A Study of Multiple Immunotherapy-Based Treatment Combinations in Hormone Receptor (HR)-Positive Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Breast Cancer

This study is designed to evaluate the efficacy, safety, and pharmacokinetics of several immunotherapy-based combination treatments in participants with inoperable locally advanced or metastatic HR-positive, HER2-negative breast cancer who have progressed during or following treatment with a cyclin-dependent kinase (CDK) 4/6 inhibitor in the first- or second-line setting, such as palbociclib, ribociclib, or abemaciclib. The study will be performed in two stages. During Stage 1, participants will be randomized to fulvestrant (control) or an atezolizumab-containing doublet or triplet combination. Those who experience disease progression, loss of clinical benefit, or unacceptable toxicity may be eligible to receive a new triplet combination treatment in Stage 2 until loss of clinical benefit or unacceptable toxicity. New treatment arms may be added and/or existing treatment arms may be closed during the course of the study on the basis of ongoing clinical efficacy and safety as well as the current treatments available.


Eligibility Criteria:
Inclusion Criteria for Both Stages:

* Measurable disease per RECIST v1.1
* Adequate hematologic and end organ function
* Disease progression during or after first- or second-line hormonal therapy with CDK4/6 inhibitor

Inclusion Criteria for Stage 1:

* Eastern Cooperative Oncology Group (ECOG) performance status 0-1
* Metastatic or inoperable, locally advanced, histologically or cytologically confirmed invasive HR-positive HER2-negative breast cancer
* Recommended for endocrine therapy, and cytotoxic chemotherapy not indicated at study entry
* Recurrence or progression following most recent systemic breast cancer therapy
* Disease progression during or after first- or second-line hormonal therapy for locally advanced or metastatic disease
* Postmenopausal according to protocol-defined criteria
* Life expectancy \>3 months
* Available tumor specimen for determination of PD-L1 status

Inclusion Criteria for Stage 2:

* ECOG performance status of 0-2
* Ability to initiate treatment within 3 months after disease progression or unacceptable toxicity on a Stage 1 regimen

Exclusion Criteria for Both Stages:

* Significant or uncontrolled comorbid disease as specified in the protocol
* Uncontrolled tumor-related pain
* Autoimmune disease except for stable/controlled hypothyroidism, Type 1 diabetes mellitus, or certain dermatologic conditions
* Positive human immunodeficiency virus test
* Active hepatitis B or C
* Active tuberculosis
* Severe infection within 4 weeks and/or antibiotics within 2 weeks prior to study treatment
* Prior allogeneic stem cell or solid organ transplantation
* History of malignancy other than breast cancer within 2 years prior to screening except those with negligible risk of metastasis/death
* History of or known hypersensitivity to study drug or excipients
* For patients entering Stage 2, recovery from all immunotherapy-related adverse events to Grade 1 or better or to baseline at the time of consent

Exclusion Criteria for Stage 1:

* Prior fulvestrant or cytotoxic chemotherapy for metastatic breast cancer, or certain other agents as specified in the protocol
* Unresolved AEs from prior anti-cancer therapy
* Eligibility only for the control arm
* Prior treatment with inhibitors as specified in the protocol

Exclusion Criteria for Stage 2:

* Unacceptable toxicity with atezolizumab during Stage 1
* Uncontrolled cardiovascular disease or coagulation disorder, including use of anticoagulants as specified in the protocol
* Significant abdominal or intestinal manifestations within 6 months prior to treatment
* Grade 2 or higher proteinuria