BTN1A1 expression in colon cancer: Implications for immunotherapy and patient stratification.

249 Background: Butyrophilin 1A1 (BTN1A1) is a promising immune checkpoint protein offering a novel option for immunotherapy. We discovered that BTN1A1 and PD-L1 expression are mutually exclusive through the JAK/STAT pathway in various tumors. Recently, Nelmastobart, an antibody targeting BTN1A1, successfully completed a Phase 1 clinical trial at three sites in the United States and two in the Republic of Korea, spanning 98 weeks. This abstract focuses on the results from the Phase 1 trial in patients with colorectal cancer (CRC), emphasizing biomarker diagnostics and therapeutics derived from translational research. Methods: We conducted a first-in-human, multicenter, open-label Phase I clinical trial to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of hSTC810 monotherapy in CRC patients. Extensive analyses of BTN1A1 expression were performed using patient specimens through immunohistochemistry and multi-immunofluorescence techniques to identify critical biomarkers and accurately assess nelmastobart's anticancer activity. We then analyzed progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety alongside translational research findings using patient tissue samples. Results: A total of 47 patients were enrolled in the study. The median PFS across all cohorts was 1.9 months, while the median Kaplan-Meier estimate for OS was 12.8 months. Among the 16 CRC patients enrolled, tissue samples were obtained and analyzed using IHC in 12 patients and OPAL staining in 7 patients. The objective response rate (ORR) for CRC was 2.3%. The median progression-free survival (PFS) and overall survival (OS) were 3.6 months and 11 months, respectively. Notably, PFS, OS, and ORR strongly correlated with BTN1A1 expression levels in CRC patients. High levels of BTN1A1 expression in colorectal tumor tissues correlated with clinical outcomes, identifying BTN1A1 as a potential biomarker for predicting patient responses to targeted therapies. The mutual exclusivity of BTN1A1 and PD-L1 expression suggests that BTN1A1 could serve as a diagnostic marker to identify patients who may be unresponsive to PD-1/PD-L1 blockade therapy and might benefit from BTN1A1 blockade therapy. Conclusions: This Phase 1 clinical trial demonstrated that antibody-mediated BTN1A1 blockade effectively suppresses tumor growth in patients with BTN1A1-positive CRC. These findings suggest that BTN1A1-targeted therapies could provide a viable treatment option for patients with colon cancers that are refractory or resistant to anti-PD-1/PD-L1 therapies. Clinical trial information: NCT05231746 .