Pre-operative Trial for Breast Cancer With Nivolumab in Combination With Novel IO

Inclusion Criteria:

• Signed written informed consent

• 18 years or older at moment of inclusion;

• Female gender;

• WHO performance status 0 or 1;

• Resectable primary breast cancer stage I-III. Nodal status must be examined byultrasound, fine needle aspiration, sentinel node biopsy, or FDG-PET scan.

• The tumors must be:

• at least 10 mm (minimum cT1c) as determined by MRI

• TNBC defined as ER<10%, HER2-negative OR luminal B defined as ER≥10%,HER2-negative with either Ki67≥20% or PR =<20% OR grade 3. HER2 negative isdefined as an IHC score of <2 or 2+ with a negative ISH.

• For TNBC patients: TIL≥5%

• For LumB breast cancer patients: TIL≥1%

• For cohort 3B: N0 status, TN and TIL ≥50%

• For cohort 4B: N0 status, TNBC and TIL 30-49%

• For cohort 5B: N0 status, TNBC and TIL ≥50% ● Patients withmultifocal/multicentric breast cancer are eligible if triple negative breastcancer histology as well as sufficient TIL percentages (30-49% in cohort 4B, ≥50% in cohort 5B) have been confirmed in all tumor lesions.

Exclusion Criteria:

• evidence or suspicion of metastatic disease. Evaluation of the presence of distantmetastases may include chest X-ray, liver ultrasound, isotope bone-scan, CT-scan ofchest and abdomen and/or FDG-PET scan, according to local procedures;

• evidence of a concurrent contralateral or ipsilateral second primary infiltratingbreast cancer. Evaluation of the presence of a concurrent second primary breastcancer may include mammography, breast ultrasound and/or MRI breast;

• other malignancy except carcinoma in situ and basal-cell and squamous carcinoma ofthe skin, unless the other malignancy was treated ≥5 years ago with curative intentwithout the use of chemotherapy or radiotherapy

• previous radiation therapy or chemotherapy;

• prior treatment with checkpoint inhibitors (including anti- PD1, -PD-L1, -CTLA-4);

• concurrent anti-cancer treatment, neoadjuvant therapy or another investigationaldrug;