A phase II single-arm, open-label trial of T-DM1 (ado-trastuzumab emtansine) and neratinib for HER2-positive breast cancer with molecular residual disease (KAN-HER2 MRD).

Mitchell Elliott Division of Medical Oncology & Hematology, Department of Medicine, Princess Margaret Cancer Centre and University of Toronto, Toronto, ON, Canada info_outline Mitchell Elliott, Jesús Fuentes Antrás, Philippe Echelard, Nicholas Meti, Alisa Nguyen, Michelle Liu, Carolina Sanabria Salas, Christopher Gareth Smith, Moira Katherine Rushton, Lillian L. Siu, Hal K. Berman, Philippe L. Bedard, David W. Cescon

Authors Mitchell Elliott Division of Medical Oncology & Hematology, Department of Medicine, Princess Margaret Cancer Centre and University of Toronto, Toronto, ON, Canada info_outline Mitchell Elliott, Jesús Fuentes Antrás, Philippe Echelard, Nicholas Meti, Alisa Nguyen, Michelle Liu, Carolina Sanabria Salas, Christopher Gareth Smith, Moira Katherine Rushton, Lillian L. Siu, Hal K. Berman, Philippe L. Bedard, David W. Cescon Organizations Division of Medical Oncology & Hematology, Department of Medicine, Princess Margaret Cancer Centre and University of Toronto, Toronto, ON, Canada, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada, Toronto General Hospital Division of Anatomical Pathology, Toronto, ON, Canada, Gerald Bronfman Department of Oncology, St. Mary's Hospital Center, McGill University, Montréal, QC, Canada, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada, Princess Margaret Cancer Centre, Toronto, ON, Canada, Neogenomics Ltd, Babraham Research Park, Cambridge, United Kingdom, The Ottawa Hospital Cancer Centre, Ottawa, ON, Canada, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada, Department of Pathology and Laboratory Medicine, University Health Network, Toronto, ON, Canada, Princess Margaret Cancer Center, University Health Network and University of Toronto, Toronto, ON, Canada Abstract Disclosures Research Funding Other Foundation Ontario Institute for Cancer Research (OICR) Clinical Acceleration Team Award, Princess Margaret Cancer Foundation, Knight therapeutics, NeoGenomics Background: HER2-positive breast cancer is a biologically and clinically aggressive subtype that has historically been associated with poor outcomes, but for which there are now multiple effective targeted therapies. Patients who have residual disease following standard neoadjuvant therapy have an elevated risk of metastatic recurrence. In addition, the detection of circulating tumor DNA (ctDNA) in the adjuvant period is strongly associated with relapse and can further stratify patients with residual disease. The ctDNA-based detection of molecular residual disease (MRD) is an emerging strategy to identify patients for treatment intensification, and may enable the development of novel curative treatment strategies for “recurrence interception”. Preclinical and clinical evidence support the investigation of neratinib, an irreversible inhibitor of the HER2 tyrosine kinase, in combination with standard T-DM1 in the adjuvant setting for patients with HER2-positive breast cancer and evidence of MRD. Methods: KAN-HER2 MRD is a multicentre, investigator-initiated, open label, single arm phase II trial to evaluate the addition of neratinib to standard T-DM1 in patients with detected MRD. Participants with HER2-positive breast cancer and residual disease following neoadjuvant therapy are pre-screened (Part A) for MRD using a tumor-informed assay (NeoGenomics RaDaR). Those with ctDNA detected following 2-6 cycles of adjuvant T-DM1 will proceed to the interventional phase (Part B) where neratinib is added to standard T-DM1 at the previously-determined recommended phase 2 combination dose of 160 mg/day, in continuous cycles. The primary endpoint is the rate of ctDNA clearance at 12 weeks after treatment initiation (ctDNAwk12); the study is designed with a 2-stage approach and has sufficient power to detect a clearance rate of 40%. Secondary endpoints include MRD rates and their clinical correlates, invasive disease free survival (iDFS), and safety. Bio-specimens including diagnostic biopsies, residual disease, and peripheral blood are being collected from all participants for additional correlative studies. Enrolment in Part A was initiated at the first trial site (Princess Margaret Cancer Centre) in December 2022. KAN-HER2 represents the first reported MRD-directed interception trial for HER2-positive breast cancer. Clinical trial information: NCT05388149.