Translational breast cancer research – Theodoros Foukakis' Group

A Randomized Trial of Trastuzumab Deruxtecan and Biology-Driven Selection of Neoadjuvant Treatment for HER2-positive Breast Cancer: ARIADNE

Background

Around 15-20 percent of breast cancers are characterized by the overexpression of human epidermal growth factor receptor 2 (HER2) protein on the surface of the cancer cells. With the advancements in treatment and the advent of effective anti-HER2 targeted therapies, the prognosis of HER2-positive breast cancer has improved markedly. Neoadjuvant therapy is the standard of care for HER2-positive breast cancer, and includes treatment with docetaxel, carboplatin, trastuzumab and pertuzumab. An advantage of neoadjuvant therapy is that the effect can be evaluated at an early stage and allows for change of treatment or additional treatment after surgery. Novel antibody-drug conjugates (ADC) show high efficacy and tolerable side-effect profiles in the treatment of metastatic HER2-positive breast cancer. Trastuzumab deruxtecan (T-DXd) is an ADC that is composed of a humanized monoclonal antibody specifically targeting HER2, with the same amino acid sequence as trastuzumab, a cleavable tetrapeptide-based linker, and a potent topoisomerase I inhibitor as the cytotoxic drug. 

While escalating therapy with currently available agents is not likely to further improve outcomes of patients with HER2-positive breast cancer due to the already excellent patient survival, the next evolutionary step should be to carefully de-escalate therapy while simultaneously avoiding undertreating patients. The aim of the ARIADNE study is to employ biology-driven stratification for tailored neoadjuvant therapy, both according to underlying biology and to response to therapy. As such, both de-escalation and escalation are integrated and strictly predefined. The use of a potent ADC (T-DXd) and careful patient selection may lead to both higher efficacy and a more tolerable toxicity profile.

About ARIADNE

ARIADNE is an academic, international, open label, randomized and comparative phase IIB trial. A total of 370 patients with non-metastatic HER2-positive breast cancer and an indication for neoadjuvant therapy will be included and randomized 1:1 to receive either i) a taxane, carboplatin, trastuzumab and pertuzumab for three cycles or ii) trastuzumab deruxtecan (T-DXd) for three cycles. Further treatment is based on the intrinsic molecular subtype determined in a pretreatment biopsy by the Prosigna® assay: HER2-enriched (approx 65%) patients continue with the same treatment for three more cycles. Estrogen receptor (ER) positive and luminal (approx 25%) patients receive trastuzumab and pertuzumab for three cycles, combined with letrozole and ribociclib for two cycles. ER-negative and luminal or basal-like (approx 10%) patients either continue with the same treatment for three more cycles in case of radiologic complete response, or in 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 (pCR) at the molecularly HER2-enriched population, defined as ypT0/Tis, ypN0, as determined by a pathologist blinded to treatment assignment (intention-to-treat analysis).  A key secondary objective and endpoint is the discovery of biomarkers of response/resistance to administered neoadjuvant therapy at the protein, RNA and DNA levels in both tumor tissue and blood/plasma.

Objectives

Primary objective

• To compare, in terms of locally assessed pathologic complete remission (pCR) rates, standard neoadjuvant therapy versus trastuzumab deruxtecan (T-DXd) monotherapy in patients with molecularly Human Epidermal Growth Factor Receptor 2 (HER2)-enriched and clinically HER2-positive, non-metastatic breast cancer.

Key secondary objectives

• To perform translational studies on clinicopathologic factors and the tissues or peripheral blood for the discovery of prognostic or predictive biomarkers which are relevant to the treatments in the trial. 
• To compare, in terms of locally assessed pCR rates, the two patient groups of the initial randomization of molecularly unselected patients between standard and experimental therapy, regardless of administered therapy beyond cycle 3.

Other secondary objectives

•    To investigate the pCR rates for patients with HER2-positive, but non-HER2-enriched breast cancer, who will receive sequential combinations of T-DXd and either ribociclib combined with endocrine therapy and dual HER2-blockade for Estrogen Receptor (ER) positive and molecularly luminal cancers (de-escalated, chemotherapy-free regimen) or response-adjusted therapy for normal-like, basal-like or ER-negative and luminal cancers (escalated therapy). 

•    Efficacy measures for the comparison of standard and experimental treatment, both time-to-event (relapse-free, distant disease-free and overall survival) and short-term endpoints (pathologic response according to residual cancer burden [RCB], rates of complete radiologic response).

•    To evaluate the effect of standard and experimental treatment in the type of surgery performed in the breast and the axilla 

•    To evaluate patient reported outcomes (PRO) measures for health-related quality of life in the two treatment arms. 

•    To evaluate the safety and tolerability of the two treatments arms 

Endpoints

Primary endpoint

• Locally assessed rate of pCR at the molecularly HER2-enriched population, defined as ypT0/Tis, ypN0, as determined at the surgical specimen by a pathologist blinded to treatment assignment (intention-to-treat analysis). 

Key secondary endpoints

• Locally assessed rate of pCR, defined as ypT0/Tis, ypN0, at the two patient groups of the initial randomization of TCHP versus T-DXd, regardless of administered therapy after cycle 3 
• Event-free survival (EFS), defined as time from randomization to disease progression, breast cancer relapse, contralateral breast cancer, other malignant neoplasms, or death by any cause, for each molecular group, including the comparison of TCHP versus TDXd in HER2-enriched patients, and at the two patient groups of the initial randomization of TCHP versus T-DXd 
• Discovery of biomarkers of response/resistance to administered neoadjuvant therapy at the protein, RNA and DNA levels in both tumor tissue and blood/plasma, as described in detail in section 9.

Patient selection criteria

Key inclusion criteria

• Age ≥ 18
• HER2-positive breast cancer (IHC 3+ or 2+ and ISH ratio ≥2)
• cT2N0 or any cT with positive nodal status (TNM 8^th edition)
• LVEF ≥ 50%
• ECOG PS 0-1
• Adequate liver, kidney and marrow function
• Availability of tumor and blood samples

Key exclusion criteria

• Presence of distant metastases
• Participation in other interventional trials
• History of other cancer during the past 5 years
• Any history of invasive breast cancer
• Active cardiac disease
• Patients with ER+ breast cancer under chronic treatment with strong CYP3A inhibitors or inducers
• Lung comorbidities as defined in the protocol
• Cardiac comorbidities as defined in the protocol