A Study to Evaluate the Efficacy and Safety of Trastuzuma... | NCT02924883

ID	Type	Description	Link
2015-004189-27	EudraCT Number

Label	Type	Description	Intervention Names
Trastuzumab Emtansine + Atezolizumab	Experimental	Atezolizumab 1200 milligrams (mg) intravenous (IV) infusion or matching Placebo followed by trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor (approximately 29 months)	Drug: Atezolizumab Drug: Trastuzumab emtansine Other: Placebo
Trastuzumab Emtansine + Placebo	Active Comparator	Placebo matched to atezolizumab followed by trastuzumab emtansine 3.6 mg/kg IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the sponsor (approximately 29 months)	Drug: Trastuzumab emtansine Other: Placebo

Name	Type	Description	Arm Group Labels	Other Names
Atezolizumab	Drug	Atezolizumab 1200 mg IV infusion	Trastuzumab Emtansine + Atezolizumab

Measure	Description	Time Frame
Progression-Free Survival (PFS) as Determined by Investigator's Tumor Assessment Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1)	PFS was defined as the time from randomization to the first occurrence of disease progression or death from any cause, whichever occurred first, on the basis of investigator assessments. Progression was defined as at least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 millimeter (mm) or the appearance of one or more new lesions.	Baseline up to approximately 15 months
Percentage of Participants With Adverse Events	An adverse event is any untoward medical occurrence in a participant 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.	Baseline up to study completion, approximately 40 months

Measure	Description	Time Frame
Overall Survival (OS)	OS was defined as the time from randomization to death from any cause.	Baseline up to study completion or death, whichever occurs first, approximately 40 months
Percentage of Participants With Objective Response (OR) as Determined by Investigator's Tumor Assessment Using RECIST v1.1

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Archival tumor samples must be obtained from primary and/or metastatic sites
Able to submit tumor tissue that is evaluable for programmed death- ligand 1 (PD-L1) expression
HER-2 positive BC as defined by an immunohistochemistry score of 3 or gene amplified by in-situ hybridization as defined by a ratio of greater than or equal to (>=) 2.0 for the number of HER2 gene copies to the number of chromosome 17 copies
Histologically or cytologically confirmed invasive BC: incurable, unresectable, locally advanced BC previously treated with multimodality therapy or metastatic BC
Prior treatment for BC in the: adjuvant; unresectable locally advanced; or metastatic settings; which must include both, a taxane and trastuzumab (alone or in combination with another agent)
Progression must have occurred during or after most recent treatment for locally advanced/metastatic BC or within 6 months after completing adjuvant therapy
Participants must have measurable disease that is evaluable as per RECIST v1.1
Eastern Cooperative Oncology Group Performance Status of 0 or 1
Negative serum pregnancy test within 7 days of enrollment for pre-menopausal women and for women less than 12 months after the onset of menopause
Use of highly effective method of contraception as defined by the protocol

Exclusion Criteria:

Prior treatment with trastuzumab emtansine, cluster of differentiation 137 agonists, anti-programmed death-1, or anti-PD-L1 therapeutic antibody or pathway-targeting agents
Receipt of any anti-cancer drug/biologic or investigational treatment within 21 days prior to Cycle 1 Day 1 except hormone therapy, which can be given up to 7 days prior to Cycle 1 Day 1; recovery of treatment related toxicity consistent with other eligibility criteria
Radiation therapy within 2 weeks prior to Cycle 1, Day 1
History of exposure to the cumulative doses of anthracyclines
History of other malignancy within the previous 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage I uterine cancer, or participants who have undergone potentially curative therapy with no evidence of disease and are deemed by the treating physician to be at low risk for recurrence
Cardiopulmonary dysfunction, symptomatic pleural effusion, pericardial effusion, or ascites
Participants with severe infection within 4 weeks prior to randomization, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
Current severe, uncontrolled systemic disease
Major surgical procedure or significant traumatic injury within 28 days prior to randomization or anticipation of the need for major surgery during the course of study treatment
Clinically significant history of liver disease, including cirrhosis, current alcohol abuse, autoimmune hepatic disorders, sclerosis cholangitis or active infection with human immunodeficiency virus, hepatitis B virus, or hepatitis C virus
Need for current chronic corticosteroid therapy (>=10 mg of prednisone per day or an equivalent dose of other anti-inflammatory corticosteroids)
Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for greater than (>) 2 weeks prior to randomization
Participants with known central nervous system disease
Leptomeningeal disease
History of autoimmune disease
Prior allogeneic stem cell or solid organ transplantation
Active tuberculosis
Receipt of a live, attenuated vaccine within 4 weeks prior to randomization or anticipation that such a live, attenuated vaccine will be required during the study
Treatment with systemic immunostimulatory agents within 4 weeks or five half-lives of the drug (whichever is shorter) prior to randomization
Treatment with systemic corticosteroids or other systemic immunosuppressive medications within 2 weeks prior to randomization, or anticipated requirement for systemic immunosuppressive medications during the trial
Participants who are breastfeeding, or intending to become pregnant during the study

Name	Affiliation	Role
Clinical Trials	Hoffmann-La Roche	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Breastlink Med Group Inc		Orange	California	92868	United States
University of Colorado

PubMed Identifier	Type	Citation	Retractions
33002436	Derived	Emens LA, Esteva FJ, Beresford M, Saura C, De Laurentiis M, Kim SB, Im SA, Wang Y, Salgado R, Mani A, Shah J, Lambertini C, Liu H, de Haas SL, Patre M, Loi S. Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): a phase 2, multicentre, randomised, double-blind trial. Lancet Oncol. 2020 Oct;21(10):1283-1295. doi: 10.1016/S1470-2045(20)30465-4.

ID	Title	Description
FG000	Trastuzumab Emtansine + Atezolizumab	Atezolizumab 1200 milligrams (mg) intravenous (IV) infusion followed by trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor (up to study duration of approximately 40 months)

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Aug 9, 2017	Dec 9, 2018

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

Progression-Free Survival (PFS) as Determined by Investigator's Tumor Assessment Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1)

PFS was defined as the time from randomization to the first occurrence of disease progression or death from any cause, whichever occurred first, on the basis of investigator assessments. Progression was defined as at least a 20% increase in the sum of diameters of target lesions with an absolute increase of at least 5 millimeter (mm) or the appearance of one or more new lesions.

The intent-to-treat (ITT) population included all randomized participants grouped according to the treatment assigned at randomization.

Posted

Median

95% Confidence Interval

months

Baseline up to approximately 15 months

ID	Title	Description
OG000	Trastuzumab Emtansine + Placebo	Placebo matched to atezolizumab followed by trastuzumab emtansine 3.6 mg/kg IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the sponsor (up to study duration of approximately 40 months)
OG001	Trastuzumab Emtansine + Atezolizumab	Atezolizumab 1200 milligrams (mg) intravenous (IV) infusion followed by trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor (up to study duration of approximately 40 months)

Units	Counts
Participants	OG00069 OG001133

Title

Denominators

Categories

Title	Measurements
	OG0006.8(4.0 to 11.1) OG0018.2(5.8 to 10.7)

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		Log Rank	The 2-sided log-rank test, was stratified by world region (Western Europe vs U.S. vs Rest of World) and PD-L1 status (IC 0 vs IC 1/2/3).	0.3332		Hazard Ratio (HR)	0.82				95	0.55	1.23					Superiority

Primary

Percentage of Participants With Adverse Events

An adverse event is any untoward medical occurrence in a participant 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.

The safety analysis population consisted of all participants who received at least one dose of study drug. Safety analyses were based on the treatment that participants actually received.

Posted

Number

percentage of participants

Baseline up to study completion, approximately 40 months

ID	Title	Description
OG000	Trastuzumab Emtansine + Placebo	Placebo matched to atezolizumab followed by trastuzumab emtansine 3.6 mg/kg IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the sponsor (up to study duration of approximately 40 months)
OG001	Trastuzumab Emtansine + Atezolizumab	Atezolizumab 1200 milligrams (mg) intravenous (IV) infusion followed by trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor (up to study duration of approximately 40 months)

Secondary

Overall Survival (OS)

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

The ITT population included all randomized participants grouped according to the treatment assigned at randomization.

Posted

Median

95% Confidence Interval

Months

Baseline up to study completion or death, whichever occurs first, approximately 40 months

ID	Title	Description
OG000	Trastuzumab Emtansine + Placebo	Placebo matched to atezolizumab followed by trastuzumab emtansine 3.6 mg/kg IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the sponsor (up to study duration of approximately 40 months)
OG001	Trastuzumab Emtansine + Atezolizumab	Atezolizumab 1200 milligrams (mg) intravenous (IV) infusion followed by trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor (up to study duration of approximately 40 months)

Units	Counts
Participants

Secondary

Percentage of Participants With Objective Response (OR) as Determined by Investigator's Tumor Assessment Using RECIST v1.1

An OR was defined as a complete or partial response determined on 2 consecutive occasions ≥ 4 weeks apart using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete response was defined as the disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must be < 10 mm on the short axis. Partial response was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum. Participants who had no post-baseline tumor assessment were counted as non-responders.

The ITT population included all randomized participants grouped according to the treatment assigned at randomization. In Participants with baseline measurable disease were considered for OR. In the atezolizumab arm, one patient was not ORR evaluable.

Posted

Number

Percentage of participants

Baseline up to approximately 15 months

ID	Title	Description
OG000	Trastuzumab Emtansine + Placebo	Placebo matched to atezolizumab followed by trastuzumab emtansine 3.6 mg/kg IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the sponsor (up to study duration of approximately 40 months)
OG001	Trastuzumab Emtansine + Atezolizumab	Atezolizumab 1200 milligrams (mg) intravenous (IV) infusion followed by trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor (up to study duration of approximately 40 months)

Secondary

Duration of OR as Determined by Investigator's Tumor Assessment Using RECIST v1.1

Duration of OR was defined as the time from the first tumor assessment that was judged to indicate that the patient had an objective response to the time of first documented disease progression using RECIST v1.1 per investigator assessment or death from any cause, whichever occurred first.

The ITT population included all randomized participants grouped according to the treatment assigned at randomization. Participants with OR were considered for duration of OR.

Posted

Median

95% Confidence Interval

Months

Baseline up to approximately 15 months

ID	Title	Description
OG000	Trastuzumab Emtansine + Placebo	Placebo matched to atezolizumab followed by trastuzumab emtansine 3.6 mg/kg IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the sponsor (up to study duration of approximately 40 months)
OG001	Trastuzumab Emtansine + Atezolizumab	Atezolizumab 1200 milligrams (mg) intravenous (IV) infusion followed by trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor (up to study duration of approximately 40 months)

Secondary

Maximum Serum Concentration (Cmax) of Trastuzumab Emtansine

Average post infusion Trastuzumab Emtansine concentration

PK population included all participants who received at least one dose of trastuzumab emtansine with at least one post-dose concentration data point.

Posted

Geometric Mean

Geometric Coefficient of Variation

ug/mL

Pre-infusion (0 hour [h]), 30 minutes (min) after end of infusion (EOI) (over 90 min) on Day 1 Cycles 1 and 4; pre-infusion (0 h) on Day 1 Cycle 2 (each cycle = 21 days); at any time during study treatment/early discontinuation visit (approx. 40 months)

ID	Title	Description
OG000	Trastuzumab Emtansine + Atezolizumab	Atezolizumab 1200 milligrams (mg) intravenous (IV) infusion followed by trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor (up to study duration of approximately 40 months)
OG001	Trastuzumab Emtansine + Placebo	Placebo matched to atezolizumab followed by trastuzumab emtansine 3.6 mg/kg IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the sponsor (up to study duration of approximately 40 months)

Secondary

Cmax of Deacetyl Mercapto 1-Oxopropyl Maytansine (DM1)

Average post infusion Deacetyl Mercapto 1-Oxopropyl Maytansine concentration of trastuzumab emtansine infusion

PK population included all participants who received at least one dose of trastuzumab emtansine with at least one post-dose concentration data point.

Posted

Geometric Mean

Geometric Coefficient of Variation

ng/mL

Pre-infusion (0 h) on Day 1 Cycle 1 and 30 min after EOI (over 90 min) on Day 1 Cycles 1 and 4 (each cycle = 21 days)

ID	Title	Description
OG000	Trastuzumab Emtansine + Placebo	Placebo matched to atezolizumab followed by trastuzumab emtansine 3.6 mg/kg IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the sponsor (up to study duration of approximately 40 months)
OG001	Trastuzumab Emtansine + Atezolizumab	Atezolizumab 1200 milligrams (mg) intravenous (IV) infusion followed by trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor (up to study duration of approximately 40 months)

Secondary

Cmax of Total Trastuzumab

PK population included all participants who received at least one dose of trastuzumab emtansine with at least one post-dose concentration data point.

Posted

Geometric Mean

Geometric Coefficient of Variation

ug/mL

Pre-infusion (0 h), 30 min after EOI (over 90 min) on Day 1 Cycles 1 and 4; pre-infusion (0 h) on Day 1 Cycle 2 (each cycle = 21 days)

ID	Title	Description
OG000	Trastuzumab Emtansine + Placebo	Placebo matched to atezolizumab followed by trastuzumab emtansine 3.6 mg/kg IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the sponsor (up to study duration of approximately 40 months)
OG001	Trastuzumab Emtansine + Atezolizumab	Atezolizumab 1200 milligrams (mg) intravenous (IV) infusion followed by trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor (up to study duration of approximately 40 months)

Units	Counts
Participants

Secondary

Cmax of Atezolizumab

Average post infusion atezolizumab concentration

PK population included all participants who received at least one dose of trastuzumab emtansine with at least one post-dose concentration data point.

Posted

Geometric Mean

Geometric Coefficient of Variation

ug/mL

Pre-infusion (0 h), 30 min after EOI (over 60 min) on Day 1 Cycles 1 and 4; pre-infusion (0 h) on Day 1 Cycles 2, 3, 8, and every 8 cycles thereafter (each cycle=21 days) up to 120 days after treatment completion/early discontinuation (approx. 40 months)

ID	Title	Description
OG000	Trastuzumab Emtansine + Atezolizumab	Atezolizumab 1200 milligrams (mg) intravenous (IV) infusion followed by trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor (up to study duration of approximately 40 months)

Units	Counts
Participants	OG000

Secondary

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

ATAs are antibodies that inactivate the therapeutic effects of Atezolizumab. Patients are considered to be ATA positive if they are ATA negative at baseline but develop an ATA response following study drug administration (treatment-induced ATA response), or if they are ATA positive at baseline and the titer of one or more post-baseline samples is at least 4-fold greater (i.e., ≥ 0.60 titer units) than the titer of the baseline sample (treatment-enhanced ATA response).

The analysis population included a patient with an ATA assay result from at least one post-baseline sample.

Posted

Number

Percentage of participants

Pre-infusion (0 h) on Day 1 Cycles 1, 2, 3, 4, 8, and every 8 cycles thereafter (each cycle = 21 days) up to 120 days after treatment completion or early discontinuation (approximately 40 months)

ID	Title	Description
OG000	Trastuzumab Emtansine + Atezolizumab	Atezolizumab 1200 milligrams (mg) intravenous (IV) infusion followed by trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor (up to study duration of approximately 40 months)

Units	Counts
Participants

Secondary

Percentage of Participants With ATAs to Trastuzumab Emtansine

ATAs are antibodies that inactivate the therapeutic effects of Trastuzumab Emtansine. Patients are considered to be ATA positive if they are ATA negative at baseline but develop an ATA response following study drug administration (treatment-induced ATA response), or if they are ATA positive at baseline and the titer of one or more post-baseline samples is at least 4-fold greater (i.e., ≥ 0.60 titer units) than the titer of the baseline sample (treatment-enhanced ATA response).

The analysis population included a patient with an ATA assay result from at least one post-baseline sample

Posted

Number

Percentage of Participants

Pre-infusion (0 h) on Day 1 Cycles 1 and 4 (each cycle = 21 days); and at any time during study treatment/early discontinuation visit (approximately 40 months)

ID	Title	Description
OG000	Trastuzumab Emtansine + Placebo	Placebo matched to atezolizumab followed by trastuzumab emtansine 3.6 mg/kg IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the sponsor (up to study duration of approximately 40 months)
OG001	Trastuzumab Emtansine + Atezolizumab	Atezolizumab 1200 milligrams (mg) intravenous (IV) infusion followed by trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor (up to study duration of approximately 40 months)

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Pneumonia	Infections and infestations	MedDRA v22.1	Systematic Assessment	EG0004 events4 affected133 at risk EG0011 events1 affected67 at risk
Appendicitis	Infections and infestations	MedDRA v22.1	Systematic Assessment	EG0000 events0 affected133 at risk EG0011 events1 affected67 at risk
Influenza	Infections and infestations	MedDRA v22.1	Systematic Assessment	EG0002 events2 affected133 at risk EG0010 events0 affected67 at risk
Vomiting	Gastrointestinal disorders	MedDRA v22.1	Systematic Assessment	EG0003 events3 affected133 at risk EG0010 events0 affected67 at risk
Nausea	Gastrointestinal disorders	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0011 events1 affected67 at risk
Colitis	Gastrointestinal disorders	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Constipation	Gastrointestinal disorders	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Enteritis	Gastrointestinal disorders	MedDRA v22.1	Systematic Assessment	EG0000 events0 affected133 at risk EG0011 events1 affected67 at risk
Pneumonitis	Respiratory, thoracic and mediastinal disorders	MedDRA v22.1	Systematic Assessment	EG0002 events2 affected133 at risk EG0011 events1 affected67 at risk
Asthma	Respiratory, thoracic and mediastinal disorders	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Pneumothorax	Respiratory, thoracic and mediastinal disorders	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA v22.1	Systematic Assessment	EG0002 events2 affected133 at risk EG0010 events0 affected67 at risk
Anaemia	Blood and lymphatic system disorders	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Seizure	Nervous system disorders	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0011 events1 affected67 at risk
Dehydration	Metabolism and nutrition disorders	MedDRA v22.1	Systematic Assessment	EG0000 events0 affected133 at risk EG0011 events1 affected67 at risk
Vertigo	Ear and labyrinth disorders	MedDRA v22.1	Systematic Assessment	EG0000 events0 affected133 at risk EG0011 events1 affected67 at risk
Disseminated intravascular coagulation	Blood and lymphatic system disorders	MedDRA v22.1	Systematic Assessment	EG0000 events0 affected133 at risk EG0011 events1 affected67 at risk
Atrial thrombosis	Cardiac disorders	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Cardiac failure	Cardiac disorders	MedDRA v22.1	Systematic Assessment	EG0000 events0 affected133 at risk EG0011 events1 affected67 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA v22.1	Systematic Assessment	EG0000 events0 affected133 at risk EG0012 events2 affected67 at risk
Intra-abdominal haemorrhage	Gastrointestinal disorders	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Asthenia	General disorders	MedDRA v22.1	Systematic Assessment	EG0000 events0 affected133 at risk EG0011 events1 affected67 at risk
Fatigue	General disorders	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Influenza like illness	General disorders	MedDRA v22.1	Systematic Assessment	EG0002 events2 affected133 at risk EG0011 events1 affected67 at risk
Malaise	General disorders	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Non-cardiac chest pain	General disorders	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Pyrexia	General disorders	MedDRA v22.1	Systematic Assessment	EG00012 events10 affected133 at risk EG0010 events0 affected67 at risk
Haemophagocytic lymphohistiocytosis	Immune system disorders	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Abscess jaw	Infections and infestations	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Breast cellulitis	Infections and infestations	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Catheter site infection	Infections and infestations	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Device related infection	Infections and infestations	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Infectious pleural effusion	Infections and infestations	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Lower respiratory tract infection	Infections and infestations	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Respiratory tract infection	Infections and infestations	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Sepsis	Infections and infestations	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0012 events2 affected67 at risk
Soft tissue infection	Infections and infestations	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Urinary tract infection	Infections and infestations	MedDRA v22.1	Systematic Assessment	EG0003 events3 affected133 at risk EG0015 events2 affected67 at risk
Hip fracture	Injury, poisoning and procedural complications	MedDRA v22.1	Systematic Assessment	EG0000 events0 affected133 at risk EG0011 events1 affected67 at risk
Lower limb fracture	Injury, poisoning and procedural complications	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Subdural haemorrhage	Injury, poisoning and procedural complications	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Alanine aminotransferase increased	Investigations	MedDRA v22.1	Systematic Assessment	EG0003 events3 affected133 at risk EG0010 events0 affected67 at risk
Aspartate aminotransferase increased	Investigations	MedDRA v22.1	Systematic Assessment	EG0003 events3 affected133 at risk EG0010 events0 affected67 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Osteonecrosis of jaw	Musculoskeletal and connective tissue disorders	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA v22.1	Systematic Assessment	EG0000 events0 affected133 at risk EG0011 events1 affected67 at risk
Pathological fracture	Musculoskeletal and connective tissue disorders	MedDRA v22.1	Systematic Assessment	EG0000 events0 affected133 at risk EG0011 events1 affected67 at risk
Cancer pain	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Hepatic adenoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Uterine leiomyoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Brain oedema	Nervous system disorders	MedDRA v22.1	Systematic Assessment	EG0002 events2 affected133 at risk EG0010 events0 affected67 at risk
Cerebral haemorrhage	Nervous system disorders	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Encephalopathy	Nervous system disorders	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0011 events1 affected67 at risk
Neuropathy peripheral	Nervous system disorders	MedDRA v22.1	Systematic Assessment	EG0000 events0 affected133 at risk EG0011 events1 affected67 at risk
Confusional state	Psychiatric disorders	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Panic attack	Psychiatric disorders	MedDRA v22.1	Systematic Assessment	EG0000 events0 affected133 at risk EG0011 events1 affected67 at risk
IgA nephropathy	Renal and urinary disorders	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Interstitial lung disease	Respiratory, thoracic and mediastinal disorders	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0010 events0 affected67 at risk
Pleural effusion	Respiratory, thoracic and mediastinal disorders	MedDRA v22.1	Systematic Assessment	EG0001 events1 affected133 at risk EG0011 events1 affected67 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA v22.1	Systematic Assessment	EG00030 events24 affected133 at risk EG0017 events6 affected67 at risk
Neutropenia	Blood and lymphatic system disorders	MedDRA v22.1	Systematic Assessment	EG00021 events13 affected133 at risk EG0014 events4 affected67 at risk
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA v22.1	Systematic Assessment	EG000105 events42 affected133 at risk EG00122 events12 affected67 at risk
Constipation	Gastrointestinal disorders	MedDRA v22.1	Systematic Assessment	EG00038 events29 affected133 at risk EG00115 events10 affected67 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA v22.1	Systematic Assessment	EG00050 events34 affected133 at risk EG00118 events15 affected67 at risk
Dyspepsia	Gastrointestinal disorders	MedDRA v22.1	Systematic Assessment	EG00021 events14 affected133 at risk EG0013 events3 affected67 at risk
Nausea	Gastrointestinal disorders	MedDRA v22.1	Systematic Assessment	EG00084 events51 affected133 at risk EG00137 events29 affected67 at risk
Stomatitis	Gastrointestinal disorders	MedDRA v22.1	Systematic Assessment	EG00021 events13 affected133 at risk EG0012 events2 affected67 at risk
Vomiting	Gastrointestinal disorders	MedDRA v22.1	Systematic Assessment	EG00036 events27 affected133 at risk EG00119 events15 affected67 at risk
Nasopharyngitis	Infections and infestations	MedDRA v22.1	Systematic Assessment	EG00020 events15 affected133 at risk EG0018 events6 affected67 at risk
Fall	Injury, poisoning and procedural complications	MedDRA v22.1	Systematic Assessment	EG00014 events10 affected133 at risk EG0019 events3 affected67 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA v22.1	Systematic Assessment	EG00037 events26 affected133 at risk EG0019 events8 affected67 at risk
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA v22.1	Systematic Assessment	EG00026 events24 affected133 at risk EG00116 events10 affected67 at risk
Dizziness	Nervous system disorders	MedDRA v22.1	Systematic Assessment	EG00018 events18 affected133 at risk EG00110 events9 affected67 at risk
Dysgeusia	Nervous system disorders	MedDRA v22.1	Systematic Assessment	EG0006 events6 affected133 at risk EG0016 events5 affected67 at risk
Headache	Nervous system disorders	MedDRA v22.1	Systematic Assessment	EG00062 events38 affected133 at risk EG00127 events17 affected67 at risk
Paraesthesia	Nervous system disorders	MedDRA v22.1	Systematic Assessment	EG00016 events9 affected133 at risk EG0012 events2 affected67 at risk
Anxiety	Psychiatric disorders	MedDRA v22.1	Systematic Assessment	EG0002 events2 affected133 at risk EG0016 events6 affected67 at risk
Insomnia	Psychiatric disorders	MedDRA v22.1	Systematic Assessment	EG00015 events14 affected133 at risk EG0012 events2 affected67 at risk
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA v22.1	Systematic Assessment	EG00028 events25 affected133 at risk EG00112 events10 affected67 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA v22.1	Systematic Assessment	EG00019 events16 affected133 at risk EG0016 events5 affected67 at risk
Epistaxis	Respiratory, thoracic and mediastinal disorders	MedDRA v22.1	Systematic Assessment	EG00039 events28 affected133 at risk EG00113 events10 affected67 at risk
Pruritus	Skin and subcutaneous tissue disorders	MedDRA v22.1	Systematic Assessment	EG00030 events23 affected133 at risk EG0015 events4 affected67 at risk
Rash	Skin and subcutaneous tissue disorders	MedDRA v22.1	Systematic Assessment	EG00042 events32 affected133 at risk EG00111 events6 affected67 at risk
Hypertension	Vascular disorders	MedDRA v22.1	Systematic Assessment	EG0004 events4 affected133 at risk EG0014 events4 affected67 at risk
Hypothyroidism	Endocrine disorders	MedDRA v22.1	Systematic Assessment	EG00019 events18 affected133 at risk EG0013 events3 affected67 at risk
Dry eye	Eye disorders	MedDRA v22.1	Systematic Assessment	EG00012 events11 affected133 at risk EG0014 events4 affected67 at risk
Lacrimation increased	Eye disorders	MedDRA v22.1	Systematic Assessment	EG0009 events7 affected133 at risk EG0011 events1 affected67 at risk
Vision blurred	Eye disorders	MedDRA v22.1	Systematic Assessment	EG0008 events7 affected133 at risk EG0011 events1 affected67 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA v22.1	Systematic Assessment	EG00020 events17 affected133 at risk EG0013 events3 affected67 at risk
Abdominal pain upper	Gastrointestinal disorders	MedDRA v22.1	Systematic Assessment	EG00010 events10 affected133 at risk EG0018 events3 affected67 at risk
Dry mouth	Gastrointestinal disorders	MedDRA v22.1	Systematic Assessment	EG00023 events22 affected133 at risk EG00110 events9 affected67 at risk
Asthenia	General disorders	MedDRA v22.1	Systematic Assessment	EG00035 events23 affected133 at risk EG0016 events5 affected67 at risk
Chills	General disorders	MedDRA v22.1	Systematic Assessment	EG00027 events19 affected133 at risk EG0018 events6 affected67 at risk
Fatigue	General disorders	MedDRA v22.1	Systematic Assessment	EG00087 events53 affected133 at risk EG00143 events30 affected67 at risk
Influenza like illness	General disorders	MedDRA v22.1	Systematic Assessment	EG00016 events12 affected133 at risk EG0018 events8 affected67 at risk
Mucosal inflammation	General disorders	MedDRA v22.1	Systematic Assessment	EG00021 events16 affected133 at risk EG0011 events1 affected67 at risk
Oedema peripheral	General disorders	MedDRA v22.1	Systematic Assessment	EG0009 events7 affected133 at risk EG0014 events4 affected67 at risk
Pyrexia	General disorders	MedDRA v22.1	Systematic Assessment	EG00072 events44 affected133 at risk EG00118 events12 affected67 at risk
Sinusitis	Infections and infestations	MedDRA v22.1	Systematic Assessment	EG0009 events7 affected133 at risk EG0012 events2 affected67 at risk
Upper respiratory tract infection	Infections and infestations	MedDRA v22.1	Systematic Assessment	EG00028 events18 affected133 at risk EG00112 events9 affected67 at risk
Urinary tract infection	Infections and infestations	MedDRA v22.1	Systematic Assessment	EG00010 events9 affected133 at risk EG00110 events8 affected67 at risk
Alanine aminotransferase increased	Investigations	MedDRA v22.1	Systematic Assessment	EG00044 events31 affected133 at risk EG00118 events13 affected67 at risk
Aspartate aminotransferase increased	Investigations	MedDRA v22.1	Systematic Assessment	EG00056 events40 affected133 at risk EG00119 events14 affected67 at risk
Blood alkaline phosphatase increased	Investigations	MedDRA v22.1	Systematic Assessment	EG00012 events11 affected133 at risk EG0018 events6 affected67 at risk
Gamma-glutamyltransferase increased	Investigations	MedDRA v22.1	Systematic Assessment	EG0007 events7 affected133 at risk EG0012 events2 affected67 at risk
Weight decreased	Investigations	MedDRA v22.1	Systematic Assessment	EG00013 events13 affected133 at risk EG0013 events3 affected67 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA v22.1	Systematic Assessment	EG00052 events30 affected133 at risk EG00114 events12 affected67 at risk
Hypokalaemia	Metabolism and nutrition disorders	MedDRA v22.1	Systematic Assessment	EG00016 events13 affected133 at risk EG0015 events4 affected67 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA v22.1	Systematic Assessment	EG00019 events15 affected133 at risk EG0019 events8 affected67 at risk
Bone pain	Musculoskeletal and connective tissue disorders	MedDRA v22.1	Systematic Assessment	EG0008 events8 affected133 at risk EG0018 events3 affected67 at risk
Muscle spasms	Musculoskeletal and connective tissue disorders	MedDRA v22.1	Systematic Assessment	EG00013 events10 affected133 at risk EG0018 events7 affected67 at risk
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	MedDRA v22.1	Systematic Assessment	EG00012 events10 affected133 at risk EG0016 events6 affected67 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA v22.1	Systematic Assessment	EG00010 events9 affected133 at risk EG0015 events4 affected67 at risk
Neuropathy peripheral	Nervous system disorders	MedDRA v22.1	Systematic Assessment	EG00020 events18 affected133 at risk EG0018 events7 affected67 at risk
Peripheral sensory neuropathy	Nervous system disorders	MedDRA v22.1	Systematic Assessment	EG00011 events11 affected133 at risk EG0016 events5 affected67 at risk
Polyneuropathy	Nervous system disorders	MedDRA v22.1	Systematic Assessment	EG0002 events2 affected133 at risk EG0014 events4 affected67 at risk
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	MedDRA v22.1	Systematic Assessment	EG0008 events7 affected133 at risk EG0011 events1 affected67 at risk
Dry skin	Skin and subcutaneous tissue disorders	MedDRA v22.1	Systematic Assessment	EG00012 events11 affected133 at risk EG0010 events0 affected67 at risk

ID	Term
D009371	Neoplasms by Site
D009369	Neoplasms
D001941	Breast Diseases
D012871	Skin Diseases
D017437	Skin and Connective Tissue Diseases

ID	Term
D008453	Maytansine
D018942	Macrolides
D007783	Lactones
D009930	Organic Chemicals
D047029	Lactams, Macrocyclic
D047028	Macrocyclic Compounds
D011083	Polycyclic Compounds
D000068878	Trastuzumab
D061067	Antibodies, Monoclonal, Humanized
D000911	Antibodies, Monoclonal
D000906	Antibodies
D007136	Immunoglobulins
D007162	Immunoproteins
D001798	Blood Proteins
D011506	Proteins
D000602	Amino Acids, Peptides, and Proteins
D012712	Serum Globulins
D005916	Globulins

ID	Title	Description
BG000	Trastuzumab Emtansine + Atezolizumab	Atezolizumab 1200 milligrams (mg) intravenous (IV) infusion followed by trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor (up to study duration of approximately 40 months)
BG001	Trastuzumab Emtansine + Placebo	Placebo matched to atezolizumab followed by trastuzumab emtansine 3.6 mg/kg IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the sponsor (up to study duration of approximately 40 months)
BG002	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	Trastuzumab Emtansine + Atezolizumab	Atezolizumab 1200 milligrams (mg) intravenous (IV) infusion followed by trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the Sponsor (up to study duration of approximately 40 months)	42	133	52	133	130	133
EG001	Trastuzumab Emtansine + Placebo	Placebo matched to atezolizumab followed by trastuzumab emtansine 3.6 mg/kg IV infusion on Day 1 Cycle 1 and thereafter on Day 1 of each 21-day cycle until disease progression, unmanageable toxicity, or study termination by the sponsor (up to study duration of approximately 40 months)	22	67	16	67	62	67