The SOLTI VALENTINE phase 2 study explored HER3-DXd as a promising treatment for high-risk hormone receptor–positive/HER2-negative early breast cancer, showing the therapy’s ability to induce strong immune responses.
A phase 2 study, SOLTI VALENTINE, is exploring innovative treatment strategies for high-risk hormone receptor (HR)-positive/HER2-negative early breast cancer (EBC). This type of breast cancer is known for its persistent risk of recurrence, even with standard chemotherapy (CT) plus endocrine therapy (ET). The study focuses on HER3-DXd, a first-in-class HER3-directed antibody–drug conjugate that has shown promising results in various breast cancer subtypes. Previous research, such as the SOLTI TOT-HER3 study, demonstrated that a single dose of HER3-DXd could enhance immune cell infiltration and clinical response in HR-positive/HER2-negative EBC patients.
The SOLTI VALENTINE trial is a phase 2, open-label, randomized study that enrolled patients with operable stage II or III high-risk HR-positive/HER2-negative EBC, characterized by a Ki-67 index of at least 20% and/or high genomic risk. Participants were randomly assigned to 1 of 3 treatment arms: HER3-DXd alone, HER3-DXd plus ET, or standard CT. The primary endpoint was the pathologic complete response (pCR) rate at surgery, which indicates the absence of any invasive cancer cells in the breast and lymph nodes. Secondary endpoints include residual cancer burden, overall response rate, changes in CelTIL scores (a measure of immune cell infiltration), safety, invasive disease-free survival, and overall survival.
From November 2022 to September 2023, 122 patients were enrolled; 50 HER3-DXd, 48 HER3-DXd plus ET, and 24 CT patients. Preliminary results from the study show that the pCR rates for all 3 treatment arms were similar, ranging from 2.1% to 4.2%. While these pCR rates are lower than initially anticipated, the study is not powered to formally compare pCR rates among the treatment arms. However, the study did observe a significant increase in CelTIL scores from baseline to cycle 2, day 1 (C2D1) in both HER3-DXd arms, indicating a robust immune response. Furthermore, the change in CelTIL score at C2D1 correlated with radiologic response in the HER3-DXd arms, suggesting that CelTIL could serve as a potential biomarker for treatment response.
Importantly, both HER3-DXd arms demonstrated a lower incidence of grade ≥3 treatment-emergent adverse events (TEAEs) compared with the CT arm. Specifically, the HER3-DXd arms reported a 14% to 14.6% incidence of grade ≥3 TEAEs, while the CT arm had a 45.8% incidence. This suggests that HER3-DXd could provide a more tolerable treatment option for patients with high-risk HR-positive/HER2-negative EBC.
Although the SOLTI VALENTINE trial is still ongoing, the early findings suggest that HER3-DXd, with or without ET, could be a viable alternative to standard CT for patients with high-risk HR-positive/HER2-negative EBC. The therapy’s ability to induce a strong immune response while exhibiting a lower incidence of severe adverse events makes it a promising candidate for further investigation. Ongoing translational analyses, along with the evaluation of long-term survival outcomes, will provide a more comprehensive understanding of HER3-DXd’s efficacy and potential role in the treatment of high-risk HR-positive/HER2-negative early breast cancer.
Oliveira M, et al. Primary results of SOLTI VALENTINE: neoadjuvant randomized phase II trial of HER3-DXd alone or in combination with letrozole for high-risk hormone receptor positive (HR+)/HER2-negative (neg) early breast cancer (EBC). Presented at: San Antonio Breast Cancer Symposium. December 10, 2024; San Antonio, TX. Abstract SESS-3562.