BTN1A1 H-score and multiplex biomarker profiling predict clinical benefit from nelmastobart plus capecitabine in advanced colorectal cancer: Phase Ib/II study

초록

Background BTN1A1 is a novel immune checkpoint implicated in tumor immune evasion. Nelmastobart, a humanized anti-BTN1A1 IgG4 monoclonal antibody, has demonstrated good safety and preliminary clinical efficacy in a first-in-human study. Translational analyses from phase I suggest that BTN1A1 and nuclear YAP1 co-expression may drive chemoresistance in colorectal cancer (CRC). We present phase Ib findings evaluating the efficacy and predictive biomarkers of Nelmastobart in combination with capecitabine, with a focus on BTN1A1 H-score and spatial profiling of YAP1, SLFN11, and Ki-67/PD-L1 co-expression. Methods Patients with refractory or metastatic CRC received Nelmastobart plus capecitabine in a standard 3+3 dose-escalation design to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D). Pretreatment biopsies were evaluated by pathologist-read immunohistochemistry (IHC) to determine BTN1A1 H-score (range 0–300), and by multiplex IHC for quantification of nuclear YAP1+ SLFN11+, and Ki-67/PD-L1+ cells. Primary endpoints included progression-free survival (PFS) and objective response rate (ORR). Biomarker correlations with PFS were assessed using Spearman rank correlation. Results Multiplex IHC was successfully performed on 25 patient tumor samples. Higher BTN1A1 H-scores correlated with longer PFS: patients with H-scores ≥250 (n=3) achieved a median PFS of 6.3 months, compared to 4.2 months for scores 150–249 (n=7) and 4.0 months for scores <150 (n=15). Baseline enrichment of YAP1+ tumor cells, SLFN11+ cells, and Ki-67/PD-L1+ co-expressing cells were each associated with improved PFS. No new safety signals were observed, and the combination therapy was well tolerated. Conclusions Nelmastobart demonstrated encouraging clinical activity and safety in heavily pretreated CRC patients. High BTN1A1 H-score and enrichment of YAP1+, SLFN11+, and Ki-67/PD-L1+ subsets correlated with improved PFS, supporting their use as predictive biomarkers. These findings support the ongoing randomized phase II trial and highlight BTN1A1 inhibition as a promising biomarker-driven strategy for immune modulation in CRC.