Neoadjuvant Trastuzumab, Pertuzumab and Tucatinib Without Chemotherapy in HER2-positive Breast Cancer: the TRAIN-4 Study

Neoadjuvant Trastuzumab, Pertuzumab and Tucatinib Without Chemotherapy in HER2-positive Breast Cancer: the TRAIN-4 Study

This is a single-center, phase 1b study evaluating the safety and feasibility of a neoadjuvant treatment with tucatinib, trastuzumab and pertuzumab in stage II-IIIA HER2-positive breast cancer.

High pathological complete response (pCR)-rates are seen using different neoadjuvant chemotherapy schedules with trastuzumab and pertuzumab in HER2-positive stage II - III breast cancer patients. However, a subset of patients with stage II-III HER2-positive breast cancer can be treated with HER2-blockade alone. These patients can potentially be totally spared from chemotherapy-associated toxicity. The proportion of patients whom can successfully be treated without chemotherapy could potentially be increased by selecting great responders using DCE-MRI and by adding tucatinib to trastuzumab and pertuzumab alone. The aim of this study is to evaluate the safety and efficacy of neoadjuvant treatment with tucatinib, trastuzumab and pertuzumab.

Inclusion Criteria:

1. Signed written informed consent

2. Histologically confirmed primary invasive breast cancer

3. Stage II - IIIA primary breast cancer according to TNM-staging (8th edition, AJCC); (largest tumor diameter on DCE-MRI ≥ 2cm (cT2-3) and/or cN1-2 confirmed with FNA or histology)

4. HER2 overexpression defined as circumferential membrane staining that is complete, intense and in >10% of invasive tumor cells (IHC 3+) on pre-treatment biopsy

5. Known estrogen- and progesterone-receptor expression of the invasive tumor

   a. ER-negative or PR-negative is defined as <10% of invasive tumor cell nuclei are immunoreactive in the presence of evidence that the sample can express ER and/or PR

6. WHO performance status 0-1

7. Age ≥ 18 years

8. LVEF ≥50% measured by echocardiography or MUGA

9. Eligible for neoadjuvant treatment

10. Laboratory requirements within 21 days prior to enrollment:

    1. Adequate bone marrow function (ANC ≥1.5 x 109/l, platelets ≥100 x 109/l);
    2. Adequate hepatic function (ALAT, ASAT and bilirubin ≤2.5 times upper limit of normal). Subjects with Gilbert's syndrome may have a total bilirubin ≥2.5 × the ULN range, if no evidence of biliary obstruction exists.
    3. Adequate renal function: creatinine clearance >50 ml/min estimated using the Cockcroft-Gault equation or MDRD equation, or based on a 24-hour urine collection measurement.

Exclusion Criteria:

1. Current pregnancy or breastfeeding
2. Current or previous other malignancy unless treated without systemic therapy and more than five years ago
3. Psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule
4. Use of a strong CYP3A4 or CYP2C8 inhibitor within five half-lives of the inhibitor, or used a strong CYP3A4 or CYP2C8 inducer within five days prior to first dose of study treatment
5. Known chronic liver disease
6. History of inflammatory bowel disease or bowel resection
7. Contraindications for MRI
8. Inflammatory breast cancer, cT4 and/or cN3 tumors
9. Occult breast cancer (cT0)