Off-label use of fam-trastuzumab deruxtecan in desmoplastic small round cell tumor.

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11504 Background: Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive sarcoma which remains almost universally fatal despite intensive, multi-modality therapy. Human epidermal growth factor receptor 2 (HER2) has been identified as a potential therapeutic target of relevance for DSRCT as both a pathway and cell surface expression marker. These observations prompted HER2 specific investigations in our DSRCT clinical cohort and subsequent off-label treatment with T-DXd, an antibody-drug conjugate consisting of a humanized anti-HER2 monoclonal antibody linked to a topoisomerase I inhibitor payload. Methods: A tumor microarray (TMA) of 52 unique DSRCT patient samples was analyzed by 2 immunohistochemical (IHC) assays (4B5, CB11), and a cohort of 61 DSRCT patient samples was analyzed by RNAseq. Additionally, 16 patients with relapsed/refractory DSRCT in need of therapy and enrolled on an institutional biobanking and genomic profiling protocol were identified, underwent IHC testing and RNAseq when feasible (fresh or archival tissue), and received off-label T-DXd. Results: TMA IHC analyses noted minimal HER2 IHC positivity using 4B5, with only 3/52 cases scoring above 10% membranous staining and composite IHC scores ranging from 11 to 15. IHC with clone CB11 uncovered 12.7-fold more HER2 reactivity with 38/52 cases scoring above 10%, and composite IHC scores ranging from 12.5 to 140. HER2 expression levels by RNAseq were analyzed in the context of 346 solid tumor patients with 22 histologies treated within the pediatrics department at MSK. Across these histologies DSRCT had the third highest HER2 expression level overall (surpassed only by papillary thyroid cancer and schwannoma). Median transcripts per million (TPM) expression level across the entire cohort was 9.8 (range 1-116.3), and for DSRCT was 41.8 (range 6.3-116.3). All 16 patients experienced clinical benefit (confirmed stable disease or partial response) with minimal toxicity, limited predominantly to myelosuppression, nausea and constipation. There were no episodes of interstitial lung disease. Notably, 8 of 16 patients all of whom had prior exposure to irinotecan achieved a decrease of at least 30% in the sum of the longest diameters of retrospectively selected target lesions, equivalent to a RECIST partial response (PR) (50% overall response rate). In this small series, response rate did not appear to correlate with available IHC or RNAseq data, with some patients achieving PR with no discernable membranous IHC expression. Conclusions: These results suggest that T-DXd is active in DSRCT and support the biomarker agnostic formal clinical trial which is planned with the Children’s Oncology Group.

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