Trastuzumab Deruxtecan Is Active in Desmoplastic Small Round Cell Tumor

PURPOSE Desmoplastic small round cell tumor (DSRCT) is a rare sarcoma which remains almost universally fatal despite multimodality therapy. Human epidermal growth factor receptor 2 (HER2) has been identified as a potential therapeutic target prompting HER2-specific investigations and subsequent off-label treatment with fam-trastuzumab deruxtecan (T-DXd) in our DSRCT clinical cohort. METHODS Fifty-two and 61 DSRCT patient samples were analyzed by immunohistochemical (IHC) assays and RNAseq, respectively. In addition, 19 patients at a single institution with DSRCT in need of therapy underwent IHC testing and RNAseq when feasible and received off-label T-DXd (monotherapy n = 14, alternating with another agent n = 2, concomitantly in combination n = 2; measurable disease n = 17, adjuvant setting n = 2). RESULTS HER2 expression levels by RNAseq were analyzed in the context of 346 patients with solid tumor and 23 histologies, with DSRCT having the third highest HER2 expression level overall and a median transcripts per million (TPM) expression level of 41.8 (range, 6.3-116.3). While TMA IHC analyses noted minimal HER2 IHC positivity using 4B5, IHC with clones 29D8 and CB11 uncovered 8.7- to 12.7-fold more HER2 reactivity, respectively. All 17 patients with measurable disease experienced clinical benefit (stable disease or partial response PR) with minimal toxicity. In addition, 9 of 17 patients achieved a RECIST PR (53% overall response rate). The response rate did not correlate with available IHC or RNAseq data, and some patients with no membranous IHC expression achieved PR. CONCLUSION These data show that T-DXd is active in DSRCT and support the planned biomarker-agnostic formal clinical trial with the Children's Oncology Group.