Inclusion Criteria:  Age ≥ 18 years old ECOG performance status ≤ 2 Female Diagnosis : histologically or cytologically confirmed HER2-positive tumour status according to the ASCO-CAP guidelines (defined as a 3+ score on immunohistochemistry (IHC) and/or positive by in situ hybridisation (ISH)) with brain metastases, estrogen receptor and progesteron receptor status Cohort 1: with CNS metastases pre-treated with local approaches for the previous CNS events and currently progressive but locally treated CNS metastasis Cohort 2: with a first diagnosis of CNS metastases, asymptomatic or paucisymptomatic not needing immediate local therapy Cohort 3: with confirmed LM defined as the presence of malignant cells in the CSF or combination of typical symptoms and MRI findings Specific criteria for cohorts 1 and 2 only: Must have radiologically confirmed metastatic brain lesion by MRI measurable by RANO-BM criteria Specific criteria for cohort 3 only: LM defined as the presence of malignant cells in the CSF or combination of typical symptoms and MRI findings for cohort 3 Subjects should have received at least 1 previous line for the metastatic disease including taxanes based chemotherapy in combination with trastuzumab and pertuzumab (if available) unless contraindicated. Prior tucatinib is not an exclusion criteria. Corticosteroids may be used as long as subjects are on a stable or decreasing dose for at least 7 days prior to study enrolment Serum pregnancy test (for subjects of childbearing potential) negative within 7 days prior to first neratinib administration Women of childbearing potential must agree to use 1 highly effective or 2 effective methods of contraception (as defined at the protocol section 6.8.1) during the course of the study and at least 7 months after the last administration of study treatment.  Adequate bone marrow function as defined below:  Absolute neutrophil count ≥1500/µL or 1.5x109/L Hemoglobin ≥ 9 g/dL Platelets ≥100000/µL or 100x109/L  Adequate liver function as defined below:  Serum total bilirubin ≤ 1.5 x ULN. In case of known Gilbert's syndrome < 3 x ULN is allowed AST (SGOT)/ALT (SGPT) ≤ 2.5 x ULN (except in case of liver metastases AST/ALT ≤ 5 x ULN)  Adequate renal function as defined below:  • Creatinine ≤ 1.5 x UNL or creatinine clearance >60 mL/min  Signed Informed Consent form (ICF) obtained prior to any study related procedure LVEF > 55% Inclusion criterion applicable to FRANCE only 1)16) Affiliated to the French Social Security System  Exclusion Criteria:  CNS disease requiring immediate neurosurgical intervention (e.g. resection, shunt placement, etc.) Any unresolved toxicity ≥ CTCAE grade 2 (except alopecia) from previous anti-cancer therapy Is ineligible for or has already received all chemotherapy options among the physician's choice Any evidence of severe or uncontrolled systemic disease such as clinically significant cardiovascular, pulmonary, hepatic, renal or metabolic disease Specific criteria for cohort 2 only: Previous local treatment for CNS metastases Specific criteria for cohort 2 only: Oligometastatic disease restricted to the CNS and for which a local treated is considered as the most appropriate treatment by the investigator. Known DPD deficiency* tested by measuring the level of uracil in the blood, or by checking for the presence of certain mutations in the gene for DPD according to EMA recommendation in case investigator's choice is capecitabine Received an investigational anti-cancer drug within four weeks or five half-lives (whichever is shorter) of study drug administration Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of drugs Known HIV, Hepatitis B or Hepatitis C infection Pregnant and/or lactating women Subject with a significant medical, neuro-psychiatric, or surgical condition, currently uncontrolled by treatment, which, in the principal investigator's opinion, may interfere with completion of the study Contra-indication for contrast-enhanced MRI (either hypersensitivity to Gd chelate or absolute contra-indication for MRI such as non compatible cardiac stimulator) * Testing of subjects for DPD deficiency in case of capecitabine is proposed according to local practices Exclusion criterion applicable to FRANCE only Vulnerable persons according to the article L.1121-6 of the Public Health Code, adults who are the subject of a measure of legal protection or unable to express their consent according to article L.1121-8 of the Public Health Code