Randomised trial of trastuzumab deruxtecan and biology-driven selection of neoadjuvant treatment for HER2-positive breast cancer: a study protocol of ARIADNE

Abstract

Introduction: Neoadjuvant therapy is the standard of care for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC). Studies on first-generation antibody-drug conjugates, such as trastuzumab emtansine (T-DM1), showed equal or slightly lower efficacy than chemotherapy combined with dual HER2 blockade. Trastuzumab deruxtecan (T-DXd) is a next-generation conjugate approved for the treatment of metastatic HER2-positive and HER2-low BC, with greatly improved efficacy compared to T-DM1.

Methods and analysis: ARIADNE is an academic, international, open-label, randomised, comparative phase IIB trial. A total of 370 patients with non-metastatic HER2-positive BC and an indication for neoadjuvant therapy will be included and randomised 1:1 to receive either (1) docetaxel (or paclitaxel), carboplatin, trastuzumab (H) and pertuzumab (P) for three cycles or (2) T-DXd for three cycles. Further treatment is based on the intrinsic molecular subtype determined by the Prosigna assay: patients with HER2-enriched disease (estimated 60%) continue the same treatment for three more cycles. Patients with oestrogen receptor (ER)-positive and luminal (estimated 30%) disease receive H and P for three cycles, combined with letrozole and ribociclib for two cycles. Patients with ER-negative and luminal, basal-like or normal-like disease (estimated 10%) either continue the same treatment for three more cycles in the case of a radiologic complete response, or, in the case of no complete response, they receive four cycles of dose-dense epirubicin and cyclophosphamide. The primary endpoint of ARIADNE is locally assessed rate of pathologic complete response in the molecularly HER2-enriched population, defined as ypT0/Tis, ypN0, as determined by a pathologist blinded to treatment assignment (intention-to-treat (ITT) analysis). Key secondary endpoints include time-to-event endpoints (event-free, recurrence-free, distant recurrence-free and overall survival), safety, health-related quality of life and translational studies.

Ethics and dissemination: The study has been approved by the Swedish Medical Products Agency (Läkemedelsverket), the Swedish Ethical Review Authority (Etikprövningsmyndigheten) and the Norwegian Ethics Committee for Clinical Trials on Medicinal Products and Medical Devices, as well as by the review boards at all participating centres. Applications for ethical approval in Belgium, the Netherlands and Italy are ongoing. We intend to publish the results of the study in a scientific journal. The study results will be submitted to the European Union (EU) database within 1 year after the end of the clinical trial (CT).

Trial registration number: EU CT registration number: 2022-501504-95-00; ClinicalTrials.gov identifier: NCT05900206.

Keywords: Breast tumours; Clinical trials; Drug Therapy.

Figure 1. Study scheme of the ARIADNE trial. CR, complete response; cT2–4, clinical extent of primary tumour, stage T2–T4; DD, dose-dense; EC, epirubicin and cyclophosphamide; ER, oestrogen receptor; H, trastuzumab; HER2, human epidermal growth factor receptor 2; P, pertuzumab; PAM50, Prediction Analyis of Microarray 50; pCR, pathologic complete response; R, randomization; TCHP, docetaxel, carboplatin, trastuzumab, pertuzumab; T-DM1, trastuzumab emtansine and T-DXd, trastuzumab deruxtecan.

Figure 2. List of study interventions before the start of the treatment, during the treatment and at the follow-up phase. ¹Eastern Cooperative Oncology Group performance status, symptoms, vital signs, oxygen saturation and assessment of primary tumour and regional lymph nodes. ²Haematology, serum chemistry, N-terminal pro brain natriuretic peptide, troponin T. Also FSH, oestradiol (sensitive assay), antimüllerian hormone and pregnancy test 7 days before the start of the study therapy for premenopausal and perimenopausal patients. ³Core biopsy, postcycle 3, is only performed on patients with radiologically residual cancer measuring at least 10 mm according to MRI. ⁴Chest CT scan only for patients who will continue with three additional cycles with trastuzumab deruxtecan. ⁵Breast MRI is optional postcycle. ⁶Pulmonary function tests, including DLCO, are recommended but not obligatory. ⁷ECG is done at baseline and thereafter if clinically indicated. For patients treated with ribociclib, it is performed per local guidelines. ⁸Left Ventricular Ejection Fraction (LVEF) is obtained at baseline, postcycle 6, during the adjuvant phase according to local practice, 1 year postoperatively and 5 years postoperatively. ⁹Patient-reported outcomes (PROs) include the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Instrument QLQ-C30 and the EORTC QLQ-BR23 instrument. PROs are obtained at baseline, after three cycles of NAT, at the end of NAT, 1 year after surgery and 5 years after surgery. aPTT: activated partial thromboplastin time; DLCO: Diffusing Capacity of the Lungs for Carbon Monoxide; INR: international normalized ratio; NAT: neoadjuvant therapy; QLQ-BR23: Breast cancer Quality of Life questionnaire; QLQ-C30: Core Quality of Life questionnaire.