Purpose:

B7 homolog 3 (B7-H3) is a promising target for antibody–drug conjugates, with ifinatamab deruxtecan demonstrating an objective response rate of 54.8% in previously treated extensive-stage small cell lung cancer (SCLC). This analysis aimed to characterize B7-H3 RNA expression with reference to SCLC molecular subtypes (SCLC-A, SCLC-N, SCLC-P, and SCLC-I) and immune-related parameters.

Experimental Design:

Tumor RNA expression and mutational burden for 1,721 patients with SCLC were derived from a real-world database (Caris Life Sciences). A predominant molecular subtype was assigned based on RNA expression using a gene-ratio classifier. PD-L1 expression was assessed by IHC (antibody 22C3; positive cutoff: tumor proportion score ≥1%).

Results:

The predominant molecular subtype was SCLC-A in 848 (49.3%), SCLC-N in 202 (11.7%), SCLC-P in 142 (8.3%), SCLC-I in 291 (16.9%), and equivocal in 238 (13.8%) samples. B7-H3 expression was high and consistent among subtypes (q > 0.05), whereas DLL3 and SEZ6 expression each differed significantly (both q < 0.0001). PD-L1 positivity was similar across B7-H3 expression quartiles (range, 39.2%–46.5%). Median (95% confidence interval) B7-H3 expression was comparable between patients with and without prior immunotherapy [18.7 (16.5–21.2) and 17.3 (16.4–18.1) transcripts per million, respectively]. B7-H3 was not correlated with a T-cell signature but showed a strong correlation with HAVCR2/TIM3, CD86, PDCD1LG2/PD-L2, and M2 macrophages.

Conclusions:

B7-H3 showed consistent, high expression across SCLC molecular subtypes, whereas DLL3 and SEZ6 expression varied significantly. These data suggest that B7-H3–targeting antibody–drug conjugates may be active across SCLC subtypes, consistent with the high reported response rates.

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©2025 The Authors; Published by the American Association for Cancer Research
2025
American Association for Cancer Research
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First page of Multidimensional Analysis of B7 Homolog 3 RNA Expression in Small Cell Lung Cancer Molecular Subtypes<alt-title alt-title-type="short"><italic>B7-H3</italic> Expression in SCLC Molecular Subtypes</alt-title>

Supplementary data

Supplementary Figure 1

Supplementary Figure 1. Expression of B7-H3, DLL3, and SEZ6 according to biopsy site.

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Supplementary Figure 2

Supplementary Figure 2. Heatmap showing Spearman’s correlation matrix for pairwise comparisons of gene expression variables. Spearman’s correlation coefficient (r) values and associated color coding are shown only for correlations that were statistically significant (P < 0.05).

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Supplementary Figure 3

Supplementary Figure 3. Gene signature expression according to B7-H3 expression quartile in patients with SCLC.

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Supplementary Figure 4

Supplementary Figure 4. Expression of B7-H3 in patients with PNET (n = 212), according to classification as low- or high-grade tumors based on MKI67/Ki-67 mRNA expression. Median age was 66 years (range, 19–89+) and 135 patients (63.7%) were female. Expression levels were quantified as log2(TPM +1). Boxplots indicate the median, interquartile range, and range of values, with diamonds representing outliers.

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