使用一种研究性Integrin beta-6 IHC检测评估非鳞状非小细胞肺癌标本中Integrin beta-6表达的肿瘤异质性

Rapidly evolving investigational targeted therapies, such as antibody drug conjugates (ADCs), are introducing novel targets in oncology. An investigational ADC, sigvotatug vedotin (SV), is currently being studied in non-small cell lung cancer (NSCLC) and is directed to the novel target integrin beta-6 (IB6). IB6 is overexpressed in multiple solid tumor types and is a proposed negative prognostic indicator in many cancers, including NSCLC. Integrin Beta-6 IHC 6.2A1 pharmDx is an immunohistochemistry assay developed for the detection of IB6 protein expression and is being used to assess IB6 expression in the ongoing Be6A-Lung-01 trial. Recent data showed this assay is sensitive, specific and precise at detecting IB6 protein expression in a large set of non-squamous NSCLC (nsqNSCLC) specimens. Tumor heterogeneity, originating from genomic instability, is a hallmark of cancer. Tumor heterogeneity in relation to changes in Integrin Beta-6 clinical diagnostic status needs to be understood. Here we present data on IB6 biomarker heterogeneity and further elaborate on the assay's reproducibility as it relates to clinically relevant assay parameters. This assay uses Monoclonal Mouse Anti-Human Integrin Beta-6, Clone 6.2A1 on the Dako Omnis staining platform. IB6 expression in nsqNSCLC was evaluated by calculating the percentage of viable invasive tumor cells showing partial or complete IB6 membrane and/or cytoplasmic staining at ≥2+ staining intensity. The clinical diagnostic status of IB6 High or IB6 Low was determined using the cutoff ≥50%. Tumor heterogeneity was assessed by comparing staining across 200 µm of an FFPE block (intra-block, n=52), between blocks from the same tumor (intra-case, n=44), and between blocks from primary and metastatic tumor sites in the same patient (n=30 patients). Other clinically relevant assay parameters were also tested, including tissue section thickness, glass slide vs. digital whole slide image (WSI) scoring, and preanalytical variables. Intra-block resulted in 96.3% overall agreement (OA) (n=52). Intra-case resulted in 95.5% OA (n=44). Primary vs. metastatic comparisons resulted in 83.3% OA (n=30). Tissue section thickness resulted in 99.1% OA. Evaluation of IB6 on glass slides compared to WSIs resulted in 98.9% OA. There was no significant difference in the detection of IB6 positivity across ischemia times of 0.5-72 hours and 10% NBF fixation times of 6-72 hours. Integrin Beta-6 IHC 6.2A1 pharmDx demonstrates high reproducibility with respect to tissue heterogeneity around the ≥50% diagnostic cutoff, indicating there is uniformity in biomarker expression across and within tumor sites for nsqNSCLC. These preliminary findings may provide confidence that assessment of IB6 expression can be reliably performed across tumor sites and within tumor sites.