A Study of Cobimetinib Plus Atezolizumab Versus Pembrolizumab in Participants With Previously Untreated Advanced BRAFv600 Wild-Type Melanoma

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03273153
• Collaborator: (none)
• Enrollment: 446
• Locations: 121
• Arms: 2
• Actual Duration (Months): 38.3
• Patients Per Site: 3.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a Phase III, multicenter, open-label, randomized study designed to evaluate the efficacy, safety, and pharmacokinetics of cobimetinib plus atezolizumab compared with pembrolizumab in treatment-naive participants with advanced BRAFV600 wild-type melanoma.

Condition or Disease	Intervention/Treatment	Phase
Advanced BRAFV600 Wild-type Melanoma	Drug: Cobimetinib; Drug: Atezolizumab; Drug: Pembrolizumab	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 446 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase III, Open-Label, Multicenter, Two Arm, Randomized Study to Investigate the Efficacy and Safety of Cobimetinib Plus Atezolizumab Versus Pembrolizumab in Patients With Previously Untreated Advanced BRAF V600 Wild-Type Melanoma
• Actual Study Start Date: Dec 11, 2017
• Actual Primary Completion Date: Apr 15, 2019
• Actual Study Completion Date: Feb 19, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cobimetinib and Atezolizumab Participants will receive 60 mg of cobimetinib orally from Days 1 to 21 along with 840 mg of atezolizumab by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle until investigator-determined disease progression, unacceptable toxicity, death, patient or physician decision to withdraw, or pregnancy, whichever occurs first. There will be no cobimetinib administration for 7 days (Days 22-28) in each cycle.	Drug: Cobimetinib; Cobimetinib 60 mg tablets orally once daily on a 21 days on, 7 days off schedule.; Drug: Atezolizumab; Atezolizumab 840 mg as IV infusion once in every 2 weeks.
Active Comparator: Pembrolizumab Participants will receive 200 mg of pembrolizumab administered by IV infusion every 3 weeks (Q3W) until investigator-determined disease progression, unacceptable toxicity, death, patient or physician decision to withdraw, or pregnancy, whichever occurs first.	Drug: Pembrolizumab; Pembrolizumab 200 mg as IV infusion once in every 3 weeks.

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) as Determined by the Independent Review Committee (IRC) [Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months]

   PFS is defined as the time from randomization to the first occurrence of disease progression, as determined by an IRC according to RECIST v1.1, or death from any cause, whichever occurs first. Progressive disease (PD) for target lesion: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/=5 mm. PD for non-target lesion: Unequivocal progression of existing non-target lesions.

Secondary Outcome Measures

1. PFS as Determined by the Investigator [Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months]

   PFS is defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first. Progressive disease (PD) for target lesion: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/=5 mm. PD for non-target lesion: Unequivocal progression of existing non-target lesions.

2. Objective Response as Determined by the Investigator [Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months]

   Objective response rate is defined as the percentage of participants with a complete response (CR) or a partial response (PR) on two consecutive occasions >/=4 weeks apart, as determined by the investigator through the use of RECIST v1.1. For target lesion, CR: the disappearance of all target lesions, any pathological lymph nodes must have a reduction in short axis to <10 mm. PR: at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. For non-target lesion, CR: the disappearance of all non-target lesions and (if applicable) normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis).

3. Objective Response as Determined by IRC [Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months]

   Objective response, defined as a complete response or partial response on two consecutive occasions ≥4 weeks apart, as determined by IRC according to RECIST v1.1

4. Disease Control Rate (DCR) [Week 16]

   DCR is defined as the proportion of participants with a complete response, a partial response, or stable disease at 16 weeks. For target lesion, CR: the disappearance of all target lesions, any pathological lymph nodes must have a reduction in short axis to <10 mm. PR: at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. For non-target lesion, CR: the disappearance of all non-target lesions and (if applicable) normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis). Stable disease (SD): neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD.

5. Overall Survival (OS) [Up to 7 years]

   OS is defined as the time from randomization to death from any cause.

6. Duration of Objective Response Determined by the IRC [Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months]

   Duration of objective response, defined as the time from the first occurrence of a documented objective response to disease progression, as determined by an IRC according to RECIST v1.1, or death from any cause, whichever occurs first.

7. Duration of Objective Response Determined by the Investigator [Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 weeks]

   Duration of objective response is defined as the time from the first occurrence of a documented objective response to disease progression, as determined by the investigator through use of RECIST v1.1, or death from any cause, whichever occurs first.

8. Two-year Landmark Survival [At 2 years]

   Two-year landmark survival is defined as survival at 2 years.

9. Change From Baseline in Health-related Quality of Life (HRQoL) Scores [Up to approximately 16 months. Follow up is reported at weeks after participant treatment discontinuation, which could occur at any time during the study. Total time frame does not exceed 16 months.]

   HRQoL scores are assessed through global health status (GHS)/ quality of life (QoL) subscale of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ C30). These are based on questions 29 and 30 of the EORTC QLQ-C30. These questions on global health status/QoL scale are coded on 7-point scale (1=very poor to 7=excellent). Raw scores will be linearly transformed to obtain the score ranging from 0 to 100, where higher score represents a higher ("better") level of functioning.

10. Number of Participants With Adverse Events (AEs) [Up to approximately 16 months]

    An adverse event is any untoward medical occurrence in a patient administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.

11. Number of Participants With Abnormal Vital Signs [Up to 7 years]

    Vital signs will include temperature pulse rate, respiratory rate, and systolic and diastolic blood pressure.

12. Number of Participants With Laboratory Abnormalities [Up to approximately 16 months]

    Participants with laboratory abnormalities (values outside of a defined range) will be reported.

13. Plasma Concentration of Cobimetinib [Days 1 and 15 of Cycle 1]

    Plasma concentration of cobimetinib at specified time points will be reported.

14. Serum Concentration of Atezolizumab [Day 1 of Cycle 1, 2, 3 and 30 days after treatment discontinuation]

    Serum concentration of atezolizumab at specified time points will be reported.

15. Percentage of Participants With Anti-drug Antibodies (ADAs) [Day 1 of Cycle 1, 2, 3 and 30 days after treatment discontinuation]

    Participants with ADAs during the study relative to the prevalence of ADAs at baseline will be reported.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

Disease-Specific Inclusion Criteria

• Histologically confirmed locally advanced and unresectable or metastatic melanoma

• Naive to prior systemic anti-cancer therapy for melanoma

• Documentation of BRAFV600 wild-type status in melanoma tumor tissue through use of a clinical mutation test approved by the local health authority

• A representative, formalin-fixed, paraffin-embedded (FFPE) tumor specimen in a paraffin block (preferred) or 20 slides containing unstained, freshly cut, serial sections must be submitted along with an associated pathology report prior to study entry. If 20 slides are not available or the tissue block is not of sufficient size, the patient may still be eligible for the study, after discussion with and approval by the Medical Monitor

• Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

• Age >=18 years at time of signing Informed Consent Form

• Ability to comply with the study protocol, in the investigator's judgment

• Histologically or cytologically confirmed BRAFV600 wild-type melanoma

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

• Life expectancy >=3 months

• Adequate hematologic and end-organ function

• For women of childbearing potential: agreement to remain abstinent or use at least two forms of effective contraceptive with a failure rate of < 1% per year during the treatment period and for at least 3 months after the last dose of cobimetinib and at least 5 months after the last dose of atezolizumab or pembrolizumab

• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures (e.g. condom), and agreement to refrain from donating sperm, for at least 3 months after the last dose of cobimetinib

• Willingness and ability of patients to report selected study outcomes (e.g., GHS and HRQoL) using an electronic device or paper backup questionnaires.

Exclusion Criteria:

General Exclusion Criteria

• Inability to swallow medications

• Malabsorption condition that would alter the absorption of orally administered medications

• Pregnancy, breastfeeding, or intention of becoming pregnant during the study

• History of severe hypersensitivity reactions to components of the cobimetinib, atezolizumab, or pembrolizumab formulations

• Current or recent treatment with therapeutic antibiotics, live attenuated vaccines or systemic immunostimulatory/immunosuppresive medication

• Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study Cancer-Related Exclusion Criteria

• Ocular melanoma

• Major surgery or radiotherapy within 21 days prior to Day 1 of Cycle 1 or anticipation of needing such procedure while receiving study treatment

• Uncontrolled tumor-related pain

• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage more than once every 28 days

• Active or untreated central nervous system (CNS) metastases Exclusions Related to Cardiovascular Disease

• Unstable angina, new-onset angina within last 3 months, myocardial infarction within the last 6 months prior to Day 1 of Cycle 1, or current congestive heart failure classified as New York Heart Association Class II or higher

• Left ventricular ejection fraction (LVEF) below institutional lower limit of normal or <50%, whichever is lower

• Poorly controlled hypertension, defined as sustained, uncontrolled, non-episodic baseline hypertension consistently above 159/99 mmHg despite optimal medical management

• History or presence of an abnormal electrocardiogram (ECG) that is clinically significant in the investigator's opinion, including complete left bundle branch block, second- or third degree heart block, or evidence of prior myocardial infarction Exclusions Related to Infections

• HIV infection

• Active tuberculosis infection

• Severe infections within 4 weeks prior to Day 1 of Cycle 1, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia

• Signs or symptoms of clinically relevant infection within 2 weeks prior to Day 1 of Cycle 1

• Treatment with oral or IV antibiotics within 2 weeks prior to Day 1 of Cycle 1

• Active or chronic viral hepatitis B or C infection Exclusions Related to Ocular Disease

• Known risk factors for ocular toxicity Exclusions Related to Autoimmune Conditions and Immunomodulatory Drugs

• Active or history of autoimmune disease or immune deficiency

• Prior allogeneic stem cell or solid organ transplantation

• History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan

• Treatment with systemic immunosuppressive medications within 2 weeks prior to Day 1, Cycle 1 Exclusions Related to Other Medical Conditions or Medications

• Active malignancy (other than melanoma) or a prior malignancy within the past 3 years

• Any Grade >=3 hemorrhage or bleeding event within 28 days of Day 1 of Cycle 1

• History of stroke, reversible ischemic neurological defect, or transient ischemic attack within 6 months prior to Day 1

• Proteinuria >3.5 gm/24 hr

• Consumption of foods, supplements, or drugs that are strong or moderate CYP3A4 enzyme inducers or inhibitors at least 7 days prior to Day 1 of Cycle 1 and during study treatment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arizona Cancer Center	Tucson	Arizona	United States	85719
2	City of Hope Comprehensive Cancer Center	Duarte	California	United States	91010
3	USC Norris Cancer Center	Los Angeles	California	United States	90033
4	USC Norris Cancer Center; USC Oncology Hematology Newport Beach	Newport Beach	California	United States	92663
5	University of California at Irvine Medical Center; Department of Oncology	Orange	California	United States	92868
6	Stanford Comprehensive Cancer Center	Stanford	California	United States	94305
7	UF Health Cancer Center at Orlando Health	Orlando	Florida	United States	32824
8	Florida Cancer Specialist, North Region	Saint Petersburg	Florida	United States	33705
9	Moffitt Cancer Center	Tampa	Florida	United States	33612
10	Florida Cancer Specialists	West Palm Beach	Florida	United States	33401
11	Northwestern University	Chicago	Illinois	United States	60611
12	Massachusetts General Hospital;Hematology/ Oncology	Boston	Massachusetts	United States	02114
13	University of Michigan; Michigan Institute for Clinical and Health Research (MICHR)	Ann Arbor	Michigan	United States	48109
14	Dartmouth-Hitchcock Medical Center; Hematology/Oncology	Lebanon	New Hampshire	United States	03756
15	Morristown Medical Center	Morristown	New Jersey	United States	07962
16	Forsythe Memorial Hospital Inc., dba Novant Health Oncology Specialists	Winston-Salem	North Carolina	United States	27103
17	TriHealth Hatton Institute; Surgical Education	Cincinnati	Ohio	United States	45220
18	St. Luke's University Health network	Bethlehem	Pennsylvania	United States	18015
19	Thomas Jefferson University Hospital;Medical Oncology	Philadelphia	Pennsylvania	United States	19107
20	SCRI Tennessee Oncology Chattanooga	Chattanooga	Tennessee	United States	37404
21	Sarah Cannon Research Institute	Nashville	Tennessee	United States	37203
22	M.D Anderson Cancer Center; Uni of Texas At Houston	Houston	Texas	United States	77030
23	West Virginia University Hospitals Inc	Morgantown	West Virginia	United States	26056
24	Cairns Base Hospital	Cairns	Queensland	Australia	4870
25	Townsville General Hospital	Douglas	Queensland	Australia	4184
26	Princess Alexandra Hospital	Woolloongabba	Queensland	Australia	4102
27	Royal Hobart Hospital	Hobart	Tasmania	Australia	7000
28	Fiona Stanley Hospital	Murdoch	Western Australia	Australia	6150
29	Cliniques Universitaires St-Luc	Bruxelles		Belgium	1200
30	AZ Groeninge	Kortrijk		Belgium	8500
31	UZ Leuven Gasthuisberg	Leuven		Belgium	3000
32	Instituto Nacional de Cancer - INCa; Oncologia	Rio de Janeiro	RJ	Brazil	20560-120
33	Hospital das Clinicas - UFRGS	Porto Alegre	RS	Brazil	90035-903
34	Hopital Avicenne; Dermatologie	Bobigny		France	93009
35	Hopital Saint Andre CHU De Bordeaux; Dermatologie	Bordeaux		France	33075
36	Chu Site Du Bocage;Dermatologie	Dijon		France	21079
37	CHU de Grenoble - Hôpital Nord	Grenoble		France	38043
38	Centre Hospitalier Le Mans; Dermatologie	Le Mans		France	72037
39	Hopital Claude Huriez; Sce Dermatologie	Lille		France	59037
40	Hopital Timone Adultes; Dermatologie	Marseille		France	13385
41	CHU de Nantes; Cancéro-dermatologie	Nantes		France	44093
42	Hopital l Archet 2; Ginestriere, Service de; Dermatologie	Nice cedex 3		France	06200
43	Groupe Hospitalier Bichat Claude Bernard	Paris		France	75018
44	Hopital Saint Louis; Dermatologie 1	Paris		France	75475
45	Hopital Robert Debre; DERMATOLOGIE	Reims		France	51092
46	Centre Eugene Marquis; Service d'oncologie	Rennes		France	35042
47	Hopital Charles Nicolle; Dermatologie Serv.	Rouen		France	76031
48	Institut Universitaire du Cancer - Oncopole Toulouse (IUCT-O)	Toulouse		France	31059
49	Institut Gustave Roussy; Dermatologie	Villejuif		France	94805
50	Universitätsklinikum "Carl Gustav Carus"; Klinik und Poliklinik für Dermatologie	Dresden		Germany	01307
51	HELIOS Klinikum Erfurt; Klinik für Dermatologie & Allergologie	Erfurt		Germany	99089
52	Universitatsklinikum Essen; Klinik für Dermatologie	Essen		Germany	45147
53	Klinik Johann Wolfgang von Goethe Uni; Klinik für Dermatologie, Venerologie und Allergologie	Frankfurt		Germany	60590
54	SRH Wald-Klinikum Gera; Klinik für Hautkrankheiten und Allergologie	Gera		Germany	07548
55	Medizinische Hochschule Hannover; Klinik für Dermatologie, Allergologie und Venerologie	Hannover		Germany	30625
56	UKSH Kiel; Klinik für Dermatologie, Venerologie und Allergologie	Kiel		Germany	24105
57	Universitatsklinikum Mainz; Klinik und Poliklinik fur Dermatologie	Mainz		Germany	55131
58	Klinikum Mannheim Klinik fuer Dermatologie, Venerologie und Allergologie	Mannheim		Germany	68167
59	Johannes Wesling Klinikum Minden	Minden		Germany	32429
60	Klinikum der Ludwigs-Maximilians-Universität München; Dermatologie	München		Germany	80337
61	Fachklinik Hornheide; Dermatologie	Münster		Germany	48157
62	Zentrum für Dermatoonkologie, Universitäts-Hautklinik Tübingen	Tübingen		Germany	72076
63	Anticancer Hospital Ag. Savas ; 2Nd Dept. of Oncology - Internal Medicine	Athens		Greece	115 22
64	Laiko General Hospital Athen	Athens		Greece	115 27
65	Metropolitan Hospital; Dept. of Oncology	Pireaus		Greece	185 47
66	Bioclinic Thessaloniki	Thessaloniki		Greece	546 22
67	Orszagos Onkologiai Intezet; Borgyogyaszati Osztaly	Budapest		Hungary	1122
68	Pecsi Tudomanyegyetem AOK; Borgyogyaszati Klinika	Pecs		Hungary	7632
69	University of Szeged Szent-Györgyi Albert Clinical Center; Department of Dermatology and Allergology	Szeged		Hungary	6720
70	Azienda Osp Uni Seconda Università Degli Studi Di Napoli; Unità Operativa Oncologia Medica	Napoli	Campania	Italy	80131
71	IRCCS Istituto Nazionale Tumori Fondazione Pascale; Oncologia Medica B	Napoli	Campania	Italy	80131
72	A.O. Universitaria Policlinico Di Modena; Ematologia	Modena	Emilia-Romagna	Italy	41100
73	IFO - Istituto Regina Elena; Oncologia Medica	Roma	Lazio	Italy	00144
74	IRCCS Istituto Nazionale Per La Ricerca Sul Cancro (IST); Oncologia Medica A	Genova	Liguria	Italy	16132
75	Irccs Istituto Nazionale Dei Tumori (Int);S.C. Medicina Oncologica 2	Milano	Lombardia	Italy	20133
76	Irccs Istituto Europeo Di Oncologia (IEO); Oncologia Medica	Milano	Lombardia	Italy	20141
77	Fondazione Del Piemonte Per L'oncologia Ircc Di Candiolo; Dipartimento Oncologico	Candiolo	Piemonte	Italy	10060
78	A.O.U. Cons. Policlinico Bari - Consorzlale Policlinico; Scienze Biomediche e Oncologia Umana	Bari	Puglia	Italy	70124
79	Azienda Ospedaliero - Universitaria Pisana U.O. Oncologia Medica 2 Universitaria - Polo Oncologico	Pisa	Toscana	Italy	56126
80	IOV - Istituto Oncologico Veneto IRCCS	Padova	Veneto	Italy	35128
81	Samsung Medical Center	Seoul		Korea, Republic of	(0)6351
82	Seoul National University Hospital	Seoul		Korea, Republic of	03080
83	Severance Hospital, Yonsei University Health System	Seoul		Korea, Republic of	03722
84	Asan Medical Center	Seoul		Korea, Republic of	05505
85	Antoni Van Leeuwenhoek Ziekenhuis; Inwendige Geneeskunde	Amsterdam		Netherlands	1066 CX
86	Amphia Ziekenhuis, locatie Langendijk;Oncology	Breda		Netherlands	4818 CK
87	Erasmus Mc - Daniel Den Hoed Kliniek; Interne Oncologie	Rotterdam		Netherlands	3015AA
88	Zuyderland ziekenhuis locatie Geleen	Sittard-Geleen		Netherlands	6162 BG
89	Copernicus Podmiot Medyczny Sp. z o.o. Wojewodzkie Centrum Onkologii	Gdansk		Poland	80-219
90	COZL Oddzial Onkologii Klinicznej z pododdzialem Chemioterapii Dziennej	Lublin		Poland	20-090
91	Szpital Kliniczny im. Heliodora Święcickiego UM w Poznaniu.	Poznań		Poland	60-780
92	Zachodniopomorskie Centrum Onkologii, Osrodek Innowacyjnosci, Rozwoju i Badan Klinicznych	Szczecin		Poland	71-730
93	Narodowy Instytut Onkologii im. Marii Skłodowskiej-Curie - Państwowy Instytut Badawczy	Warszawa		Poland	02-781
94	Dolnoslaskie Centrum Onkologii	Wrocław		Poland	53-413
95	Moscow City Oncology Hospital #62	Moscovskaya Oblast	Moskovskaja Oblast	Russian Federation	143423
96	FSBSI "Russian Oncological Scientific Center n.a. N.N. Blokhin"	Moscow		Russian Federation	115478
97	FBI "Scientific Research Institute of Oncology n. a. N. N. Petrov"	Saint-Petersburg		Russian Federation
98	St. Petersburg Oncology Hospital	St Petersburg		Russian Federation	198255
99	Hospital Universitari Germans Trias i Pujol; Servicio de Oncologia	Badalona	Barcelona	Spain	08916
100	Hospital Universitario Son Espases; Servicio de Oncologia	Palma De Mallorca	Islas Baleares	Spain	07014
101	Complejo Hospitalario Universitario de Santiago (CHUS) ; Servicio de Oncologia	Santiago de Compostela	LA Coruña	Spain	15706
102	Hospital Universitario Materno Infantil de Gran Canaria; Servicio de Oncologia	Las Palmas de Gran Canaria	LAS Palmas	Spain	35016
103	Clinica Universitaria de Navarra; Servicio de oncología	Pamplona	Navarra	Spain	31008
104	Hospital Univ Vall d'Hebron; Servicio de Oncologia	Barcelona		Spain	08035
105	Hospital Clínic i Provincial; Servicio de Oncología	Barcelona		Spain	08036
106	Hospital General Universitario Gregorio Marañon; Servicio de Oncologia	Madrid		Spain	28007
107	Hospital Ramon y Cajal; Servicio de Oncologia	Madrid		Spain	28034
108	Hospital Universitario 12 de Octubre; Servicio de Oncologia	Madrid		Spain	28041
109	Hospital Universitario La Paz; Servicio de Oncologia	Madrid		Spain	28046
110	Hospital Universitario Virgen Macarena; Servicio de Oncologia	Sevilla		Spain	41009
111	Instituto Valenciano Oncologia; Oncologia Medica	Valencia		Spain	46009
112	Hospital General Universitario de Valencia; Servicio de oncologia	Valencia		Spain	46014
113	Hospital Universitario Miguel Servet; Servicio Oncologia	Zaragoza		Spain	50009
114	BRISTOL ONCOLOGY CENTRE; CLINICAL TRIALS UNIT; R & D department	Bristol		United Kingdom	BS2 8HW
115	Western General Hospital; Edinburgh Cancer Center	Edinburgh		United Kingdom	EH4 2XU
116	Leicester Royal Infirmary; Dept. of Medical Oncology	Leicester		United Kingdom	LE1 5WW
117	University College London Hospital	London		United Kingdom	NW1 - 2PG
118	Guys & St Thomas Hospital; Department of Oncology	London		United Kingdom	SE1 9RT
119	University Hospitals of North Midlands NHS Trust-Royal Stoke University Hospital	Stoke-On-Trent		United Kingdom	ST4 6QG
120	Singleton Hospital; Pharmacy	Swansea		United Kingdom	SA2 8QA
121	Royal Cornwall Hospital	Truro		United Kingdom	TR1 3LQ

Sponsors and Collaborators

• Hoffmann-La Roche

Investigators

• Study Chair: Clinical Trials, Hoffmann-La Roche

Study Documents (Full-Text)

• Study Protocol - Sep 19, 2018
• Statistical Analysis Plan - Feb 3, 2020

More Information

Publications

None provided.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT03273153
• Other Study ID Numbers: CO39722; 2016-004387-18
• First Posted: Sep 6, 2017
• Last Update Posted: Jun 11, 2021
• Last Verified: Jun 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Melanoma; Pembrolizumab; Atezolizumab

Study Results

Participant Flow

Arm/Group Title	Pembrolizumab	Cobimetinib and Atezolizumab
Arm/Group Description	Participants received 200 mg of intravenous (IV) pembrolizumab every 3 weeks (Q3W) until investigator-determined disease progression, unacceptable toxicity, death, patient or physician decision to withdraw, or pregnancy, whichever occurred first.	Participants received 60 mg of cobimetinib by mouth (PO) on a 21 days on, 7 days off schedule (dosing on Days 1-21, followed by no dosing on Days 22-28) plus 840 mg of atezolizumab by IV infusion of Days 1 and 15 of each 28-day cycle.
Period Title: Overall Study
STARTED	224	222
COMPLETED	0	0
NOT COMPLETED	224	222

Baseline Characteristics

Arm/Group Title	Pembrolizumab	Cobimetinib and Atezolizumab	Total
Arm/Group Description	Participants received 200 mg of intravenous (IV) pembrolizumab every 3 weeks (Q3W) until investigator-determined disease progression, unacceptable toxicity, death, patient or physician decision to withdraw, or pregnancy, whichever occurred first.	Participants received 60 mg of cobimetinib by mouth (PO) on a 21 days on, 7 days off schedule (dosing on Days 1-21, followed by no dosing on Days 22-28) plus 840 mg of atezolizumab by IV infusion of Days 1 and 15 of each 28-day cycle.	Total of all reporting groups
Overall Participants	224	222	446
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	63.5 (12.9)	63.6 (13.1)	63.6 (13.0)
Sex: Female, Male (Count of Participants)
Female	83 37.1%	93 41.9%	176 39.5%
Male	141 62.9%	129 58.1%	270 60.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	7 3.1%	15 6.8%	22 4.9%
Not Hispanic or Latino	190 84.8%	180 81.1%	370 83%
Unknown or Not Reported	27 12.1%	27 12.2%	54 12.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	6 2.7%	6 2.7%	12 2.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 0.4%	6 2.7%	7 1.6%
White	198 88.4%	188 84.7%	386 86.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	19 8.5%	22 9.9%	41 9.2%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS) as Determined by the Independent Review Committee (IRC)
Description	PFS is defined as the time from randomization to the first occurrence of disease progression, as determined by an IRC according to RECIST v1.1, or death from any cause, whichever occurs first. Progressive disease (PD) for target lesion: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/=5 mm. PD for non-target lesion: Unequivocal progression of existing non-target lesions.
Time Frame	Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pembrolizumab	Cobimetinib and Atezolizumab
Arm/Group Description	Participants received 200 mg of intravenous (IV) pembrolizumab every 3 weeks (Q3W) until investigator-determined disease progression, unacceptable toxicity, death, patient or physician decision to withdraw, or pregnancy, whichever occurred first.	Participants received 60 mg of cobimetinib by mouth (PO) on a 21 days on, 7 days off schedule (dosing on Days 1-21, followed by no dosing on Days 22-28) plus 840 mg of atezolizumab by IV infusion of Days 1 and 15 of each 28-day cycle.
Measure Participants	224	222
Median (95% Confidence Interval) [Months]	5.7	5.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Pembrolizumab, Cobimetinib and Atezolizumab
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2954
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.15
	Confidence Interval	(2-Sided) 95%; 0.88 to 1.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	PFS as Determined by the Investigator
Description	PFS is defined as the time from randomization to the first occurrence of disease progression, as determined by the investigator according to RECIST v1.1, or death from any cause, whichever occurs first. Progressive disease (PD) for target lesion: At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters on study (including baseline). In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of >/=5 mm. PD for non-target lesion: Unequivocal progression of existing non-target lesions.
Time Frame	Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pembrolizumab	Cobimetinib and Atezolizumab
Arm/Group Description	Participants received 200 mg of intravenous (IV) pembrolizumab every 3 weeks (Q3W) until investigator-determined disease progression, unacceptable toxicity, death, patient or physician decision to withdraw, or pregnancy, whichever occurred first.	Participants received 60 mg of cobimetinib by mouth (PO) on a 21 days on, 7 days off schedule (dosing on Days 1-21, followed by no dosing on Days 22-28) plus 840 mg of atezolizumab by IV infusion of Days 1 and 15 of each 28-day cycle.
Measure Participants	224	222
Median (95% Confidence Interval) [Months]	7.2	5.6

3. Secondary Outcome

Title	Objective Response as Determined by the Investigator
Description	Objective response rate is defined as the percentage of participants with a complete response (CR) or a partial response (PR) on two consecutive occasions >/=4 weeks apart, as determined by the investigator through the use of RECIST v1.1. For target lesion, CR: the disappearance of all target lesions, any pathological lymph nodes must have a reduction in short axis to <10 mm. PR: at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. For non-target lesion, CR: the disappearance of all non-target lesions and (if applicable) normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis).
Time Frame	Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pembrolizumab	Cobimetinib and Atezolizumab
Arm/Group Description	Participants received 200 mg of intravenous (IV) pembrolizumab every 3 weeks (Q3W) until investigator-determined disease progression, unacceptable toxicity, death, patient or physician decision to withdraw, or pregnancy, whichever occurred first.	Participants received 60 mg of cobimetinib by mouth (PO) on a 21 days on, 7 days off schedule (dosing on Days 1-21, followed by no dosing on Days 22-28) plus 840 mg of atezolizumab by IV infusion of Days 1 and 15 of each 28-day cycle.
Measure Participants	221	222
Number (95% Confidence Interval) [Percentage of Participants]	36.7 16.4%	27.9 12.6%

4. Secondary Outcome

Title	Objective Response as Determined by IRC
Description	Objective response, defined as a complete response or partial response on two consecutive occasions ≥4 weeks apart, as determined by IRC according to RECIST v1.1
Time Frame	Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pembrolizumab	Cobimetinib and Atezolizumab
Arm/Group Description	Participants received 200 mg of intravenous (IV) pembrolizumab every 3 weeks (Q3W) until investigator-determined disease progression, unacceptable toxicity, death, patient or physician decision to withdraw, or pregnancy, whichever occurred first.	Participants received 60 mg of cobimetinib by mouth (PO) on a 21 days on, 7 days off schedule (dosing on Days 1-21, followed by no dosing on Days 22-28) plus 840 mg of atezolizumab by IV infusion of Days 1 and 15 of each 28-day cycle.
Measure Participants	206	204
Number (95% Confidence Interval) [Percentage of Participants]	31.6 14.1%	26.0 11.7%

5. Secondary Outcome

Title	Disease Control Rate (DCR)
Description	DCR is defined as the proportion of participants with a complete response, a partial response, or stable disease at 16 weeks. For target lesion, CR: the disappearance of all target lesions, any pathological lymph nodes must have a reduction in short axis to <10 mm. PR: at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. For non-target lesion, CR: the disappearance of all non-target lesions and (if applicable) normalization of tumor marker level, all lymph nodes must be non-pathological in size (<10 mm short axis). Stable disease (SD): neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD.
Time Frame	Week 16

Outcome Measure Data

Analysis Population Description

The analysis for this outcome measure was limited to participants meeting the criteria provided in the description.

Arm/Group Title	Pembrolizumab	Cobimetinib and Atezolizumab
Arm/Group Description	Participants received 200 mg of intravenous (IV) pembrolizumab every 3 weeks (Q3W) until investigator-determined disease progression, unacceptable toxicity, death, patient or physician decision to withdraw, or pregnancy, whichever occurred first.	Participants received 60 mg of cobimetinib by mouth (PO) on a 21 days on, 7 days off schedule (dosing on Days 1-21, followed by no dosing on Days 22-28) plus 840 mg of atezolizumab by IV infusion of Days 1 and 15 of each 28-day cycle.
Measure Participants	221	222
Investigator-assessed	49.8 22.2%	46.8 21.1%
IRC-assessed	44.2 19.7%	45.6 20.5%

6. Secondary Outcome

Title	Overall Survival (OS)
Description	OS is defined as the time from randomization to death from any cause.
Time Frame	Up to 7 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	Duration of Objective Response Determined by the IRC
Description	Duration of objective response, defined as the time from the first occurrence of a documented objective response to disease progression, as determined by an IRC according to RECIST v1.1, or death from any cause, whichever occurs first.
Time Frame	Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Duration of Objective Response Determined by the Investigator
Description	Duration of objective response is defined as the time from the first occurrence of a documented objective response to disease progression, as determined by the investigator through use of RECIST v1.1, or death from any cause, whichever occurs first.
Time Frame	Every 8 weeks (wks) from Day (D) 1 of Cycle (C) 1 through approximately 16 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	Two-year Landmark Survival
Description	Two-year landmark survival is defined as survival at 2 years.
Time Frame	At 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Secondary Outcome

Title	Change From Baseline in Health-related Quality of Life (HRQoL) Scores
Description	HRQoL scores are assessed through global health status (GHS)/ quality of life (QoL) subscale of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ C30). These are based on questions 29 and 30 of the EORTC QLQ-C30. These questions on global health status/QoL scale are coded on 7-point scale (1=very poor to 7=excellent). Raw scores will be linearly transformed to obtain the score ranging from 0 to 100, where higher score represents a higher ("better") level of functioning.
Time Frame	Up to approximately 16 months. Follow up is reported at weeks after participant treatment discontinuation, which could occur at any time during the study. Total time frame does not exceed 16 months.

Outcome Measure Data

Analysis Population Description

The analysis population for this endpoint was the patient reported outcome (PRO) population evaluable participants for EORTC QLQ-C30.

Arm/Group Title	Pembrolizumab	Cobimetinib and Atezolizumab
Arm/Group Description	Participants received 200 mg of intravenous (IV) pembrolizumab every 3 weeks (Q3W) until investigator-determined disease progression, unacceptable toxicity, death, patient or physician decision to withdraw, or pregnancy, whichever occurred first.	Participants received 60 mg of cobimetinib by mouth (PO) on a 21 days on, 7 days off schedule (dosing on Days 1-21, followed by no dosing on Days 22-28) plus 840 mg of atezolizumab by IV infusion of Days 1 and 15 of each 28-day cycle.
Measure Participants	174	160
Baseline value	73.27 (20.41)	73.85 (19.73)
Week 4	-2.99 (17.05)	-9.14 (20.83)
Week 8	-3.15 (18.67)	-5.21 (18.18)
Week 12	-1.77 (19.93)	-7.65 (21.20)
Week 16	1.16 (15.02)	-6.44 (20.58)
Week 20	1.69 (17.50)	-6.31 (19.17)
Week 24	-1.84 (19.82)	-2.49 (15.98)
Week 28	2.46 (19.07)	-3.86 (19.10)
Week 32	-0.88 (22.41)	-4.66 (20.94)
Week 36	4.17 (20.56)	-6.00 (18.24)
Week 40	7.22 (19.38)	-4.63 (21.62)
Week 44	0.46 (19.27)	1.67 (12.91)
Week 48	7.64 (13.04)	0.00 (15.96)
Week 52	1.67 (12.36)	8.33 (15.21)
Week 56	-11.11 (17.21)	-2.08 (4.17)
Week 60	-8.33 (11.79)	-4.17 (5.89)
Week 64	33.33 (NA)
Treatment Discontinuation	-6.05 (22.53)	-14.42 (25.68)
Follow-up 4	-7.64 (14.85)	-2.27 (18.67)
Follow-up 8	-14.25 (21.96)	-14.10 (24.15)
Follow-up 12	-21.38 (24.34)	-24.31 (28.08)
Follow-up 16	-13.73 (19.53)	-23.61 (23.26)
Follow-up 20	-20.83 (26.53)	-8.33 (12.91)
Follow-up 24	-17.71 (29.36)	-10.00 (14.91)
Follow-up 28	-27.78 (22.15)	-16.67 (23.57)

11. Secondary Outcome

Title	Number of Participants With Adverse Events (AEs)
Description	An adverse event is any untoward medical occurrence in a patient administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events.
Time Frame	Up to approximately 16 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pembrolizumab	Cobimetinib and Atezolizumab
Arm/Group Description	Participants received 200 mg of intravenous (IV) pembrolizumab every 3 weeks (Q3W) until investigator-determined disease progression, unacceptable toxicity, death, patient or physician decision to withdraw, or pregnancy, whichever occurred first.	Participants received 60 mg of cobimetinib by mouth (PO) on a 21 days on, 7 days off schedule (dosing on Days 1-21, followed by no dosing on Days 22-28) plus 840 mg of atezolizumab by IV infusion of Days 1 and 15 of each 28-day cycle.
Measure Participants	216	220
Number [Number of Participants]	191 85.3%	218 98.2%

12. Secondary Outcome

Title	Number of Participants With Abnormal Vital Signs
Description	Vital signs will include temperature pulse rate, respiratory rate, and systolic and diastolic blood pressure.
Time Frame	Up to 7 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

13. Secondary Outcome

Title	Number of Participants With Laboratory Abnormalities
Description	Participants with laboratory abnormalities (values outside of a defined range) will be reported.
Time Frame	Up to approximately 16 months

Outcome Measure Data

Analysis Population Description

Participants with at least one post-baseline assessment for a given laboratory value were included in this assessment.

Arm/Group Title	Pembrolizumab	Cobimetinib and Atezolizumab
Arm/Group Description	Participants received 200 mg of intravenous (IV) pembrolizumab every 3 weeks (Q3W) until investigator-determined disease progression, unacceptable toxicity, death, patient or physician decision to withdraw, or pregnancy, whichever occurred first.	Participants received 60 mg of cobimetinib by mouth (PO) on a 21 days on, 7 days off schedule (dosing on Days 1-21, followed by no dosing on Days 22-28) plus 840 mg of atezolizumab by IV infusion of Days 1 and 15 of each 28-day cycle.
Measure Participants	216	220
SGPT/ALT	1 0.4%	1 0.5%
Amylase	4 1.8%	5 2.3%
SGOT/AST	0 0%	2 0.9%
Calcium	0 0%	1 0.5%
Creatine Kinase	1 0.4%	17 7.7%
Creatinine	1 0.4%	4 1.8%
Glucose	8 3.6%	13 5.9%
Triacylglycerol Lipase	8 3.6%	10 4.5%
Magnesium	3 1.3%	2 0.9%
Phosphorus	6 2.7%	10 4.5%
Potassium	1 0.4%	6 2.7%
Sodium	2 0.9%	4 1.8%
Uric Acid	36 16.1%	30 13.5%
Hemoglobin	2 0.9%	2 0.9%
Lymphocytes Abs	6 2.7%	15 6.8%
Neutrophils, Total, Abs	0 0%	1 0.5%
Total Leukocyte Count	3 1.3%	0 0%

14. Secondary Outcome

Title	Plasma Concentration of Cobimetinib
Description	Plasma concentration of cobimetinib at specified time points will be reported.
Time Frame	Days 1 and 15 of Cycle 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

15. Secondary Outcome

Title	Serum Concentration of Atezolizumab
Description	Serum concentration of atezolizumab at specified time points will be reported.
Time Frame	Day 1 of Cycle 1, 2, 3 and 30 days after treatment discontinuation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

16. Secondary Outcome

Title	Percentage of Participants With Anti-drug Antibodies (ADAs)
Description	Participants with ADAs during the study relative to the prevalence of ADAs at baseline will be reported.
Time Frame	Day 1 of Cycle 1, 2, 3 and 30 days after treatment discontinuation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	For up to 135 days after the last dose of study drug, or until a new systemic anti-cancer therapy was initiated, whichever occurred first.
Arm/Group Title	Pembrolizumab		Cobimetinib and Atezolizumab
Arm/Group Description	Participants received 200 mg of intravenous (IV) pembrolizumab every 3 weeks (Q3W) until investigator-determined disease progression, unacceptable toxicity, death, patient or physician decision to withdraw, or pregnancy, whichever occurred first.		Participants received 60 mg of cobimetinib by mouth (PO) on a 21 days on, 7 days off schedule (dosing on Days 1-21, followed by no dosing on Days 22-28) plus 840 mg of atezolizumab by IV infusion of Days 1 and 15 of each 28-day cycle.
All Cause Mortality
	Pembrolizumab		Cobimetinib and Atezolizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	42/216 (19.4%)		45/220 (20.5%)
Serious Adverse Events
	Pembrolizumab		Cobimetinib and Atezolizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	45/216 (20.8%)		97/220 (44.1%)
Blood and lymphatic system disorders
Anaemia	1/216 (0.5%)		2/220 (0.9%)
Thrombocytopenia	0/216 (0%)		1/220 (0.5%)
Cardiac disorders
Atrial fibrillation	1/216 (0.5%)		3/220 (1.4%)
Atrial flutter	1/216 (0.5%)		1/220 (0.5%)
Angina pectoris	0/216 (0%)		1/220 (0.5%)
Bradycardia	1/216 (0.5%)		0/220 (0%)
Cardiac failure acute	0/216 (0%)		1/220 (0.5%)
Cardiac tamponade	1/216 (0.5%)		0/220 (0%)
Myocarditis	0/216 (0%)		1/220 (0.5%)
Tachyarrhythmia	0/216 (0%)		1/220 (0.5%)
Endocrine disorders
Adrenal insufficiency	1/216 (0.5%)		0/220 (0%)
Eye disorders
Chorioretinopathy	0/216 (0%)		1/220 (0.5%)
Diplopia	1/216 (0.5%)		0/220 (0%)
Visual impairment	0/216 (0%)		1/220 (0.5%)
Gastrointestinal disorders
Diarrhoea	1/216 (0.5%)	1	9/220 (4.1%)	11
Vomiting	0/216 (0%)		5/220 (2.3%)
Abdominal pain upper	3/216 (1.4%)		1/220 (0.5%)
Abdominal pain	1/216 (0.5%)		2/220 (0.9%)
Colitis	0/216 (0%)		2/220 (0.9%)
Nausea	0/216 (0%)		2/220 (0.9%)
Ascites	0/216 (0%)		1/220 (0.5%)
Autoimmune colitis	1/216 (0.5%)		0/220 (0%)
Gastric ulcer	1/216 (0.5%)		0/220 (0%)
Gastrointestinal haemorrhage	1/216 (0.5%)		0/220 (0%)
Gastrointestinal obstruction	0/216 (0%)		1/220 (0.5%)
Haematochezia	0/216 (0%)		1/220 (0.5%)
Haemorrhoids	0/216 (0%)		1/220 (0.5%)
Intestinal obstruction	1/216 (0.5%)		0/220 (0%)
Pancreatitis	1/216 (0.5%)		0/220 (0%)
Rectal haemorrhage	1/216 (0.5%)		0/220 (0%)
Stomatitis	0/216 (0%)		1/220 (0.5%)
Subileus	0/216 (0%)		1/220 (0.5%)
Thrombosis mesenteric vessel	0/216 (0%)		1/220 (0.5%)
General disorders
Pyrexia	2/216 (0.9%)		12/220 (5.5%)
Asthenia	3/216 (1.4%)		4/220 (1.8%)
Fatigue	0/216 (0%)		3/220 (1.4%)
General physical health deterioration	1/216 (0.5%)		1/220 (0.5%)
Chest pain	1/216 (0.5%)		0/220 (0%)
Death	42/216 (19.4%)		45/220 (20.5%)
Malaise	0/216 (0%)		1/220 (0.5%)
Multiple organ dysfunction syndrome	0/216 (0%)		1/220 (0.5%)
Non-cardiac chest pain	0/216 (0%)		1/220 (0.5%)
Hepatobiliary disorders
Hepatic failure	1/216 (0.5%)	1	0/220 (0%)	0
Hepatic pain	0/216 (0%)	0	1/220 (0.5%)	1
Hepatitis	1/216 (0.5%)	1	0/220 (0%)	0
Immune system disorders
Hypersensitivity	0/216 (0%)		1/220 (0.5%)
Infections and infestations
Sepsis	0/216 (0%)		6/220 (2.7%)
Erysipelas	1/216 (0.5%)		3/220 (1.4%)
Urinary tract infection	1/216 (0.5%)		2/220 (0.9%)
Pneumonia	1/216 (0.5%)		1/220 (0.5%)
Urosepsis	0/216 (0%)		2/220 (0.9%)
Cellulitis	0/216 (0%)		1/220 (0.5%)
Dacryocystitis	1/216 (0.5%)		0/220 (0%)
Device related sepsis	1/216 (0.5%)		0/220 (0%)
Diarrhoea infectious	0/216 (0%)		1/220 (0.5%)
Encephalitis	0/216 (0%)		1/220 (0.5%)
Endocarditis	0/216 (0%)		1/220 (0.5%)
Infection	1/216 (0.5%)		0/220 (0%)
Influenza	1/216 (0.5%)		0/220 (0%)
Lower respiratory tract infection	0/216 (0%)		1/220 (0.5%)
Lung infection	0/216 (0%)		1/220 (0.5%)
Respiratory tract infection	0/216 (0%)		1/220 (0.5%)
Spleen tuberculosis	1/216 (0.5%)		0/220 (0%)
Superinfection viral	1/216 (0.5%)		0/220 (0%)
Toxic shock syndrome	0/216 (0%)		1/220 (0.5%)
Upper respiratory tract infection	1/216 (0.5%)		0/220 (0%)
Vascular device infection	0/216 (0%)		1/220 (0.5%)
Wound infection	0/216 (0%)		1/220 (0.5%)
Injury, poisoning and procedural complications
Infusion related reaction	0/216 (0%)		3/220 (1.4%)
Ankle fracture	0/216 (0%)		1/220 (0.5%)
Fall	0/216 (0%)		1/220 (0.5%)
Hip fracture	1/216 (0.5%)		0/220 (0%)
Upper limb fracture	1/216 (0.5%)		0/220 (0%)
Investigations
Blood bilirubin increased	1/216 (0.5%)		2/220 (0.9%)
Blood creatine phosphokinase increased	1/216 (0.5%)		2/220 (0.9%)
Blood creatinine increased	1/216 (0.5%)		2/220 (0.9%)
Aspartate aminotransferase increased	0/216 (0%)		2/220 (0.9%)
Alanine aminotransferase increased	0/216 (0%)		1/220 (0.5%)
General physical condition abnormal	0/216 (0%)		1/220 (0.5%)
Transaminases increased	1/216 (0.5%)		0/220 (0%)
Metabolism and nutrition disorders
Hyperglycaemia	1/216 (0.5%)		1/220 (0.5%)
Dehydration	0/216 (0%)		1/220 (0.5%)
Diabetes mellitus	1/216 (0.5%)		0/220 (0%)
Hypoglycaemia	1/216 (0.5%)		0/220 (0%)
Hyponatraemia	0/216 (0%)		1/220 (0.5%)
Hypovolaemia	1/216 (0.5%)		0/220 (0%)
Musculoskeletal and connective tissue disorders
Rhabdomyolysis	0/216 (0%)		1/220 (0.5%)
Dupuytren's contracture	0/216 (0%)		1/220 (0.5%)
Muscular weakness	0/216 (0%)		1/220 (0.5%)
Myositis	1/216 (0.5%)		0/220 (0%)
Scleroderma	0/216 (0%)		1/220 (0.5%)
Spinal pain	1/216 (0.5%)		0/220 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer	0/216 (0%)		1/220 (0.5%)
Tumour haemorrhage	1/216 (0.5%)		0/220 (0%)
Tumour pain	1/216 (0.5%)		0/220 (0%)
Nervous system disorders
Ischaemic stroke	1/216 (0.5%)		3/220 (1.4%)
Seizure	1/216 (0.5%)		1/220 (0.5%)
Syncope	0/216 (0%)		2/220 (0.9%)
Autoimmune encephalopathy	0/216 (0%)		1/220 (0.5%)
Autoimmune neuropathy	0/216 (0%)		1/220 (0.5%)
Brain oedema	1/216 (0.5%)		0/220 (0%)
Dyskinesia	0/216 (0%)		1/220 (0.5%)
Encephalitis autoimmune	0/216 (0%)		1/220 (0.5%)
Intracranial pressure increased	0/216 (0%)		1/220 (0.5%)
Leukoencephalopathy	1/216 (0.5%)		0/220 (0%)
Monoparesis	1/216 (0.5%)		0/220 (0%)
Nervous system disorder	0/216 (0%)		1/220 (0.5%)
Presyncope	0/216 (0%)		1/220 (0.5%)
Radiculopathy	1/216 (0.5%)		0/220 (0%)
Transient ischaemic attack	1/216 (0.5%)		0/220 (0%)
Renal and urinary disorders
Renal failure	0/216 (0%)		3/220 (1.4%)
Acute kidney injury	0/216 (0%)		2/220 (0.9%)
Bladder perforation	1/216 (0.5%)		0/220 (0%)
Haematuria	0/216 (0%)		1/220 (0.5%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	4/216 (1.9%)		2/220 (0.9%)
Dyspnoea	2/216 (0.9%)		3/220 (1.4%)
Haemoptysis	0/216 (0%)		2/220 (0.9%)
Cough	0/216 (0%)		1/220 (0.5%)
Interstitial lung disease	0/216 (0%)		1/220 (0.5%)
Pleural effusion	1/216 (0.5%)		0/220 (0%)
Skin and subcutaneous tissue disorders
Rash	1/216 (0.5%)	1	4/220 (1.8%)	4
Dermatitis acneiform	0/216 (0%)	0	3/220 (1.4%)	3
Dermatitis	0/216 (0%)	0	1/220 (0.5%)	1
Dermatitis allergic	0/216 (0%)	0	1/220 (0.5%)	1
Dermatitis exfoliative generalised	0/216 (0%)	0	1/220 (0.5%)	1
Pemphigoid	0/216 (0%)		1/220 (0.5%)
Rash macular	0/216 (0%)	0	1/220 (0.5%)	1
Vascular disorders
Hypotension	1/216 (0.5%)		1/220 (0.5%)
Haematoma	0/216 (0%)		1/220 (0.5%)
Hypertension	1/216 (0.5%)		0/220 (0%)
Orthostatic hypotension	0/216 (0%)		1/220 (0.5%)
Other (Not Including Serious) Adverse Events
	Pembrolizumab		Cobimetinib and Atezolizumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	162/216 (75%)		209/220 (95%)
Blood and lymphatic system disorders
Anaemia	12/216 (5.6%)	12	30/220 (13.6%)	41
Endocrine disorders
Hyperthyroidism	19/216 (8.8%)	19	7/220 (3.2%)	7
Hypothyroidism	15/216 (6.9%)	15	13/220 (5.9%)	14
Gastrointestinal disorders
Abdominal pain	13/216 (6%)	16	22/220 (10%)	26
Constipation	18/216 (8.3%)	21	30/220 (13.6%)	33
Diarrhoea	35/216 (16.2%)	44	118/220 (53.6%)	246
Dry mouth	6/216 (2.8%)	6	16/220 (7.3%)	17
Nausea	26/216 (12%)	30	53/220 (24.1%)	59
Stomatitis	3/216 (1.4%)	4	12/220 (5.5%)	16
Vomiting	15/216 (6.9%)	15	39/220 (17.7%)	49
General disorders
Asthenia	39/216 (18.1%)	43	55/220 (25%)	76
Fatigue	41/216 (19%)	53	42/220 (19.1%)	61
Oedema peripheral	13/216 (6%)	13	45/220 (20.5%)	63
Pyrexia	15/216 (6.9%)	16	62/220 (28.2%)	82
Infections and infestations
Folliculitis	1/216 (0.5%)	1	13/220 (5.9%)	20
Rash pustular	1/216 (0.5%)	1	12/220 (5.5%)	12
Urinary tract infection	2/216 (0.9%)	2	12/220 (5.5%)	14
Investigations
Alanine aminotransferase increased	14/216 (6.5%)	14	26/220 (11.8%)	36
Amylase increased	7/216 (3.2%)	8	14/220 (6.4%)	23
Aspartate aminotransferase increased	14/216 (6.5%)	14	38/220 (17.3%)	50
Blood creatine phosphokinase increased	9/216 (4.2%)	12	76/220 (34.5%)	108
Blood lactate dehydrogenase increased	4/216 (1.9%)	4	12/220 (5.5%)	14
Lipase increased	12/216 (5.6%)	14	22/220 (10%)	39
Metabolism and nutrition disorders
Decreased appetite	16/216 (7.4%)	18	30/220 (13.6%)	33
Hyperglycaemia	9/216 (4.2%)	11	16/220 (7.3%)	20
Musculoskeletal and connective tissue disorders
Arthralgia	24/216 (11.1%)	30	14/220 (6.4%)	15
Back pain	19/216 (8.8%)	19	12/220 (5.5%)	15
Myalgia	10/216 (4.6%)	10	13/220 (5.9%)	15
Pain in extremity	7/216 (3.2%)	8	11/220 (5%)	11
Nervous system disorders
Dizziness	7/216 (3.2%)	10	14/220 (6.4%)	18
Headache	17/216 (7.9%)	18	24/220 (10.9%)	30
Respiratory, thoracic and mediastinal disorders
Cough	18/216 (8.3%)	20	17/220 (7.7%)	20
Dyspnoea	16/216 (7.4%)	16	15/220 (6.8%)	21
Skin and subcutaneous tissue disorders
Dermatitis acneiform	3/216 (1.4%)	3	50/220 (22.7%)	62
Dry skin	11/216 (5.1%)	12	14/220 (6.4%)	17
Erythema	6/216 (2.8%)	6	12/220 (5.5%)	13
Pruritis	30/216 (13.9%)	37	39/220 (17.7%)	48
Rash	25/216 (11.6%)	34	89/220 (40.5%)	132
Rash maculo-papular	5/216 (2.3%)	6	26/220 (11.8%)	36
Vascular disorders
Hypertension	11/216 (5.1%)	15	21/220 (9.5%)	26

Limitations/Caveats

[Not Specified]

More Information

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.