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PURPOSE To investigate the efficacy and safety of trastuzumab deruxtecan, an antibody-drug conjugate targeting human epidermal growth factor receptor 2 (HER2) with a topoisomerase I inhibitor payload, in patients with uterine carcinosarcoma (UCS) expressing HER2. PATIENTS AND METHODS Patients with recurrent UCS with HER2 immunohistochemistry scores ≥1+ previously treated with chemotherapy were included. Patients were assigned to the HER2-high (immunohistochemistry score ≥2+; n = 22) or low (immunohistochemistry score of 1+; n = 10) groups for primary and exploratory analyses, respectively. Trastuzumab deruxtecan 6.4 or 5.4 mg/kg was administered intravenously once every 3 weeks until unacceptable toxicity or disease progression. Dose modification was based on the updated recommended phase II dose for breast cancer to be 5.4 mg/kg. The primary end point was the objective response rate by central review in the HER2-high group. Secondary end points included the overall response rate (ORR) in the HER2-high group by investigator assessment, ORR in the HER2-low group, progression-free survival (PFS), overall survival (OS), and safety. RESULTS The ORR by central review in the HER2-high and HER2-low groups were 54.5% (95% CI, 32.2 to 75.6) and 70.0% (95% CI, 34.8 to 93.3) and those by investigator assessments were 68.2% and 60.0%, respectively. The median PFS and OS in the HER2-high and HER2-low groups were 6.2 and 13.3 months and 6.7 months and not reached, respectively. Grade ≥ 3 adverse events occurred in 20 patients (61%). Grades 1-2 and 3 pneumonitis/interstitial lung disease occurred in eight (24%) and one (3%) patient, respectively. CONCLUSION Trastuzumab deruxtecan has efficacy in patients with UCS, regardless of HER2 status. The safety profile was generally consistent with that previously reported. Toxicities were manageable with appropriate monitoring and treatment.

TPS10059 Background: Enhancer of zeste homolog enzymes (EZH1 and EZH2) form parts of the polycomb repressive complex 2 and regulate gene expression by catalyzing the tri-methylation of lysine 27 residue of histone H3. SMARCB1/INI1 is one of the core components of the SWI/SNF chromatin remodeling complex, with the loss of SMARCB1/INI1 causing the oncogenic activation of EZH2 and EZH1. The inhibition of EZH2 or both EZH2 and EZH1 can be effective against various hematological malignancies and SMARCB1/INI1-deficient solid tumors. Valemetostat tosylate (DS-3201b; valemetostat) is a potential first-in-class dual inhibitor of EZH1 and EZH2 that targets epigenetic regulations by inhibiting both EZH1 and EZH2 enzymes. A phase 2 single-arm study showed that valemetostat demonstrated promising response rates in Japanese patients with relapsed or refractory adult T-cell leukemia/lymphoma (Yoshimitsu M et al., presented at ASH Annual Meeting, 2021). Tumors characterized by SMARCB1/INI1 deficiency (a SWI/SNF mutation), such as malignant rhabdoid tumors, epithelioid sarcoma, or synovial sarcoma are quite frequently observed during childhood and adolescence, among whom valemetostat is expected to show antitumor effects. Methods: This open-label multi-center phase I trial evaluates the safety and efficacy of valemetostat in pediatric, adolescent, and young adult patients with refractory/relapsed solid tumors. The inclusion criteria are relapsed, refractory, or progressive metastatic disease; >3 and 50 (assessed by Karnofsky Performance score in patients >16 years old, and Lansky Performance score in patients 2) are assessed using a 3+3 design during the dose escalation cohort. After determining the recommended phase 2 dose (RP2D) during dose escalation cohort, up to 30 patients will be further enrolled, and the safety and efficacy data of valemetostat are determined in the expanded cohort. The primary endpoint is the incidence of dose limiting toxicity, whereas the secondary endpoints include safety, pharmacokinetics, overall response rate, progression-free survival. The overall response rate of the tumors with SMARCB1/INI1 deficiency or SWI/SNF mutation is also evaluated as a secondary endpoint. Exploratory endpoint includes overall survival. Enrollment into this trial began in March 2020, and enrollment into the dose escalation cohort was completed. Enrollment into the expanded cohort began in November 2021. Clinical Trial Information: jRCT2031190268.