HER3 belongs to the type I transmembrane tyrosine kinase family of receptors and activates intracellular signaling pathways, mainly the PI3K/AKT and MAPK/ERK pathways, upon dimerization with other HER family members (2, 5)

HER3 belongs to the type I transmembrane tyrosine kinase family of receptors and activates intracellular signaling pathways, mainly the PI3K/AKT and MAPK/ERK pathways, upon dimerization with other HER family members (2, 5). the mRNA-based ERBB3 expression by central assessment. The primary endpoint is a CelTIL score after one single dose. A translational research plan is also included to provide biological information and to evaluate secondary and exploratory objectives of the study. Trial Registration Number: EudraCT 2019-004964-23; NCT number: “type”:”clinical-trial”,”attrs”:”text”:”NCT04610528″,”term_id”:”NCT04610528″NCT04610528. gene, is broadly expressed in various types of human cancer. HER3 has been associated with poor patient outcomes (1) and therapeutic agent resistance, including resistance to anti-EGFR, anti-HER2 inhibitors (2), and endocrine therapy (3, 4). HER3 belongs to the type I transmembrane tyrosine kinase family of receptors and activates intracellular signaling pathways, mainly the PI3K/AKT and MAPK/ERK pathways, upon dimerization with other HER family members (2, 5). These observations have resulted in the development of investigational HER3 directed agents in HER3-expressing breast cancer and other solid tumors. Patritumab deruxtecan (HER3-DXd; U3-1402), a potential first-in-class HER3 directed antibody drug conjugate (ADC), is currently under development to act on these previously mentioned targets (6). In addition to its antitumor efficacy by binding HER3 ligand and the release of the cytotoxic payload in the tumor cells (7), patritumab deruxtecan enhanced the infiltration of innate and adaptive immune cells in preclinical models (8). These preclinical data have shown that patritumab deruxtecan can elicit potent antitumor immunity even in the setting of tumors insensitive to PD-1 and PD-L1 immune checkpoint inhibitors and that its efficacy is more pronounced in the presence of PD-1 inhibition, suggesting that patritumab INCB39110 (Itacitinib) deruxtecan sensitizes insensitive tumors to PD-1 blockade and has synergistic effects (8). In the clinical setting, an early report of a clinical trial suggested that patritumab deruxtecan could be safely administered and it demonstrated promising antitumor efficacy (the overall response and the disease control rate were 42.9 and 90.5%, respectively) in heavily pretreated HER3-expressing metastatic breast cancer (9); these results are in accordance with more recent preliminary data from heavily pretreated EGFR-mutated non-small INCB39110 (Itacitinib) cell lung carcinoma patients, in whom the overall response rate was 25%, and the disease control rate was 70% (10). Although no validated HER3 assay has been established to date, recent studies support the role of HER3 immunohistochemistry (IHC) as a potential biomarker (11C13). However, there are important limitations with IHC-based assays, such as different sensitivities of the antibodies used, their low dynamic range, their subjectivity in scoring, and their difficulty in establishing suitable cut-offs. Therefore, clinical implementation of a robust genomic assay would represent an important advancement. To overcome these limitations, we plan to test the prospective use of an mRNA-based expression assay using the nCounter platform (Nanostring Technologies, Seattle, USA) developed by our group (14). WNT-4 The role of the host immune system in breast cancer is becoming an important topic to study for several reasons. First, the immune response has a fundamental role in the efficacy of drug therapy. In all breast cancer subtypes, baseline high TIL grade is associated with a significantly higher pCR rate after neoadjuvant chemotherapy (15). Second, the recent success of therapeutic agents capable of activating immune responses to cancer, such INCB39110 (Itacitinib) as anti-PD1/PDL1 or anti-CTLA4 inhibitors, allows innovative treatment strategies (16). Third, high tumor-infiltrating lymphocytes (TILs) counts and immune-related gene expression signatures in the primary tumor are consistently associated with better survival in triple-negative breast cancer and HER2-positive breast cancer (15, 17C19). On the other hand, the prognostic value of assessing TILs in HR-positive/HER2-negative breast cancer remains unclear according to a few studies (15, 20). The TOT-HER3 (a window-of-opportunity study of patritumab deruxtecan, a HER3 directed ADC in operable breast cancer according to expression) trial is designed to assess whether a single dose of patritumab deruxtecan can increase immune infiltration and the lysis of tumor cells during short-term preoperative treatment in hormone receptor (HR)-positive/HER2-negative primary breast cancer. Short-term preoperative studies are a validated strategy for evaluating the impact of targeted therapies using the decrease in tumor cellularity and the increase in immune infiltration as a surrogate endpoint of treatment benefit (21, 22). The primary endpoint of TOT-HER3 is changes in the CelTIL score, a novel combined biomarker based on stromal TILs and tumor cellularity. Access to tumor tissue before and after the investigational treatment enables comprehensive analysis of biomarker INCB39110 (Itacitinib) changes, thus providing critical insights into the optimal patient.