A Study of Trastuzumab Emtansine in Combination With Atezolizumab or Placebo as a Treatment for Participants With Human Epidermal Growth Factor 2 (HER2)-Positive and Programmed Death-ligand 1 (PD-L1)-Positive Locally Advanced (LABC) or Metastatic Breast Cancer (MBC)

Study Overview
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Brief Summary
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This study will evaluate the efficacy, safety and patient-reported outcomes of trastuzumab emtansine plus atezolizumab compared with trastuzumab emtansine plus placebo in participants with HER2-positive and PD-L1-positive LABC or MBC.Participants must have progressed either during or after prior trastuzumab- (+/- pertuzumab) and taxane-based therapy for LABC/MBC; or during (or within 6 months after completing) trastuzumab- (+/-pertuzumab) and taxane-based therapy in the neoadjuvant and/or adjuvant setting.

Official Title
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A Randomized, Multicenter, Double-Blind, Placebo-Controlled Phase III Study of the Efficacy and Safety of Trastuzumab Emtansine in Combination With Atezolizumab or Placebo in Patients With HER2-Positive and PD-L1-Positive Locally Advanced or Metastatic Breast Cancer Who Have Received Prior Trastuzumab- (+/- Pertuzumab) and Taxane-Based Therapy (KATE3)

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: Trastuzumab Emtansine
* Drug: Atezolizumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HER2+ and PD-L1+ locally advanced (LABC) or metastatic breast cancer (MBC) Progression must have occurred during most recent treatment for LABC/MBC or during, or within 6 months after completing, neoadjuvant and/or adjuvant therapy Prior treatment with trastuzumab (+/- pertuzumab) and taxane in the neoadjuvant and/or adjuvant, locally advanced, or metastatic setting No more than two prior lines of therapy in the metastatic setting Measurable disease per RESIST version 1.1 Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Life expectancy >= 6 months Adequate hematologic and end-organ function For women of childbearing potential: agreement to remain abstinent or use contraception, and agreement to refrain from donating eggs For men: agreement to remain abstinent or use contraceptive measures, and agreement to refrain from donating sperm Exclusion Criteria: Prior treatment with trastuzumab emtansine in metastatic setting History of exposure to cumulative doses of anthracyclines Symptomatic or actively progressing central nervous system (CNS) metastases; asymptomatic CNS lesions ≤ 2cm without clinical requirement for local intervention or asymptomatic patients with treated CNS lesions are eligible Current Grade >= 3 peripheral neuropathy Cardiopulmonary dysfunction History of malignancy within 5 years prior to initiation of study treatment, with the exception of the cancer under investigation and malignancies with a negligible risk of metastasis or death History of leptomeningeal disease Active or history of autoimmune disease or immune deficiency Active hepatitis B, hepatitis C and/or tuberculosis Prior allogeneic stem cell or solid organ transplantation Receipt of a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, during treatment, or within 5 months following the last dose of study treatment Pregnancy or lactation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm A: Trastuzumab Emtansine and Placebo<br>Placebo matched to atezolizumab followed by trastuzumab emtansine 3.6 milligrams per kilogram (mg/kg) intravenous (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. | Drug: Trastuzumab Emtansine<br>* Trastuzumab emtansine 3.6 mg/kg IV infusion<br>* Other names: Kadcyla, T-DM1, RO5304020;Other: Placebo<br>* Placebo matched to atezolizumab<br>|
| Experimental: Arm B: Trastuzumab Emtansine and Atezolizumab<br>Atezolizumab 1200 mg IV infusion 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. | Drug: Trastuzumab Emtansine<br>* Trastuzumab emtansine 3.6 mg/kg IV infusion<br>* Other names: Kadcyla, T-DM1, RO5304020;Drug: Atezolizumab<br>* Atezolizumab 1200 mg IV infusion<br>* Other names: Tecentriq, RO5541267, MPDL3280A;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) as Determined by Investigator's Assessment Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 (v1.1) | Following the Sponsor's decision to prematurely terminate the study, no formal testing will be performed and the outcome measure will only be reported in a descriptive way. | Baseline until disease progression, death or end of study (approximately 78 months) | 
| Overall Survival (OS) | Following the Sponsor's decision to prematurely terminate the study, no formal testing will be performed and the outcome measure will only be reported in a descriptive way. | From baseline until death or end of study (approximately 78 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Objective Response Rate (ORR) as Determined by Investigator's Assessment Using RECIST v1.1 |  | Baseline until disease progression, death or end of study (approximately 78 months) | 
| Duration of Objective Response (DOR) as Determined by Investigator Assessment Using RECIST v1.1 |  | Baseline until disease progression, death or end of study (approximately 78 months) | 
| PFS as Determined by a Blinded Independent Central Review Committee Using RECIST v1.1 | Following the Sponsor's decision to prematurely terminate the study, this analysis will not be conducted. | Baseline until disease progression, death or end of study (approximately 78 months) | 
| PFS in Participants with Baseline Brain Metastases as Determined by Investigator Assessment Using RECIST v1.1 |  | Baseline until disease progression, death or end of study (approximately 78 months) | 
| OS in Participants with Baseline Brain Metastases |  | From baseline until death or end of study (approximately 78 months) | 
| Central Nervous System (CNS) PFS as Determined by Investigator Assessment Using RECIST v1.1 in Participants with or Without Baseline CNS Metastases |  | Baseline until disease progression, death or end of study (approximately 78 months) | 
| Mean Absolute Scores in Function (Physical, Role) and Global Health Status (GHS)/Quality of Life (QoL) as Measured by the European Organisation for Research and Treatment of Cancer (EORTC QLQ-C30) | Following the Sponsor's decision to prematurely terminate the study, this analysis will not be conducted. | From Cycle 1 until 3 months after study completion | 
| Mean Change-From-Baseline Scores in Function (Physical, Role) and GHS/QoL as Measured by the EORTC QLQ-C30 | Following the Sponsor's decision to prematurely terminate the study, this analysis will not be conducted. | From Cycle 1 until 3 months after study completion | 
| Percentage of Participants with Clinically Meaningful Deterioration in GHS/QoL Physical, and Role Function as Measured by the EORTC QLQ-C30 | Following the Sponsor's decision to prematurely terminate the study, this analysis will not be conducted. | From Cycle 1 until 3 months after study completion | 
| Percentage of Participants with Adverse Events (AEs) According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0 |  | Baseline up to end of study (approximately 78 months) | 
| Maximum Serum Concentration (Cmax) of Trastuzumab Emtansine | Following the Sponsor's decision to prematurely terminate the study, this outcome measure is no longer applicable. Accordingly, the corresponding analysis will not be performed. | Day 1 of Cycles 1, 2 and 4 (each cycle=21 days) and during study treatment completion/early discontinuation visit (approximately 78 months) | 
| Cmax of Atezolizumab | Following the Sponsor's decision to prematurely terminate the study, this outcome measure is no longer applicable. Accordingly, the corresponding analysis will not be performed. | Day 1 of Cycles 1, 2, 3, 4 and 8 and every 8 cycles thereafter (each cycle=21 days) and during study treatment completion/early discontinuation visit (approximately 78 months) | 
| Percentage of Participants With Anti-Drug Antibodies (ADAs) to Trastuzumab Emtansine | Following the Sponsor's decision to prematurely terminate the study, this outcome measure is no longer applicable. Accordingly, the corresponding analysis will not be performed. | Day 1 of Cycles 1, 2 and 4 (each cycle=21 days) and during study treatment completion/early discontinuation visit (approximately 78 months) | 
| Percentage of Participants With ADAs to Atezolizumab | Following the Sponsor's decision to prematurely terminate the study, this outcome measure is no longer applicable. Accordingly, the corresponding analysis will not be performed. | Day 1 of Cycles 1, 2, 3, 4 and 8 and every 8 cycles thereafter (each cycle=21 days) and during study treatment completion/early discontinuation visit (approximately 78 months) |