Neratinib Plus T-DM1 for HER2-Positive BC With Molecular Residual Disease

The circulating tumor DNA (ctDNA)-based detection of molecular residual disease (MRD) may identify patients who are at higher risk for relapse and therefore are candidates for treatment intensification to mitigate this risk. In this context, addition of the irreversible HER2 tyrosine kinase inhibitor (TKI) neratinib to standard trastuzumab emtansine (T-DM1) in the adjuvant setting is being evaluated as an MRD-directed interception strategy in patients with HER2-positive breast cancer (BC) with MRD positivity.

The KAN-HER2 MRD trial (NCT05388149) is a multicenter, investigator-initiated, open-label, single-arm, phase 2 trial that is evaluating the addition of neratinib to standard T-DM1 in patients with MRD-positive disease. Inclusion criteria are patients ≥18 years old with histologically confirmed, resected HER2-positive stage I-III BC, with evidence of residual invasive disease following prior neoadjuvant trastuzumab-based chemotherapy (+/- pertuzumab) or while receiving 2 to 6 cycles of adjuvant T-DM1. Exclusion criteria include prior therapy with any HER2 TKI and evidence of suspected or confirmed metastatic disease. MRD is detected using a tumor-informed assay (NeoGenomics RaDaR) in patients following neoadjuvant therapy or 2 to 6 cycles of adjuvant T-DM1. Eligible patients with evidence of MRD will receive neratinib in addition to standard T-DM1 at the previously determined recommended phase 2 combination dose of 160 mg/day, in continuous cycles.

The primary end point is the rate of ctDNA clearance at 12 weeks after treatment initiation; secondary end points include MRD rates and their clinical correlates, invasive-disease-free survival, and safety. Correlative studies will be performed on samples collected from diagnostic biopsies, residual disease, and peripheral blood of enrolled patients.

The estimated enrollment is 15 patients. Enrollment in the study was initiated at the first trial site (Princess Margaret Cancer Centre, Toronto, Ontario, Canada) in December 2022. The estimated study completion date is July 2025.

Source:

Elliott M, Antrás JF, Echelard P, et al. 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). Abstract presented at: ASCO Annual Meeting, June 2-6, 2023; Chicago, IL. Abstract TPS620.