156TiP Impact of neoadjuvant immunotherapy in early stage breast cancer before standard therapy (BIS-Program)

Immune checkpoint inhibitors (ICIs) are one of the major therapeutic advances in cancer treatment. Anti-PD(L)1 ICIs have been shown to improve progression-free survival and OS, in patients with metastatic triple-negative breast cancer (TNBC), and pCR and event-free survival in patients with early TNBC. Nevertheless, some patients treated with anti-PD(L)1 ICIs experience recurrence or do not achieve sustained clinical benefit. Expanding the efficacy and therapeutic target of currently available ICIs is an area of high unmet need. Several targeted agents (e.g. anti-VEGF, PI3KCA or AKT inhibitors) have been shown to impact the tumor-immune microenvironment (TIME) by influencing aspects of the immune response. Preclinical evidence supports the notion that AKT/VEGF inhibition can enhance anti-PDL1/PD1 efficacy through its effect on the TIME. BIS Program is a window of opportunity trial designed to evaluate the biological effects of immunotherapy-based treatment combinations in patients (pts) with stage I-III, untreated, HER2-positive (HER2+)or TNBC that are eligible for upfront surgery or neoadjuvant systemic treatment (NST). The study, which will recruit 210 pts(147 in the TNBC cohort and 63 in the HER2+ cohort), builds on an adaptive, open, prospective randomized model that aims to determine whether short-treatment immunotherapy increases the level of activated GzmB+/CD8+ T cells between baseline and post-treatment samples. In the TNBC Cohort: pts are randomized 1:2:2:2 to observation, Atezolizumab (Atz), Atz + Ipatasertib or Atz + Bevacizumab; in the HER2+ cohort: pts are randomized 1:2 to observation or Atz + Trastuzumab + Pertuzumab. Primary endpoint: Two-fold increase in GzmB+/CD8+ T cell levels from baseline to post-study treatment samples. Secondary objectives: Effect of study treatment on pCR, immune biomarkers, and immune-related gene expression. Two FFPE and one frozen sample are collected at (1) the time of enrollment and (2)following surgical treatment in those who undergo upfront surgery or dedicated biopsy after study treatment in those who undergo NST. Blood samples will be collected at the time of enrollment, before surgery or the start of NST, and at the end of the study visit. NCT05180006. Gustave Roussy, Cancer Campus, Grand Paris. This research collaboration was supported through the imCORE network on behalf of F. Hoffmann-La Roche.