Introduction: Synovial sarcoma predominantly affects adolescents and young adults. Doxorubicin with or without ifosfamide therapy is the standard first-line treatment for unresectable or metastatic synovial sarcoma. However, there is no standard second-line chemotherapy regimen. The purpose of the current study was to evaluate the outcomes of second-line chemotherapy for patients with synovial sarcoma. Methods: We retrospectively evaluated the outcomes of 61 patients with unresectable or metastatic synovial sarcoma who had received first-line chemotherapy at our institution between 1997 and 2017. Patients who received second-line chemotherapy were included in the analysis. Outcomes of the chemotherapy were evaluated. Results: Among the 61 patients treated with first-line chemotherapy, we identified 32 patients who received second-line chemotherapy. Most patients (62.5%) were under 40 years of age. Regarding second-line chemotherapy regimens, 6 (18.8%) patients were treated with doxorubicin with/without ifosfamide, 6 (18.8%) with ifosfamide and etoposide, 4 (12.5%) with docetaxel and gemcitabine, 5 (15.6%) with pazopanib, 2 (6.2%) with trabectedin, and 1 (3.1%) with eribulin. The overall response rate according to the Response Evaluation Criteria in Solid Tumors for all patients was 9.4%. Eleven patients (34.3%) achieved disease-control for > 6 months. The median follow-up duration was 15.2 months. The 1-year progression-free and overall survival rates were 33.1% and 67.1%, respectively. Conclusion: Our exploratory study revealed that the response rate of second-line chemotherapy regimens for patients with synovial sarcoma was 9.4%. Therefore, there is an urgent need to develop more active therapeutic regimens for synovial sarcomas.

Prognostic value of hematologic indices and their association with the tumor microenvironment (TME) remain unclear in advanced soft tissue sarcoma (STS). We aimed to evaluate their prognostic value and correlation with the TME status in advanced STS treated with first-line doxorubicin (DXR) therapy. Clinical data and three hematological indices, including lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio, and neutrophil-to-lymphocyte ratio, were collected from 149 patients with advanced STS. The TME status was pathologically examined by CD3, CD68, and CD20 staining of resected tumor slides. In a multivariate Cox analysis, low LMR and absence of primary tumor resection were independently associated with worse overall survival (OS) (HR 3.93, p = 0.001; HR 1.71, p = 0.03). A prognostic model using these variables predicted OS with greater area under curves than those obtained using Systemic Inflammatory Score and Glasgow Prognostic Score. The LMR significantly correlated with the tumoral CD3/CD68-positive cell ratio in surgical specimens (R = 0.959, p = 0.04). In conclusion, LMR was a prognostic factor in advanced STS treated with first-line DXR therapy. LMR could partially reflect anti-tumor immunity in the TME and have the prognostic value. The potential role of LMR as an indicator of TME status warrants further investigation.

Background: Capicua-double homeobox 4 (CIC-DUX4)-rearranged sarcomas (CDS) are extremely rare and highly aggressive sarcomas. There is no standard therapy for the patients with advanced CDS, and therapeutic development is needed. We evaluated preclinical efficacy of trastuzumab deruxtecan (T-DXd), a humanized monoclonal HER2-targeting antibody conjugated to a topoisomerase 1 inhibitor, DXd, in patient-derived xenograft (PDX) models with CDS. Methods: Patient-derived tumor tissue was transplanted into subcutaneous around the flank of female NOG mice, which were treated with vehicle or T-DXd (3 mg/kg, intravenous, Day0) when the mean tumor volume reached 200 mm3. Tumor volume was assessed twice weekly for 3 weeks to assess the efficacy of T-DXd. Results: This study included 3 CDS-derived PDXs. HER2 expression was low in one PDX and not expressed in two PDXs. One PDX was established from a specimen at initial diagnosis, two were established from specimens after prior-chemotherapy. T-DXd demonstrated significant tumor growth delay compared to vehicle in all PDX models investigated. One PDX with no efficacy was HER2-negative and had a treatment history of topoisomerase I inhibitor. In contrast, PDX of HER2-negative topoisomerase I inhibitor-resistant Ewing sarcoma was also administered T-DXd under the same conditions and was found to be refractory. Conclusion: The present study showed that a therapeutic potential of T-DXd in CDS patients, including HER2-negative. Citation Format: Yuki Kojima, Shigehiro Yagishita, Kazuki Sudo, Tatsunori Shimoi, Shintaro Iwata, Shun-ichi Watanabe, Chitose Ogawa, Akihiko Yoshida, Yasushi Yatabe, Kan Yonemori, Akinobu Hamada. Trastuzumab deruxtecan, antibody-drug conjugate targeting HER2, effectively inhibits growth of patient-derived xenograft model with CIC-rearranged sarcoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3995.

Objective eribulin, an anticancer agent that inhibits microtubule growth, along with trabectedin and pazopanib, has been approved for the treatment of advanced soft tissue sarcoma (STS). However, there has been no consensus on the optimal second-line therapy among these three agents following treatment failure with doxorubicin. Recently, the effects of eribulin on the tumor microenvironment and immunity have been reported in breast cancer, and peripheral blood immune markers have also been reported to be a predictor of eribulin efficacy, though this remains unverified in STS. We aimed to evaluate the predictive value of various peripheral blood immune markers in STS patients treated with eribulin. Methods we retrospectively reviewed the medical records of STS patients treated with eribulin and examined whether peripheral blood immune markers at different time points could be prognostic factors for STS patients treated with eribulin. Results several peripheral blood immune markers were significantly associated with progression-free survival (PFS), specifically neutrophil-to-lymphocyte ratio (NLR) prestart (NLR before the initial administration of eribulin) (P = 0.019) and absolute lymphocyte count (ALC)8D (ALC on Day 8 of the first administration of eribulin) (P = 0.037). NLR prestart (P = 0.001) was significantly associated with overall survival. The combination of NLR prestart and ALC8D determined the PFS of STS patients treated with eribulin. Conclusions the combined indicator of low NLR prestart and high ALC8D predicted the survival of patients treated with eribulin as well as the histology of L-sarcoma. Though further validation was needed, this finding would provide valuable prognostic factor that help treatment decision in the absence of consensus on the optimal second-line therapy following doxorubicin treatment in STS patients.

SummaryOcular toxicities arising from anti-cancer drugs occur sporadically and are sometimes underestimated because they are not life-threatening. Reports focusing on ocular toxicities from cancer therapy are limited. We investigated the detailed progress of ocular toxicities of anti-cancer drugs including first-in-class ones. A retrospective review of medical records was conducted for patients who were involved in early phase clinical trials with scheduled ophthalmologic examinations according to their protocols between January 2014 and August 2021. Patients with ocular toxicity suspected to be related to the investigational drugs in the ophthalmic examination were investigated in detail. In total, 37 ocular toxicities related to investigational drugs occurred in 7.6% of patients (33/434). The median age of the 33 patients was 61 years (range, 33–76 years), and 20 were male. Causal drugs with a high incidence of ocular toxicities were HSP90 inhibitors and FGFR inhibitors. Retinopathy was most frequent, while conjunctivitis, dry eye, keratitis, keratopathy, and uveitis were also observed. Dim vision as a subjective finding was a unique adverse event. Most patients developed ocular toxicities even though their dose was below the drug’s maximum tolerated dose. Except for one case, all ocular toxicities occurred bilaterally. About 60% (22/37) of ocular toxicity cases needed a temporary hold of the drug. All except for three cases fully recovered. This study reported the risks and timing of the onset of a variety of ocular toxicities of anti-cancer drugs, which were fundamentally controllable. (Trial registration number. Retrospectively registered)