155TiP A randomised phase II trial of neoadjuvant multi-agent chemotherapy (CHT) OR patritumab deruxtecan (HER3-DXd; U3-1402) +/- endocrine therapy (ET) for high-risk hormone receptor-positive (HR+/HER2-) early breast cancer (EBC): SOLTI-2103 VALENTINE trial

The decision of neoadjuvant treatment for high-risk HR+/HER2- EBC remains a challenge. Despite the availability of both CHT and ET, the risk of recurrence persists over time, highlighting the need for additional therapeutic strategies. In the TOT-HER3 trial, we have shown that a single dose of HER3-DXd, a first-in-class HER3 directed antibody drug conjugate, is associated with clinical response, increased immune infiltration and proliferation suppression, as well as a consistent and manageable safety profile in patients (pts) with HR+/HER2-negative early breast cancer (Prat et al. ESMO Breast 2022). These data have informed the design of the VALENTINE trial of HER3-DXd in the neoadjuvant setting. VALENTINE is a parallel, exploratory, three-arm, randomised, open-label, exploratory study in pts with primary operable HR+/HER2-negative breast cancer with Ki67 IHC ≥ 20% and/or high genomic risk (defined by gene signature), aiming to evaluate the clinical benefit and biological effects of HER3-DXd (with/without letrozole (LET)) as a neoadjuvant treatment. A total of 120 treatment naïve pts will be randomly assigned in a 2:2:1 ratio to receive (1) HER3-DXd (5.6 mg/kg) every 21 days for 6 cycles; (2) HER3-DXd plus daily LET +/- LHRH analogs every 21 days for 6 cycles; (3) standard of care CHT consisting of 4 cycles of EC/AC (epirubicin 90 mg/m2 or doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 14/21 days) followed by weekly 80mg/m2 paclitaxel during 12 weeks. The primary endpoint is the rate of pathological complete response (ypT0/is ypN0) at surgery. Baseline, on-treatment (C2D1), and surgical specimens will be collected for molecular characterization and evaluation of response (ERBB3 gene expression, HER3 IHC; CelTIL change, research-based PAM50 subtypes). Additional samples for pharmacokinetic, genomic and circulating biomarkers will also be collected. Secondary endpoints include rate of residual cancer burden, overall response rate, invasive disease-free survival at 3 and 5 years and safety. An interim and final analysis are pre-planned. EudraCT 2022-001181-36. NCT05569811, First Posted: February 18, 2021. SOLTI Cancer Research Group. Daiichi Sankyo Inc.