-CTCAE GH Worst PBV Grade 0	36	1	12	5
Phosphate -CTCAE GL Worst PBV Grade 0	25	1	7	4
Sodium-CTCAE GL Worst PBV Grade 0	28	1	10	3
Sodium-CTCAE GH Worst PBV Grade 0	35	1	12	4
Urate-CTCAE GH Worst PBV Grade 0	37	1	12	5
Albumin-CTCAE GL Worst PBV Grade 1	13	0	6	0
Alkaline Phosphatase-CTCAE GH Worst PBV Grade 1	10	0	3	4
Alanine AT-CTCAE GH Worst PBV Grade 1	6	0	2	1
Amylase-CTCAE GH Worst PBV Grade 1	1	0	2	0
Aspartate AT-CTCAE GH Worst PBV Grade 1	6	0	4	2
Bilirubin-CTCAE GH Worst PBV Grade 1	0	0	0	0
Creatine Kinase-CTCAE GH Worst PBV Grade 1	14	1	4	2
Creatinine-CTCAE GH Worst PBV Grade 1	25	1	4	3
Gamma GT-CTCAE GH Worst PBV Grade 1	9	0	2	1
Glucose -CTCAE GL Worst PBV Grade 1	6	1	1	0
Glucose-CTCAE GH Worst PBV Grade 1	2	0	1	1
Potassium-CTCAE GL Worst PBV Grade 1	3	0	1	0
Potassium-CTCAE GH Worst PBV Grade 1	4	0	3	2
Magnesium -CTCAE GL Worst PBV Grade 1	2	0	2	1
Magnesium-CTCAE GH Worst PBV Grade 1 1	1	0	0	0
Phosphate -CTCAE GL Worst PBV Grade 1	2	0	1	1
Sodium-CTCAE GL Worst PBV Grade 1	7	0	2	2
Sodium-CTCAE GH Worst PBV Grade 1	2	0	0	1
Urate-CTCAE GH Worst PBV Grade 1	0	0	0	0
Albumin-CTCAE GL Worst PBV Grade 2	7	0	3	1
Alkaline Phosphatase-CTCAE GH Worst PBV Grade 2	3	0	2	1
Alanine AT-CTCAE GH Worst PBV Grade 2	2	0	0	0
Amylase-CTCAE GH Worst PBV Grade 2	0	0	0	1
Aspartate AT-CTCAE GH Worst PBV Grade 2	3	0	0	0
Bilirubin-CTCAE GH Worst PBV Grade 2	0	0	0	0
Creatine Kinase-CTCAE GH Worst PBV Grade 2	3	0	0	0
Creatinine-CTCAE GH Worst PBV Grade 2	11	0	8	1
Gamma GT-CTCAE GH Worst PBV Grade 2	1	0	2	2
Glucose -CTCAE GL Worst PBV Grade 2	0	0	0	0
Glucose-CTCAE GH Worst PBV Grade 2	0	0	0	0
Potassium -CTCAE GL Worst PBV Grade 2	0	0	0	0
Potassium-CTCAE GH Worst PBV Grade 2	1	0	0	0
Magnesium -CTCAE GL Worst PBV Grade 2	0	0	0	0
Magnesium-CTCAE GH Worst PBV Grade 2	0	0	0	0
Phosphate -CTCAE GL Worst PBV Grade 2	7	0	3	0
Sodium-CTCAE GL Worst PBV Grade 2	0	0	0	0
Sodium-CTCAE GH Worst PBV Grade 2	0	0	0	0
Urate-CTCAE GH Worst PBV Grade 2	0	0	0	0
Albumin-CTCAE GL Worst PBV Grade 3	1	0	2	1
Alkaline Phosphatase-CTCAE GH Worst PBV Grade 3	2	0	0	0
Alanine AT-CTCAE GH Worst PBV Grade 3	1	0	1	0
Amylase-CTCAE GH Worst PBV Grade 3	0	0	0	0
Aspartate AT-CTCAE GH Worst PBV Grade 3	1	0	0	1
Bilirubin-CTCAE GH Worst PBV Grade 3	0	0	0	0
Creatine Kinase-CTCAE GH Worst PBV Grade 3	0	0	2	0
Creatinine-CTCAE GH Worst PBV Grade 3	0	0	0	0
Gamma GT-CTCAE GH Worst PBV Grade 3	7	0	3	3
Glucose -CTCAE GL Worst PBV Grade 3	0	0	0	0
Glucose-CTCAE GH Worst PBV Grade 3	1	0	1	0
Potassium -CTCAE GL Worst PBV Grade 3	0	0	0	0
Potassium-CTCAE GH Worst PBV Grade 3	0	0	0	0
Magnesium -CTCAE GL Worst PBV Grade 3	0	0	0	0
Magnesium-CTCAE GH Worst PBV Grade 3	0	0	0	0
Phosphate -CTCAE GL Worst PBV Grade 3	1	0	1	0
Sodium-CTCAE GL Worst PBV Grade 3	2	0	0	0
Sodium-CTCAE GH Worst PBV Grade 3	0	0	0	0
Urate-CTCAE GH Worst PBV Grade 3	0	0	0	0
Albumin-CTCAE GL Worst PBV Grade 4	0	0	0	0
Alkaline Phosphatase-CTCAE GH Worst PBV Grade 4	0	0	0	0
Alanine AT-CTCAE GH Worst PBV Grade 4	1	0	0	1
Amylase-CTCAE GH Worst PBV Grade 4	2	0	0	0
Aspartate AT-CTCAE GH Worst PBV Grade 4	0	0	0	0
Bilirubin-CTCAE GH Worst PBV Grade 4	0	0	0	0
Creatine Kinase-CTCAE GH Worst PBV Grade 4	0	0	0	0
Creatinine-CTCAE GH Worst PBV Grade 4	0	0	0	0
Gamma GT-CTCAE GH Worst PBV Grade 4	0	0	0	0
Glucose-CTCAE GL Worst PBV Grade 4	0	0	0	0
Glucose-CTCAE GH Worst PBV Grade 4	1	0	0	0
Potassium-CTCAE GL Worst PBV Grade 4	0	0	0	0
Potassium-CTCAE GH Worst PBV Grade 4	0	0	0	0
Magnesium-CTCAE GL Worst PBV Grade 4	0	0	0	0
Magnesium-CTCAE GH Worst PBV Grade 4	0	0	0	0
Phosphate-CTCAE GL Worst PBV Grade 4	2	0	0	0
Sodium-CTCAE GL Worst PBV Grade 4	0	0	0	0
Sodium-CTCAE GH Worst PBV Grade 4	0	0	0	0
Urate-CTCAE GH Worst PBV Grade 4	0	0	0	0
Albumin-CTCAE GL Worst PBV Missing	1	0	1	1
Alkaline Phosphatase-CTCAE GH Worst PBV Missing	1	0	1	0
Alanine AT-CTCAE GH Worst PBV Missing	1	0	1	0
Amylase-CTCAE GH Worst PBV Missing	8	0	2	4
Aspartate AT-CTCAE GH Worst PBV Missing	1	0	1	0
Bilirubin-CTCAE GH Worst PBV Missing	1	0	1	0
Creatine Kinase-CTCAE GH Worst PBV Missing	1	0	1	1
Creatinine-CTCAE GH Worst PBV Missing	1	0	1	1
Gamma GT-CTCAE GH Worst PBV Missing	1	0	1	0
Glucose-CTCAE GL Worst PBV Missing	8	0	1	1
Glucose-CTCAE GH Worst PBV Missing	8	0	1	1
Potassium-CTCAE GL Worst PBV Missing	1	0	1	1
Potassium-CTCAE GH Worst PBV Missing	1	0	1	1
Magnesium-CTCAE GL Worst PBV Missing	1	0	1	1
Magnesium-CTCAE GH Worst PBV Missing	1	0	1	1
Phosphate-CTCAE GL Worst PBV Missing	1	0	1	1
Sodium-CTCAE GL Worst PBV Missing	1	0	1	1
Sodium-CTCAE GH Worst PBV Missing	1	0	1	1
Urate-CTCAE GH Worst PBV Missing	1	0	1	1

No statistical analyses for this end point

Secondary: Number of Subjects With Newly Occurring Notably Abnormal Vital Signs: Part I

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End point title

Number of Subjects With Newly Occurring Notably Abnormal Vital Signs: Part I ^[12]

End point description

Vital signs evaluated were: Low/high systolic blood pressure (BP) (millimeter of Mercury [mmHg]): less than or equal to (<=) 90 mmHg with decrease from baseline of >=20 mmHg / >=160 mmHg with increase from baseline of >=20 mmHg; low/high diastolic BP [mmHg]: <=50 mmHg with decrease from baseline of >=15 mmHg / >=100 mmHg with increase from baseline of >=15 mmHg; low/high pulse rate (beats per minute [bpm]): <=50 bpm with decrease from baseline of >=15 bpm / >=120 bpm with increase from baseline of >=15 bpm; low/high weight (kilogram [kg]): >=20% decrease/increase from baseline; and low/high body temperature (degree Celsius [C]): <=36 C / >= 37.5 C. Safety set for Part I evaluated. All subjects reported under ‘Number of Subjects Analyzed’ contributed data to the table but may not have evaluable data for every row. Here, "n" signifies number of subjects evaluable for specified rows.

End point type

Secondary

End point timeframe

During study treatment (maximum treatment exposure for Part I was 403.7 weeks)

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	75	83
Units: Subjects
Sitting Pulse Rate: High (n= 75, 79)	2	8
Sitting Pulse Rate: Low (n= 75, 80)	5	4
Sitting Systolic BP: High (n= 74, 80)	18	5
Sitting Systolic BP: Low (n= 75, 78)	3	2
Sitting Diastolic BP: High (n= 75, 79)	11	4
Sitting Diastolic BP: Low (n= 74, 80)	5	3
Weight: High (n= 74, 71)	0	2
Weight: Low (n= 74, 71)	0	0
Body temperature: High (n= 74, 79)	14	14
Body temperature: Low (n= 60, 71)	44	36

No statistical analyses for this end point

Secondary: Number of Subjects With Newly Occurring Notably Abnormal Vital Signs: Part II

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End point title

Number of Subjects With Newly Occurring Notably Abnormal Vital Signs: Part II ^[13]

End point description

Vital signs evaluated were: Low/high systolic BP (mmHg): <=90 mmHg with decrease from baseline of >=20 mmHg / >=160 mmHg with increase from baseline of >=20 mmHg; low/high diastolic BP [mmHg]: <=50 mmHg with decrease from baseline of >=15 mmHg / >=100 mmHg with increase from baseline of >=15 mmHg; low/high pulse rate (bpm): <=50 bpm with decrease from baseline of >=15 bpm / >=120 bpm with increase from baseline of >=15 bpm; low/high weight (kg): >=20% decrease/increase from baseline; and low/high body temperature (C): <=36 C / >= 37.5 C. Safety set for Part II evaluated. All subjects reported under ‘Number of Subjects Analyzed’ contributed data to the table but may not have evaluable data for every row. Here, "n" signifies number of subjects evaluable for specified rows.

End point type

Secondary

End point timeframe

During study treatment (maximum treatment exposure for Part II was 97.0 weeks)

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	38	1	13	6
Units: Subjects
Sitting Pulse Rate: High (n= 37, 1, 13, 6)	2	0	0	1
Sitting Pulse Rate: Low (n= 37, 1, 13, 6)	1	0	0	0
Sitting Systolic BP: High (n= 37, 1, 11, 6)	2	0	4	0
Sitting Systolic BP: Low (n= 37, 1, 13, 6)	0	0	0	0
Sitting Diastolic BP: High (n= 37, 1, 13, 6)	2	0	1	0
Sitting Diastolic BP: Low (n= 37, 1, 13, 6)	1	0	0	0
Weight: High (n= 36, 1, 13, 5)	0	0	0	0
Weight: Low (n= 36, 1, 13, 5)	1	0	0	0
Body temperature: High (n= 36, 1, 13, 6)	3	0	1	1
Body temperature: Low (n= 30, 1, 11, 5)	14	1	6	3

No statistical analyses for this end point

Secondary: Number of Subjects With Notable Electrocardiograms (ECG) Values: Part I

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End point title

Number of Subjects With Notable Electrocardiograms (ECG) Values: Part I ^[14]

End point description

Abnormality categories were: Heart rate (HR): increase from baseline >25% and to a value >100 bpm, decrease from baseline >25% and to a value <60 bpm; PR: increase from baseline >25% and to a value >200 millisecond (ms); QRS: increase from baseline >25% and to a value >110 ms; QT: increase from baseline >30 ms, increase from baseline >60 ms, new interval >450 ms, new interval >480 ms, new interval >500 ms; and Corrected QT interval by Fridericia (QTcF): increase from baseline >30 ms, increase from baseline >60 ms, new interval >450 ms, new interval >480 ms, new interval >500 ms. New = newly occurred post-baseline value. Safety set for Part I evaluated. All subjects reported under ‘Number of Subjects Analyzed’ contributed data to the table but may not have evaluable data for every row. Here, "n" signifies number of subjects evaluable for specified rows. In results reported below, increase from baseline has been abbreviated as IFB, and decrease from baseline as DFB.

End point type

Secondary

End point timeframe

During study treatment (maximum treatment exposure for Part I was 403.7 weeks)

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	75	83
Units: Subjects
HR: IFB >25% & to a value >100 bpm (n = 74, 80)	10	5
HR: DFB>25% & to a value <60 bpm (n = 74, 80)	37	23
PR: IFB >25% & to a value >200 ms (n = 72, 80)	5	1
QRS: IFB >25% & to a value >110 ms (n = 75, 80)	3	0
QT: IFB >30 ms (n = 75, 80)	61	48
QT: IFB >60 ms (n = 75, 80)	29	15
QT: New Interval >450 ms (n = 75, 78)	24	4
QT: New Interval >480 ms (n = 75, 80)	5	3
QT: New Interval >500 ms (n = 75, 80)	3	0
QTcF: IFB >30 ms (n = 75, 80)	46	31
QTcF: IFB >60 ms (n = 75, 80)	4	2
QTcF: New Interval >450 ms (n = 74, 77)	28	15
QTcF: New Interval >480 ms (n = 75, 80)	4	0
QTcF: New Interval >500 ms (n = 75, 80)	1	0

No statistical analyses for this end point

Secondary: Number of Subjects With Notable ECG Values: Part II

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End point title

Number of Subjects With Notable ECG Values: Part II ^[15]

End point description

Abnormality categories were: HR: increase from baseline >25% and to a value >100 bpm, decrease from baseline >25% and to a value <60 bpm; PR: increase from baseline >25% and to a value >200 ms; QRS: increase from baseline >25% and to a value >110 ms; QT: increase from baseline >30 ms, increase from baseline >60 ms, new interval >450 ms, new interval >480 ms, new interval >500 ms; and QTcF: increase from baseline >30 ms, increase from baseline >60 ms, new interval >450 ms, new interval >480 ms, new interval >500 ms. New = newly occurred post-baseline value. Safety set for Part II evaluated. All subjects reported under ‘Number of Subjects Analyzed’ contributed data to the table but may not have evaluable data for every row. Here, "n" signifies number of subjects evaluable for specified rows. In results reported below, increase from baseline has been abbreviated as IFB, and decrease from baseline as DFB. Here “99999” = data not available as there was no subject evaluable.

End point type

Secondary

End point timeframe

During study treatment (maximum treatment exposure for Part II was 97.0 weeks)

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	38	1	13	6
Units: Subjects
HR: IFB>25% & to a value >100 bpm (n=38, 1, 13, 6)	3	0	2	1
HR: DFB>25% & to a value <60 bpm (n=38, 1, 13, 6)	14	0	7	0
PR: IFB>25% & to a value >200 ms (n=37, 1, 13, 6)	1	0	2	0
QRS: IFB>25% & to a value >110 ms (n=38, 1, 13, 6)	0	0	0	0
QT: IFB>30 ms (n=38, 1, 13, 6)	24	0	9	0
QT: IFB>60 ms (n=38, 1, 13, 6)	2	0	0	0
QT: New Interval >450 ms (n=37, 0, 13, 6)	3	99999	3	0
QT: New Interval >480 ms (n=38, 1, 13, 6)	1	0	0	0
QT: New Interval >500 ms (n=38, 1, 13, 6)	0	0	0	0
QTcF: IFB>30 ms (n=38, 1, 13, 6)	11	0	2	1
QTcF: IFB>60 ms (n=38, 1, 13, 6)	0	0	0	0
QTcF: New Interval >450 ms (n=37, 1, 13, 5)	14	0	3	0
QTcF: New Interval >480 ms (n=38, 1, 13, 6)	0	0	0	0
QTcF: New Interval >500 ms (n=38, 1, 13, 6)	0	0	0	0

No statistical analyses for this end point

Secondary: Number of Subjects With At least One Dose Interruption: Part I

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End point title

Number of Subjects With At least One Dose Interruption: Part I ^[16]

End point description

In this endpoint, number of subjects with at least 1 dose interruption for encorafenib and binimetinib, respectively were reported. Safety set included all subjects who received at least 1 dose of encorafenib or binimetinib for Part I and had at least 1 valid post-baseline safety assessment.

End point type

Secondary

End point timeframe

During study treatment (maximum treatment exposure for Part I was 403.7 weeks)

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	75	83
Units: Subjects
Encorafenib	46	40
Binimetinib	44	41

No statistical analyses for this end point

Secondary: Number of Subjects With At least One Dose Interruption: Part II

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End point title

Number of Subjects With At least One Dose Interruption: Part II ^[17]

End point description

In this endpoint, number of subjects with at least 1 dose interruption for encorafenib, binimetinib, and each third combination agent were reported. Safety set included all subjects who received at least 1 dose of 3rd combination agent for Part II and had at least 1 valid post-baseline safety assessment. Here, "n" signifies number of subjects evaluable for specified drug. Here “99999” signifies that data not available as there was no subject evaluable.

End point type

Secondary

End point timeframe

During study treatment (maximum treatment exposure for Part II was 97.0 weeks)

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	38	1	13	6
Units: Subjects
Encorafenib (n =38, 1, 13, 6)	14	0	4	2
Binimetinib (n =38, 1, 13, 6)	13	0	5	3
Ribociclib (n =38, 0, 0, 0)	11	99999	99999	99999
Infigratinib (n =0, 1, 0, 0)	99999	0	99999	99999
Capmatinib (n =0, 0, 13, 0)	99999	99999	5	99999
Buparlisib (n =0, 0, 0, 6)	99999	99999	99999	2

No statistical analyses for this end point

Secondary: Number of Subjects With At least One Dose Reduction: Part I

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End point title

Number of Subjects With At least One Dose Reduction: Part I ^[18]

End point description

In this endpoint, number of subjects with at least 1 dose reduction for encorafenib and binimetinib, respectively were reported. Safety set included all subjects who received at least 1 dose of encorafenib or binimetinib for Part I and had at least 1 valid post-baseline safety assessment.

End point type

Secondary

End point timeframe

During study treatment (maximum treatment exposure for Part I was 403.7 weeks)

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	75	83
Units: Subjects
Encorafenib	9	14
Binimetinib	32	28

No statistical analyses for this end point

Secondary: Number of Subjects With At least One Dose Reduction: Part II

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End point title

Number of Subjects With At least One Dose Reduction: Part II ^[19]

End point description

In this endpoint, number of subjects with at least 1 dose reduction for encorafenib, binimetinib, and each third combination agent were reported. Safety set included all subjects who received at least 1 dose of 3rd combination agent for Part II and had at least 1 valid post-baseline safety assessment. Here, "n" signifies number of subjects evaluable for specified drug. Here “99999” signifies that data not available as there was no subject evaluable.

End point type

Secondary

End point timeframe

During study treatment (maximum treatment exposure for Part II was 97.0 weeks)

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	38	1	13	6
Units: Subjects
Encorafenib (n = 38, 1, 13, 6)	1	0	0	1
Binimetinib (n = 38, 1, 13, 6)	11	0	5	3
Ribociclib (n = 38, 0, 0, 0)	1	99999	99999	99999
Infigratinib (n = 0, 1, 0, 0)	99999	0	99999	99999
Capmatinib (n = 0, 0, 13, 0)	99999	99999	7	99999
Buparlisib (n = 0, 0, 0, 6)	99999	99999	99999	1

No statistical analyses for this end point

Secondary: Actual Dose Intensity: Part I

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End point title

Actual Dose Intensity: Part I ^[20]

End point description

Dose intensity across all cycles = cumulative dose/duration of exposure. Safety set included all subjects who received at least 1 dose of encorafenib or binimetinib for Part I and had at least 1 valid post-baseline safety assessment.

End point type

Secondary

End point timeframe

During study treatment (maximum treatment exposure for Part I was 403.7 weeks)

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	75	83
Units: Milligram per day
arithmetic mean (standard deviation)
Encorafenib	425.311 ( 53.5392 )	408.711 ( 65.5297 )
Binimetinib	81.920 ( 13.0994 )	82.083 ( 10.9117 )

No statistical analyses for this end point

Secondary: Actual Dose Intensity: Part II

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End point title

Actual Dose Intensity: Part II ^[21]

End point description

Dose intensity across all cycles = cumulative dose/duration of exposure. Safety set included all subjects who received at least 1 dose of 3rd combination agent for Part II and had at least 1 valid post-baseline safety assessment. Here, "n" signifies number of subjects evaluable for specified drug. Here “99999” signifies: 1) that data (both mean and standard deviation) is not available as there was no subject evaluable or 2) standard deviation not available as only 1 subject was evaluable.

End point type

Secondary

End point timeframe

During study treatment (maximum treatment exposure for Part II was 97.0 weeks)

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	38	1	13	6
Units: Milligram per day
arithmetic mean (standard deviation)
Encorafenib (n =38, 1, 13, 6)	197.856 ( 42.6637 )	450.000 ( 99999 )	195.945 ( 8.4015 )	405.014 ( 102.5218 )
Binimetinib (n =38, 1, 13, 6)	79.749 ( 14.7267 )	90.000 ( 99999 )	87.373 ( 3.6593 )	78.791 ( 20.1538 )
Ribociclib (n =38, 0, 0, 0)	486.628 ( 79.4485 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Infigratinib (n =0, 1, 0, 0)	99999 ( 99999 )	60.227 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Capmatinib (n =0, 0, 13, 0)	99999 ( 99999 )	99999 ( 99999 )	579.519 ( 259.1157 )	99999 ( 99999 )
Buparlisib (n =0, 0, 0, 6)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	72.206 ( 15.7019 )

No statistical analyses for this end point

Secondary: Progression-Free Survival (PFS): Part I

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End point title

Progression-Free Survival (PFS): Part I ^[22]

End point description

PFS was defined as the time from the start date of study drug in Part I until documented PD or death due to any cause. All subjects who had not progressed or died at the time of the data cut-off were censored at the date of last tumor assessment (other than those who were unknown or missing) prior to cut-off date or start date of new anti-neoplastic therapy, whichever is earlier. Per RECIST 1.1, 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. For Part I, FAS consisted of all subjects who received at least 1 dose (partial or full) of encorafenib or binimetinib.

End point type

Secondary

End point timeframe

From start of study drug until documented PD or death due to any cause (maximum treatment exposure for Part I was 403.7 weeks)

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	75	83
Units: Months
median (confidence interval 95%)	11.1 (8.1 to 15.0)	3.3 (2.1 to 4.7)

No statistical analyses for this end point

Secondary: PFS: Part II

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End point title

PFS: Part II ^[23]

End point description

PFS : time from the start date of study drug in Part II until documented PD or death due to any cause. All subjects who had not progressed or died at the time of the data cut-off were censored at the date of last tumor assessment (other than those who were unknown or missing) prior to cut-off date or start date of new anti-neoplastic therapy, whichever is earlier. Per RECIST 1.1, 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. FAS for Part II evaluated. Here “99999” signifies: 1) 95% CI not available as only 1 subject was evaluable and 2) Upper limit of 95% CI could not be estimated as there were insufficient number of subjects with events.

End point type

Secondary

End point timeframe

From start of study drug until documented PD or death due to any cause (maximum treatment exposure for Part II was 97.0 weeks)

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	38	1	13	6
Units: Months
median (confidence interval 95%)	2.1 (1.7 to 2.1)	2.1 (-99999 to 99999)	2.1 (1.0 to 3.7)	1.4 (0.4 to 99999)

No statistical analyses for this end point

Secondary: Duration of Response (DOR): Part I

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End point title

Duration of Response (DOR): Part I ^[24]

End point description

DOR: time between date of first documented response (CR or PR) and date of first documented progression or death due to underlying cancer. If there was no progression or death due to underlying cancer, then the subject was censored at the date of last tumor assessment other than unknown. CR: disappearance of all non-nodal target lesions (TLs). Any pathological lymph nodes assigned as TLs must have had a reduction in short axis to <10 mm. Disappearance of all non-TLs. All lymph nodes assigned a non-TL must be non-pathological in size (<10 mm short axis). PR: at least a 30% decrease in sum of diameter of all TLs, taking as reference baseline sum of diameters. PD: at least a 20% increase in sum of diameter of all measured TLs, taking as the reference the smallest sum of diameter of all TLs recorded at or after baseline. Sum must also demonstrate an absolute increase of at least 5 mm. FAS for Part I was evaluated. Here, "Number of Subjects Analyzed" signifies confirmed responders.

End point type

Secondary

End point timeframe

From date of first documented response (CR or PR) till the date of first documented progression or death due to underlying cancer or censoring date (maximum treatment exposure for Part I was 403.7 weeks)

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	55	21
Units: Months
median (confidence interval 95%)	10.9 (8.1 to 14.1)	5.6 (3.9 to 13.0)

No statistical analyses for this end point

Secondary: DOR: Part II

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End point title

DOR: Part II ^[25]

End point description

DOR: time between date of first documented response (CR or PR) & date of first documented progression or death due to underlying cancer. If there was no progression or death due to underlying cancer, then the subject was censored at the date of last tumor assessment other than unknown. CR: disappearance of all non-nodal TLs. Any pathological lymph nodes assigned as TLs must have had a reduction in short axis to <10mm. Disappearance of all non-TLs. All lymph nodes assigned a non-TL must be non-pathological in size (<10mm short axis). PR: at least 30% decrease in sum of diameter of all TLs, taking as reference baseline sum of diameters. PD: at least 20% increase in sum of diameter of all measured TLs, taking as reference the smallest sum of diameter of all TLs recorded at or after baseline. Sum must also demonstrate an absolute increase of at least 5mm. FAS Part II was evaluated. "Number of Subjects Analyzed"=confirmed responders; “99999”=95%CI unavailable as only 1 subject evaluable.

End point type

Secondary

End point timeframe

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	1	0 ^[26]	0 ^[27]	0 ^[28]
Units: Months
median (confidence interval 95%)	2.1 (-99999 to 99999)	( to )	( to )	( to )

Notes
[26] - Subject was not a confirmed responder.
[27] - None of the subjects were confirmed responders.
[28] - None of the subjects were confirmed responders.

No statistical analyses for this end point

Secondary: TTR: Part II

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End point title

TTR: Part II ^[29]

End point description

TTR was defined as the time between the start date of study drug in Part II and first documented response (CR or PR). RECIST v1.1: a) CR = disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions had a reduction in short axis to <10 mm. Disappearance of all non-target lesions. In addition, all lymph nodes assigned a non-target lesion must be non-pathological in size (<10 mm short axis) and b) PR = at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameter. For Part II, FAS consisted of all subjects who received at least 1 dose of encorafenib or binimetinib or the assigned third agent following the assignment of the triple combination treatment. Here, "Number of Subjects Analyzed" signifies subjects evaluable for this endpoint who were responders. Here “99999” signifies: 95% CI not available as only 1 subject was evaluable.

End point type

Secondary

End point timeframe

From start date of study drug till first documented response (CR or PR) (maximum treatment exposure for Part II was 97.0 weeks)

Notes
[29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	1	0 ^[30]	0 ^[31]	0 ^[32]
Units: Months
median (confidence interval 95%)	4.1 (-99999 to 99999)	( to )	( to )	( to )

Notes
[30] - Subject was not a responder.
[31] - None of the subjects were responders.
[32] - None of the subjects were responders.

No statistical analyses for this end point

Secondary: Time to Response (TTR): Part I

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End point title

Time to Response (TTR): Part I ^[33]

End point description

TTR was defined as the time between the start date of study drug in Part I and first documented response (CR or PR). RECIST v1.1: a) CR = disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions had a reduction in short axis to <10 mm. Disappearance of all non-target lesions. In addition, all lymph nodes assigned a non-target lesion must be non-pathological in size (<10 mm short axis) and b) PR = at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. For Part I, FAS consisted of all subjects who received at least 1 dose (partial or full) of encorafenib or binimetinib. Here, ‘Number of Subjects Analyzed’ signifies subjects evaluable for this endpoint who were responders.

End point type

Secondary

End point timeframe

From start date of study drug till first documented response (CR or PR) (maximum treatment exposure for Part I was 403.7 weeks)

Notes
[33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	52	16
Units: Months
median (confidence interval 95%)	1.4 (1.38 to 1.41)	0.72 (0.72 to 0.82)

No statistical analyses for this end point

Secondary: Disease Control Rate (DCR): Part I

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End point title

Disease Control Rate (DCR): Part I ^[34]

End point description

DCR = percentage of subjects with a best overall response of CR or PR or SD. CR = disappearance of all non-nodal TLs. Any pathological lymph nodes assigned as TLs had a reduction in short axis to <10 mm. Disappearance of all non-TLs. All lymph nodes assigned a non-TL must be non-pathological in size (<10 mm short axis). PR = at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD = neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD. 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 TLs 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. For Part I, FAS consisted of all subjects who received at least 1 dose (partial or full) of encorafenib or binimetinib.

End point type

Secondary

End point timeframe

From start date of study drug till first documented response (CR or PR or SD) (maximum treatment exposure for Part I was 403.7 weeks)

Notes
[34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	75	83
Units: Percentage of subjects
number (confidence interval 95%)	92.0 (83.4 to 97.0)	42.2 (31.4 to 53.5)

No statistical analyses for this end point

Secondary: DCR: Part II

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End point title

DCR: Part II ^[35]

End point description

DCR = percentage of subjects with a best overall response of CR or PR or SD. CR = disappearance of all non-nodal TLs. Any pathological lymph nodes assigned as TLs had a reduction in short axis to <10 mm. Disappearance of all non-TLs. All lymph nodes assigned a non-TL must be non-pathological in size (<10 mm short axis). PR = at least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters. SD = neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which would qualify for PD. 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 TLs 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. FAS for Part II evaluated. Here “99999” signifies: 95% CI not available as only 1 subject was evaluable.

End point type

Secondary

End point timeframe

From start date of study drug till first documented response (CR or PR or SD) (maximum treatment exposure for Part II was 97.0 weeks)

Notes
[35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	38	1	13	6
Units: Percentage of subjects
number (confidence interval 95%)	26.3 (13.4 to 43.1)	0 (-99999 to 99999)	15.4 (1.9 to 45.4)	16.7 (0.4 to 64.1)

No statistical analyses for this end point

Secondary: Overall Survival (OS): Part II

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End point title

Overall Survival (OS): Part II ^[36]

End point description

OS was defined as the time from date of randomization/start of treatment to date of death due to any cause. If a subject was not known to have died, survival was censored at the date of last known date subject alive. For Part II, FAS consisted of all subjects who received at least 1 dose of encorafenib or binimetinib or the assigned third agent following the assignment of the triple combination treatment. Here “99999” signifies: 1) Upper limit was not estimable due to insufficient number of subjects with events, and 2) 95% CI not available as only 1 subject was evaluable.

End point type

Secondary

End point timeframe

From date of randomization/start of treatment to date of death due to any cause or censoring date (maximum treatment exposure for Part II was 97.0 weeks)

Notes
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part II: Encorafenib + Binimetinib + Ribociclib	Part II: Encorafenib + Binimetinib + Infigratinib	Part II: Encorafenib + Binimetinib + Capmatinib	Part II: Encorafenib + Binimetinib + Buparlisib
Number of subjects analysed	38	1	13	6
Units: Months
median (confidence interval 95%)	10.4 (6.0 to 16.7)	20.8 (-99999 to 99999)	5.6 (1.7 to 99999)	2.5 (0.4 to 99999)

No statistical analyses for this end point

Secondary: Summary of Genomic Biomarkers From Tumor Samples: Part I

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End point title

Summary of Genomic Biomarkers From Tumor Samples: Part I ^[37]

End point description

Number of subjects with multiple alterations in genomic biomarkers like biomarker BRAF, CCND1, CDK4, EGFR, FGFR1, FGFR4, KRAS, MET, NRAS, PIK3CA, and PTEN were reported and alterations included copy number variant/copy number ratio (CNV/CNR), rearrangement, short variant. It was not necessary that all biomarkers had all alterations. For Part I, FAS consisted of all subjects who received at least 1 dose (partial or full) of encorafenib or binimetinib. In results reported below, Rearrangement/Genomic Position has been abbreviated as R/GP and baseline as B.

End point type

Secondary

End point timeframe

Baseline up to end of treatment (EOT) (maximum treatment exposure for Part I was 403.7 weeks)

Notes
[37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	75	83
Units: Subjects
BRAF: CNV/CNR at B	4	9
BRAF: CNV/CNR at EOT	2	3
BRAF: R/GP at B chr7:140482508-140482692	0	1
BRAF: R/GP at B chr7:140487121-140487285	0	1
BRAF: R/GP at B chr7:140487916-140488167	0	1
BRAF: R/GP at B chr7:140488878-140489055	0	1
BRAF: R/GP at B cchr7:140489413-140489576	0	1
BRAF: R/GP at B chr7:140490446-140490656	0	1
BRAF: R/GP at B chr7:140491528-140491878	0	1
BRAF: R/GP at B chr7:140491580-140491878	0	1
BRAF: R/GP at B chr7:140492969-140493301	0	1
BRAF: R/GP at EOT chr7:140481691-140482150	1	0
BRAF: R/GP at EOT chr7:140482057-140482467	0	1
BRAF: R/GP at EOT chr7:140482081-140482482	1	0
BRAF: R/GP at EOT chr7:140482088-140482296	0	1
BRAF: R/GP at EOT chr7:140482167-140482382	1	0
BRAF: R/GP at EOT chr7:140482495-140482731	0	1
BRAF: R/GP at EOT chr7:140482644-140482867	0	1
BRAF: R/GP at EOT chr7:140483058-140483257	1	0
BRAF: R/GP at EOT chr7:140486136-140486408	1	0
BRAF: R/GP at EOT chr7:140486274-140486561	0	1
BRAF: R/GP at EOT chr7:140489019-140489575	0	1
BRAF: R/GP at EOT chr7:140489219-140489431	1	0
BRAF: R/GP at EOT chr7:140489830-140490002	0	1
BRAF: R/GP at EOT chr7:140491411-140491879	0	1
BRAF: R/GP at EOT chr7:140492091-140492240	1	0
BRAF: R/GP at EOT chr7:140492379-140492708	0	1
BRAF: R/GP at EOT chr7:140492714-140492997	0	1
BRAF: R/GP at EOT chr7:140493601-140493951	0	1
BRAF: R/GP at EOT chr7:140493858-140494232	1	0
BRAF: Short variant/amino acid change at B V600E	46	53
BRAF: Short variant/amino acid change at B V600G	1	0
BRAF: Short variant/amino acid change at B V600K	4	7
BRAF: Short variant/amino acid change at B V600R	1	0
BRAF: Short variant/amino acid change at EOT V600E	18	19
BRAF: Short variant/amino acid change at EOT V600K	0	4
BRAF: Short variant/amino acid change at EOT V600R	1	0
CCND1: CNV/CNR at B	1	0
CDK4: CNV/CNR at B	3	2
EGFR: CNV/CNR at B	1	3
EGFR: CNV/CNR at EOT	1	1
FGFR1: CNV/CNR at B	1	0
FGFR1: CNV/CNR at EOT	1	0
FGFR4: CNV/CNR at B	1	0
KRAS: CNV/CNR at B	2	0
MET: CNV/CNR at B	4	6
MET: CNV/CNR at EOT	3	5
MET: R/GP at EOT chr7:116321020-116321260	1	0
NRAS: CNV/CNR at B	0	1
PIK3CA: CNV/CNR at B	1	0
PTEN: CNV/CNR at B	4	13
PTEN: CNV/CNR at EOT	5	10
PTEN: R/GP at EOT chr10:89720538-89720776	0	1

No statistical analyses for this end point

Secondary: Plasma Concentration for Encorafenib (LGX): Part I

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End point title

Plasma Concentration for Encorafenib (LGX): Part I ^[38]

End point description

In results reported below, following abbreviations have been used: Cycle 1 (C1), Day 1 (D1), Day 8 (D8), Day 15 (D15), Day 21 (D21), Cycle 2 (C2), Cycle 3 (C3), Cycle 4 (C4), Cycle 5 (C5) and end of treatment (EOT). Maximum treatment exposure for Part I was of 403.7 weeks. Pharmacokinetic analysis set (PAS) consisted of all subjects who had at least one blood sample providing evaluable pharmacokinetic (PK) data. Here, “n” signifies number of subjects evaluable for specified time points.

End point type

Secondary

End point timeframe

C1 (1.5 hrs post-dose on D1; pre-dose, 1.5 hrs post-dose on D15); C2 (pre-dose on D8 and D21); C3 pre-dose on D15; C4 pre-dose on D15; C5 pre-dose on D15; EOT

Notes
[38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	75	78
Units: Nanogram per milliliter
geometric mean (geometric coefficient of variation)
C1 D1, 1.5 hr (n = 59, 55)	4820 ( 114.2 )	4480 ( 124.4 )
C1 D15, Pre-dose (n= 68, 59)	10.0 ( 81.6 )	13.8 ( 104.4 )
C1 D15, 1.5 hr (n = 52, 54)	2470 ( 116.7 )	2910 ( 91.6 )
C2 D8, Pre-dose (n =69, 48)	9.96 ( 81.7 )	14.7 ( 117.5 )
C2 D21, Pre-dose (n =62, 41)	9.04 ( 84.2 )	15.6 ( 156.3 )
C3 D15, Pre-dose (n =68, 41)	8.43 ( 82.3 )	11.2 ( 114.3 )
C4 D15, Pre-dose (n =63, 30)	9.21 ( 100.3 )	12.3 ( 108.9 )
C5 D15, Pre-dose (n = 56, 30)	8.84 ( 59.4 )	11.9 ( 72.7 )
EOT (n = 35, 47)	19.6 ( 399.9 )	34.5 ( 890.3 )

No statistical analyses for this end point

Secondary: Plasma Concentration for Encorafenib (LGX): Part II

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End point title

Plasma Concentration for Encorafenib (LGX): Part II

End point description

In results reported below, following abbreviations have been used: Cycle 1 (C1), Day 1 (D1), Day 8 (D8), Day 15 (D15), Day 16 (D16), Day 21 (D21), Cycle 2 (C2), Cycle 3 (C3), Cycle 4 (C4), Cycle 5 (C5). Maximum treatment exposure for Part II was of 97.0 weeks. PAS consisted of all subjects who had at least one blood sample providing evaluable PK data. Here, “n” signifies number of subjects evaluable for specified time points. In results reported below, “99999” suggests that a) geometric mean available but no geometric coefficient of variation: dispersion not available as there was only 1 subject evaluable and where subjects evaluable were 2: dispersion not available as out of 2 subjects, 1 subject had BLQ value; b) no geometric mean and geometric coefficient of variation: below limit of the quantitation (BLQ) value.

End point type

Secondary

End point timeframe

C1 (1.5, 4 hrs post-dose on D1; pre-dose on D8; pre-dose, 0.5, 1.5, 2.5, 4, 6, 8 hrs post-dose on D15; 24 hrs post-dose on D16; pre-dose on D21); C2 (pre-dose on D1 and D15); C3 pre-dose on D1; C4 pre-dose on D1; C5 pre-dose on D1; EOT

End point values	Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 60mg	Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 90mg	Part II:Encorafenib 450mg/Binimetinib 45mg+Infigratinib 75mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 200mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 300mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 400mg	Part II:Encorafenib 100mg/Binimetinib 30mg+Ribociclib 600mg	Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 400mg	Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 600mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 400mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 600mg
Number of subjects analysed	3	3	1	5	1	5	1	1	3	1	29
Units: Nanogram per milliliter
geometric mean (geometric coefficient of variation)
C1 D1: 1.5 hrs (n=0,2,1,2,1,3,1,1,2,0,22)	99999 ( 99999 )	3430 ( 17.6 )	1860 ( 99999 )	1130 ( 3.8 )	3750 ( 99999 )	1770 ( 62.9 )	878 ( 99999 )	2030 ( 99999 )	847 ( 28.1 )	99999 ( 99999 )	1600 ( 85.6 )
C1 D1: 4 hrs (n=0,0,0,0,0,0,1,1,3,0,24)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	238 ( 99999 )	297 ( 99999 )	626 ( 65.7 )	99999 ( 99999 )	596 ( 51.1 )
C1 D8: Pre-dose (n=3,2,1,3,1,4,1,1,2,1,23)	8.97 ( 89.0 )	21.3 ( 150.6 )	12.4 ( 99999 )	10.3 ( 54.4 )	6.21 ( 99999 )	11.7 ( 56.4 )	12.5 ( 99999 )	15.2 ( 99999 )	9.39 ( 15.9 )	7.15 ( 99999 )	16.2 ( 116.1 )
C1 D15: Pre-dose (n=3,2,1,4,1,4,1,1,2,0,22)	11.2 ( 106.3 )	18.6 ( 159.4 )	7.74 ( 99999 )	9.95 ( 40.1 )	7.95 ( 99999 )	13.5 ( 35.0 )	9.28 ( 99999 )	10.3 ( 99999 )	7.75 ( 37.3 )	99999 ( 99999 )	20.9 ( 188.5 )
C1 D15: 0.5 hr (n=3,2,1,5,1,4,1,1,2,0,22)	437 ( 228.2 )	625 ( 19.5 )	1690 ( 99999 )	262 ( 345.5 )	139 ( 99999 )	127 ( 216.1 )	8.55 ( 99999 )	601 ( 99999 )	473 ( 1248.5 )	99999 ( 99999 )	175 ( 252.7 )
C1 D15: 1.5 hrs (n=3,2,1,5,1,4,1,1,2,0,22)	3050 ( 59.6 )	2150 ( 54.6 )	2100 ( 99999 )	1550 ( 62.4 )	2890 ( 99999 )	2500 ( 27.9 )	366 ( 99999 )	1960 ( 99999 )	1450 ( 3.9 )	99999 ( 99999 )	1850 ( 69.7 )
C1 D15: 2.5 hrs (n=3,2,1,5,0,4,1,1,1,0,22)	1420 ( 39.6 )	1320 ( 30.0 )	1020 ( 99999 )	808 ( 55.0 )	99999 ( 99999 )	1550 ( 34.4 )	622 ( 99999 )	981 ( 99999 )	686 ( 99999 )	99999 ( 99999 )	1510 ( 48.2 )
C1 D15: 4 hrs (n=3,2,1,4,1,4,1,0,2,0,23)	649 ( 37.5 )	770 ( 6.2 )	397 ( 99999 )	453 ( 24.3 )	1160 ( 99999 )	667 ( 20.4 )	389 ( 99999 )	99999 ( 99999 )	478 ( 39.6 )	99999 ( 99999 )	1020 ( 34.3 )
C1 D15: 6 hrs (n=3,2,1,5,1,4,1,1,2,0,19)	246 ( 94.6 )	433 ( 45.0 )	211 ( 99999 )	165 ( 68.8 )	266 ( 99999 )	317 ( 26.8 )	209 ( 99999 )	199 ( 99999 )	203 ( 11.1 )	99999 ( 99999 )	567 ( 51.5 )
C1 D15: 8 hrs (n=3,2,0,5,1,3,1,1,2,0,20)	180 ( 94.5 )	276 ( 103.8 )	99999 ( 99999 )	115 ( 55.4 )	257 ( 99999 )	217 ( 34.5 )	142 ( 99999 )	132 ( 99999 )	109 ( 2.6 )	99999 ( 99999 )	412 ( 62.3 )
C1 D16: 24 hrs (n=3,2,1,4,1,4,1,1,2,0,24)	11.3 ( 45.3 )	25.1 ( 2066.8 )	6.76 ( 99999 )	8.10 ( 43.1 )	5.20 ( 99999 )	15.0 ( 20.9 )	10.7 ( 99999 )	7.85 ( 99999 )	10.8 ( 106.1 )	99999 ( 99999 )	22.8 ( 199.0 )
C1 D21: Pre-dose (n=0,0,1,0,0,0,1,1,2,1,20)	99999 ( 99999 )	99999 ( 99999 )	10.4 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	13.6 ( 99999 )	13.9 ( 99999 )	12.4 ( 60.4 )	20.3 ( 99999 )	17.5 ( 106.4 )
C2 D1: Pre-dose (n=3,2,1,5,1,3,1,1,2,1,18)	13.5 ( 193.0 )	32.6 ( 202.9 )	12.7 ( 99999 )	19.9 ( 210.5 )	2.91 ( 99999 )	14.0 ( 30.3 )	8.50 ( 99999 )	82.5 ( 99999 )	8.19 ( 42.2 )	19.2 ( 99999 )	11.9 ( 100.9 )
C2 D15: Pre-dose (n=1,1,1,4,0,4,1,1,2,1,14)	41.3 ( 99999 )	15.6 ( 99999 )	13.9 ( 99999 )	9.68 ( 36.5 )	99999 ( 99999 )	8.49 ( 70.5 )	11.1 ( 99999 )	16.5 ( 99999 )	12.3 ( 24.3 )	8.95 ( 99999 )	21.3 ( 115.3 )
C3 D1: Pre-dose (n=1,0,1,2,0,4,0,1,0,0,15)	13.9 ( 99999 )	99999 ( 99999 )	20.5 ( 99999 )	23.2 ( 33.1 )	99999 ( 99999 )	10.1 ( 72.1 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	9.34 ( 125.7 )
C4 D1: Pre-dose (n=1,0,0,0,0,2,1,1,0,0,6)	30.2 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	12.5 ( 11.4 )	5.95 ( 99999 )	7.28 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	13.1 ( 21.8 )
C5 D1: Pre-dose (n=1,0,0,0,0,0,1,1,0,0,5)	749 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	10.7 ( 99999 )	9.84 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	9.15 ( 44.0 )
EOT (n =2,1,1,3,1,4,1,1,2,1,22)	1.77 ( 99999 )	99999 ( 99999 )	14.3 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	13.9 ( 66.6 )	8.24 ( 99999 )	6.81 ( 99999 )	24.5 ( 259.8 )	99999 ( 99999 )	16.6 ( 265.0 )

No statistical analyses for this end point

Secondary: Plasma Concentration for Binimetinib (MEK) and its Metabolite: Part I

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End point title

Plasma Concentration for Binimetinib (MEK) and its Metabolite: Part I ^[39]

End point description

AR00426032 is metabolite of binimetinib. Maximum treatment exposure for Part I was of 403.7 weeks. PAS consisted of all subjects who had at least one blood sample providing evaluable PK data. All subjects reported under ‘Number of Subjects Analyzed’ contributed data to the table but may not have evaluable data for every row. Here, “n” signifies number of subjects evaluable for specified time points.

End point type

Secondary

End point timeframe

C1 (1.5 hrs post-dose on D1; pre-dose, 1.5 hrs post-dose on D15); C2 (pre-dose on D8 and D21); C3 pre-dose on D15; C4 pre-dose on D15; C5 pre-dose on D15; EOT

Notes
[39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was not evaluated for all arms.

End point values	Part I: Encorafenib + Binimetinib (naive)	Part I: Encorafenib + Binimetinib (non-naive)
Number of subjects analysed	75	78
Units: Nanogram per milliliter
geometric mean (geometric coefficient of variation)
Binimetinib: C1 D1, 1.5 hr (n =58, 60)	551 ( 88.8 )	482 ( 73.4 )
Binimetinib: C1 D15, Pre-dose (n =66, 56)	40.3 ( 63.5 )	43.3 ( 72.9 )
Binimetinib: C1 D15, 1.5 hr (n =53, 54)	461 ( 70.2 )	451 ( 50.2 )
Binimetinib: C2 D8, Pre-dose (n =69, 46)	39.9 ( 58.8 )	44.8 ( 73.0 )
Binimetinib: C2 D21, Pre-dose (n =62, 39)	38.9 ( 54.9 )	53.1 ( 78.2 )
Binimetinib: C3 D15, Pre-dose (n =65, 41)	41.9 ( 60.4 )	38.7 ( 94.6 )
Binimetinib: C4 D15, Pre-dose (n =61, 30)	36.2 ( 68.6 )	38.8 ( 57.4 )
Binimetinib: C5 D15, Pre-dose (n =56, 30)	41.3 ( 55.7 )	39.2 ( 76.1 )
Binimetinib: EOT (n =35, 47)	33.2 ( 179.4 )	52.8 ( 180.4 )
AR00426032: C1 D1, 1.5 hr (n =58, 60)	57.6 ( 93.5 )	47.5 ( 101.6 )
AR00426032: C1 D15, Pre-dose (n =66, 56)	4.13 ( 70.8 )	4.50 ( 64.0 )
AR00426032: C1 D15, 1.5 hr (n =52, 54)	30.6 ( 110.9 )	31.9 ( 84.0 )
AR00426032: C2 D8, Pre-dose (n =69, 46)	3.63 ( 60.2 )	4.17 ( 88.1 )
AR00426032: C2 D21, Pre-dose (n =62, 39)	4.11 ( 61.0 )	4.39 ( 80.2 )
AR00426032: C3 D15, Pre-dose (n =64, 41)	3.71 ( 59.5 )	3.90 ( 60.6 )
AR00426032: C4 D15, Pre-dose (n =61, 30)	3.48 ( 65.8 )	3.81 ( 56.9 )
AR00426032: C5 D15, Pre-dose (n =56, 30)	3.77 ( 66.9 )	3.36 ( 67.3 )
AR00426032: EOT (n =33, 47)	4.09 ( 90.8 )	5.88 ( 118.0 )

No statistical analyses for this end point

Secondary: Plasma Concentration for Binimetinib (MEK) and its Metabolite: Part II

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End point title

Plasma Concentration for Binimetinib (MEK) and its Metabolite: Part II

End point description

AR00426032 is metabolite of binimetinib. Maximum treatment exposure for Part II was of 97.0 weeks. PAS consisted of all subjects who had at least one blood sample providing evaluable PK data. All subjects reported under ‘Number of Subjects Analyzed’ contributed data to the table but may not have evaluable data for every row. Here, “n” signifies number of subjects evaluable for specified time points. In results reported below, “99999” suggested that a) geometric mean available but no geometric coefficient of variation: dispersion not available as there was only 1 subject evaluable and where subjects evaluable were 2: dispersion not available as out of 2 subjects, 1 subject had BLQ value; b) no geometric mean and geometric coefficient of variation: no subject evaluable, or if subjects were evaluable then all BLQ values. In results reported below, binimetinib is abbreviated as BI, AR00426032 is abbreviated as AR and pre-dose as PD.

End point type

Secondary

End point timeframe

End point values	Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 60mg	Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 90mg	Part II:Encorafenib 450mg/Binimetinib 45mg+Infigratinib 75mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 200mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 300mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 400mg	Part II:Encorafenib 100mg/Binimetinib 30mg+Ribociclib 600mg	Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 400mg	Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 600mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 400mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 600mg	Encorafenib 300mg/Binimetinib 30mg+Ribociclib 600mg	Part II:Encorafenib 450mg/Binimetinib 45mg+Ribociclib 600mg
Number of subjects analysed	3	3	1	5	1	5	1	1	3	1	29	1	1
Units: Nanogram per milliliter
geometric mean (geometric coefficient of variation)
BI,C1 D1: 1.5 hrs(n=0,2,1,2,1,3,1,1,2,0,21,1,1)	99999 ( 99999 )	410 ( 48.8 )	416 ( 99999 )	313 ( 25.6 )	1100 ( 99999 )	508 ( 130.2 )	396 ( 99999 )	649 ( 99999 )	273 ( 24.6 )	99999 ( 99999 )	446 ( 59.8 )	522 ( 99999 )	1230 ( 99999 )
BI, C1 D1: 4 hrs(n=0,0,0,0,0,0,1,1,3,0,24,1,0)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	152 ( 99999 )	106 ( 99999 )	129 ( 25.8 )	99999 ( 99999 )	215 ( 44.5 )	99.5 ( 99999 )	99999 ( 99999 )
BI, C1 D8: PD (n=3,2,1,3,1,4,1,1,2,1,21,1,0)	41.6 ( 21.7 )	51.1 ( 9.7 )	46.0 ( 99999 )	74.6 ( 34.5 )	27.2 ( 99999 )	67.4 ( 63.1 )	63.0 ( 99999 )	31.5 ( 99999 )	25.1 ( 1.7 )	27.2 ( 99999 )	51.0 ( 67.8 )	37.3 ( 99999 )	99999 ( 99999 )
BI, C1 D15: PD (n=3,2,1,4,1,4,1,1,2,0,22,1,0)	32.0 ( 17.1 )	39.1 ( 57.4 )	33.9 ( 99999 )	85.6 ( 53.7 )	47.3 ( 99999 )	50.9 ( 34.4 )	54.3 ( 99999 )	28.3 ( 99999 )	21.1 ( 23.7 )	99999 ( 99999 )	48.2 ( 70.0 )	36.2 ( 99999 )	99999 ( 99999 )
BI, C1 D15: 0.5 hr (n=3,2,1,5,1,4,1,1,2,0,22,0,0)	150 ( 36.1 )	143 ( 496.2 )	315 ( 99999 )	430 ( 26.8 )	401 ( 99999 )	180 ( 91.5 )	229 ( 99999 )	389 ( 99999 )	161 ( 54.7 )	99999 ( 99999 )	158 ( 90.1 )	99999 ( 99999 )	99999 ( 99999 )
BI, C1 D15:1.5 hrs (n=3,2,1,5,1,4,1,1,2,0,22,0,0)	386 ( 41.1 )	187 ( 351.0 )	413 ( 99999 )	489 ( 27.1 )	797 ( 99999 )	734 ( 45.6 )	261 ( 99999 )	520 ( 99999 )	313 ( 15.9 )	99999 ( 99999 )	437 ( 46.5 )	99999 ( 99999 )	99999 ( 99999 )
BI, C1 D15:2.5 hrs (n=3,2,1,5,0,4,1,1,1,0,22,1,0)	250 ( 17.1 )	143 ( 172.4 )	235 ( 99999 )	295 ( 29.7 )	99999 ( 99999 )	491 ( 38.0 )	207 ( 99999 )	331 ( 99999 )	154 ( 99999 )	99999 ( 99999 )	380 ( 31.2 )	178 ( 99999 )	99999 ( 99999 )
BI, C1 D15: 4 hrs (n=3,2,1,4,1,4,1,0,2,0,23,0,0)	147 ( 21.4 )	125 ( 62.1 )	98.0 ( 99999 )	166 ( 48.9 )	264 ( 99999 )	266 ( 32.5 )	130 ( 99999 )	99999 ( 99999 )	98.0 ( 60.0 )	99999 ( 99999 )	241 ( 28.6 )	99999 ( 99999 )	99999 ( 99999 )
BI, C1 D15: 6 hrs (n=3,2,1,5,1,4,1,1,2,0,20,0,0)	79.0 ( 36.1 )	97.3 ( 32.8 )	55.8 ( 99999 )	106 ( 53.3 )	112 ( 99999 )	141 ( 15.1 )	167 ( 99999 )	77.4 ( 99999 )	53.3 ( 36.2 )	99999 ( 99999 )	134 ( 46.5 )	99999 ( 99999 )	99999 ( 99999 )
BI, C1 D15: 8 hrs (n=3,2,0,5,1,3,1,1,2,0,20,0,0)	74.9 ( 34.7 )	59.7 ( 12.6 )	99999 ( 99999 )	107 ( 40.9 )	132 ( 99999 )	102 ( 12.4 )	116 ( 99999 )	65.5 ( 99999 )	42.2 ( 39.2 )	99999 ( 99999 )	109 ( 54.8 )	99999 ( 99999 )	99999 ( 99999 )
BI, C1 D16: 24 hrs (n=3,2,1,5,1,4,1,1,2,0,23,1,0)	44.1 ( 19.1 )	30.2 ( 59.2 )	42.1 ( 99999 )	63.2 ( 64.0 )	17.6 ( 99999 )	55.9 ( 54.0 )	78.3 ( 99999 )	29.8 ( 99999 )	23.1 ( 5.2 )	99999 ( 99999 )	55.2 ( 66.0 )	40.5 ( 99999 )	99999 ( 99999 )
BI, C1 D21: PD (n=0,0,1,0,0,0,1,1,2,1,19,1,1)	99999 ( 99999 )	99999 ( 99999 )	34.0 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	40.4 ( 99999 )	38.8 ( 99999 )	13.6 ( 80.7 )	19.6 ( 99999 )	63.2 ( 51.0 )	35.3 ( 99999 )	8.91 ( 99999 )
BI, C2 D1: PD (n=3,2,1,5,1,3,1,1,2,1,16,1,1)	38.8 ( 62.5 )	42.7 ( 27.8 )	40.5 ( 99999 )	118 ( 120.1 )	24.6 ( 99999 )	54.2 ( 32.4 )	58.3 ( 99999 )	174 ( 99999 )	23.3 ( 20.2 )	58.3 ( 99999 )	46.0 ( 71.2 )	22.4 ( 99999 )	54.1 ( 99999 )
BI, C2 D15: PD (n=1,1,1,4,1,4,1,1,2,1,14,1,1)	63.7 ( 99999 )	73.0 ( 99999 )	63.9 ( 99999 )	40.9 ( 50.8 )	18.9 ( 99999 )	49.8 ( 21.2 )	63.1 ( 99999 )	19.4 ( 99999 )	15.2 ( 18.2 )	14.1 ( 99999 )	58.4 ( 68.3 )	27.3 ( 99999 )	34.9 ( 99999 )
BI, C3 D1: PD (n=1,0,1,2,0,4,1,1,0,0,16,1,0)	50.0 ( 99999 )	99999 ( 99999 )	47.2 ( 99999 )	37.8 ( 189.6 )	99999 ( 99999 )	41.9 ( 49.0 )	53.4 ( 99999 )	4.82 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	45.0 ( 91.8 )	42.0 ( 99999 )	99999 ( 99999 )
BI, C4D1: PD (n=1,0,0,0,0,3,1,1,0,0,4,0,0)	46.1 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	53.8 ( 10.6 )	63.6 ( 99999 )	40.9 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	77.5 ( 32.1 )	99999 ( 99999 )	99999 ( 99999 )
BI, C5D1: PD (n=1,0,0,0,0,0,1,1,0,0,5,0,0)	60.0 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	42.3 ( 99999 )	28.5 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	73.8 ( 25.7 )	99999 ( 99999 )	99999 ( 99999 )
BI, EOT (n=2,1,1,3,1,4,1,1,2,1,21,0,0)	99999 ( 99999 )	99999 ( 99999 )	36.3 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	52.1 ( 18.3 )	41.0 ( 99999 )	32.3 ( 99999 )	13.8 ( 205.5 )	99999 ( 99999 )	29.0 ( 179.7 )	99999 ( 99999 )	99999 ( 99999 )
AR,C1 D1: 1.5 hrs(n=0,2,1,2,0,3,0,1,2,0,21,1,1)	99999 ( 99999 )	22.4 ( 200.6 )	12.9 ( 99999 )	11.4 ( 85.7 )	99999 ( 99999 )	35.9 ( 274.1 )	99999 ( 99999 )	22.1 ( 99999 )	8.05 ( 68.9 )	99999 ( 99999 )	19.4 ( 99.3 )	16.3 ( 99999 )	64.6 ( 99999 )
AR, C1 D1: 4 hrs(n=0,0,0,0,0,0,1,1,3,0,23,1,0)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	9.40 ( 99999 )	4.09 ( 99999 )	6.71 ( 145.3 )	99999 ( 99999 )	12.3 ( 75.3 )	4.61 ( 99999 )	99999 ( 99999 )
AR, C1 D8: PD (n=3,2,1,3,0,4,1,1,2,1,21,1,0)	3.98 ( 31.9 )	2.95 ( 165.3 )	1.21 ( 99999 )	7.10 ( 122.1 )	99999 ( 99999 )	6.34 ( 54.5 )	6.15 ( 99999 )	1.10 ( 99999 )	1.73 ( 48.7 )	2.09 ( 99999 )	5.50 ( 62.6 )	2.14 ( 99999 )	99999 ( 99999 )
AR, C1 D15: PD (n=3,2,1,4,1,4,1,1,2,0,22,1,0)	3.14 ( 74.5 )	3.80 ( 111.9 )	1.21 ( 99999 )	11.5 ( 39.5 )	4.36 ( 99999 )	5.45 ( 42.2 )	4.16 ( 99999 )	99999 ( 99999 )	3.81 ( 99999 )	99999 ( 99999 )	4.19 ( 79.2 )	1.09 ( 99999 )	99999 ( 99999 )
AR, C1 D15: 0.5 hr (n=3,2,1,5,1,4,1,1,2,0,22,0,0)	6.66 ( 43.2 )	7.43 ( 455.1 )	8.21 ( 99999 )	13.1 ( 97.8 )	11.4 ( 99999 )	9.80 ( 75.7 )	7.31 ( 99999 )	4.35 ( 99999 )	6.16 ( 490.6 )	99999 ( 99999 )	7.81 ( 119.0 )	99999 ( 99999 )	99999 ( 99999 )
AR, C1 D15:1.5 hrs (n=3,2,1,5,0,4,1,1,2,0,22,0,0)	24.9 ( 92.2 )	13.2 ( 1550.1 )	15.8 ( 99999 )	27.9 ( 85.6 )	99999 ( 99999 )	41.1 ( 25.7 )	12.9 ( 99999 )	12.6 ( 99999 )	16.1 ( 151.9 )	99999 ( 99999 )	18.3 ( 135.9 )	99999 ( 99999 )	99999 ( 99999 )
AR, C1 D15:2.5 hrs (n=3,2,1,5,0,4,1,1,1,0,22,1,0)	18.5 ( 77.0 )	11.3 ( 447.2 )	7.75 ( 99999 )	18.5 ( 88.4 )	99999 ( 99999 )	34.3 ( 51.3 )	9.71 ( 99999 )	8.51 ( 99999 )	16.2 ( 99999 )	99999 ( 99999 )	18.5 ( 81.2 )	4.73 ( 99999 )	99999 ( 99999 )
AR, C1 D15: 4 hrs (n=3,2,1,4,1,4,1,0,2,0,23,0,0)	11.8 ( 40.3 )	9.98 ( 142.4 )	3.15 ( 99999 )	9.46 ( 142.7 )	22.6 ( 99999 )	19.3 ( 76.9 )	6.76 ( 99999 )	99999 ( 99999 )	5.21 ( 81.9 )	99999 ( 99999 )	12.2 ( 78.7 )	99999 ( 99999 )	99999 ( 99999 )
AR, C1 D15: 6 hrs (n=3,2,1,5,1,4,1,1,2,0,20,0,0)	6.86 ( 61.8 )	7.66 ( 117.7 )	1.82 ( 99999 )	6.90 ( 142.3 )	8.89 ( 99999 )	9.66 ( 71.5 )	5.82 ( 99999 )	2.52 ( 99999 )	3.07 ( 95.0 )	99999 ( 99999 )	7.41 ( 80.2 )	99999 ( 99999 )	99999 ( 99999 )
AR, C1 D15: 8 hrs (n=3,2,0,5,1,3,1,1,2,0,20,0,0)	5.94 ( 76.7 )	5.24 ( 70.7 )	99999 ( 99999 )	6.49 ( 124.9 )	8.06 ( 99999 )	8.87 ( 76.5 )	5.12 ( 99999 )	1.95 ( 99999 )	2.67 ( 72.9 )	99999 ( 99999 )	6.73 ( 75.0 )	99999 ( 99999 )	99999 ( 99999 )
AR, C1 D16: 24 hrs (n=3,2,1,5,1,4,1,1,2,0,22,1,0)	3.99 ( 61.8 )	2.92 ( 159.3 )	1.27 ( 99999 )	7.79 ( 87.5 )	1.44 ( 99999 )	4.75 ( 25.4 )	6.53 ( 99999 )	1.08 ( 99999 )	3.19 ( 99999 )	99999 ( 99999 )	4.70 ( 80.2 )	1.56 ( 99999 )	99999 ( 99999 )
AR, C1 D21: PD (n=0,0,1,0,0,0,1,1,2,1,17,1,1)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	3.66 ( 99999 )	1.47 ( 99999 )	3.18 ( 99999 )	1.13 ( 99999 )	6.64 ( 56.1 )	1.65 ( 99999 )	3.11 ( 99999 )
AR, C2 D1: PD (n=3,2,1,5,0,3,1,1,2,1,15,1,1)	6.23 ( 82.0 )	3.51 ( 36.8 )	99999 ( 99999 )	13.5 ( 116.8 )	99999 ( 99999 )	5.71 ( 44.2 )	4.32 ( 99999 )	2.06 ( 99999 )	4.09 ( 99999 )	3.99 ( 99999 )	4.03 ( 58.1 )	99999 ( 99999 )	17.8 ( 99999 )
AR, C2 D15: PD (n=1,1,1,4,1,4,1,1,2,1,14,1,1)	9.97 ( 99999 )	7.52 ( 99999 )	1.07 ( 99999 )	3.27 ( 65.1 )	1.74 ( 99999 )	4.23 ( 62.5 )	8.54 ( 99999 )	1.63 ( 99999 )	1.99 ( 99999 )	1.19 ( 99999 )	5.69 ( 57.0 )	1.33 ( 99999 )	3.74 ( 99999 )
AR, C3 D1: PD (n=1,0,1,2,0,4,1,1,0,0,15,1,0)	9.74 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	6.15 ( 99999 )	99999 ( 99999 )	4.35 ( 42.3 )	4.50 ( 99999 )	1.09 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	4.46 ( 70.2 )	1.73 ( 99999 )	99999 ( 99999 )
AR, C4D1: PD (n=1,0,0,0,0,3,1,1,0,0,4,0,0)	7.10 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	5.70 ( 11.8 )	5.43 ( 99999 )	2.78 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	5.78 ( 83.0 )	99999 ( 99999 )	99999 ( 99999 )
AR, C5D1: PD (n=1,0,0,0,0,0,1,1,0,0,5,0,0)	6.05 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	8.89 ( 99999 )	1.36 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	6.11 ( 67.8 )	99999 ( 99999 )	99999 ( 99999 )
AR, EOT (n=2,1,1,3,1,4,1,1,2,1,20,0,0)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	6.68 ( 80.1 )	3.77 ( 99999 )	1.48 ( 99999 )	3.65 ( 99999 )	99999 ( 99999 )	4.24 ( 85.5 )	99999 ( 99999 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Plasma Concentration for Ribociclib (LEE) and its Metabolite: Part II

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End point title

Plasma Concentration for Ribociclib (LEE) and its Metabolite: Part II

End point description

LEQ803 is metabolite of ribociclib. Maximum treatment exposure for Part II was of 97.0 weeks. PAS consisted of all subjects who had at least one blood sample providing evaluable PK data. All subjects reported under ‘Number of Subjects Analyzed’ contributed data to the table; however, may not have evaluable data for every row. Here, “n” signifies number of subjects evaluable for specified time points. “99999” suggested that a) geometric mean available but no geometric coefficient of variation: dispersion not available as there was only 1 subject evaluable; b) no geometric mean and geometric coefficient of variation: no subjects evaluable.

End point type

Secondary

End point timeframe

End point values	Part II:Encorafenib 100mg/Binimetinib 30mg+Ribociclib 600mg	Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 400mg	Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 600mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 400mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 600mg	Part II:Encorafenib 450mg/Binimetinib 45mg+Ribociclib 600mg	Part II:Encorafenib 300mg/Binimetinib 30mg+Ribociclib 600mg
Number of subjects analysed	1	1	3	1	29	1	1
Units: Nanogram per milliliter
geometric mean (geometric coefficient of variation)
Ribociclib, C1 D1: 1.5 hrs(n=1,1,2,0,21,1,1)	220 ( 99999 )	117 ( 99999 )	107 ( 40.6 )	99999 ( 99999 )	230 ( 119.7 )	784 ( 99999 )	185 ( 99999 )
Ribociclib, C1 D1: 4 hrs(n=1,1,3,0,24,1,0)	213 ( 99999 )	84.5 ( 99999 )	205 ( 96.0 )	99999 ( 99999 )	354 ( 58.5 )	99999 ( 99999 )	268 ( 99999 )
Ribociclib, C1 D8: Pre-dose(n=1,1,2,0,22,1,1)	77.4 ( 99999 )	32.3 ( 99999 )	30.7 ( 33.5 )	99999 ( 99999 )	100 ( 49.9 )	127 ( 99999 )	80.5 ( 99999 )
Ribociclib, C1 D15: Pre-dose(n=1,1,2,0,25,1,0)	98.4 ( 99999 )	28.2 ( 99999 )	30.7 ( 24.9 )	99999 ( 99999 )	104 ( 54.2 )	99999 ( 99999 )	64.7 ( 99999 )
Ribociclib, C1 D15: 0.5 hr(n=1,1,2,0,24,0,0)	86.1 ( 99999 )	59.7 ( 99999 )	35.4 ( 66.6 )	99999 ( 99999 )	179 ( 65.0 )	99999 ( 99999 )	99999 ( 99999 )
Ribociclib, C1 D15: 1.5 hrs(n=1,1,2,0,24,0,0)	204 ( 99999 )	95.9 ( 99999 )	200 ( 240.3 )	99999 ( 99999 )	508 ( 95.2 )	99999 ( 99999 )	99999 ( 99999 )
Ribociclib, C1 D15: 2.5 hrs(n=1,1,1,0,24,1,0)	321 ( 99999 )	126 ( 99999 )	718 ( 99999 )	99999 ( 99999 )	627 ( 68.3 )	99999 ( 99999 )	393 ( 99999 )
Ribociclib, C1 D15: 4 hrs(n=1,0,2,0,25,0,0)	368 ( 99999 )	99999 ( 99999 )	341 ( 42.9 )	99999 ( 99999 )	707 ( 62.2 )	99999 ( 99999 )	99999 ( 99999 )
Ribociclib, C1 D15: 6 hrs(n=1,1,2,0,23,0,0)	434 ( 99999 )	109 ( 99999 )	239 ( 37.2 )	99999 ( 99999 )	578 ( 55.9 )	99999 ( 99999 )	99999 ( 99999 )
Ribociclib, C1 D15: 8 hrs(n=1,1,2,0,21,0,0)	311 ( 99999 )	83.6 ( 99999 )	182 ( 27.1 )	99999 ( 99999 )	477 ( 55.2 )	99999 ( 99999 )	99999 ( 99999 )
Ribociclib, C1 D16: 24 hrs(n=1,1,2,0,24,1,0)	94.0 ( 99999 )	25.6 ( 99999 )	52.7 ( 90.4 )	99999 ( 99999 )	120 ( 64.9 )	99999 ( 99999 )	91.8 ( 99999 )
Ribociclib, C1 D21: Pre-dose(n=1,0,1,0,10,1,1)	105 ( 99999 )	99999 ( 99999 )	102 ( 99999 )	99999 ( 99999 )	112 ( 75.8 )	115 ( 99999 )	69.9 ( 99999 )
Ribociclib, C2 D1: Pre-dose(n=1,1,1,1,16,0,1)	99999 ( 99999 )	19.5 ( 99999 )	1.59 ( 99999 )	1.07 ( 99999 )	7.00 ( 377.8 )	132 ( 99999 )	99999 ( 99999 )
Ribociclib, C2 D15: Pre-dose(n=1,1,2,1,15,1,1)	103 ( 99999 )	41.5 ( 99999 )	53.7 ( 51.2 )	36.0 ( 99999 )	107 ( 59.4 )	102 ( 99999 )	113 ( 99999 )
Ribociclib, C3 D1: Pre-dose(n=1,1,0,0,11,0,0)	1.16 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	4.06 ( 172.4 )	99999 ( 99999 )	99999 ( 99999 )
Ribociclib, C4 D1: Pre-dose(n=1,0,0,0,2,0,0)	1.22 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	1.59 ( 31.6 )	99999 ( 99999 )	99999 ( 99999 )
Ribociclib, C5 D1: Pre-dose(n=0,0,0,0,2,0,0)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	2.16 ( 35.5 )	99999 ( 99999 )	99999 ( 99999 )
Ribociclib, EOT(n=1,1,2,1,21,0,1)	1.94 ( 99999 )	60.3 ( 99999 )	1.49 ( 99999 )	45.8 ( 99999 )	29.0 ( 292.1 )	22.8 ( 99999 )	99999 ( 99999 )
LEQ803, C1 D1: 1.5 hrs(n=1,1,2,0,21,1,1)	57.1 ( 99999 )	70.2 ( 99999 )	68.2 ( 2.4 )	99999 ( 99999 )	47.5 ( 97.4 )	63.6 ( 99999 )	59.0 ( 99999 )
LEQ803, C1 D1: 4 hrs(n=1,1,3,0,24,1,0)	65.2 ( 99999 )	50.8 ( 99999 )	73.5 ( 20.4 )	99999 ( 99999 )	81.1 ( 55.6 )	99999 ( 99999 )	63.2 ( 99999 )
LEQ803, C1 D8: Pre-dose(n=1,1,2,0,22,1,1)	64.3 ( 99999 )	49.3 ( 99999 )	38.1 ( 9.1 )	99999 ( 99999 )	53.7 ( 36.5 )	71.2 ( 99999 )	47.2 ( 99999 )
LEQ803, C1 D15: Pre-dose(n=1,1,2,0,25,1,0)	76.0 ( 99999 )	37.1 ( 99999 )	32.9 ( 25.7 )	99999 ( 99999 )	55.1 ( 33.9 )	99999 ( 99999 )	49.2 ( 99999 )
LEQ803, C1 D15: 0.5 hr(n=1,1,2,0,24,0,0)	75.5 ( 99999 )	39.5 ( 99999 )	32.1 ( 0.7 )	99999 ( 99999 )	60.8 ( 36.9 )	99999 ( 99999 )	99999 ( 99999 )
LEQ803, C1 D15: 1.5 hrs(n=1,1,2,0,24,0,0)	92.3 ( 99999 )	72.6 ( 99999 )	82.7 ( 0.7 )	99999 ( 99999 )	112 ( 46.9 )	99999 ( 99999 )	99999 ( 99999 )
LEQ803, C1 D15: 2.5 hrs(n=1,1,1,0,24,1,0)	130 ( 99999 )	92.5 ( 99999 )	126 ( 99999 )	99999 ( 99999 )	133 ( 45.4 )	99999 ( 99999 )	137 ( 99999 )
LEQ803, C1 D15: 4 hrs(n=1,0,2,0,25,0,0)	138 ( 99999 )	99999 ( 99999 )	140 ( 23.4 )	99999 ( 99999 )	152 ( 31.2 )	99999 ( 99999 )	99999 ( 99999 )
LEQ803, C1 D15: 6 hrs(n=1,1,2,0,23,0,0)	175 ( 99999 )	90.2 ( 99999 )	111 ( 27.6 )	99999 ( 99999 )	145 ( 27.2 )	99999 ( 99999 )	99999 ( 99999 )
LEQ803, C1 D15: 8 hrs(n=1,1,2,0,21,0,0)	135 ( 99999 )	79.8 ( 99999 )	95.2 ( 50.1 )	99999 ( 99999 )	128 ( 27.6 )	99999 ( 99999 )	99999 ( 99999 )
LEQ803, C1 D16: 24 hrs(n=1,1,2,0,24,1,0)	84.5 ( 99999 )	46.8 ( 99999 )	42.5 ( 13.8 )	99999 ( 99999 )	63.1 ( 36.1 )	99999 ( 99999 )	59.6 ( 99999 )
LEQ803, C1 D21: Pre-dose(n=1,0,1,0,10,1,1)	73.8 ( 99999 )	99999 ( 99999 )	43.7 ( 99999 )	99999 ( 99999 )	58.1 ( 39.1 )	80.2 ( 99999 )	52.9 ( 99999 )
LEQ803, C2 D1: Pre-dose(n=1,1,1,1,16,0,1)	6.68 ( 99999 )	14.5 ( 99999 )	4.10 ( 99999 )	2.70 ( 99999 )	8.48 ( 154.5 )	80.8 ( 99999 )	99999 ( 99999 )
LEQ803, C2 D15: Pre-dose(n=1,1,2,1,15,1,1)	90.0 ( 99999 )	45.6 ( 99999 )	45.7 ( 6.8 )	28.0 ( 99999 )	58.3 ( 42.7 )	61.1 ( 99999 )	66.8 ( 99999 )
LEQ803, C3 D1: Pre-dose(n=1,1,0,0,11,0,0)	7.88 ( 99999 )	2.75 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	7.57 ( 61.4 )	99999 ( 99999 )	99999 ( 99999 )
LEQ803, C4 D1: Pre-dose(n=1,0,0,0,2,0,0)	7.19 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	5.72 ( 6.9 )	99999 ( 99999 )	99999 ( 99999 )
LEQ803, C5 D1: Pre-dose(n=0,0,0,0,2,0,0)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	6.07 ( 28.9 )	99999 ( 99999 )	99999 ( 99999 )
LEQ803, EOT(n=1,1,2,1,21,0,1)	10.4 ( 99999 )	69.3 ( 99999 )	5.06 ( 4.6 )	23.5 ( 99999 )	20.6 ( 152.2 )	31.2 ( 99999 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Plasma Concentration for Infigratinib (BGJ) and its Metabolites: Part II

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End point title

Plasma Concentration for Infigratinib (BGJ) and its Metabolites: Part II

End point description

BHS697 and CQM157 are metabolites of infigratinib. Maximum treatment exposure for Part II was of 97.0 weeks. PAS consisted of all subjects who had at least one blood sample providing evaluable PK data. Here, “n” signifies number of subjects evaluable for specified time points. In results reported below, “99999” suggested that a) geometric mean available but no geometric coefficient of variation: dispersion not available as there was only 1 subject evaluable; b) no geometric mean and geometric coefficient of variation: no subjects evaluable and where subjects were evaluable: BLQ value.

End point type

Secondary

End point timeframe

C1 (1.5 hrs post-dose on D1; pre-dose on D8; pre-dose, 0.5, 1.5, 2.5, 4, 6 hrs post-dose on D15; 24 hrs post-dose on D16; pre-dose on D21); C2 (pre-dose on D1 and D15); C3 pre-dose on D1; EOT

End point values	Part II:Encorafenib 450mg/Binimetinib 45mg+Infigratinib 75mg
Number of subjects analysed	1
Units: Nanogram per milliliter
geometric mean (geometric coefficient of variation)
Infigratinib, C1 D1: 1.5 hrs (n =1)	15.0 ( 99999 )
Infigratinib, C1 D8: Pre-dose (n =1)	2.67 ( 99999 )
Infigratinib, C1 D15: Pre-dose (n =1)	2.49 ( 99999 )
Infigratinib, C1 D15: 0.5 hr (n =1)	3.39 ( 99999 )
Infigratinib, C1 D15: 1.5 hrs (n =1)	15.2 ( 99999 )
Infigratinib, C1 D15: 2.5 hrs (n =1)	27.5 ( 99999 )
Infigratinib, C1 D15: 4 hrs (n =1)	24.7 ( 99999 )
Infigratinib, C1 D15: 6 hrs (n =1)	20.5 ( 99999 )
Infigratinib, C1 D16: 24 hrs (n =0)	99999 ( 99999 )
Infigratinib, C1 D21: Pre-dose (n =1)	2.05 ( 99999 )
Infigratinib, C2 D1: Pre-dose (n =1)	99999 ( 99999 )
Infigratinib, C2 D15: Pre-dose (n =1)	4.65 ( 99999 )
Infigratinib, C3 D1: Pre-dose (n =1)	99999 ( 99999 )
Infigratinib, EOT (n =1)	2.42 ( 99999 )
BHS697, C1 D1: 1.5 hrs (n =1)	4.83 ( 99999 )
BHS697, C1 D8: Pre-dose (n =1)	2.17 ( 99999 )
BHS697, C1 D15: Pre-dose (n =1)	1.64 ( 99999 )
BHS697, C1 D15: 0.5 hr (n =1)	2.14 ( 99999 )
BHS697, C1 D15: 1.5 hrs (n =1)	6.83 ( 99999 )
BHS697, C1 D15: 2.5 hrs (n =1)	8.53 ( 99999 )
BHS697, C1 D15: 4 hrs (n =1)	6.89 ( 99999 )
BHS697, C1 D15: 6 hrs (n =1)	5.57 ( 99999 )
BHS697, C1 D16: 24 hrs (n =0)	99999 ( 99999 )
BHS697, C1 D21: Pre-dose (n =1)	1.37 ( 99999 )
BHS697, C2 D1: Pre-dose (n =1)	99999 ( 99999 )
BHS697, C2 D15: Pre-dose (n =1)	2.83 ( 99999 )
BHS697, C3 D1: Pre-dose (n =1)	99999 ( 99999 )
BHS697, EOT (n =1)	1.69 ( 99999 )
CQM157, C1 D1: 1.5 hrs (n =1)	13.0 ( 99999 )
CQM157, C1 D8: Pre-dose (n =1)	14.1 ( 99999 )
CQM157, C1 D15: Pre-dose (n =1)	11.1 ( 99999 )
CQM157, C1 D15: 0.5 hr (n =1)	12.0 ( 99999 )
CQM157, C1 D15: 1.5 hrs (n =1)	21.3 ( 99999 )
CQM157, C1 D15: 2.5 hrs (n =1)	28.3 ( 99999 )
CQM157, C1 D15: 4 hrs (n =1)	25.0 ( 99999 )
CQM157, C1 D15: 6 hrs (n =1)	32.2 ( 99999 )
CQM157, C1 D16: 24 hrs (n =0)	99999 ( 99999 )
CQM157, C1 D21: Pre-dose (n =1)	9.65 ( 99999 )
CQM157, C2 D1: Pre-dose (n =1)	99999 ( 99999 )
CQM157, C2 D15: Pre-dose (n =1)	15.5 ( 99999 )
CQM157, C3 D1: Pre-dose (n =1)	99999 ( 99999 )
CQM157, EOT (n =1)	11.9 ( 99999 )

No statistical analyses for this end point

Secondary: Plasma Concentration for Capmatinib (INC): Part II

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End point title

Plasma Concentration for Capmatinib (INC): Part II

End point description

Maximum treatment exposure for Part II was of 97.0 weeks. PAS consisted of all subjects who had at least one blood sample providing evaluable PK data. All subjects reported under ‘Number of Subjects Analyzed’ contributed data to the table; however, may not have evaluable data for every row. Here, “n” signifies number of subjects evaluable for specified time points.In results reported below, “99999” suggested that a) geometric mean available but no geometric coefficient of variation: dispersion not available as there was only 1 subject evaluable; b) no geometric mean and geometric coefficient of variation: no subjects evaluable and where subjects were evaluable: BLQ value.

End point type

Secondary

End point timeframe

C1 (1.5 hrs post-dose on D1; pre-dose on D8; pre-dose, 0.5, 1.5, 2.5, 4, 6, 8 hrs post-dose on D15; 24 hrs post-dose on D16); C2 (pre-dose on D1 and D15); C3 pre-dose on D1; C4 pre-dose on D1; C5 pre-dose on D1; EOT

End point values	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 200mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 400mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 300mg
Number of subjects analysed	5	5	1
Units: Nanogram per milliliter
geometric mean (geometric coefficient of variation)
C1 D1: 1.5 hrs (n =3, 1, 2)	362 ( 268.6 )	715 ( 133.2 )	3600 ( 99999 )
C1 D8: Pre-dose (n =3, 1, 4)	74.3 ( 97.2 )	129 ( 49.4 )	44.4 ( 99999 )
C1 D15: Pre-dose (n =4, 1, 4)	89.3 ( 35.7 )	173 ( 41.2 )	71.4 ( 99999 )
C1 D15: 0.5 hr (n =5, 1, 4)	196 ( 103.8 )	314 ( 49.0 )	1880 ( 99999 )
C1 D15: 1.5 hrs (n =5, 1, 4)	636 ( 78.2 )	1830 ( 38.3 )	3670 ( 99999 )
C1 D15: 2.5 hrs (n =5, 0, 4)	545 ( 81.2 )	1530 ( 18.4 )	99999 ( 99999 )
C1 D15: 4 hrs (n =4, 1, 4)	401 ( 17.3 )	950 ( 39.1 )	1230 ( 99999 )
C1 D15: 6 hrs (n =5, 1, 4)	157 ( 63.2 )	487 ( 23.3 )	264 ( 99999 )
C1 D15: 8 hrs (n =5, 1, 3)	120 ( 50.0 )	390 ( 10.5 )	268 ( 99999 )
C1 D16: 24 hrs (n =5, 1, 4)	79.6 ( 103.1 )	269 ( 68.7 )	58.1 ( 99999 )
C2 D1: Pre-dose (n =5, 1, 3)	151 ( 107.6 )	227 ( 42.0 )	38.7 ( 99999 )
C2 D15: Pre-dose (n =3, 1, 3)	65.2 ( 31.0 )	166 ( 80.9 )	50.5 ( 99999 )
C3 D1: Pre-dose (n =2, 0, 3)	114 ( 113.4 )	96.5 ( 17.9 )	99999 ( 99999 )
C4 D1: Pre-dose (n =0, 0, 3)	99999 ( 99999 )	175 ( 44.8 )	99999 ( 99999 )
C5 D1: Pre-dose (n =0, 1, 0)	99999 ( 99999 )	99999 ( 99999 )	41.8 ( 99999 )
EOT (n =3, 1, 4)	99999 ( 99999 )	65.4 ( 155.0 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Plasma Concentration for Buparlisib (BKM): Part II

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End point title

Plasma Concentration for Buparlisib (BKM): Part II

End point description

Maximum treatment exposure for Part II was of 97.0 weeks. PAS consisted of all subjects who had at least one blood sample providing evaluable PK data. All subjects reported under ‘Number of Subjects Analyzed’ contributed data to the table; however, may not have evaluable data for every row. Here, “n” signifies number of subjects evaluable for specified time points. In results reported below, “99999” suggested that a) geometric mean available but no geometric coefficient of variation: dispersion not available as there was only 1 subject evaluable; b) no geometric mean and geometric coefficient of variation: no subjects evaluable and where subjects were evaluable: BLQ value.

End point type

Secondary

End point timeframe

End point values	Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 60mg	Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 90mg
Number of subjects analysed	3	3
Units: Nanogram per milliliter
geometric mean (geometric coefficient of variation)
C1 D1: 1.5 hrs (n =1, 1)	213 ( 99999 )	213 ( 99999 )
C1 D8: Pre-dose (n =3, 2)	45.0 ( 75.2 )	119 ( 3.6 )
C1 D15: Pre-dose (n =3, 2)	49.7 ( 115.9 )	97.3 ( 16.2 )
C1 D15: 0.5 hr (n =3, 2)	139 ( 13.4 )	229 ( 21.5 )
C1 D15: 1.5 hrs (n =3, 2)	266 ( 51.5 )	312 ( 10.9 )
C1 D15: 2.5 hrs (n =3, 2)	176 ( 42.2 )	268 ( 11.9 )
C1 D15: 4 hrs (n =3, 2)	115 ( 44.0 )	235 ( 39.4 )
C1 D15: 6 hrs (n =3, 2)	94.2 ( 40.0 )	171 ( 26.4 )
C1 D15: 8 hrs (n =3, 2)	87.4 ( 63.9 )	111 ( 25.5 )
C1 D16: 24 hrs (n =3, 2)	41.8 ( 82.9 )	101 ( 1.4 )
C2 D1: Pre-dose (n =3, 2)	54.7 ( 134.9 )	110 ( 51.2 )
C2 D15: Pre-dose (n =1, 1)	99.3 ( 99999 )	138 ( 99999 )
C3 D1: Pre-dose (n =1, 0)	81.2 ( 99999 )	99999 ( 99999 )
C4 D1: Pre-dose (n =1, 0)	73.2 ( 99999 )	99999 ( 99999 )
C5 D1: Pre-dose (n =1, 0)	122 ( 99999 )	99999 ( 99999 )
EOT (n =2, 1)	1.84 ( 53.4 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Maximum Observed Plasma Concentration at Steady State (Cmax,ss) for Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Infigratinib, Infigratinib Metabolites, Capmatinib, and Buparlisib: Part II

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End point title

Maximum Observed Plasma Concentration at Steady State (Cmax,ss) for Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Infigratinib, Infigratinib Metabolites, Capmatinib, and Buparlisib: Part II

End point description

AR00426032 = binimetinib metabolite, LEQ803 = ribociclib metabolite, BHS697 and CQM157 = infigratinib metabolites. PAS consisted of all subjects who had at least one blood sample providing evaluable PK data. All subjects reported under ‘Number of Subjects Analyzed’ contributed data to the table; however, may not have evaluable data for every row. Here, “n” signifies number of subjects evaluable for specified drugs. In results reported below, “99999” suggested that a) geometric mean available but no geometric coefficient of variation: dispersion not available as there was only 1 subject evaluable; b) no geometric mean and geometric coefficient of variation: no subjects evaluable.

End point type

Secondary

End point timeframe

C1 D15: 0.5 hour ± 10 (minutes) min; 1 hour ± 10 min; 1.5 hour ± 15 min; 2 hour ± 15 min; 2.5 hour ± 15 min; 4 hour ± 30 min; 6 hour ± 30 min; 8 hour ± 60 min; 24 hour ± 2 hour

End point values	Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 60mg	Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 90mg	Part II:Encorafenib 450mg/Binimetinib 45mg+Infigratinib 75mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 200mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 300mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 400mg	Part II:Encorafenib 100mg/Binimetinib 30mg+Ribociclib 600mg	Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 400mg	Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 600mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 400mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 600mg	Part II:Encorafenib 300mg/Binimetinib 30mg+Ribociclib 600mg
Number of subjects analysed	3	3	1	5	1	5	1	1	3	1	29	1
Units: Nanogram per milliliter
geometric mean (geometric coefficient of variation)
Encorafenib (n=3,2,1,5,1,4,1,1,2,1,25,0)	3060 ( 58.8 )	2150 ( 54.6 )	2100 ( 99999 )	1600 ( 62.0 )	2890 ( 99999 )	2570 ( 23.0 )	622 ( 99999 )	1960 ( 99999 )	1860 ( 32.1 )	2010 ( 99999 )	2030 ( 40.6 )	99999 ( 99999 )
Binimetinib (n=3,2,1,5,1,4,1,1,2,1,24,1)	386 ( 41.1 )	221 ( 237.6 )	413 ( 99999 )	515 ( 17.0 )	797 ( 99999 )	858 ( 13.0 )	261 ( 99999 )	520 ( 99999 )	313 ( 15.9 )	584 ( 99999 )	489 ( 31.3 )	291 ( 99999 )
AR00426032 (n=3,2,1,5,1,4,1,1,2,1,24,1)	24.9 ( 92.2 )	18.1 ( 591.2 )	15.8 ( 99999 )	27.9 ( 85.6 )	22.6 ( 99999 )	47.1 ( 29.2 )	12.9 ( 99999 )	12.6 ( 99999 )	16.1 ( 151.9 )	19.4 ( 99999 )	23.7 ( 94.1 )	9.04 ( 99999 )
Ribociclib (n=0,0,0,0,0,0,1,1,2,1,26,1)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	434 ( 99999 )	126 ( 99999 )	428 ( 84.2 )	282 ( 99999 )	753 ( 70.6 )	597 ( 99999 )
LEQ803 (n=0,0,0,0,0,0,1,1,2,1,26,1)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	175 ( 99999 )	93.2 ( 99999 )	144 ( 19.2 )	67.5 ( 99999 )	156 ( 36.2 )	138 ( 99999 )
Infigratinib (n=0,0,1,0,0,0,0,0,0,0,0,0)	99999 ( 99999 )	99999 ( 99999 )	27.5 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
BHS697 (n=0,0,1,0,0,0,0,0,0,0,0,0)	99999 ( 99999 )	99999 ( 99999 )	8.53 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
CQM157 (n=0,0,1,0,0,0,0,0,0,0,0,0)	99999 ( 99999 )	99999 ( 99999 )	32.2 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Capmatinib (n=0,0,0,5,1,4,0,0,0,0,0,0)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	722 ( 85.3 )	3670 ( 99999 )	1920 ( 31.8 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Buparlisib (n=3,2,0,5,1,4,0,0,0,0,0,0)	266 ( 51.5 )	312 ( 10.9 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Time to Reach Cmax at Steady State (Tmax, ss) for Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Infigratinib, Infigratinib Metabolites, Capmatinib, and Buparlisib: Part II

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End point title

Time to Reach Cmax at Steady State (Tmax, ss) for Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Infigratinib, Infigratinib Metabolites, Capmatinib, and Buparlisib: Part II

End point description

End point type

Secondary

End point timeframe

C1 D15: 0.5 hour ± 10 min; 1 hour ± 10 min; 1.5 hour ± 15 min; 2 hour ± 15 min; 2.5 hour ± 15 min; 4 hour ± 30 min; 6 hour ± 30 min; 8 hour ± 60 min; 24 hour ± 2 hour

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 60mg

Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 90mg

Part II:Encorafenib 450mg/Binimetinib 45mg+Infigratinib 75mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 200mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 300mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 400mg

Part II:Encorafenib 100mg/Binimetinib 30mg+Ribociclib 600mg

Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 400mg

Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 600mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 400mg

Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 600mg

Part II:Encorafenib 300mg/Binimetinib 30mg+Ribociclib 600mg

Number of subjects analysed

Units: Hour

median (full range (min-max))

Encorafenib (n=3,2,1,5,1,4,1,1,2,1,25,0)

1.33 (0.58 to 1.50)

1.54 (1.50 to 1.58)

1.50 (1.50 to 1.50)

1.50 (0.50 to 1.53)

1.50 (1.50 to 1.50)

1.50 (1.50 to 2.50)

2.37 (2.37 to 2.37)

1.47 (1.47 to 1.47)

1.00 (0.50 to 1.50)

1.50 (1.50 to 1.50)

1.58 (0.63 to 6.17)

99999 (-99999 to 99999)

Binimetinib (n=3,2,1,5,1,4,1,1,2,1,24,1)

1.50 (1.33 to 1.67)

2.75 (1.50 to 4.00)

1.50 (1.50 to 1.50)

1.50 (0.50 to 1.58)

1.50 (1.50 to 1.50)

1.50 (1.50 to 2.50)

1.38 (1.38 to 1.38)

1.47 (1.47 to 1.47)

1.50 (1.50 to 1.50)

1.58 (0.50 to 4.08)

1.08 (1.08 to 1.08)

AR00426032 (n=3,2,1,5,1,4,1,1,2,1,24,1)

1.50 (1.33 to 1.67)

2.75 (1.50 to 4.00)

1.50 (1.50 to 1.50)

1.50 (1.50 to 1.58)

4.00 (4.00 to 4.00)

1.92 (1.50 to 2.50)

1.38 (1.38 to 1.38)

1.47 (1.47 to 1.47)

1.50 (1.50 to 1.50)

1.65 (0.67 to 4.08)

1.08 (1.08 to 1.08)

Ribociclib (n=0,0,0,0,0,0,1,1,2,1,26,1)

99999 (-99999 to 99999)

5.92 (5.92 to 5.92)

2.45 (2.45 to 2.45)

3.18 (2.33 to 4.03)

1.50 (1.50 to 1.50)

3.65 (1.50 to 6.00)

0.50 (0.50 to 0.50)

LEQ803 (n=0,0,0,0,0,0,1,1,2,1,26,1)

99999 (-99999 to 99999)

5.92 (5.92 to 5.92)

4.98 (4.98 to 4.98)

3.18 (2.33 to 4.03)

1.50 (1.50 to 1.50)

4.12 (1.55 to 7.00)

1.08 (1.08 to 1.08)

Infigratinib (n=0,0,1,0,0,0,0,0,0,0,0,0)

99999 (-99999 to 99999)

2.50 (2.50 to 2.50)

99999 (-99999 to 99999)

BHS697 (n=0,0,1,0,0,0,0,0,0,0,0,0)

99999 (-99999 to 99999)

2.50 (2.50 to 2.50)

99999 (-99999 to 99999)

CQM157 (n=0,0,1,0,0,0,0,0,0,0,0,0)

99999 (-99999 to 99999)

5.75 (5.75 to 5.75)

99999 (-99999 to 99999)

Capmatinib (n=0,0,0,5,1,4,0,0,0,0,0,0)

99999 (-99999 to 99999)

1.53 (1.50 to 2.58)

1.50 (1.50 to 1.50)

1.50 (1.50 to 2.50)

99999 (-99999 to 99999)

Buparlisib (n=3,2,0,0,0,0,0,0,0,0,0,0)

1.50 (1.33 to 1.67)

1.50 (1.50 to 1.50)

99999 (-99999 to 99999)

99999 (99999 to 99999)

99999 (-99999 to 99999)

No statistical analyses for this end point

Secondary: Area Under the Concentration-time Curve From Time Zero to Time tau at Steady-State (AUCtau,ss) for Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Capmatinib, and Buparlisib: Part II

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End point title

Area Under the Concentration-time Curve From Time Zero to Time tau at Steady-State (AUCtau,ss) for Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Capmatinib, and Buparlisib: Part II

End point description

AR00426032 = binimetinib metabolite, LEQ803 = ribociclib metabolite. PAS consisted of all subjects who had at least one blood sample providing evaluable PK data. All subjects reported under ‘Number of Subjects Analyzed’ contributed data to the table; however, may not have evaluable data for every row. Here, “n” signifies number of subjects evaluable for specified drugs. In results reported below, “99999” suggested that a) geometric mean available but no geometric coefficient of variation: dispersion not available as there was only 1 subject evaluable; b) no geometric mean and geometric coefficient of variation: no subjects evaluable.

End point type

Secondary

End point timeframe

C1 D15: 0.5 hour ± 10 min; 1 hour ± 10 min; 1.5 hour ± 15 min; 2 hour ± 15 min; 2.5 hour ± 15 min; 4 hour ± 30 min; 6 hour ± 30 min; 8 hour ± 60 min; 24 hour ± 2 hour

End point values	Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 60mg	Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 90mg	Part II:Encorafenib 450mg/Binimetinib 45mg+Infigratinib 75mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 200mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 300mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 400mg	Part II:Encorafenib 100mg/Binimetinib 30mg+Ribociclib 600mg	Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 400mg	Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 600mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 400mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 600mg	Part II:Encorafenib 300mg/Binimetinib 30mg+Ribociclib 600mg
Number of subjects analysed	3	3	1	5	1	5	1	1	3	1	29	1
Units: Hour*nanogram per milliliter
geometric mean (geometric coefficient of variation)
Encorafenib (n=3,2,1,5,1,4,1,1,2,1,23,0)	9080 ( 42.2 )	10100 ( 18.4 )	7420 ( 99999 )	4990 ( 42.6 )	10800 ( 99999 )	8570 ( 10.6 )	3490 ( 99999 )	6000 ( 99999 )	5740 ( 7.1 )	6200 ( 99999 )	11300 ( 41.1 )	99999 ( 99999 )
Binimetinib (n=3,2,1,5,1,4,1,1,2,1,23,1)	1580 ( 17.0 )	1220 ( 105.7 )	1260 ( 99999 )	2180 ( 29.4 )	3040 ( 99999 )	2760 ( 4.8 )	1700 ( 99999 )	1900 ( 99999 )	1140 ( 21.1 )	1740 ( 99999 )	2270 ( 29.5 )	99999 ( 99999 )
AR00426032 (n=3,2,1,5,1,4,1,1,2,1,22,1)	116 ( 66.8 )	94.4 ( 222.2 )	42.0 ( 99999 )	124 ( 113.9 )	135 ( 99999 )	182 ( 43.1 )	81.5 ( 99999 )	47.0 ( 99999 )	57.9 ( 128.5 )	66.9 ( 99999 )	115 ( 92.6 )	41.1 ( 99999 )
Ribociclib (n=0,0,0,0,0,0,1,1,2,1,22,1)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	5630 ( 99999 )	1650 ( 99999 )	3730 ( 62.5 )	2320 ( 99999 )	9230 ( 60.9 )	5960 ( 99999 )
LEQ803 (n=0,0,0,0,0,0,1,1,2,1,22,1)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	1640 ( 99999 )	1900 ( 24.9 )	930 ( 99999 )	2540 ( 31.3 )	2300 ( 99999 )
Capmatinib (n=0,0,0,5,1,4,0,0,0,0,0,0)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	3070 ( 52.6 )	12200 ( 99999 )	8420 ( 22.0 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Buparlisib (n=3,2,0,0,0,0,0,0,0,0,0,0)	2130 ( 54.6 )	3400 ( 18.5 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Elimination Half-life at Steady State (t1/2, ss) of Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Capmatinib, and Buparlisib: Part II

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End point title

Elimination Half-life at Steady State (t1/2, ss) of Encorafenib, Binimetinib, Binimetinib Metabolite, Ribociclib, Ribociclib Metabolite, Capmatinib, and Buparlisib: Part II

End point description

AR00426032 = binimetinib metabolite, LEQ803 = ribociclib metabolite. Elimination half-life means the time required for the plasma concentration to decline by 50% during the elimination phase. PAS consisted of all subjects who had at least one blood sample providing evaluable PK data. All subjects reported under ‘Number of Subjects Analyzed’ contributed data to the table; however, may not have evaluable data for every row. Here, “n” signifies number of subjects evaluable for specified drugs. In results reported below, “99999” suggested that a) geometric mean available but no geometric coefficient of variation: dispersion not available as there was only 1 subject evaluable; b) no geometric mean and geometric coefficient of variation: no subjects evaluable.

End point type

Secondary

End point timeframe

C1 D15: 0.5 hour ± 10 min; 1 hour ± 10 min; 1.5 hour ± 15 min; 2 hour ± 15 min; 2.5 hour ± 15 min; 4 hour ± 30 min; 6 hour ± 30 min; 8 hour ± 60 min; 24 hour ± 2 hour

End point values	Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 60mg	Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 90mg	Part II:Encorafenib 450mg/Binimetinib 45mg+Infigratinib 75mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 200mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 300mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 400mg	Part II:Encorafenib 100mg/Binimetinib 30mg+Ribociclib 600mg	Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 400mg	Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 600mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 400mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 600mg	Part II:Encorafenib 300mg/Binimetinib 30mg+Ribociclib 600mg
Number of subjects analysed	3	3	1	5	1	5	1	1	3	1	29	1
Units: Hour
arithmetic mean (standard deviation)
Encorafenib (n=3,2,1,5,1,4,1,1,2,1,20,0)	3.75 ( 0.302 )	5.89 ( 4.32 )	3.57 ( 99999 )	4.18 ( 1.85 )	3.41 ( 99999 )	3.96 ( 0.233 )	4.27 ( 99999 )	3.75 ( 99999 )	4.32 ( 1.62 )	3.83 ( 99999 )	3.60 ( 0.711 )	99999 ( 99999 )
Binimetinib (n=3,2,1,4,0,4,1,1,2,1,22,1)	8.35 ( 3.52 )	3.48 ( 0.484 )	1.60 ( 99999 )	10.3 ( 6.29 )	99999 ( 99999 )	5.88 ( 2.77 )	5.84 ( 99999 )	3.82 ( 99999 )	5.38 ( 3.39 )	10.9 ( 99999 )	4.13 ( 1.42 )	99999 ( 99999 )
AR00426032 (n=3,2,1,2,1,3,0,1,2,1,17,0)	6.35 ( 1.21 )	4.14 ( 0.683 )	1.59 ( 99999 )	7.95 ( 4.03 )	2.86 ( 99999 )	5.64 ( 2.49 )	99999 ( 99999 )	4.34 ( 99999 )	6.24 ( 4.43 )	99999 ( 99999 )	5.91 ( 3.00 )	99999 ( 99999 )
Ribociclib (n=0,0,0,0,0,0,0,1,2,1,18,1)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	9.01 ( 99999 )	8.44 ( 2.21 )	10.7 ( 99999 )	7.77 ( 1.95 )	10.1 ( 99999 )
LEQ803 (n=0,0,0,0,0,0,0,1,2,1,11,0)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	19.9 ( 99999 )	14.1 ( 4.04 )	19.2 ( 99999 )	16.0 ( 4.50 )	99999 ( 99999 )
Capmatinib (n=0,0,0,2,1,1,0,0,0,0,0,0)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	2.18 ( 0.0599 )	2.50 ( 99999 )	2.82 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Buparlisib (n=3,0,0,0,0,0,0,0,0,0,0,0)	15.4 ( 4.62 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Apparent Total Plasma Clearance at Steady State (Cl, ss/F) of Encorafenib, Binimetinib, Ribociclib, Capmatinib, and Buparlisib: Part II

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End point title

Apparent Total Plasma Clearance at Steady State (Cl, ss/F) of Encorafenib, Binimetinib, Ribociclib, Capmatinib, and Buparlisib: Part II

End point description

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. PAS consisted of all subjects who had at least one blood sample providing evaluable PK data. All subjects reported under ‘Number of Subjects Analyzed’ contributed data to the table; however, may not have evaluable data for every row. Here, “n” signifies number of subjects evaluable for specified drugs. In results reported below, “99999” suggested that a) geometric mean available but no geometric coefficient of variation: dispersion not available as there was only 1 subject evaluable; b) no geometric mean and geometric coefficient of variation: no subjects evaluable.

End point type

Secondary

End point timeframe

C1 D15: 0.5 hour ± 10 min; 1 hour ± 10 min; 1.5 hour ± 15 min; 2 hour ± 15 min; 2.5 hour ± 15 min; 4 hour ± 30 min; 6 hour ± 30 min; 8 hour ± 60 min; 24 hour ± 2 hour

End point values	Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 60mg	Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 90mg	Part II:Encorafenib 450mg/Binimetinib 45mg+Infigratinib 75mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 200mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 300mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 400mg	Part II:Encorafenib 100mg/Binimetinib 30mg+Ribociclib 600mg	Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 400mg	Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 600mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 400mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 600mg	Part II:Encorafenib 300mg/Binimetinib 30mg+Ribociclib 600mg
Number of subjects analysed	3	3	1	5	1	5	1	1	3	1	29	1
Units: Liter per hour
geometric mean (geometric coefficient of variation)
Encorafenib (n =3,2,1,5,1,4,1,1,2,1,20,0)	49.6 ( 42.1 )	44.7 ( 18.4 )	60.7 ( 99999 )	40.1 ( 42.6 )	18.6 ( 99999 )	23.4 ( 10.7 )	28.7 ( 99999 )	33.3 ( 99999 )	34.9 ( 6.9 )	32.2 ( 99999 )	19.5 ( 44.3 )	99999 ( 99999 )
Binimetinib (n =3,2,1,5,1,4,1,1,2,1,23,0)	28.5 ( 14.8 )	36.9 ( 105.7 )	35.6 ( 99999 )	20.8 ( 28.1 )	15.1 ( 99999 )	16.3 ( 5.0 )	17.4 ( 99999 )	15.8 ( 99999 )	26.5 ( 22.6 )	25.9 ( 99999 )	19.9 ( 29.2 )	99999 ( 99999 )
Ribociclib (n =0,0,0,0,0,0,0,1,2,1,19,1)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	243 ( 99999 )	161 ( 61.1 )	173 ( 99999 )	62.4 ( 58.5 )	99.3 ( 99999 )
Capmatinib (n =0,0,0,5,1,3,0,0,0,0,0,0)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	65.9 ( 52.2 )	24.8 ( 99999 )	45.7 ( 24.4 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Buparlisib (n =3,1,0,0,0,0,0,0,0,0,0,0)	28.2 ( 53.6 )	23.2 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Apparent Volume of Distribution at Steady State (Vz, ss/F) of Encorafenib, Binimetinib, Ribociclib, Capmatinib, and Buparlisib: Part II

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End point title

Apparent Volume of Distribution at Steady State (Vz, ss/F) of Encorafenib, Binimetinib, Ribociclib, Capmatinib, and Buparlisib: Part II

End point description

Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution is the apparent volume of distribution at steady-state. PAS consisted of all subjects who had at least one blood sample providing evaluable PK data. All subjects reported under ‘Number of Subjects Analyzed’ contributed data to the table; however, may not have evaluable data for every row. Here, “n” signifies number of subjects evaluable for specified drugs. In results reported below, “99999” suggested that a) geometric mean available but no geometric coefficient of variation: dispersion not available as there was only 1 subject evaluable; b) no geometric mean and geometric coefficient of variation: no subjects evaluable.

End point type

Secondary

End point timeframe

C1 D15: 0.5 hour ± 10 min; 1 hour ± 10 min; 1.5 hour ± 15 min; 2 hour ± 15 min; 2.5 hour ± 15 min; 4 hour ± 30 min; 6 hour ± 30 min; 8 hour ± 60 min; 24 hour ± 2 hour

End point values	Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 60mg	Part II:Encorafenib 450mg/Binimetinib 45mg+Buparlisib 90mg	Part II:Encorafenib 450mg/Binimetinib 45mg+Infigratinib 75mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 200mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 300mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Capmatinib 400mg	Part II:Encorafenib 100mg/Binimetinib 30mg+Ribociclib 600mg	Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 400mg	Part II:Encorafenib 200mg/Binimetinib 30mg+Ribociclib 600mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 400mg	Part II:Encorafenib 200mg/Binimetinib 45mg+Ribociclib 600mg	Part II:Encorafenib 300mg/Binimetinib 30mg+Ribociclib 600mg
Number of subjects analysed	3	3	1	5	1	5	1	1	3	1	29	1
Units: Liter
geometric mean (geometric coefficient of variation)
Encorafenib (n =3,2,1,5,1,4,1,1,2,1,20,0)	268 ( 45.4 )	324 ( 69.8 )	313 ( 99999 )	226 ( 92.9 )	91.7 ( 99999 )	133 ( 13.5 )	177 ( 99999 )	180 ( 99999 )	210 ( 32.3 )	178 ( 99999 )	99.3 ( 46.0 )	99999 ( 99999 )
Binimetinib (n =3,2,1,4,0,4,1,1,2,1,22,0)	324 ( 58.3 )	185 ( 83.4 )	82.5 ( 99999 )	244 ( 75.9 )	99999 ( 99999 )	125 ( 56.1 )	147 ( 99999 )	86.8 ( 99999 )	184 ( 111.8 )	406 ( 99999 )	113 ( 48.5 )	99999 ( 99999 )
Ribociclib (n =0,0,0,0,0,0,0,1,2,1,18,1)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	3160 ( 99999 )	1930 ( 30.5 )	2660 ( 99999 )	677 ( 65.0 )	1440 ( 99999 )
Capmatinib (n =0,0,0,2,1,1,0,0,0,0,0,0)	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	190 ( 30.3 )	89.5 ( 99999 )	233 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Buparlisib (n =3,0,0,0,0,0,0,0,0,0,0,0)	604 ( 17.4 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )

No statistical analyses for this end point

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Clinical trials

Clinical Trial Results: The LOGIC 2 Trial A Phase II, Multi-Center, Open-Label Study Of Sequential LGX818/MEK162 Combination Followed By A Rational Combination With Targeted Agents After Progression, To Overcome Resistance In Adult Patients With Locally Advanced Or Metastatic BRAF V600 Melanoma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Overall Response Rate (ORR): Part II

Primary: Overall Response Rate (ORR): Part II

Secondary: Number of Subjects With Dose Limiting Toxicities (DLTs) in Cycle 1: Part II

Secondary: Number of Subjects With Dose Limiting Toxicities (DLTs) in Cycle 1: Part II

Secondary: Number of Subjects With Adverse Events (AEs) and Serious AEs (SAEs): Part I

Secondary: Number of Subjects With Adverse Events (AEs) and Serious AEs (SAEs): Part I

Secondary: Number of Subjects With AEs and SAEs: Part II

Secondary: Number of Subjects With AEs and SAEs: Part II

Secondary: Number of Subjects With Worst Post-baseline Hematology Results Based on Common Terminology Criteria for Adverse Events (CTCAE) Grade: Part I

Secondary: Number of Subjects With Worst Post-baseline Hematology Results Based on Common Terminology Criteria for Adverse Events (CTCAE) Grade: Part I

Secondary: Number of Subjects With Worst Post-baseline Hematology Results Based on CTCAE Grade: Part II

Secondary: Number of Subjects With Worst Post-baseline Hematology Results Based on CTCAE Grade: Part II

Secondary: Number of Subjects With Worst Post-baseline Serum Chemistry Results Based on CTCAE Grade: Part I

Secondary: Number of Subjects With Worst Post-baseline Serum Chemistry Results Based on CTCAE Grade: Part I

Secondary: Number of Subjects With Worst Post-baseline Serum Chemistry Results Based on CTCAE Grade: Part II

Secondary: Number of Subjects With Worst Post-baseline Serum Chemistry Results Based on CTCAE Grade: Part II

Secondary: Number of Subjects With Newly Occurring Notably Abnormal Vital Signs: Part I

Secondary: Number of Subjects With Newly Occurring Notably Abnormal Vital Signs: Part I

Secondary: Number of Subjects With Newly Occurring Notably Abnormal Vital Signs: Part II

Secondary: Number of Subjects With Newly Occurring Notably Abnormal Vital Signs: Part II

Secondary: Number of Subjects With Notable Electrocardiograms (ECG) Values: Part I

Secondary: Number of Subjects With Notable Electrocardiograms (ECG) Values: Part I

Secondary: Number of Subjects With Notable ECG Values: Part II

Secondary: Number of Subjects With Notable ECG Values: Part II

Secondary: Number of Subjects With At least One Dose Interruption: Part I

Secondary: Number of Subjects With At least One Dose Interruption: Part I

Secondary: Number of Subjects With At least One Dose Interruption: Part II

Secondary: Number of Subjects With At least One Dose Interruption: Part II

Secondary: Number of Subjects With At least One Dose Reduction: Part I

Secondary: Number of Subjects With At least One Dose Reduction: Part I

Secondary: Number of Subjects With At least One Dose Reduction: Part II

Secondary: Number of Subjects With At least One Dose Reduction: Part II

Secondary: Actual Dose Intensity: Part I

Secondary: Actual Dose Intensity: Part I

Secondary: Actual Dose Intensity: Part II

Secondary: Actual Dose Intensity: Part II

Secondary: Progression-Free Survival (PFS): Part I

Secondary: Progression-Free Survival (PFS): Part I

Secondary: PFS: Part II

Secondary: PFS: Part II

Secondary: Duration of Response (DOR): Part I

Secondary: Duration of Response (DOR): Part I

Secondary: DOR: Part II

Secondary: DOR: Part II

Secondary: TTR: Part II

Secondary: TTR: Part II

Secondary: Time to Response (TTR): Part I

Secondary: Time to Response (TTR): Part I

Secondary: Disease Control Rate (DCR): Part I

Secondary: Disease Control Rate (DCR): Part I

Secondary: DCR: Part II

Secondary: DCR: Part II

Secondary: Overall Survival (OS): Part II

Secondary: Overall Survival (OS): Part II

Secondary: Summary of Genomic Biomarkers From Tumor Samples: Part I

Secondary: Summary of Genomic Biomarkers From Tumor Samples: Part I

Secondary: Plasma Concentration for Encorafenib (LGX): Part I

Secondary: Plasma Concentration for Encorafenib (LGX): Part I

Secondary: Plasma Concentration for Encorafenib (LGX): Part II

Secondary: Plasma Concentration for Encorafenib (LGX): Part II

Secondary: Plasma Concentration for Binimetinib (MEK) and its Metabolite: Part I

Secondary: Plasma Concentration for Binimetinib (MEK) and its Metabolite: Part I

Secondary: Plasma Concentration for Binimetinib (MEK) and its Metabolite: Part II

Secondary: Plasma Concentration for Binimetinib (MEK) and its Metabolite: Part II

Secondary: Plasma Concentration for Ribociclib (LEE) and its Metabolite: Part II

Secondary: Plasma Concentration for Ribociclib (LEE) and its Metabolite: Part II

Secondary: Plasma Concentration for Infigratinib (BGJ) and its Metabolites: Part II

Secondary: Plasma Concentration for Infigratinib (BGJ) and its Metabolites: Part II

Secondary: Plasma Concentration for Capmatinib (INC): Part II

Secondary: Plasma Concentration for Capmatinib (INC): Part II

Clinical Trial Results:
The LOGIC 2 Trial A Phase II, Multi-Center, Open-Label Study Of Sequential LGX818/MEK162 Combination Followed By A Rational Combination With Targeted Agents After Progression, To Overcome Resistance In Adult Patients With Locally Advanced Or Metastatic BRAF V600 Melanoma