A Study to Investigate Efficacy and Safety of Cobimetinib... | NCT02788279

ID	Type	Description	Link
2016-000202-11	EudraCT Number

Label	Type	Description	Intervention Names
Atezolizumab	Experimental	Participants will receive atezolizumab monotherapy 1200 milligrams (mg) intravenous (IV) on Day 1 in a 21-day cycle until disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.	Drug: Atezolizumab (MPDL3280A), an Engineered Anti-PDL1 Antibody
Cobimetinib + Atezolizumab	Experimental	Participants will receive cobimetinib 60 mg orally on Days 1 to 21 plus atezolizumab 840 mg IV on Day 1 and Day 15 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.	Drug: Atezolizumab (MPDL3280A), an Engineered Anti-PDL1 Antibody Drug: Cobimetinib
Regorafenib	Active Comparator	Participants will receive regorafenib 160 mg orally on Days 1 to 21 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.	Drug: Regorafenib

Name	Type	Description	Arm Group Labels	Other Names
Atezolizumab (MPDL3280A), an Engineered Anti-PDL1 Antibody	Drug	Participants will receive atezolizumab IV at 840 mg on Day 1 and Day 15 in a 28-day cycle as a combination therapy or at 1200 mg on Day 1 in a 21-day cycle as a monotherapy until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.

Measure	Description	Time Frame
Overall Survival (OS)	Overall survival is defined as the time (in months) between the date of randomization and the date of death due to any cause. Participants who were not reported as having died at the date of analysis were censored at the date when they were last known to be alive. Participants who did not have post-baseline information were censored at the date of randomization + 1 day. Median OS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley.	From randomization up to death due to any cause (up to approximately 20 months)

Measure	Description	Time Frame
Progression-Free Survival (PFS) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)	PFS was defined as the time from randomization to disease progression as determined by the investigator with the use of RECIST v1.1 or death due to any cause, whichever occurred earlier. Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm). For non-target lesions, disease progression was defined as unequivocal progression of existing lesions. The appearance of one or more new lesions was also considered progression. Participants who did not have post-baseline information were censored at the date of randomization + 1 day. Median OS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Disease-specific inclusion criteria:

Histologically confirmed adenocarcinoma originating from the colon or rectum (Stage 4 American Joint Committee on Cancer [AJCC] 7th edition)
Experienced disease progression or was intolerant to at least two systemic chemotherapy regimens for metastatic colorectal cancer that must have included fluroropyrimidines, irinotecan, and oxaliplatin; adjuvant regimen can be considered as one chemotherapy regimen for metastatic disease if the participant had disease recurrence within 6 months of completion; disease progression must have occurred within 3 months of the last systemic therapy administration

General inclusion criteria:

Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Anticipated life expectancy greater than or equal to (>=) 3 months
Adequate hematologic and end organ function
Women of childbearing potential must agree to appropriately use an effective form of contraception (failure rate of less than [<] 1 percent [%] per year) during the treatment period, within 5 months after the last dose of atezolizumab, and within 3 months after the last dose of cobimetinib and regorafenib
Men must agree not to donate sperm or have intercourse with a female partner without using appropriate barrier contraception during the treatment period and for 3 months after the last dose of either cobimetinib or regorafenib
Provide an archival or newly obtained tumor tissue sample

Exclusion Criteria:

After the approximate 5% cap for microsatellite (MSI)-high participants is reached, only MSI-stable participants will be eligible
Once the 50% cap for wild-type RAS has been reached, only extended RAS-mutant participants will be eligible
Major surgery or radiotherapy within 21 days prior to Cycle 1 Day 1 or anticipation of needing such procedure while receiving study treatment
Treatment with any anti-cancer agent within 14 days prior to Cycle 1 Day 1
Uncontrolled tumor-related pain. Participants requiring narcotic pain medication must be on a stable regimen at study entry
Uncontrolled pleural effusion, pericardial effusion or ascites requiring repeated drainage more than once every 28 days. Indwelling drainage catheters (e.g., PleurX®) are allowed
Active or untreated central nervous system (CNS) metastases are excluded
Prior therapy with any cancer immunotherapy, MEK inhibitor, or regorafenib
Participants with active malignancy (other than CRC) or a prior malignancy within the past 3 years are excluded. Participants with completely resected cutaneous melanoma (early stage), basal cell carcinoma, cutaneous squamous cell carcinoma, cervical carcinoma in-situ, breast carcinoma in-situ, and localized prostate cancer are eligible
Unstable angina, new onset angina within last 3 months, myocardial infarction within last 6 months and current congestive heart failure New York Heart Association Class II or higher
Left ventricular ejection fraction (LVEF) below institutional lower limit of normal or below 50%, whichever is lower
Poorly controlled hypertension, defined as a blood pressure consistently above 150/90 millimeters of Mercury (mmHg) despite optimal medical management
Human immunodeficiency virus (HIV) infection
Active tuberculosis infection
Severe infections within 2 weeks prior to Cycle 1 Day 1
Active or chronic viral hepatitis B or C infection
History of or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for central serous retinopathy, retinal vein occlusion, or neovascular macular degeneration
Participants will be excluded if they currently have any of the risk factors as defined in the study protocol for retinal vein occlusion
History of autoimmune disease
History of idiopathic pulmonary fibrosis, organizing pneumonia, bronchiolitis obliterans, drug-induced pneumonitis, or idiopathic pneumonitis
History of organ transplantation including allogeneic bone marrow transplantation
Inability to swallow medications
Malabsorption condition that would alter the absorption of orally administered medications
Pregnant, lactating, breastfeeding, or intending to become pregnant during the study
Administration of a live, attenuated vaccine within 4 weeks before randomization or anticipation of a live attenuated vaccine will be required during the study

Name	Affiliation	Role
Clinical Trials	Hoffmann-La Roche	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
City of Hope Comprehensive Cancer Center		Duarte	California	91010	United States
Yale Cancer Center; Medical Oncology

PubMed Identifier	Type	Citation	Retractions
37741832	Derived	Taraborrelli L, Senbabaoglu Y, Wang L, Lim J, Blake K, Kljavin N, Gierke S, Scherl A, Ziai J, McNamara E, Owyong M, Rao S, Calviello AK, Oreper D, Jhunjhunwala S, Argiles G, Bendell J, Kim TW, Ciardiello F, Wongchenko MJ, de Sauvage FJ, de Sousa E Melo F, Yan Y, West NR, Murthy A. Tumor-intrinsic expression of the autophagy gene Atg16l1 suppresses anti-tumor immunity in colorectal cancer. Nat Commun. 2023 Sep 23;14(1):5945. doi: 10.1038/s41467-023-41618-7.
36310331

ID	Title	Description
FG000	Regorafenib	Participants received regorafenib 160 milligrams (mg) orally once daily on Days 1 to 21 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.
FG001

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Nov 28, 2017	Mar 8, 2019

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Overall Survival (OS)

Overall survival is defined as the time (in months) between the date of randomization and the date of death due to any cause. Participants who were not reported as having died at the date of analysis were censored at the date when they were last known to be alive. Participants who did not have post-baseline information were censored at the date of randomization + 1 day. Median OS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley.

Analysis was performed on the ITT population.

Posted

Median

95% Confidence Interval

months

From randomization up to death due to any cause (up to approximately 20 months)

ID	Title	Description
OG000	Regorafenib	Participants received regorafenib 160 milligrams (mg) orally once daily on Days 1 to 21 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.
OG001	Cobimetinib + Atezolizumab	Participants received cobimetinib 60 mg orally on Days 1 to 21 plus atezolizumab 840 mg IV on Day 1 and Day 15 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.
OG002	Atezolizumab	Participants received atezolizumab monotherapy 1200 mg intravenous (IV) on Day 1 in a 21-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.

Units	Counts
Participants	OG00090 OG001183 OG00290

Title

Denominators

Categories

Title	Measurements
	OG0008.51(6.41 to 10.71) OG0018.87(7.00 to 10.61) OG0027.10(6.05 to 10.05)

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001		Stratified Log-Rank	Stratification factors included extended RAS mutation status and time since diagnosis of first metastasis.	0.9871		Hazard Ratio (HR)	1.00			2-Sided	95	0.73	1.38			Hazard ratio was estimated using stratified Cox regression.		Superiority
OG000 OG002

Secondary

Progression-Free Survival (PFS) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1)

PFS was defined as the time from randomization to disease progression as determined by the investigator with the use of RECIST v1.1 or death due to any cause, whichever occurred earlier. Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, including baseline. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 millimeters (mm). For non-target lesions, disease progression was defined as unequivocal progression of existing lesions. The appearance of one or more new lesions was also considered progression. Participants who did not have post-baseline information were censored at the date of randomization + 1 day. Median OS was estimated by Kaplan-Meier method and 95% CI was assessed using the method of Brookmeyer and Crowley.

Analysis was performed on the ITT population.

Posted

Median

95% Confidence Interval

months

From randomization up to disease progression or death due to any cause (up to approximately 20 months)

ID	Title	Description
OG000	Regorafenib	Participants received regorafenib 160 milligrams (mg) orally once daily on Days 1 to 21 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.
OG001	Cobimetinib + Atezolizumab

Secondary

Percentage of Participants With Investigator-Assessed Objective Response of Complete Response (CR) or Partial Response (PR) According to RECIST Version 1.1

PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker levels (as applicable to non-target lesions). Objective response and its 95% CI were calculated using the Clopper-Pearson method.

Analysis was performed on evaluable participants in the ITT population with measurable disease at baseline, as determined by the investigator.

Posted

Number

95% Confidence Interval

percentage of participants

From randomization up to death due to any cause (up to approximately 20 months)

ID	Title	Description
OG000	Regorafenib	Participants received regorafenib 160 milligrams (mg) orally once daily on Days 1 to 21 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.
OG001	Cobimetinib + Atezolizumab	Participants received cobimetinib 60 mg orally on Days 1 to 21 plus atezolizumab 840 mg IV on Day 1 and Day 15 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.

Secondary

Duration of Response (DOR) According to RECIST Version 1.1

DOR is defined as the period measured from the date of the first occurrence of a CR or PR (whichever status is recorded first) until the first date that progressive disease or death is documented. Disease progression was determined on the basis of investigator assessment with use of RECIST v1.1. Median DOR was estimated using the Kaplan-Meier method, and the 95% CI was calculated using the method of Brookmeyer and Crowley.

DOR was assessed in participants who had an objective response during the study.

Posted

Median

95% Confidence Interval

months

From first occurrence of CR or PR up to disease progression or death due to any cause (up to approximately 20 months)

ID	Title	Description
OG000	Regorafenib	Participants received regorafenib 160 milligrams (mg) orally once daily on Days 1 to 21 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.
OG001	Cobimetinib + Atezolizumab	Participants received cobimetinib 60 mg orally on Days 1 to 21 plus atezolizumab 840 mg IV on Day 1 and Day 15 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.

Secondary

Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life-C30 Questionnaire (EORTC QLQ-C30) Physical Functioning Sub-scale Score

The EORTC QLQ-C30 questionnaire consisted of 30 questions generating five functional scores (physical, role, cognitive, emotional, and social); a global health status/global quality of life scale score; three symptom scale scores (fatigue, pain, and nausea and vomiting); and six stand alone one-item scores that capture additional symptoms (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) and perceived financial burden. All the scales and single-item scores were linearly transformed so that each score ranged from 0 to 100. A higher score on the global health and functioning subscales is indicative of better functioning.

Analysis was performed on PRO-evaluable population. Here, 'Overall Number of Participants Analyzed' signifies the number of participants evaluable for this outcome measure and 'Number Analyzed' signifies the number of participants evaluable at specified time point.

Posted

Mean

Standard Deviation

units of a scale

Baseline, end of the study (up to approximately 2.5 years)

ID	Title	Description
OG000	Regorafenib	Participants received regorafenib 160 milligrams (mg) orally once daily on Days 1 to 21 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.
OG001	Cobimetinib + Atezolizumab

Secondary

Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life-C30 Questionnaire (EORTC QLQ-C30) Global Quality of Life Sub-scale Score at the End of the Study

Posted

Mean

Standard Deviation

units of a scale

Baseline, end of the study (up to approximately 2.5 years)

ID	Title	Description
OG000	Regorafenib	Participants received regorafenib 160 milligrams (mg) orally once daily on Days 1 to 21 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.
OG001	Cobimetinib + Atezolizumab

Secondary

Percentage of Participants With Adverse Events (AEs)

Analysis was performed on the SAF population.

Posted

Number

percentage of participants

Baseline, end of the study (up to approximately 2.5 years)

ID	Title	Description
OG000	Regorafenib	Participants received regorafenib 160 milligrams (mg) orally once daily on Days 1 to 21 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.
OG001	Cobimetinib + Atezolizumab	Participants received cobimetinib 60 mg orally on Days 1 to 21 plus atezolizumab 840 mg IV on Day 1 and Day 15 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.
OG002	Atezolizumab	Participants received atezolizumab monotherapy 1200 mg intravenous (IV) on Day 1 in a 21-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.

Secondary

Plasma Concentration of Cobimetinib

The pharmacokinetic (PK) evaluable population included all participants who received any dose of study medication and who had at least one post-baseline PK sample available. Only included participants in the Cobimetnib arm

Posted

Geometric Mean

Geometric Coefficient of Variation

Nanogram/milliliter (ng/mL)

Predose (0 hours) and 3 to 6 hours after dose on Day 15 of Cycles 1 and 4 (1 cycle = 28 days) (up to approximately 2.5 years).

ID	Title	Description
OG000	Cobimetinib + Atezolizumab	Participants received cobimetinib 60 mg orally on Days 1 to 21 plus atezolizumab 840 mg IV on Day 1 and Day 15 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.

Units	Counts
Participants	OG000

Secondary

Serum Concentration of Atezolizumab

Pre-infusion (0 hours) on Day 1 of Cycles 1 to 4; 30 minutes post-infusion on Day 1 of Cycles 1 and 4; pre-infusion (0 hours) on Day 1 of Cycle 8 and every 8 cycles thereafter; at treatment discontinuation; 120 days after treatment discontinuation (up to approximately 2.5 years) (1 cycle = 28 days)

The pharmacokinetic (PK) evaluable population included all participants who received any dose of study medication and who had at least one post-baseline PK sample available. Also, only included participants to whom Atezolizumab was administered.

Posted

Geometric Mean

Geometric Coefficient of Variation

microgram/milliliter (ug/mL)

Pre-infusion (0 hours) on Day 1 of Cycle 1 up to approximately 2.5 years. Detailed time frame is explained in the outcome measure description field.

ID	Title	Description
OG000	Atezolizumab	Participants received atezolizumab monotherapy 1200 mg intravenous (IV) on Day 1 in a 21-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.
OG001	Cobimetinib + Atezolizumab	Participants received cobimetinib 60 mg orally on Days 1 to 21 plus atezolizumab 840 mg IV on Day 1 and Day 15 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.

Secondary

Percentage of Participants With Anti-Therapeutic Antibodies (ATAs) to Atezolizumab

Analysis was performed on the SAF population and included participants with at least one predose and one postdose ATA assessment.

Posted

Number

percentage of participants

Pre-infusion (0 hours) on Day 1 of Cycles 1 to 4, 8, and every 8 cycles thereafter; at treatment discontinuation; 120 days after treatment discontinuation (up to approximately 2.5 years) (1 cycle = 28 days)

ID	Title	Description
OG000	Cobimetinib + Atezolizumab	Participants received cobimetinib 60 mg orally on Days 1 to 21 plus atezolizumab 840 mg IV on Day 1 and Day 15 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.
OG001	Atezolizumab	Participants received atezolizumab monotherapy 1200 mg intravenous (IV) on Day 1 in a 21-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.

Units	Counts
Participants

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
ANAEMIA	Blood and lymphatic system disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0015 events5 affected179 at risk EG0020 events0 affected90 at risk
ATRIAL FIBRILLATION	Cardiac disorders	MedDRA version 21.1	Systematic Assessment	EG0001 events1 affected80 at risk EG0010 events0 affected179 at risk EG0020 events0 affected90 at risk
LEFT VENTRICULAR DYSFUNCTION	Cardiac disorders	MedDRA version 21.1	Systematic Assessment	EG0001 events1 affected80 at risk EG0010 events0 affected179 at risk EG0020 events0 affected90 at risk
ADRENAL INSUFFICIENCY	Endocrine disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
MACULOPATHY	Eye disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
ABDOMINAL PAIN	Gastrointestinal disorders	MedDRA version 21.1	Systematic Assessment	EG0002 events2 affected80 at risk EG0012 events2 affected179 at risk EG0021 events1 affected90 at risk
ANAL HAEMORRHAGE	Gastrointestinal disorders	MedDRA version 21.1	Systematic Assessment	EG0001 events1 affected80 at risk EG0010 events0 affected179 at risk EG0020 events0 affected90 at risk
COLITIS	Gastrointestinal disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0012 events2 affected179 at risk EG0021 events1 affected90 at risk
COLONIC FISTULA	Gastrointestinal disorders	MedDRA version 21.1	Systematic Assessment	EG0001 events1 affected80 at risk EG0010 events0 affected179 at risk EG0020 events0 affected90 at risk
CONSTIPATION	Gastrointestinal disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
DIARRHOEA	Gastrointestinal disorders	MedDRA version 21.1	Systematic Assessment	EG0003 events3 affected80 at risk EG0016 events6 affected179 at risk EG0020 events0 affected90 at risk
GASTROINTESTINAL HAEMORRHAGE	Gastrointestinal disorders	MedDRA version 21.1	Systematic Assessment	EG0001 events1 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
ILEUS	Gastrointestinal disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
INTESTINAL PERFORATION	Gastrointestinal disorders	MedDRA version 21.1	Systematic Assessment	EG0002 events2 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
LOWER GASTROINTESTINAL HAEMORRHAGE	Gastrointestinal disorders	MedDRA version 21.1	Systematic Assessment	EG0001 events1 affected80 at risk EG0010 events0 affected179 at risk EG0020 events0 affected90 at risk
NAUSEA	Gastrointestinal disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
PANCREATITIS	Gastrointestinal disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
RECTAL HAEMORRHAGE	Gastrointestinal disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0010 events0 affected179 at risk EG0021 events1 affected90 at risk
SMALL INTESTINAL OBSTRUCTION	Gastrointestinal disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0010 events0 affected179 at risk EG0021 events1 affected90 at risk
SUBILEUS	Gastrointestinal disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
UPPER GASTROINTESTINAL HAEMORRHAGE	Gastrointestinal disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
VOLVULUS OF SMALL BOWEL	Gastrointestinal disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
VOMITING	Gastrointestinal disorders	MedDRA version 21.1	Systematic Assessment	EG0001 events1 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
ASTHENIA	General disorders	MedDRA version 21.1	Systematic Assessment	EG0001 events1 affected80 at risk EG0010 events0 affected179 at risk EG0020 events0 affected90 at risk
CHILLS	General disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
DEATH	General disorders	MedDRA version 21.1	Systematic Assessment	EG0001 events1 affected80 at risk EG0010 events0 affected179 at risk EG0020 events0 affected90 at risk
FATIGUE	General disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
GENERAL PHYSICAL HEALTH DETERIORATION	General disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
INFLAMMATION	General disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
INFLUENZA LIKE ILLNESS	General disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
MUCOSAL INFLAMMATION	General disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
PYREXIA	General disorders	MedDRA version 21.1	Systematic Assessment	EG0003 events3 affected80 at risk EG00115 events12 affected179 at risk EG0022 events2 affected90 at risk
AUTOIMMUNE HEPATITIS	Hepatobiliary disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0010 events0 affected179 at risk EG0021 events1 affected90 at risk
BILE DUCT OBSTRUCTION	Hepatobiliary disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0010 events0 affected179 at risk EG0021 events1 affected90 at risk
CHOLANGITIS	Hepatobiliary disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0012 events1 affected179 at risk EG0020 events0 affected90 at risk
HYPERSENSITIVITY	Immune system disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0010 events0 affected179 at risk EG0021 events1 affected90 at risk
ABDOMINAL HERNIA INFECTION	Infections and infestations	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0010 events0 affected179 at risk EG0021 events1 affected90 at risk
BACTERAEMIA	Infections and infestations	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
BACTERIAL SEPSIS	Infections and infestations	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
INFECTION	Infections and infestations	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
LUNG INFECTION	Infections and infestations	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
ORAL CANDIDIASIS	Infections and infestations	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
PNEUMONIA	Infections and infestations	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0013 events2 affected179 at risk EG0020 events0 affected90 at risk
PNEUMONIA PNEUMOCOCCAL	Infections and infestations	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
PULMONARY SEPSIS	Infections and infestations	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0021 events1 affected90 at risk
PYELONEPHRITIS	Infections and infestations	MedDRA version 21.1	Systematic Assessment	EG0001 events1 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
PYELONEPHRITIS ACUTE	Infections and infestations	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
RESPIRATORY TRACT INFECTION	Infections and infestations	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
RHINOVIRUS INFECTION	Infections and infestations	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
SEPSIS	Infections and infestations	MedDRA version 21.1	Systematic Assessment	EG0002 events2 affected80 at risk EG0014 events4 affected179 at risk EG0020 events0 affected90 at risk
STREPTOCOCCAL BACTERAEMIA	Infections and infestations	MedDRA version 21.1	Systematic Assessment	EG0001 events1 affected80 at risk EG0010 events0 affected179 at risk EG0020 events0 affected90 at risk
URINARY TRACT INFECTION	Infections and infestations	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0012 events2 affected179 at risk EG0020 events0 affected90 at risk
HIP FRACTURE	Injury, poisoning and procedural complications	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
INFUSION RELATED REACTION	Injury, poisoning and procedural complications	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0013 events3 affected179 at risk EG0020 events0 affected90 at risk
LUMBAR VERTEBRAL FRACTURE	Injury, poisoning and procedural complications	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
STOMA SITE HAEMORRHAGE	Injury, poisoning and procedural complications	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0010 events0 affected179 at risk EG0021 events1 affected90 at risk
BLOOD CREATINE PHOSPHOKINASE INCREASED	Investigations	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0012 events2 affected179 at risk EG0020 events0 affected90 at risk
INFLUENZA A VIRUS TEST POSITIVE	Investigations	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
INTERNATIONAL NORMALISED RATIO INCREASED	Investigations	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
DECREASED APPETITE	Metabolism and nutrition disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0010 events0 affected179 at risk EG0021 events1 affected90 at risk
DEHYDRATION	Metabolism and nutrition disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
HYPONATRAEMIA	Metabolism and nutrition disorders	MedDRA version 21.1	Systematic Assessment	EG0001 events1 affected80 at risk EG0012 events2 affected179 at risk EG0020 events0 affected90 at risk
BACK PAIN	Musculoskeletal and connective tissue disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0010 events0 affected179 at risk EG0021 events1 affected90 at risk
MUSCULAR WEAKNESS	Musculoskeletal and connective tissue disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0012 events2 affected179 at risk EG0021 events1 affected90 at risk
ATAXIA	Nervous system disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
CEREBROVASCULAR ACCIDENT	Nervous system disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0012 events2 affected179 at risk EG0020 events0 affected90 at risk
COGNITIVE DISORDER	Nervous system disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
DIZZINESS	Nervous system disorders	MedDRA version 21.1	Systematic Assessment	EG0001 events1 affected80 at risk EG0010 events0 affected179 at risk EG0020 events0 affected90 at risk
ENCEPHALOPATHY	Nervous system disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
GUILLAIN-BARRE SYNDROME	Nervous system disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
METABOLIC ENCEPHALOPATHY	Nervous system disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
NONINFECTIVE ENCEPHALITIS	Nervous system disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
SYNCOPE	Nervous system disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0012 events2 affected179 at risk EG0020 events0 affected90 at risk
TRANSIENT ISCHAEMIC ATTACK	Nervous system disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
CONFUSIONAL STATE	Psychiatric disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
DELIRIUM	Psychiatric disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0021 events1 affected90 at risk
SUICIDE ATTEMPT	Psychiatric disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
ACUTE KIDNEY INJURY	Renal and urinary disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
NEPHRITIS	Renal and urinary disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
STERILE PYURIA	Renal and urinary disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
VAGINAL HAEMORRHAGE	Reproductive system and breast disorders	MedDRA version 21.1	Systematic Assessment	EG0001 events1 affected80 at risk EG0010 events0 affected179 at risk EG0020 events0 affected90 at risk
DYSPNOEA	Respiratory, thoracic and mediastinal disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0012 events1 affected179 at risk EG0021 events1 affected90 at risk
HYPOXIA	Respiratory, thoracic and mediastinal disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
PLEURAL EFFUSION	Respiratory, thoracic and mediastinal disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0021 events1 affected90 at risk
PNEUMONITIS	Respiratory, thoracic and mediastinal disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0021 events1 affected90 at risk
PNEUMOTHORAX	Respiratory, thoracic and mediastinal disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
RASH	Skin and subcutaneous tissue disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
HYPOTENSION	Vascular disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0011 events1 affected179 at risk EG0020 events0 affected90 at risk
PELVIC VENOUS THROMBOSIS	Vascular disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG0010 events0 affected179 at risk EG0021 events1 affected90 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
ANAEMIA	Blood and lymphatic system disorders	MedDRA version 21.1	Systematic Assessment	EG0009 events8 affected80 at risk EG00128 events25 affected179 at risk EG0025 events5 affected90 at risk
THROMBOCYTOPENIA	Blood and lymphatic system disorders	MedDRA version 21.1	Systematic Assessment	EG0002 events2 affected80 at risk EG00110 events10 affected179 at risk EG0020 events0 affected90 at risk
ABDOMINAL PAIN	Gastrointestinal disorders	MedDRA version 21.1	Systematic Assessment	EG00027 events21 affected80 at risk EG00134 events30 affected179 at risk EG00219 events13 affected90 at risk
ABDOMINAL PAIN UPPER	Gastrointestinal disorders	MedDRA version 21.1	Systematic Assessment	EG0002 events2 affected80 at risk EG0013 events3 affected179 at risk EG0028 events7 affected90 at risk
CONSTIPATION	Gastrointestinal disorders	MedDRA version 21.1	Systematic Assessment	EG00019 events17 affected80 at risk EG00141 events33 affected179 at risk EG00212 events11 affected90 at risk
DIARRHOEA	Gastrointestinal disorders	MedDRA version 21.1	Systematic Assessment	EG00059 events30 affected80 at risk EG001200 events115 affected179 at risk EG00223 events17 affected90 at risk
DRY MOUTH	Gastrointestinal disorders	MedDRA version 21.1	Systematic Assessment	EG0004 events4 affected80 at risk EG0019 events9 affected179 at risk EG0022 events2 affected90 at risk
DYSPEPSIA	Gastrointestinal disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG00110 events10 affected179 at risk EG0022 events2 affected90 at risk
NAUSEA	Gastrointestinal disorders	MedDRA version 21.1	Systematic Assessment	EG00013 events12 affected80 at risk EG00193 events67 affected179 at risk EG00223 events19 affected90 at risk
PROCTALGIA	Gastrointestinal disorders	MedDRA version 21.1	Systematic Assessment	EG0004 events4 affected80 at risk EG0012 events2 affected179 at risk EG0020 events0 affected90 at risk
STOMATITIS	Gastrointestinal disorders	MedDRA version 21.1	Systematic Assessment	EG00021 events13 affected80 at risk EG00118 events18 affected179 at risk EG0020 events0 affected90 at risk
VOMITING	Gastrointestinal disorders	MedDRA version 21.1	Systematic Assessment	EG00010 events9 affected80 at risk EG00179 events52 affected179 at risk EG00215 events13 affected90 at risk
ASTHENIA	General disorders	MedDRA version 21.1	Systematic Assessment	EG00022 events17 affected80 at risk EG00154 events37 affected179 at risk EG00219 events12 affected90 at risk
CHEST PAIN	General disorders	MedDRA version 21.1	Systematic Assessment	EG0004 events4 affected80 at risk EG0015 events5 affected179 at risk EG0022 events2 affected90 at risk
CHILLS	General disorders	MedDRA version 21.1	Systematic Assessment	EG0004 events4 affected80 at risk EG00115 events14 affected179 at risk EG0025 events4 affected90 at risk
FACE OEDEMA	General disorders	MedDRA version 21.1	Systematic Assessment	EG0000 events0 affected80 at risk EG00112 events10 affected179 at risk EG0020 events0 affected90 at risk
FATIGUE	General disorders	MedDRA version 21.1	Systematic Assessment	EG00046 events38 affected80 at risk EG00175 events65 affected179 at risk EG00228 events24 affected90 at risk
MUCOSAL INFLAMMATION	General disorders	MedDRA version 21.1	Systematic Assessment	EG0008 events6 affected80 at risk EG00119 events16 affected179 at risk EG0026 events4 affected90 at risk
OEDEMA PERIPHERAL	General disorders	MedDRA version 21.1	Systematic Assessment	EG0003 events3 affected80 at risk EG00132 events27 affected179 at risk EG0029 events8 affected90 at risk
PYREXIA	General disorders	MedDRA version 21.1	Systematic Assessment	EG00025 events20 affected80 at risk EG00167 events53 affected179 at risk EG00213 events12 affected90 at risk
UPPER RESPIRATORY TRACT INFECTION	Infections and infestations	MedDRA version 21.1	Systematic Assessment	EG0004 events3 affected80 at risk EG0016 events4 affected179 at risk EG0026 events6 affected90 at risk
URINARY TRACT INFECTION	Infections and infestations	MedDRA version 21.1	Systematic Assessment	EG0008 events4 affected80 at risk EG00110 events8 affected179 at risk EG0022 events2 affected90 at risk
ALANINE AMINOTRANSFERASE INCREASED	Investigations	MedDRA version 21.1	Systematic Assessment	EG0006 events5 affected80 at risk EG00117 events10 affected179 at risk EG0025 events5 affected90 at risk
ASPARTATE AMINOTRANSFERASE INCREASED	Investigations	MedDRA version 21.1	Systematic Assessment	EG0008 events7 affected80 at risk EG00127 events16 affected179 at risk EG0028 events6 affected90 at risk
BLOOD ALKALINE PHOSPHATASE INCREASED	Investigations	MedDRA version 21.1	Systematic Assessment	EG0001 events1 affected80 at risk EG00114 events14 affected179 at risk EG00211 events8 affected90 at risk
BLOOD BILIRUBIN INCREASED	Investigations	MedDRA version 21.1	Systematic Assessment	EG0007 events4 affected80 at risk EG0013 events3 affected179 at risk EG0022 events2 affected90 at risk
BLOOD CREATINE PHOSPHOKINASE INCREASED	Investigations	MedDRA version 21.1	Systematic Assessment	EG0005 events3 affected80 at risk EG00139 events22 affected179 at risk EG0020 events0 affected90 at risk
BLOOD CREATININE INCREASED	Investigations	MedDRA version 21.1	Systematic Assessment	EG0006 events5 affected80 at risk EG0013 events3 affected179 at risk EG0020 events0 affected90 at risk
BLOOD THYROID STIMULATING HORMONE INCREASED	Investigations	MedDRA version 21.1	Systematic Assessment	EG0004 events4 affected80 at risk EG0015 events3 affected179 at risk EG0023 events3 affected90 at risk
LIPASE INCREASED	Investigations	MedDRA version 21.1	Systematic Assessment	EG0007 events6 affected80 at risk EG00110 events9 affected179 at risk EG0022 events1 affected90 at risk
WEIGHT DECREASED	Investigations	MedDRA version 21.1	Systematic Assessment	EG00018 events17 affected80 at risk EG0019 events8 affected179 at risk EG0027 events7 affected90 at risk
DECREASED APPETITE	Metabolism and nutrition disorders	MedDRA version 21.1	Systematic Assessment	EG00040 events34 affected80 at risk EG00157 events49 affected179 at risk EG00227 events21 affected90 at risk
HYPOCALCAEMIA	Metabolism and nutrition disorders	MedDRA version 21.1	Systematic Assessment	EG0005 events5 affected80 at risk EG0017 events7 affected179 at risk EG0022 events2 affected90 at risk
HYPOKALAEMIA	Metabolism and nutrition disorders	MedDRA version 21.1	Systematic Assessment	EG0004 events3 affected80 at risk EG00117 events14 affected179 at risk EG0021 events1 affected90 at risk
HYPOPHOSPHATAEMIA	Metabolism and nutrition disorders	MedDRA version 21.1	Systematic Assessment	EG0007 events7 affected80 at risk EG00111 events11 affected179 at risk EG0023 events3 affected90 at risk
ARTHRALGIA	Musculoskeletal and connective tissue disorders	MedDRA version 21.1	Systematic Assessment	EG0006 events5 affected80 at risk EG00114 events14 affected179 at risk EG0028 events8 affected90 at risk
BACK PAIN	Musculoskeletal and connective tissue disorders	MedDRA version 21.1	Systematic Assessment	EG00010 events8 affected80 at risk EG00121 events17 affected179 at risk EG00215 events13 affected90 at risk
MUSCLE SPASMS	Musculoskeletal and connective tissue disorders	MedDRA version 21.1	Systematic Assessment	EG0006 events6 affected80 at risk EG0013 events3 affected179 at risk EG0020 events0 affected90 at risk
MUSCULOSKELETAL PAIN	Musculoskeletal and connective tissue disorders	MedDRA version 21.1	Systematic Assessment	EG0004 events4 affected80 at risk EG0015 events5 affected179 at risk EG0022 events2 affected90 at risk
MYALGIA	Musculoskeletal and connective tissue disorders	MedDRA version 21.1	Systematic Assessment	EG00010 events7 affected80 at risk EG00112 events9 affected179 at risk EG0023 events3 affected90 at risk
PAIN IN EXTREMITY	Musculoskeletal and connective tissue disorders	MedDRA version 21.1	Systematic Assessment	EG0008 events6 affected80 at risk EG00116 events12 affected179 at risk EG0026 events6 affected90 at risk
DIZZINESS	Nervous system disorders	MedDRA version 21.1	Systematic Assessment	EG0003 events3 affected80 at risk EG00112 events10 affected179 at risk EG0020 events0 affected90 at risk
HEADACHE	Nervous system disorders	MedDRA version 21.1	Systematic Assessment	EG00012 events10 affected80 at risk EG00121 events17 affected179 at risk EG00211 events11 affected90 at risk
INSOMNIA	Psychiatric disorders	MedDRA version 21.1	Systematic Assessment	EG0003 events3 affected80 at risk EG0019 events9 affected179 at risk EG0026 events6 affected90 at risk
COUGH	Respiratory, thoracic and mediastinal disorders	MedDRA version 21.1	Systematic Assessment	EG00010 events8 affected80 at risk EG00135 events33 affected179 at risk EG00212 events12 affected90 at risk
DYSPHONIA	Respiratory, thoracic and mediastinal disorders	MedDRA version 21.1	Systematic Assessment	EG00027 events19 affected80 at risk EG0010 events0 affected179 at risk EG0021 events1 affected90 at risk
DYSPNOEA	Respiratory, thoracic and mediastinal disorders	MedDRA version 21.1	Systematic Assessment	EG00013 events13 affected80 at risk EG00141 events36 affected179 at risk EG00212 events12 affected90 at risk
EPISTAXIS	Respiratory, thoracic and mediastinal disorders	MedDRA version 21.1	Systematic Assessment	EG0007 events7 affected80 at risk EG0019 events9 affected179 at risk EG0020 events0 affected90 at risk
OROPHARYNGEAL PAIN	Respiratory, thoracic and mediastinal disorders	MedDRA version 21.1	Systematic Assessment	EG0006 events5 affected80 at risk EG0018 events7 affected179 at risk EG0022 events2 affected90 at risk
DERMATITIS ACNEIFORM	Skin and subcutaneous tissue disorders	MedDRA version 21.1	Systematic Assessment	EG0002 events2 affected80 at risk EG00156 events46 affected179 at risk EG0023 events2 affected90 at risk
DRY SKIN	Skin and subcutaneous tissue disorders	MedDRA version 21.1	Systematic Assessment	EG0001 events1 affected80 at risk EG00114 events14 affected179 at risk EG0023 events3 affected90 at risk
ERYTHEMA	Skin and subcutaneous tissue disorders	MedDRA version 21.1	Systematic Assessment	EG0005 events5 affected80 at risk EG0013 events2 affected179 at risk EG0020 events0 affected90 at risk
PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME	Skin and subcutaneous tissue disorders	MedDRA version 21.1	Systematic Assessment	EG00070 events42 affected80 at risk EG0013 events3 affected179 at risk EG0021 events1 affected90 at risk
PRURITUS	Skin and subcutaneous tissue disorders	MedDRA version 21.1	Systematic Assessment	EG0002 events2 affected80 at risk EG00125 events22 affected179 at risk EG0023 events3 affected90 at risk
RASH	Skin and subcutaneous tissue disorders	MedDRA version 21.1	Systematic Assessment	EG00019 events17 affected80 at risk EG001122 events85 affected179 at risk EG0028 events8 affected90 at risk
RASH MACULO-PAPULAR	Skin and subcutaneous tissue disorders	MedDRA version 21.1	Systematic Assessment	EG0003 events3 affected80 at risk EG00112 events11 affected179 at risk EG0021 events1 affected90 at risk
HYPERTENSION	Vascular disorders	MedDRA version 21.1	Systematic Assessment	EG00031 events25 affected80 at risk EG00110 events9 affected179 at risk EG0026 events4 affected90 at risk

ID	Term
D007414	Intestinal Neoplasms
D005770	Gastrointestinal Neoplasms
D004067	Digestive System Neoplasms
D009371	Neoplasms by Site
D009369	Neoplasms
D004066	Digestive System Diseases
D005767	Gastrointestinal Diseases
D003108	Colonic Diseases
D007410	Intestinal Diseases
D012002	Rectal Diseases

ID	Title	Description
BG000	Regorafenib	Participants received regorafenib 160 milligrams (mg) orally once daily on Days 1 to 21 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.
BG001	Cobimetinib + Atezolizumab	Participants received cobimetinib 60 mg orally on Days 1 to 21 plus atezolizumab 840 mg IV on Day 1 and Day 15 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.
BG002	Atezolizumab	Participants received atezolizumab monotherapy 1200 mg intravenous (IV) on Day 1 in a 21-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.
BG003	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Regorafenib	Participants received regorafenib 160 milligrams (mg) orally once daily on Days 1 to 21 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.	62	90	19	90	78	80
EG001	Cobimetinib + Atezolizumab	Participants received cobimetinib 60 mg orally on Days 1 to 21 plus atezolizumab 840 mg IV on Day 1 and Day 15 in a 28-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.	136	183	71	183	173	179
EG002	Atezolizumab	Participants received atezolizumab monotherapy 1200 mg intravenous (IV) on Day 1 in a 21-day cycle until disease progression according to RECIST Version 1.1, unacceptable toxicity, death, participant's or physician decision to withdraw, or pregnancy, whichever occurs first.	72	90	15	90	81	90