Multidimensional Analysis of B7 homolog 3 (B7-H3) RNA Expression in Small-cell Lung Cancer Molecular Subtypes

Abstract Purpose: B7 homolog 3 (B7-H3) is a promising target for antibody–drug conjugates (ADCs), 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 1721 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. Programmed death ligand-1 (PD-L1) expression was assessed by immunohistochemistry (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 samples (13.8%). B7‑H3 expression was high and consistent among subtypes (q > 0.05), whereas DLL3 and SEZ6 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 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 B7-H3–targeting ADCs may be active across SCLC subtypes, consistent with the high reported response rates.