Immune checkpoint inhibitors given in monotherapy in advanced breast cancer have shown modest benefit in first-line, but very limited efficacy in later lines. Thus, combination therapies are needed.

Response following anti-PD1/PD-L1 monotherapy is associated with large survival benefit in the advanced setting.

Previous studies of the intrinsic subtypes have shown that Basal-like and HER2-E are associated with higher expression of immune-related genes or higher infiltration of stromal tumor infiltrating lymphocytes compared to the luminal subtypes. Immune infiltration in BC is associated with chemo/antiHER2 responsiveness and potentially benefit from anti-PD-1/PD-L1 inhibitors.

In addition, one emerging biomarker of response to anti-PD-1 therapy is the tumor mutational burden (I.e. the total number of mutations per coding area of a tumor genome). The HER2-E and Basal-like profiles have been associated with high mutational burden.

A range of studies have been initiated including several phase II/III studies evaluating atezolizumab in combination with different chemotherapeutic compounds routinely used in breast cancer, but none with predefined biomarker beyond the expression of PD-L1 by IHC

Inclusion Criteria:

• Male or female (Premenopausal or postmenopausal women)
• ECOG 0 to 2
• Histologically confirmed adenocarcinoma of the breast, metastatic or unresectable locally advanced.
• All patients must have received at least trastuzumab and other anti-HER2 ADCs (including but not limited to T-DM1).
• Measurable disease according to RECIST 1.1 criteria.
• Adequate organ function
• Baseline LVEF ≥50%
• Participants with asymptomatic brain metastases are eligible.

Exclusion Criteria:

• Treatment with any investigational anticancer drug within 14 days of the start of study treatment.
• Patient has received Vinorelbine or any other vinca alkaloids previously immediately prior to initiate study treatment.
• History of other malignant tumors in the past 3 years
• Known or suspected leptomeningeal disease (LMD)/ poorly controlled (> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to brain metastases.
• Symptomatic hypercalcemia requiring treatment with bisphosphonates in the 14 days prior to inclusion
• Cardiopulmonary dysfunction
• Any other severe, uncontrolled
• Major surgery in the 28 days prior to enrolment
• Infection with HIV or active Hepatitis B and/or Hepatitis C.
• History of trastuzumab intolerance, including grade 3-4 infusion reaction or hypersensitivity.
• Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab formulation
• History of autoimmune disease,
• Prior allogeneic stem cell or solid organ transplantation
• History of idiopathic pulmonary fibrosis, drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest CT scan. (Note: History of radiation pneumonitis in the radiation field [fibrosis] is permitted.)
• Active tuberculosis
• Receipt of a live, attenuated vaccine within 4 weeks prior to enrollment
• Prior treatment with CD137 agonists, anti-PD-1, or anti-PD-L1 therapeutic antibody or immune checkpoint targeting agents
• Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin [IL]-2) within 4 weeks or five half-lives of the drug prior to enrolment
• Treatment with systemic immunosuppressive medications within 2 weeks prior to enrolment, or anticipated requirement for systemic immunosuppressive medications during the trial.