Off-label use of fam-trastuzumab deruxtecan-nxki with early activity in a cohort of patients with desmoplastic small round cell tumor.

Abstract

11584 Background: Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive sarcoma occurring predominantly in pediatric, adolescent and young adult biologic males, and is molecularly characterized by the pathognomonic EWSR1-WT1 fusion. Despite aggressive multi-modality therapy outcomes for those with DSRCT remain poor, and more effective therapies are urgently required. Prior pre-clinical data and transcriptomic analyses of DSRCT patients has suggested the relevance of the ERBB2 pathway in this disease, prompting the off-label use of fam-trastuzumab deruxtecan-nxki (T-DXd) in the treatment of patients of DSRCT patient with relapsed and refractory disease. Methods: Patients with relapsed/refractory DSRCT received T-DXd 5.4 mg/kg intravenously in 21-day cycles. Whole body PET and CT of the chest, abdomen and pelvis were used for monitoring. Response was correlated with HER2 immunohistochemistry (IHC) status and transcriptomic analysis by RNA sequencing (RNAseq) when available. Results: Seven patients received the agent, and at the time of submission 3 patients had at least one follow up imaging test after receiving between 6 and 9 cycles of T-DXd. Treatment was overall well tolerated with the only grade 3 toxicity of transaminitis (in patients with known liver metastases), which self-resolved. All other toxicities including constipation, nausea, and fatigue were grade 2 or less. All 3 patients have experienced clinical benefit including one patient with a RECIST 1.1 partial response and two patients with stable disease. Additionally, favorable responses were noted by PET imaging. Four additional patients with relapsed/refractory DSRCT have initiated off-label treatment with T-DXd and are pending imaging responses. 7/7 and 4/7 patients have available IHC and ERBB2 RNA expression data available respectively. All ERBB2 RNA expression data is elevated when compared with the median across all evaluated pediatric tumors in our institutional series. Conclusions: The use of anti-HER2 therapy in a limited and unselected group of heavily pre-treated DSRCT patients is demonstrating an early signal of activity with minimal toxicity and suggests that formal assessment as monotherapy or in other relevant combinations in clinical trials is warranted. Further correlation with IHC and RNAseq expression data may help optimize correlatives and/or generate biomarkers for future clinical trials.