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Multidimensional Analysis of B7 Homolog 3 RNA Expression in Small Cell Lung Cancer Molecular Subtypes
Carl M Gay1, Taofeek K Owonikoko2, Lauren A Byers1
1Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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.
Insights
B7-H3 is highly expressed across all small cell lung cancer (SCLC) subtypes, indicating its potential as a therapeutic target. This consistent expression supports the use of B7-H3-targeting antibody-drug conjugates for SCLC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- B7 homolog 3 (B7-H3) is a target for antibody-drug conjugates in extensive-stage small cell lung cancer (SCLC).
- Ifinatamab deruxtecan showed a 54.8% response rate in previously treated SCLC patients.
Purpose of the Study:
- To analyze B7-H3 RNA expression in relation to SCLC molecular subtypes (SCLC-A, SCLC-N, SCLC-P, SCLC-I).
- To investigate the correlation between B7-H3 expression and immune-related parameters.
Main Methods:
- Utilized a real-world database (Caris Life Sciences) of 1,721 SCLC patients.
- Assigned molecular subtypes based on RNA expression using a gene-ratio classifier.
- Assessed PD-L1 expression via immunohistochemistry (IHC).
Main Results:
- B7-H3 expression was high and consistent across all SCLC subtypes (q > 0.05).
- DLL3 and SEZ6 expression varied significantly between subtypes (q < 0.0001).
- PD-L1 positivity was similar across B7-H3 expression quartiles (39.2%-46.5%) and comparable in patients with or without prior immunotherapy.
Conclusions:
- B7-H3 exhibits consistent, high expression across SCLC molecular subtypes.
- DLL3 and SEZ6 expression show significant variability among subtypes.
- B7-H3-targeting antibody-drug conjugates may be effective across diverse SCLC subtypes.
