NOvel Immunotherapy Strategies for Advanced Triple Negative Breast Cancer (TNBC) Patients: TONIC-3 Trial

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

• Tiragolumab (Drug): 600mg every 3 weeks (Q3W)
• Atezolizumab (Drug), also known as Tecentriq: 1200mg every 3 weeks (Q3W)
• Ipilimumab (Drug), also known as Yervoy: 1 mg/kg, maximum of 4 cycles

Primary outcomes

• PFS-12 [Assessed at 12 weeks]: Progression-free survival rate as measured by the proportion of patients free of progression after 12-weeks of treatment
• Incidence of adverse events [Assessed until 90 days after the last dose of study treatment or until initiation of new anti-cancer therapy, whichever occurs first]: Number of patients with adverse events as measured according to CTCAE v5.0

Secondary outcomes

• Objective response rate [Assessed at week 6, week 12 and every 12 weeks thereafter; assessed up to 120 months]: Complete response or partial response according to Response Evaluation Criteria in Solid Tumours in cancer immunotherapy trials (iRECIST) and Response Evaluation Criteria in Solid Tumours (RECIST version 1.1)
• Clinical benefit rate [Assessed at week 6, week 12 and every 12 weeks thereafter; assessed up to 120 months]: Complete response, partial response or stable disease for at least 24 weeks according to iRECIST and RECIST1.1
• Progression-free survival [Assessed at week 6, week 12 and every 12 weeks thereafter; median 12 months]: Time from randomization to data of first tumor progression
• Overall survival [Assessed monthly until date of death; median 12 months]: Time from therapy initiation to death from any cause

Sex: All, ages: 18 Years to any

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.

• Marleen Kok, MD, Principal investigator, Antoni van Leeuwenhoek