318TiP - Neoadjuvant trastuzumab, pertuzumab and tucatinib without chemotherapy in stage II-III HER2-positive breast cancer: The TRAIN-4 study

Background

Neoadjuvant treatment with chemotherapy and dual anti-HER2 directed agents results in high rates of pathologic complete responses in HER2+ breast cancer. However, toxicity is substantial and earlier reports suggest that a subset of patients can be treated without chemotherapy. Tucatinib is an orally available selective HER2 tyrosine kinase inhibitor that is effective in advanced HER2+ breast cancer. This study evaluates the safety and feasibility of a chemotherapy-free neoadjuvant regimen consisting of trastuzumab, pertuzumab and tucatinib.

Trial design

The TRAIN-4 study is a single-center, non-randomized, non-comparative phase 1b study in patients with stage II-III breast cancer with strong membranous HER2 3+ staining on immunohistochemistry. Patients start neoadjuvant treatment with trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks), pertuzumab (loading dose 840 mg, followed by 420 mg every 3 weeks) and tucatinib (300 mg twice daily). Response monitoring with DCE-MRI and (18)F-FDG PET scan takes place after three cycles. In case of functional tumor volume decrease on MRI of at least 65% (responders), patients continue to a maximum of nine cycles. In case of insufficient response (FTV<65%; non-responders), patients switch to receive six cycles of paclitaxel, carboplatin, trastuzumab and pertuzumab. After completion of neoadjuvant treatment, patients undergo surgery. Adjuvant treatment will be selected according to the local treatment protocol, including chemotherapy in case of residual disease. The primary endpoint is incidence and severity of all grade adverse events until 30 days after last study treatment administration. Feasibility, defined as the proportion of patients without disease progression until surgery, and pathological complete response rates in responders and non-responders, are main secondary study parameters. If feasible, a larger comparative study will follow to compare this regimen to the standard of care neoadjuvant treatment. The feasibility and accuracy of DCE-MRI and (18)F-FDG PET scan to predict a pathological complete response will help to select the most optimal imaging modality for the comparative trial.

Clinical trial identification

NCT06162559, release date 08-12-2023.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Seagen, now a wholly owned subsidiary of Pfizer Inc.

Disclosure

C.P. Schröder: Financial Interests, Institutional, Research Funding: Pfizer, Seagen, Siemens, Gilead, Dutch Cancer Society. R.M. Mann: Financial Interests, Institutional, Research Funding: Siemens Healthineers, Bayer Healthcare, Beckton & Dickinson, Screenpoint Medical, Koning, Lunit, PA Imaging, The Dutch Research Council, European Research Council, Dutch Cancer Society, European Union, EFRO/OP-Oost; Non-Financial Interests, Personal, Advisory Board: European Radiology; Non-Financial Interests, Personal, Other, Associate editor for breast imaging of the Radiology journal: Radiology journal; Non-Financial Interests, Personal, Member, Member of the scientific committee: European Society of Radiology; Non-Financial Interests, Personal, Member, Chair working group for diagnostics: Dutch Breast Cancer Research Group; Non-Financial Interests, Personal, Member of Board of Directors: European Society of Breast Imaging. G.S. Sonke: Financial Interests, Institutional, Research Funding: Agendia, AstraZeneca, Merck, Novartis, Roche, Seagen. All other authors have declared no conflicts of interest.