1419P - TACSTD2 (Trop-2) constitutes a promising antibody-drug conjugate target for patients with non-small cell lung cancer brain metastases

Background

Brain metastases (BM) are a frequent complication in patients with non-small lung cancer (NSCLC). Treating BM is challenging as the blood-brain barrier can limit intracranial drug delivery. Data from different trials suggest that antibody-drug conjugates (ADC) can have clinically relevant intracranial activity. This study aims to characterize the gene expression of ADC targets in NSCLC-BM to guide treatment decisions.

Methods

Gene expression data from 125 BM resected from patients with NSCLC were obtained from 3 public datasets. Gene expression of 14 ADC targets (ERBB2, ERBB3, TACSTD2, MET, GPNMB, PTK7, MSLN, CD276, TF, AXL, EGFR, SLC34A2, CEACAM5 and ROR2) was evaluated to identify those consistently expressed across the cohorts. Additionally, hierarchical clustering was used to stratify NSCLC-BM, in each dataset separately, based on the combined relative gene expression of the common 25% most variable genes: MSLN, CEACAM5 and SLC34A2. Furthermore, association between clusters and clinical covariates was assessed for one of the datasets with available data (N=63).

Results

Gene expression evaluation showed that TACSTD2 (Trop-2) was ubiquitously highly expressed across datasets, suggesting that TACSTD2 could be a promising ADC target for NSCLC-BM. Contrarily, ROR2 showed consistently lower expression and would probably not be a good candidate in NSCLC-BM. Transcriptional patterns from the 3 most variable ADC targets (MSLN, CEACAM5, and SLC34A2) yielded common subgroups in all datasets defined by the following expression levels (respectively): High/High/High, Low/High/High, High/Low/Low. These groups did not correlate with clinical covariates.

Conclusions

Gene expression evaluation of ADC targets in NSCLC-BM resulted in the identification of TACSTD2 expression across all datasets. TACSTD2 might be a promising ADC target for patients with NSCLC with BM. Further validation is warranted in terms of protein expression. Our results underscore the potential value of gene expression profiling to identify new targets and improve patient selection in the context of NSCLC-BM ADC therapy.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Instituto de Salud Carlos III (CM22/00035).

Disclosure

E. Nadal: Financial Interests, Personal, Advisory Board: Roche, Bristol Myers Squibb, Merck Sharp Dohme, Boehringer Ingelheim, Lilly, Janssen, Pfizer, Merck Serono, Daiichi Sankyo, AstraZeneca, Takeda, Amgen, Sanofi, Qiagen, Janssen; Financial Interests, Personal, Invited Speaker: Roche, Bristol Myers Squibb, Merck Sharp Dohme, Boehringer Ingelheim, Lilly, Pfizer, Sanofi, AstraZeneca, Takeda, Amgen, Qiagen, Janssen; Financial Interests, Personal and Institutional, Funding, Clinical trial funded by Roche: Roche; Financial Interests, Personal and Institutional, Funding, BMS funded a clinical trial: Bristol Myers Squibb; Financial Interests, Personal and Institutional, Funding, Merck Serono funded a clinical trial: Merck Serono; Non-Financial Interests, Advisory Role: Pfizer, Roche. All other authors have declared no conflicts of interest.