This is a single center, non-blinded, multi-cohort, non-comparative phase II trial to study the safety and efficacy of tiragolumab with atezolizumab and/or ipilimumab in advanced triple-negative breast cancer.

Programmed cell death protein 1 (PD1) -blockade is currently being approved for the neoadjuvant treatment of early TNBC as well as for first-line treatment in combination with chemotherapy for patients with Programmed cell death-ligand 1 (PD-L1) -positive TNBC with metastatic disease. However, response rates are modest, responses are not always durable and PD-L1 is a suboptimal biomarker to select patients for this regimen. Therefore, the overarching goal of this TONIC-3 study is to develop novel immunomodulatory strategies for patients with advanced TNBC making use state-of-the-art research tools to better understand the underlying cancer-immune interactions of this disease

Inclusion Criteria:

• Metastatic or incurable locally advanced triple negative breast cancer with confirmation of Estrogen receptor (ER) and Human Epidermal growth factor Receptor 2 (HER2) negativity (ER <10%, HER2 IHC 0, 1+ or 2+ with no amplification) on a histological biopsy of a metastatic lesion
• Patients with PD-L1 negative disease determined using the Combined Positivity Score (CPS<10) (Dako 22C3 IHC) OR previously treated with anti-PD(L)1 in the (neo)adjuvant or metastatic setting (irrespective of PD-L1 status).
• Metastatic lesion accessible for histological biopsy
• 18 years or older
• World Health Organisation (WHO) performance status of 0 or 1
• Maximum of three lines of chemotherapy, including antibody-drug conjugates and Poly-ADP Ribose Polymerase (PARP)-inhibitors, for metastatic disease and with evidence of progression of disease
• Measurable or evaluable disease according to RECIST1.1
• Disease Free Interval (defined as time between first diagnosis or locoregional recurrence and first metastasis) longer than 1 year. This does not apply to patients with de novo metastatic disease or patients who did not receive (neo)adjuvant chemotherapy.
• Adequate bone marrow, kidney and liver function

Exclusion Criteria:

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris
• Symptomatic brain metastases (subjects with asymptomatic brain metastases are eligible if these are free of progression for at least 4 weeks)
• History of leptomeningeal disease localization
• History of having received other anticancer therapies within 2 weeks of start of the study drug
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
• Known hypersensitivy to Chinese hamster ovary cell products or to any component of the atezolizumab or tiragolumab formulation
• History of immunodeficiency, autoimmune disease, conditions requiring immunosuppression (>10 mg daily prednisone equivalents) or chronic infections.
• Prior treatment with an anti-CTLA4 or anti-TIGIT antibody.
• Administration of live vaccine within 30 days of planned start of study therapy.
• Active other cancer
• Positive test for hepatitis B, hepatitis C, HIV and/or Epstein Barr virus (EBV)
• History of uncontrolled serious medical or psychiatric illness
• Current pregnancy pregnancy or breastfeeding.