coBRIM: A Study Comparing Vemurafenib Versus Vemurafenib Plus Cobimetinib in Participants With Metastatic Melanoma

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01689519
• Collaborator: (none)
• Enrollment: 495
• Locations: 156
• Arms: 2
• Actual Duration (Months): 78.4
• Patients Per Site: 3.2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

To evaluate the efficacy of vemurafenib in combination with cobimetinib (GDC-0973), compared with vemurafenib and placebo, in previously untreated BRAF V600 mutation-positive patients with unresectable locally advanced or metastatic melanoma, as measured by progression-free survival (PFS), assessed by the study site investigator.

Condition or Disease	Intervention/Treatment	Phase
Malignant Melanoma	Drug: Placebo; Drug: Vemurafenib; Drug: Cobimetinib	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 495 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase III, Double-Blind, Placebo-Controlled Study of Vemurafenib Versus Vemurafenib Plus GDC-0973 in Previously Untreated BRAF^600-Mutation Positive Patients With Unresectable Locally Advanced or Metastatic Melanoma
• Actual Study Start Date: Jan 8, 2013
• Actual Primary Completion Date: May 9, 2014
• Actual Study Completion Date: Jul 21, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Placebo + Vemurafenib Participants will receive placebo orally once daily on Days 1-21 of each 28-day cycle plus vemurafenib 960 milligrams (mg) orally twice a day on Days 1-28 of each 28-day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.	Drug: Placebo; Placebo supplied as tablets; Drug: Vemurafenib; Vemurafenib supplied as tablets; Other Names: RO518426
Experimental: Cobimetinib + Vemurafenib Participants will receive cobimetinib 60 mg orally once daily on Days 1-21 of each 28-day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28-day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.	Drug: Vemurafenib; Vemurafenib supplied as tablets; Other Names: RO518426 ; Drug: Cobimetinib; Cobimetinib supplied as tablets; Other Names: GDC-0973 RO5514041 XL518

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival [Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)]

   Progression-free survival was defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator using Response Evaluation Criteria in Solid Tumors v1.1, or death from any cause, whichever came first. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance of 1 or more new lesions.

Secondary Outcome Measures

1. Overall Survival [Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)]

   Overall survival was defined as the time from randomization until the date of death from any cause.

2. Percentage of Participants With an Objective Response [Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)]

   An objective response was defined as a complete response or a partial response determined on two consecutive occasions ≥ 4 weeks apart. Responses were determined by Response Evaluation Criteria in Solid Tumors v1.1. A complete response was defined as the disappearance of all target lesions or the disappearance of all non-target lesions and normalization of tumor marker level. A partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter of target lesions.

3. Duration of Response [Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)]

   Duration of response was defined as the time from first occurrence of a documented confirmed objective response until the time of disease progression, as determined by investigator review of tumor assessments using Response Evaluation Criteria in Solid Tumors v1.1 or death from any cause during the study. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance of 1 or more new lesions.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Participants with histologically confirmed melanoma, either unresectable stage IIIc or stage IV metastatic melanoma, as defined by the American Joint Committee on Cancer 7th edition. Unresectability of stage IIIc disease must have confirmation from a surgical oncologist

• Participants must be naïve to treatment for locally advanced unresectable or metastatic disease (ie, no prior systemic anti-cancer therapy for advanced disease; stage IIIc and IV). Prior adjuvant immunotherapy (including ipilimumab) is allowed

• Documentation of BRAF V600 mutation-positive status in melanoma tumor tissue (archival or newly obtained tumor samples) using the cobas 4800 BRAF V600 mutation test

• Measurable disease per RECIST v1.1

• Eastern Clinical Oncology Group performance status of 0 or 1

• Consent to provide archival for biomarker analyses

• Consent to undergo tumor biopsies for biomarker analyses

• Life expectancy greater than or equal to (≥) 12 weeks

• Adequate hematologic and end organ function

Exclusion Criteria:

• History of prior rapidly accelerated fibrosarcoma or mitogen-activated protein kinase pathway inhibitor treatment

• Palliative radiotherapy within 14 days prior to the first dose of study treatment

• Major surgery or traumatic injury within 14 days prior to first dose of study treatment

• Active malignancy other than melanoma that could potentially interfere with the interpretation of efficacy measures. Participants with a previous malignancy within the past 3 years are excluded except for participants with resected basal cell carcinoma or squamous cell carcinoma of the skin, melanoma in-situ, carcinoma in-situ of the cervix, and carcinoma in-situ of the breast

• History of or evidence of retinal pathology on ophthalmological examination that is considered a risk factor for neurosensory retinal detachment, retinal vein occlusion, or neovascular macular degeneration

• Uncontrolled glaucoma with intraocular pressure

• Serum cholesterol ≥ Grade 2

• Hypertriglyceridemia ≥ Grade 2

• Hyperglycemia (fasting) ≥ Grade 2

• History of clinically significant cardiac dysfunction

• Participants with active central nervous system (CNS) lesions (including carcinomatous meningitis) are excluded. However, participants are eligible if:

1. All known CNS lesions have been treated with stereotactic therapy or surgery, AND

2. There has been no evidence of clinical and radiographic disease progression in the CNS for ≥ 3 weeks after radiotherapy or surgery

• Current severe, uncontrolled systemic disease

• History of malabsorption or other condition that would interfere with absorption of study drugs

• Pregnant, lactating, or breast feeding women

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35233
2	The Angeles Clinic and Research Institute - W LA Office	Los Angeles	California	United States	90025
3	University of California Davis Health System	Sacramento	California	United States	95817
4	Sutter Pacific Medical Foundation	Santa Rosa	California	United States	95403
5	University Of Colorado	Aurora	Colorado	United States	80045
6	Florida Cancer Specialists - Broadway	Fort Myers	Florida	United States	33901
7	Mount Sinai Medical Center	Miami Beach	Florida	United States	33140
8	Orlando Health Inc.	Orlando	Florida	United States	32806
9	Northwestern Center For Clinical Research	Chicago	Illinois	United States	60611
10	Uni of Kansas Medical Center; Dept of Neurology	Kansas City	Kansas	United States	66160-7314
11	U of L - Physicians Pulmonology; Dept of Neuroradiology and Dept of Diagnostic Radiology	Louisville	Kentucky	United States	40202
12	Washington University School of Medicine; Dept of Medicine/Div of Medical Oncology	Saint Louis	Missouri	United States	63108
13	Dartmouth-Hitchcock Medical Center; Department of Medicine	Lebanon	New Hampshire	United States	03756
14	Novant Health Oncology Specialists	Winston-Salem	North Carolina	United States	27103
15	University Hospitals of Cleveland	Cleveland	Ohio	United States	44106
16	St. Luke's University Health network	Bethlehem	Pennsylvania	United States	18015
17	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania	United States	19107
18	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15261
19	Rhode Island Hospital; Investigational Services	Providence	Rhode Island	United States	2903
20	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
21	Chris O'Brien Lifehouse	Camperdown	New South Wales	Australia	2050
22	Lake Macquarie Private Hospital	Gateshead	New South Wales	Australia	2290
23	Lismore Base Hospital; Cancer Care & Haematology Unit	Lismore	New South Wales	Australia	2480
24	Melanoma Institute Australia	North Sydney	New South Wales	Australia	2060
25	Princess Alexandra Hospital	Woolloongabba	New South Wales	Australia	2050
26	Royal Darwin Hospital	Casuarina	Northern Territory	Australia	0811
27	Greenslopes Private Hospital	Greenslopes	Queensland	Australia	4120
28	Royal Brisbane and Women's Hospital	Herston	Queensland	Australia	4029
29	Royal Adelaide Hospital; Hepatology	Adelaide	South Australia	Australia	5000
30	Ashford Cancer Centre	Ashford SA	South Australia	Australia	5035
31	Royal Hobart Hospital	Hobart	Tasmania	Australia	7000
32	Launceston General Hospital; Gastroenterology Research	Launceston	Tasmania	Australia	7250
33	Peninsula and South Eastern Haematology and Oncology Group	Frankston	Victoria	Australia	3199
34	Austin Hospital	Heidelberg	Victoria	Australia	3084
35	Peter MacCallum Cancer Centre-East Melbourne	Melbourne	Victoria	Australia	3000
36	The Alfred Hospital	Prahan	Victoria	Australia	3181
37	Fiona Stanley Hospital	Murdoch	Western Australia	Australia	6150
38	Ordensklinikum Linz Elisabethinen	Linz		Austria	4020
39	Landesklinikum St. Pölten	St. Pölten		Austria	3100
40	Medizinische Universität Wien	Wien		Austria	1090
41	Institut Jules Bordet; Department of Medical Oncology	Bruxelles		Belgium	1000
42	Cliniques Universitaires St-Luc	Bruxelles		Belgium	1200
43	UZ Antwerpen	Edegem		Belgium	2650
44	Jessa Zkh (Campus Virga Jesse)	Hasselt		Belgium	3500
45	CHU Sart-Tilman	Liège		Belgium	4000
46	AZ Delta (Campus Rumbeke)	Roeselare		Belgium	8800
47	BC Cancer Agency Vancouver Island Cancer Centre	Victoria	British Columbia	Canada	V8R 6V5
48	Juravinski Cancer Clinic; Department of Oncology	Hamilton	Ontario	Canada	L8V 5C2
49	The Ottawa Hospital Cancer Center; General Campus	Ottawa	Ontario	Canada	K1H 1C4
50	Toronto Sunnybrook Hospital	Toronto	Ontario	Canada	M4N 3M5
51	Princess Margaret Hospital; Department of Med Oncology	Toronto	Ontario	Canada	M5G 2M9
52	London Health Sciences Centre · Victoria Hospital;Department of Pediatrics	London	Quebec	Canada	N6A 4G5
53	McGill University Health Centre/Glen Site / Royal Victoria Hospital	Montréal	Quebec	Canada	H2W 1S6
54	Masarykuv onkologicky ustav	Brno		Czechia	656 53
55	Fakultni nemocnice Hradec Kralove	Hradec Kralove		Czechia	500 05
56	Fakultní nemocnice Olomouc	Olomouc		Czechia	775 20
57	Fakultni nemocnice Ostrava	Ostrava - Poruba		Czechia	708 52
58	Multiscan s.r.o.	Pardubice		Czechia	532 03
59	Nemocnice Na Bulovce	Prague		Czechia	180 01
60	Vseobecna fakultni nemocnice v Praze	Praha 2		Czechia	128 08
61	Fakultni nemocnice Kralovske Vinohrady	Praha		Czechia	100 34
62	Fakultni nemocnice Motol; Neurologicka klinika	Praha		Czechia	150 06
63	Groupe Hospitalier Saint André - Hôpital Saint André	Bordeaux		France	33075
64	Hôpital Ambroise Paré - Boulogne-Billancourt; Respiratory	Boulogne Billancourt		France	92104
65	CHU Clermont Ferrand - Hôpital d'Estaing	Clermont Ferrand cedex 1		France	63003
66	CHU de Dijon - Hopital le Bocage	Dijon		France	21000
67	Centre Hospitalier Universitaire de Grenoble - Albert Michallon	La Tronche		France	38700
68	Hopital Claude Huriez - CHU Lille	Lille		France	59037
69	Hopital de la Timone	Marseille		France	13005
70	Hopital Saint Eloi	Montpellier		France	34295
71	CHU NANTES - Hôtel Dieu; Pharmacy	Nantes		France	44093
72	CHU Nice - Hopital de l'Archet 2	Nice		France	06202
73	Centre Hospitalier Lyon Sud	Pierre Benite		France	69495
74	Hopital Robert Debre; DERMATOLOGIE	Reims		France	51092
75	Centre Eugene Marquis; Service d'oncologie	Rennes		France	35042
76	St. Josef-Hospital; Studienambulanz	Bochum		Germany	44791
77	Elbekliniken Buxtehude GmbH	Buxtehude		Germany	21614
78	Universitätsklinikum "Carl Gustav Carus" der Technischen Universität Dresden	Dresden		Germany	01307
79	Helios Klinikum Erfurt	Erfurt		Germany	99089
80	Universitätsklinikum Essen	Essen		Germany	45147
81	Universitaetsklinikum Freiburg	Freiburg		Germany	79106
82	SRH Wald-Klinikum Gera; Klinik für Hautkrankheiten und Allergologie	Gera		Germany	07548
83	Universitätsmedizin Göttingen	Göttingen		Germany	37075
84	Universitätsklinikum Hamburg-Eppendorf	Hamburg		Germany	20246
85	Medizinische Hochschule Hannover	Hannover		Germany	30625
86	Universitätsklinikum Heidelberg	Heidelberg		Germany	69120
87	Universitaetsklinikum Schleswig-Holstein - Campus Kiel; Klinik fuer Allgemeine Innere Medizin	Kiel		Germany	24105
88	Universitaetsklinikum Koeln; Hematology/Oncology	Koeln		Germany	50937
89	Universitaetsmedizin der Johannes Gutenberg-Universitaet Mainz	Mainz		Germany	55101
90	Klinikum Mannheim GmbH Universitätsklinikum	Mannheim		Germany	68167
91	Fachklinik Hornheide	Muenster		Germany	48157
92	Klinikum der Ludwigs-Maximilians-Universitaet Muenchen	München		Germany	80337
93	Universitaetsklinikum Regensburg	Regensburg		Germany	93053
94	Universitätsklinikum Tübingen	Tuebingen		Germany	72076
95	Universitätsklinikum Wurzburg	Würzburg		Germany	97080
96	Orszagos Onkologiai Intezet	Budapest		Hungary	1122
97	Bekes Megyei Kozponti Korhaz Pandy Kalman Tagkorhaza	Gyula		Hungary	5700
98	Somogy Megyei Kaposi Mor Oktato Korhaz	Pecs		Hungary	7624
99	Szegedi Tud.Egyetem Szent-Gyorgyi Albert Klin.Kozp.	Szeged		Hungary	6720
100	Soroka Medical Center; Oncology Dept	Beer Sheva		Israel	8410100
101	Rambam Health Care Campus	Haifa		Israel	3109600
102	HADASSAH UNIVERSITY HOSPITAL, EIN KAREM; Oncology	Jerusalem		Israel	9112000
103	Rabin Medical Center-Beilinson Campus;Hematology-Oncology	Petach Tikva		Israel	4941492
104	Chaim Sheba Medical Center	Ramat Gan		Israel	5265601
105	Tel Aviv Sourasky MC, Dana children's hospital;Oncology Division	Tel Aviv		Israel	6423906
106	Istituto Nazionale Tumori Fondazione G. Pascale	Napoli	Campania	Italy	80131
107	Istituto Scientifico Romagnolo Per Lo Studio e La Cura Dei Tumori	Meldola	Emilia-Romagna	Italy	47014
108	A.O.U. Policlinico di Modena	Modena	Emilia-Romagna	Italy	40124
109	Istituto Nazionale Tumori Regina Elena IRCCS	Roma	Lazio	Italy	00144
110	Istituto Nazionale per la Ricerca sul Cancro di Genova	Genova	Liguria	Italy	16132
111	Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII (Presidio Papa Giovanni XXIII)	Bergamo	Lombardia	Italy	24127
112	Asst Degli Spedali Civili Di Brescia	Brescia	Lombardia	Italy	25100
113	Fondazione IRCCS Istituto Nazionale dei Tumori	Milano	Lombardia	Italy	20133
114	Istituto Tumori Giovanni Paolo II IRCSS; Ospedale Oncologico Bari	Bari	Puglia	Italy	70126
115	A.O.U. Senese Policlinico Santa Maria Alle Scotte	Siena	Toscana	Italy	53100
116	IOV - Istituto Oncologico Veneto IRCCS	Padova	Veneto	Italy	35128
117	Amsterdam UMC Location VUMC	Amsterdam		Netherlands	1081 HV
118	Leids Universitair Medisch Centrum; Cardiology	Leiden		Netherlands	2333 ZA
119	Maastricht University Medical Center	Maastricht		Netherlands	6229 HX
120	Auckland City Hospital	Auckland		New Zealand	1023
121	Waikato Hospital	Hamilton		New Zealand	3248
122	Radiumhospitalet	Oslo		Norway	0379
123	TSBHI Altai Territorial oncological dispensary	Barnaul		Russian Federation	656045
124	FSBSI "N. N. Blokhin Russian Cancer Research Center"	Moscow		Russian Federation	115478
125	Moscow city oncology hospital #62 of Moscow Healthcare Department	Moscow		Russian Federation	143423
126	BHI of Omsk region Clinical Oncology Dispensary	Omsk		Russian Federation	644013
127	Pyatigorsky Oncologic Dispensary	Pyatigorsk		Russian Federation	357524
128	Complexo Hospitalario Universitario de Santiago	Santiago de Compostela	LA Coruña	Spain	15706
129	Clinica Universitaria de Navarra	Pamplona	Navarra	Spain	31008
130	Hospital Universitario Virgen Macarena	Seville	Sevilla	Spain	41071
131	Hospital Clínic i Provincial de Barcelona	Barcelona		Spain	08036
132	MD Anderson Cancer Center	Madrid		Spain	28033
133	Hospital Universitario 12 de Octubre	Madrid		Spain	28041
134	Hospital General Universitario de Valencia	Valencia		Spain	46014
135	Hospital Universitario Miguel Servet	Zaragoza		Spain	50009
136	Länssjukhuset Ryhov	Jönköping		Sweden	551 85
137	Skånes Universitetssjukhus	Lund		Sweden	221 85
138	Sahlgrenska Sjukhuset	Mölnlycke		Sweden	435 33
139	Akademiska Sjukhuset	Uppsala		Sweden	751 85
140	Inselspital-Universitaetsspital Bern	Bern		Switzerland	3010
141	Kantonsspital Graubuenden	Chur		Switzerland	7000
142	Bristol Haematology and Oncology Centre	Bristol		United Kingdom	BS2 8ED
143	Addenbrooke's Hospital	Cambridge		United Kingdom	CB2 0QQ
144	Velindre Cancer Centre	Cardiff		United Kingdom	CF14 2TL
145	Western General Hospital	Edinburgh		United Kingdom	EH4 2XU
146	Beatson West of Scotland Cancer Centre	Glasgow		United Kingdom	G12 0YN
147	The Clatterbridge Cancer Centre NHS Foundation Trust	Liverpool		United Kingdom	L7 8YA
148	Barts and the London NHS Trust.	London		United Kingdom	EC1A 7BE
149	St George's Hospital; Courtyard Clinic	London		United Kingdom	SW17 0QT
150	Royal Marsden Hospital - Fulham	London		United Kingdom	SW3 6JJ
151	Royal Marsden Hospital - London	London		United Kingdom	SW3 6JJ
152	Freeman Hospital	Newcastle upon Tyne		United Kingdom	NE7 7DN
153	Nottingham University Hospitals; QMC Campus	Nottingham		United Kingdom	NG7 2UH
154	Southampton General Hospital	Southampton		United Kingdom	SO16 6YD
155	Royal Cornwall Hospital	Truro		United Kingdom	TR1 3LQ
156	New Cross Hospital	Wolverhampton		United Kingdom	WV10 0QP

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Director: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

• Study Protocol - Oct 20, 2016

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT01689519
• Other Study ID Numbers: GO28141; 2012-003008-11
• First Posted: Sep 21, 2012
• Last Update Posted: May 2, 2022
• Last Verified: Apr 1, 2022

• Keywords provided by Hoffmann-La Roche: Zelboraf; vemurafenib; RG7204; PLX4032; Genentech MEK inhibitor; Genentech BRAF inhibitor; Roche MEK inhibitor; Roche BRAF inhibitor; RO5185426; metastatic melanoma; BRAF positive melanoma; BRAF mutant melanoma; advanced melanoma; Genentech RAF inhibitor; Roche RAF inhibitor; BRAF V600E kinase inhibitor; Oncogenic BRAF inhibitor; BRAF kinase inhibitor; GDC-0973; XL518; melanoma
• Additional relevant MeSH terms: Melanoma; Vemurafenib

Study Results

Participant Flow

Pre-assignment Detail	Written informed consent for participation in the study was obtained before performing any study-specific screening tests or evaluations.

Arm/Group Title	Cobimetinib + Vemurafenib	Placebo + Vemurafenib
Arm/Group Description	Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.	Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.
Period Title: Intent to Treat
STARTED	247	248
COMPLETED	0	0
NOT COMPLETED	247	248
Period Title: Intent to Treat
STARTED	248	245
COMPLETED	0	0
NOT COMPLETED	248	245

Baseline Characteristics

Arm/Group Title	Cobimetinib + Vemurafenib	Placebo + Vemurafenib	Total
Arm/Group Description	Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.	Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.	Total of all reporting groups
Overall Participants	247	248	495
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	183 74.1%	179 72.2%	362 73.1%
>=65 years	64 25.9%	69 27.8%	133 26.9%
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	54.9 (14.0)	55.3 (13.8)	55.1 (13.9)
Sex: Female, Male (Count of Participants)
Female	101 40.9%	108 43.5%	209 42.2%
Male	146 59.1%	140 56.5%	286 57.8%
Race/Ethnicity, Customized (Count of Participants) [Number]
Asian	1 0.4%	0 0%	1 0.2%
More than one race	1 0.4%	1 0.4%	2 0.4%
Native Hawaiian or other Pacific Islande	0 0%	1 0.4%	1 0.2%
Black or African American	0 0%	0 0%	0 0%
White	227 91.9%	235 94.8%	462 93.3%
Unknown or Not Reported	16 6.5%	9 3.6%	25 5.1%
Other	2 0.8%	2 0.8%	4 0.8%
Race/Ethnicity, Customized (Count of Participants) [Number]
Hispanic or Latino	14 5.7%	12 4.8%	26 5.3%
Not Hispanic or Latino	213 86.2%	223 89.9%	436 88.1%
Not Stated	16 6.5%	10 4%	26 5.3%
Unknown	4 1.6%	3 1.2%	7 1.4%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival
Description	Progression-free survival was defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator using Response Evaluation Criteria in Solid Tumors v1.1, or death from any cause, whichever came first. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance of 1 or more new lesions.
Time Frame	Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized participants, regardless of whether or not study treatment was received.

Arm/Group Title	Cobimetinib + Vemurafenib	Placebo + Vemurafenib
Arm/Group Description	Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.	Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.
Measure Participants	247	248
Primary Analysis: 9 May 2014	9.90	6.20
Post hoc Efficacy Analysis: 16 January 2015	12.30	7.20
Extended 5-Year Analysis: 21 July 2019	12.60	7.20

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cobimetinib + Vemurafenib, Placebo + Vemurafenib
	Comments	Primary Analysis 9 May 2014
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	The analysis was stratified by geographic region and metastasis classification (disease stage).
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.51
	Confidence Interval	(2-Sided) 95%; 0.39 to 0.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cobimetinib + Vemurafenib, Placebo + Vemurafenib
	Comments	Post hoc Efficacy Analysis: 16 January 2015
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The analysis was stratified by geographic region and metastasis classification (disease stage).
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.58
	Confidence Interval	(2-Sided) 95%; 0.46 to 0.72
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cobimetinib + Vemurafenib, Placebo + Vemurafenib
	Comments	Extended 5-Year Analysis: 21 July 2019
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	The analysis was stratified by geographic region and metastasis classification (disease stage).
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 95%; 0.53 to 0.79
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Overall Survival
Description	Overall survival was defined as the time from randomization until the date of death from any cause.
Time Frame	Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized participants, regardless of whether or not study treatment was received.

Arm/Group Title	Cobimetinib + Vemurafenib	Placebo + Vemurafenib
Arm/Group Description	Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.	Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.
Measure Participants	247	248
Primary Analysis 9 May 2014	NA	NA
Post hoc Analysis 16 January 2015	NA	17.00
Final Analysis 28 August 2015	22.30	17.40
Extended 5-year Analysis 21 July 2019	22.50	17.40

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cobimetinib + Vemurafenib, Placebo + Vemurafenib
	Comments	Primary Analysis 9 May 2014
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0463
	Comments	The analysis was stratified by geographic region and metastasis classification (disease stage).
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.645
	Confidence Interval	(2-Sided) 95%; 0.42 to 1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cobimetinib + Vemurafenib, Placebo + Vemurafenib
	Comments	Post hoc Analysis 16 January 2015
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0034
	Comments	The analysis was stratified by geographic region and metastasis classification (disease stage).
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 95%; 0.49 to 0.87
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cobimetinib + Vemurafenib, Placebo + Vemurafenib
	Comments	Final Analysis 28 August 2015
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.0050
	Comments	The analysis was stratified by geographic region and metastasis classification (disease stage).
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.70
	Confidence Interval	(2-Sided) 95%; 0.55 to 0.90
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Participants With an Objective Response
Description	An objective response was defined as a complete response or a partial response determined on two consecutive occasions ≥ 4 weeks apart. Responses were determined by Response Evaluation Criteria in Solid Tumors v1.1. A complete response was defined as the disappearance of all target lesions or the disappearance of all non-target lesions and normalization of tumor marker level. A partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter of target lesions.
Time Frame	Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized participants, regardless of whether or not study treatment was received.

Arm/Group Title	Cobimetinib + Vemurafenib	Placebo + Vemurafenib
Arm/Group Description	Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.	Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.
Measure Participants	247	248
Primary Analysis: 9 May 2014	67.60 27.4%	44.80 18.1%
Post hoc Efficacy Analysis: 16 January 2015	69.60 28.2%	50.00 20.2%
Extended 5-Year Analysis: 21 July 2019	69.60 28.2%	49.60 20%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cobimetinib + Vemurafenib, Placebo + Vemurafenib
	Comments	Primary Analysis: 9 May 2014
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	22.85
	Confidence Interval	(2-Sided) 95%; 14.13 to 31.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Cobimetinib + Vemurafenib, Placebo + Vemurafenib
	Comments	Post hoc Efficacy Analysis: 16 January 2015
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	19.6
	Confidence Interval	(2-Sided) 95%; 11.0 to 28.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Cobimetinib + Vemurafenib, Placebo + Vemurafenib
	Comments	Extended 5-Year Analysis: 21 July 2019
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	20.00
	Confidence Interval	(2-Sided) 95%; 11.40 to 28.70
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Duration of Response
Description	Duration of response was defined as the time from first occurrence of a documented confirmed objective response until the time of disease progression, as determined by investigator review of tumor assessments using Response Evaluation Criteria in Solid Tumors v1.1 or death from any cause during the study. Disease progression was defined as: (1) at least a 20% increase in the sum (the increase in the sum must be at least 5 mm) of diameters of target lesions, taking as reference the smallest sum during the study; (2) unequivocal progression of existing non-target lesions; or (3) the appearance of 1 or more new lesions.
Time Frame	Baseline to the 21 July 2019 data cut-off (up to 7 years, 6 months)

Outcome Measure Data

Analysis Population Description

Intent-to-treat population: All randomized participants, regardless of whether or not study treatment was received. Only participants with an objective response were included in the analysis.

Arm/Group Title	Cobimetinib + Vemurafenib	Placebo + Vemurafenib
Arm/Group Description	Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.	Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.
Measure Participants	247	248
Primary Analysis: 9 May 2014	NA	7.29
Extended 5-Year Analysis: 21 July 2019	14.65	9.23

Adverse Events

Time Frame	Adverse events were collected from the time of each participant's randomization into the study until their last visit until 28 days after the last dose of study drug and during extended 5-year efficacy and safety follow-up analyses (Safety data cut-off: July 2019; up to 7 years, 6 months).
Adverse Event Reporting Description	1 participant was randomized in Placebo + Vem but did not receive any study treatment, 1 participant randomized in Cobi+ Vem but did not receive any study treatment, two participants were randomized in Placebo + Vem but received the Cobi+Vem. All-cause Mortality is reported for the ITT population, SAEs and AEs are reported for the safety population. 1 participant died after 30 days from the last dose of treatment, after crossing over from the Placebo + Vem to the Cobi+Vem arm.
Arm/Group Title	Cobimetinib + Vemurafenib		Placebo + Vemurafenib
Arm/Group Description	Participants received cobimetinib 60 mg orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.		Participants received placebo orally once daily on Days 1-21 of each 28 day cycle plus vemurafenib 960 mg orally twice a day on Days 1-28 of each 28 day cycle until disease progression, death, unacceptable toxicity, or withdrawal of consent, whichever occurs earliest.
All Cause Mortality
	Cobimetinib + Vemurafenib		Placebo + Vemurafenib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	160/247 (64.8%)		164/248 (66.1%)
Serious Adverse Events
	Cobimetinib + Vemurafenib		Placebo + Vemurafenib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	105/248 (42.3%)		71/245 (29%)
Blood and lymphatic system disorders
ANAEMIA	0/248 (0%)	0	1/245 (0.4%)	1
Cardiac disorders
ACUTE CORONARY SYNDROME	1/248 (0.4%)	1	0/245 (0%)	0
ATRIAL FIBRILLATION	4/248 (1.6%)	8	1/245 (0.4%)	1
CARDIAC ARREST	1/248 (0.4%)	1	0/245 (0%)	0
CARDIAC FAILURE	1/248 (0.4%)	1	2/245 (0.8%)	2
CARDIAC TAMPONADE	0/248 (0%)	0	1/245 (0.4%)	1
MYOCARDIAL INFARCTION	2/248 (0.8%)	2	0/245 (0%)	0
PERICARDIAL EFFUSION	0/248 (0%)	0	4/245 (1.6%)	4
SUPRAVENTRICULAR TACHYCARDIA	0/248 (0%)	0	1/245 (0.4%)	1
TACHYCARDIA	0/248 (0%)	0	1/245 (0.4%)	1
Endocrine disorders
HYPERTHYROIDISM	1/248 (0.4%)	1	0/245 (0%)	0
Eye disorders
CHORIORETINOPATHY	3/248 (1.2%)	5	0/245 (0%)	0
IRIDOCYCLITIS	0/248 (0%)	0	1/245 (0.4%)	1
RETINAL DETACHMENT	1/248 (0.4%)	1	0/245 (0%)	0
RETINAL HAEMORRHAGE	0/248 (0%)	0	1/245 (0.4%)	1
SEROUS RETINAL DETACHMENT	2/248 (0.8%)	2	0/245 (0%)	0
UVEITIS	0/248 (0%)	0	1/245 (0.4%)	1
Gastrointestinal disorders
ABDOMINAL PAIN	1/248 (0.4%)	1	0/245 (0%)	0
APHTHOUS ULCER	1/248 (0.4%)	1	0/245 (0%)	0
COLITIS	1/248 (0.4%)	1	0/245 (0%)	0
CONSTIPATION	1/248 (0.4%)	1	0/245 (0%)	0
DIARRHOEA	3/248 (1.2%)	3	0/245 (0%)	0
DYSPHAGIA	0/248 (0%)	0	1/245 (0.4%)	1
GASTRIC ANTRAL VASCULAR ECTASIA	1/248 (0.4%)	1	0/245 (0%)	0
GASTROINTESTINAL HAEMORRHAGE	1/248 (0.4%)	1	0/245 (0%)	0
GASTROINTESTINAL PAIN	0/248 (0%)	0	1/245 (0.4%)	1
GASTROOESOPHAGEAL REFLUX DISEASE	0/248 (0%)	0	1/245 (0.4%)	1
INGUINAL HERNIA	0/248 (0%)	0	1/245 (0.4%)	1
INTESTINAL OBSTRUCTION	0/248 (0%)	0	1/245 (0.4%)	1
INTESTINAL PERFORATION	1/248 (0.4%)	1	0/245 (0%)	0
MELAENA	0/248 (0%)	0	1/245 (0.4%)	1
OBSTRUCTION GASTRIC	1/248 (0.4%)	1	0/245 (0%)	0
PANCREATITIS	1/248 (0.4%)	1	2/245 (0.8%)	2
PERIODONTAL DISEASE	0/248 (0%)	0	1/245 (0.4%)	1
RECTAL POLYP	0/248 (0%)	0	1/245 (0.4%)	1
SMALL INTESTINAL OBSTRUCTION	3/248 (1.2%)	3	0/245 (0%)	0
VOMITING	2/248 (0.8%)	2	1/245 (0.4%)	1
General disorders
ASTHENIA	1/248 (0.4%)	1	0/245 (0%)	0
CHEST PAIN	1/248 (0.4%)	1	0/245 (0%)	0
DEATH	1/248 (0.4%)	1	1/245 (0.4%)	1
FATIGUE	1/248 (0.4%)	1	0/245 (0%)	0
GAIT DISTURBANCE	1/248 (0.4%)	1	0/245 (0%)	0
MALAISE	1/248 (0.4%)	1	0/245 (0%)	0
PERIPHERAL SWELLING	0/248 (0%)	0	1/245 (0.4%)	1
PYREXIA	7/248 (2.8%)	9	3/245 (1.2%)	3
Hepatobiliary disorders
CHOLECYSTITIS	0/248 (0%)	0	2/245 (0.8%)	2
DRUG-INDUCED LIVER INJURY	1/248 (0.4%)	1	0/245 (0%)	0
HEPATITIS ACUTE	1/248 (0.4%)	1	0/245 (0%)	0
Immune system disorders
HYPERSENSITIVITY	3/248 (1.2%)	3	0/245 (0%)	0
SARCOIDOSIS	1/248 (0.4%)	2	0/245 (0%)	0
Infections and infestations
ABDOMINAL SEPSIS	1/248 (0.4%)	1	0/245 (0%)	0
ANAL ABSCESS	1/248 (0.4%)	1	0/245 (0%)	0
ARTHRITIS BACTERIAL	0/248 (0%)	0	1/245 (0.4%)	1
CAMPYLOBACTER GASTROENTERITIS	1/248 (0.4%)	1	0/245 (0%)	0
CELLULITIS	1/248 (0.4%)	1	0/245 (0%)	0
CLOSTRIDIUM DIFFICILE COLITIS	1/248 (0.4%)	2	0/245 (0%)	0
CLOSTRIDIUM DIFFICILE INFECTION	1/248 (0.4%)	2	0/245 (0%)	0
DEVICE RELATED INFECTION	1/248 (0.4%)	1	0/245 (0%)	0
DIVERTICULITIS	1/248 (0.4%)	1	2/245 (0.8%)	2
ENTEROCOCCAL SEPSIS	1/248 (0.4%)	2	0/245 (0%)	0
ERYSIPELAS	1/248 (0.4%)	1	3/245 (1.2%)	4
GASTROENTERITIS	1/248 (0.4%)	1	1/245 (0.4%)	1
GASTROENTERITIS CLOSTRIDIAL	0/248 (0%)	0	1/245 (0.4%)	1
GASTROENTERITIS VIRAL	0/248 (0%)	0	1/245 (0.4%)	1
GASTROINTESTINAL BACTERIAL INFECTION	1/248 (0.4%)	1	0/245 (0%)	0
GENITOURINARY TRACT INFECTION	0/248 (0%)	0	1/245 (0.4%)	1
GROIN ABSCESS	1/248 (0.4%)	2	0/245 (0%)	0
INFECTION	1/248 (0.4%)	2	0/245 (0%)	0
PNEUMONIA	6/248 (2.4%)	6	3/245 (1.2%)	3
SEPSIS	1/248 (0.4%)	1	2/245 (0.8%)	2
SEPTIC SHOCK	1/248 (0.4%)	1	0/245 (0%)	0
TONSILLITIS	1/248 (0.4%)	1	0/245 (0%)	0
TUBERCULOSIS	1/248 (0.4%)	1	0/245 (0%)	0
URINARY TRACT INFECTION	2/248 (0.8%)	2	1/245 (0.4%)	1
VULVAL CELLULITIS	1/248 (0.4%)	1	0/245 (0%)	0
WOUND INFECTION	1/248 (0.4%)	1	0/245 (0%)	0
Injury, poisoning and procedural complications
FACIAL BONES FRACTURE	1/248 (0.4%)	1	0/245 (0%)	0
FALL	2/248 (0.8%)	4	0/245 (0%)	0
FEMORAL NECK FRACTURE	1/248 (0.4%)	1	1/245 (0.4%)	1
FRACTURE DISPLACEMENT	1/248 (0.4%)	1	0/245 (0%)	0
OVERDOSE	0/248 (0%)	0	1/245 (0.4%)	1
RIB FRACTURE	1/248 (0.4%)	1	1/245 (0.4%)	1
SKIN LACERATION	1/248 (0.4%)	1	0/245 (0%)	0
THORACIC VERTEBRAL FRACTURE	0/248 (0%)	0	1/245 (0.4%)	1
TRAUMATIC HAEMATOMA	1/248 (0.4%)	1	0/245 (0%)	0
UPPER LIMB FRACTURE	0/248 (0%)	0	1/245 (0.4%)	1
Investigations
ALANINE AMINOTRANSFERASE INCREASED	4/248 (1.6%)	4	2/245 (0.8%)	2
ASPARTATE AMINOTRANSFERASE INCREASED	3/248 (1.2%)	3	2/245 (0.8%)	2
BLOOD ALKALINE PHOSPHATASE INCREASED	1/248 (0.4%)	1	1/245 (0.4%)	1
BLOOD CREATINE PHOSPHOKINASE INCREASED	2/248 (0.8%)	2	0/245 (0%)	0
BLOOD CREATININE INCREASED	1/248 (0.4%)	1	0/245 (0%)	0
EJECTION FRACTION DECREASED	1/248 (0.4%)	1	1/245 (0.4%)	1
ELECTROCARDIOGRAM QT PROLONGED	0/248 (0%)	0	1/245 (0.4%)	1
ELECTROCARDIOGRAM T WAVE ABNORMAL	1/248 (0.4%)	1	0/245 (0%)	0
GAMMA-GLUTAMYLTRANSFERASE INCREASED	3/248 (1.2%)	3	1/245 (0.4%)	1
HAEMOGLOBIN DECREASED	1/248 (0.4%)	1	0/245 (0%)	0
LIPASE INCREASED	2/248 (0.8%)	2	0/245 (0%)	0
LIVER FUNCTION TEST INCREASED	1/248 (0.4%)	1	1/245 (0.4%)	1
Metabolism and nutrition disorders
DEHYDRATION	6/248 (2.4%)	6	0/245 (0%)	0
DIABETES MELLITUS	1/248 (0.4%)	1	0/245 (0%)	0
HYPERNATRAEMIA	1/248 (0.4%)	1	0/245 (0%)	0
HYPOKALAEMIA	0/248 (0%)	0	1/245 (0.4%)	1
HYPONATRAEMIA	1/248 (0.4%)	1	0/245 (0%)	0
TYPE 2 DIABETES MELLITUS	1/248 (0.4%)	1	0/245 (0%)	0
Musculoskeletal and connective tissue disorders
ARTHRALGIA	0/248 (0%)	0	1/245 (0.4%)	1
BACK PAIN	0/248 (0%)	0	1/245 (0.4%)	1
BURSITIS	1/248 (0.4%)	1	0/245 (0%)	0
MUSCULAR WEAKNESS	0/248 (0%)	0	1/245 (0.4%)	1
MUSCULOSKELETAL CHEST PAIN	1/248 (0.4%)	1	0/245 (0%)	0
MUSCULOSKELETAL PAIN	1/248 (0.4%)	1	0/245 (0%)	0
MYALGIA	1/248 (0.4%)	1	1/245 (0.4%)	1
PATHOLOGICAL FRACTURE	1/248 (0.4%)	1	0/245 (0%)	0
POLYARTHRITIS	0/248 (0%)	0	1/245 (0.4%)	1
RHABDOMYOLYSIS	1/248 (0.4%)	1	1/245 (0.4%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
ACANTHOMA	0/248 (0%)	0	1/245 (0.4%)	1
ADENOCARCINOMA OF COLON	1/248 (0.4%)	1	1/245 (0.4%)	1
BENIGN NEOPLASM	0/248 (0%)	0	1/245 (0.4%)	1
ENDOMETRIAL ADENOCARCINOMA	1/248 (0.4%)	1	0/245 (0%)	0
GASTROINTESTINAL TRACT ADENOMA	0/248 (0%)	0	1/245 (0.4%)	1
KAPOSI'S SARCOMA	0/248 (0%)	0	1/245 (0.4%)	1
KERATOACANTHOMA	0/248 (0%)	0	4/245 (1.6%)	4
LUNG ADENOCARCINOMA	0/248 (0%)	0	2/245 (0.8%)	3
MALIGNANT MELANOMA IN SITU	0/248 (0%)	0	1/245 (0.4%)	1
MUCINOUS BREAST CARCINOMA	0/248 (0%)	0	1/245 (0.4%)	1
PAPILLOMA	0/248 (0%)	0	1/245 (0.4%)	1
SQUAMOUS CELL CARCINOMA OF SKIN	0/248 (0%)	0	1/245 (0.4%)	1
TRANSITIONAL CELL CARCINOMA	2/248 (0.8%)	2	0/245 (0%)	0
TUMOUR HAEMORRHAGE	0/248 (0%)	0	1/245 (0.4%)	1
TUMOUR PAIN	0/248 (0%)	0	1/245 (0.4%)	1
Nervous system disorders
CEREBRAL HAEMORRHAGE	1/248 (0.4%)	1	0/245 (0%)	0
CEREBROVASCULAR ACCIDENT	2/248 (0.8%)	2	0/245 (0%)	0
COMA	1/248 (0.4%)	1	0/245 (0%)	0
DIZZINESS	1/248 (0.4%)	1	0/245 (0%)	0
DYSARTHRIA	1/248 (0.4%)	1	0/245 (0%)	0
DYSGEUSIA	0/248 (0%)	0	1/245 (0.4%)	1
FACIAL PARALYSIS	2/248 (0.8%)	2	1/245 (0.4%)	1
FACIAL PARESIS	1/248 (0.4%)	1	0/245 (0%)	0
GENERALISED TONIC-CLONIC SEIZURE	0/248 (0%)	0	1/245 (0.4%)	1
HAEMORRHAGIC STROKE	0/248 (0%)	0	1/245 (0.4%)	1
HEADACHE	0/248 (0%)	0	1/245 (0.4%)	1
HEMIPARESIS	2/248 (0.8%)	2	0/245 (0%)	0
HYDROCEPHALUS	0/248 (0%)	0	1/245 (0.4%)	1
ISCHAEMIC STROKE	1/248 (0.4%)	1	0/245 (0%)	0
MYASTHENIA GRAVIS	1/248 (0.4%)	1	0/245 (0%)	0
PARAESTHESIA	0/248 (0%)	0	1/245 (0.4%)	1
POLYNEUROPATHY	1/248 (0.4%)	1	0/245 (0%)	0
SEIZURE	3/248 (1.2%)	3	0/245 (0%)	0
SUBARACHNOID HAEMORRHAGE	1/248 (0.4%)	1	0/245 (0%)	0
SYNCOPE	1/248 (0.4%)	1	0/245 (0%)	0
Psychiatric disorders
MANIA	1/248 (0.4%)	1	0/245 (0%)	0
Renal and urinary disorders
ACUTE KIDNEY INJURY	3/248 (1.2%)	3	2/245 (0.8%)	3
DIABETIC NEPHROPATHY	1/248 (0.4%)	1	0/245 (0%)	0
RENAL COLIC	1/248 (0.4%)	1	0/245 (0%)	0
URETEROLITHIASIS	0/248 (0%)	0	1/245 (0.4%)	1
Reproductive system and breast disorders
CERVICAL POLYP	0/248 (0%)	0	1/245 (0.4%)	1
Respiratory, thoracic and mediastinal disorders
ATELECTASIS	0/248 (0%)	0	1/245 (0.4%)	1
DYSPNOEA	1/248 (0.4%)	1	0/245 (0%)	0
INTERSTITIAL LUNG DISEASE	1/248 (0.4%)	1	0/245 (0%)	0
PLEURAL EFFUSION	0/248 (0%)	0	3/245 (1.2%)	3
PNEUMONITIS	1/248 (0.4%)	1	0/245 (0%)	0
PULMONARY EMBOLISM	3/248 (1.2%)	3	1/245 (0.4%)	1
PULMONARY HAEMORRHAGE	0/248 (0%)	0	1/245 (0.4%)	1
Skin and subcutaneous tissue disorders
DERMATITIS EXFOLIATIVE GENERALISED	0/248 (0%)	0	2/245 (0.8%)	2
DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS	1/248 (0.4%)	1	1/245 (0.4%)	1
ERYTHEMA MULTIFORME	0/248 (0%)	0	1/245 (0.4%)	1
ERYTHEMA NODOSUM	0/248 (0%)	0	1/245 (0.4%)	1
HYPERKERATOSIS	0/248 (0%)	0	1/245 (0.4%)	1
PANNICULITIS	1/248 (0.4%)	1	0/245 (0%)	0
PHOTOSENSITIVITY REACTION	1/248 (0.4%)	1	0/245 (0%)	0
RASH	4/248 (1.6%)	4	2/245 (0.8%)	2
RASH GENERALISED	1/248 (0.4%)	1	0/245 (0%)	0
RASH MACULAR	1/248 (0.4%)	1	0/245 (0%)	0
RASH MACULO-PAPULAR	3/248 (1.2%)	3	2/245 (0.8%)	2
RASH MORBILLIFORM	1/248 (0.4%)	1	0/245 (0%)	0
URTICARIA	1/248 (0.4%)	1	0/245 (0%)	0
Vascular disorders
HYPERTENSION	1/248 (0.4%)	1	0/245 (0%)	0
HYPERTENSIVE CRISIS	2/248 (0.8%)	2	1/245 (0.4%)	1
SUBGALEAL HAEMATOMA	1/248 (0.4%)	1	0/245 (0%)	0
VASCULITIS	1/248 (0.4%)	1	0/245 (0%)	0
VENOUS THROMBOSIS LIMB	1/248 (0.4%)	1	0/245 (0%)	0
Other (Not Including Serious) Adverse Events
	Cobimetinib + Vemurafenib		Placebo + Vemurafenib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	239/248 (96.4%)		236/245 (96.3%)
Blood and lymphatic system disorders
ANAEMIA	51/248 (20.6%)	76	21/245 (8.6%)	26
Eye disorders
CHORIORETINOPATHY	30/248 (12.1%)	36	4/245 (1.6%)	9
VISION BLURRED	32/248 (12.9%)	37	8/245 (3.3%)	9
Gastrointestinal disorders
ABDOMINAL PAIN	30/248 (12.1%)	37	20/245 (8.2%)	23
ABDOMINAL PAIN UPPER	15/248 (6%)	17	18/245 (7.3%)	21
CONSTIPATION	27/248 (10.9%)	37	29/245 (11.8%)	31
DIARRHOEA	151/248 (60.9%)	311	84/245 (34.3%)	162
DYSPEPSIA	19/248 (7.7%)	22	13/245 (5.3%)	15
NAUSEA	108/248 (43.5%)	184	67/245 (27.3%)	83
STOMATITIS	17/248 (6.9%)	27	3/245 (1.2%)	3
VOMITING	69/248 (27.8%)	108	33/245 (13.5%)	42
General disorders
ASTHENIA	51/248 (20.6%)	96	43/245 (17.6%)	50
CHILLS	25/248 (10.1%)	28	14/245 (5.7%)	17
FATIGUE	93/248 (37.5%)	137	83/245 (33.9%)	99
OEDEMA PERIPHERAL	38/248 (15.3%)	49	28/245 (11.4%)	32
PYREXIA	77/248 (31%)	130	60/245 (24.5%)	77
Infections and infestations
CONJUNCTIVITIS	18/248 (7.3%)	19	8/245 (3.3%)	10
FOLLICULITIS	19/248 (7.7%)	22	12/245 (4.9%)	15
NASOPHARYNGITIS	23/248 (9.3%)	29	18/245 (7.3%)	21
UPPER RESPIRATORY TRACT INFECTION	14/248 (5.6%)	18	11/245 (4.5%)	15
URINARY TRACT INFECTION	17/248 (6.9%)	25	11/245 (4.5%)	13
Injury, poisoning and procedural complications
SUNBURN	37/248 (14.9%)	60	45/245 (18.4%)	68
Investigations
ALANINE AMINOTRANSFERASE INCREASED	65/248 (26.2%)	94	44/245 (18%)	48
ASPARTATE AMINOTRANSFERASE INCREASED	64/248 (25.8%)	87	29/245 (11.8%)	30
BLOOD ALKALINE PHOSPHATASE INCREASED	46/248 (18.5%)	67	26/245 (10.6%)	30
BLOOD BILIRUBIN INCREASED	20/248 (8.1%)	29	17/245 (6.9%)	22
BLOOD CHOLESTEROL INCREASED	16/248 (6.5%)	19	10/245 (4.1%)	10
BLOOD CREATINE PHOSPHOKINASE INCREASED	90/248 (36.3%)	171	10/245 (4.1%)	13
BLOOD CREATININE INCREASED	45/248 (18.1%)	59	20/245 (8.2%)	25
BLOOD LACTATE DEHYDROGENASE INCREASED	15/248 (6%)	30	8/245 (3.3%)	8
EJECTION FRACTION DECREASED	31/248 (12.5%)	46	12/245 (4.9%)	13
ELECTROCARDIOGRAM QT PROLONGED	12/248 (4.8%)	15	13/245 (5.3%)	19
GAMMA-GLUTAMYLTRANSFERASE INCREASED	57/248 (23%)	82	45/245 (18.4%)	61
WEIGHT DECREASED	18/248 (7.3%)	20	14/245 (5.7%)	17
Metabolism and nutrition disorders
DECREASED APPETITE	55/248 (22.2%)	75	50/245 (20.4%)	55
HYPONATRAEMIA	13/248 (5.2%)	19	3/245 (1.2%)	3
Musculoskeletal and connective tissue disorders
ARTHRALGIA	96/248 (38.7%)	172	105/245 (42.9%)	179
BACK PAIN	21/248 (8.5%)	30	15/245 (6.1%)	15
MUSCULOSKELETAL PAIN	17/248 (6.9%)	18	16/245 (6.5%)	19
MYALGIA	41/248 (16.5%)	53	33/245 (13.5%)	37
PAIN IN EXTREMITY	32/248 (12.9%)	51	40/245 (16.3%)	54
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
BASAL CELL CARCINOMA	16/248 (6.5%)	33	6/245 (2.4%)	6
KERATOACANTHOMA	5/248 (2%)	6	20/245 (8.2%)	26
MELANOCYTIC NAEVUS	5/248 (2%)	5	17/245 (6.9%)	26
SEBORRHOEIC KERATOSIS	15/248 (6%)	15	21/245 (8.6%)	24
SKIN PAPILLOMA	18/248 (7.3%)	26	30/245 (12.2%)	36
SQUAMOUS CELL CARCINOMA OF SKIN	10/248 (4%)	25	33/245 (13.5%)	66
Nervous system disorders
DIZZINESS	18/248 (7.3%)	18	7/245 (2.9%)	8
DYSGEUSIA	27/248 (10.9%)	29	16/245 (6.5%)	17
HEADACHE	50/248 (20.2%)	76	41/245 (16.7%)	50
Psychiatric disorders
ANXIETY	16/248 (6.5%)	18	11/245 (4.5%)	12
DEPRESSION	15/248 (6%)	17	11/245 (4.5%)	11
INSOMNIA	19/248 (7.7%)	24	27/245 (11%)	31
Respiratory, thoracic and mediastinal disorders
COUGH	28/248 (11.3%)	36	32/245 (13.1%)	37
DYSPNOEA	19/248 (7.7%)	26	19/245 (7.8%)	23
OROPHARYNGEAL PAIN	19/248 (7.7%)	20	22/245 (9%)	28
Skin and subcutaneous tissue disorders
ACTINIC KERATOSIS	13/248 (5.2%)	32	27/245 (11%)	31
ALOPECIA	42/248 (16.9%)	44	75/245 (30.6%)	78
DERMATITIS ACNEIFORM	37/248 (14.9%)	47	22/245 (9%)	26
DRY SKIN	37/248 (14.9%)	40	42/245 (17.1%)	46
ERYTHEMA	32/248 (12.9%)	56	36/245 (14.7%)	57
HYPERKERATOSIS	31/248 (12.5%)	39	74/245 (30.2%)	130
KERATOSIS PILARIS	13/248 (5.2%)	14	26/245 (10.6%)	30
PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME	18/248 (7.3%)	23	9/245 (3.7%)	10
PHOTOSENSITIVITY REACTION	86/248 (34.7%)	119	48/245 (19.6%)	58
PRURITUS	51/248 (20.6%)	85	48/245 (19.6%)	54
RASH	101/248 (40.7%)	158	97/245 (39.6%)	121
RASH MACULO-PAPULAR	37/248 (14.9%)	61	37/245 (15.1%)	47
SOLAR DERMATITIS	18/248 (7.3%)	34	14/245 (5.7%)	23
Vascular disorders
HYPERTENSION	50/248 (20.2%)	60	30/245 (12.2%)	33

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.