Metastatic Soft Tissue Sarcoma Research Articles

Safety And Efficacy Of Combination Lurbinectedin Plus Doxorubicin From A Phase 1b Trial In Patients With Advanced/Metastatic Soft Tissue Sarcoma

Abstract Purpose: While cytotoxic chemotherapy is standard first-line treatment for patients with metastatic soft tissue sarcoma (STS), clinical outcomes remain suboptimal. Our prior study showed lurbinectedin plus doxorubicin is well-tolerated with promising clinical activity in STS. We designed this phase 1b trial to optimize dosing as the basis for a randomized trial in leiomyosarcoma (LMS) and to further explore the safety profile and efficacy signal. Patients and Methods: Patients had advanced/metastatic STS and no prior anthracycline/lurbinectedin/trabectedin. Escalation followed a 3+3 design with 3-week cycles: lurbinectedin (3.2 mg/m2 day 1) and two doxorubicin levels (DL1: 25 mg/m2 day 1; DL2 25 mg/m2 days 1 and 8). The primary objectives were to identify the maximum tolerated dose (MTD) and recommended dose for subsequent randomized trials. Results: Ten patients were enrolled in a 6-month period. The most common treatment-emergent adverse events (TEAE) were grade (G) 2 fatigue and nausea, and G2 cytopenias with no febrile neutropenia events. There were 2 dose-limiting toxicities (DLTs) at DL2 (day 8 [G2 ALT/AST increase, G3 neutropenia]), and 1 DLT in DL1 (G3 ALT increase). These were reversible and all patients continued the study. DL1 was chosen for further study. At the time of data cutoff, the estimated median PFS is 16.5 months (95%CI 6.0-ND). The ORR was 60% (6/10 confirmed partial responses [PR]). Conclusions: In this phase 1b study, the recommended dose is lurbinectedin 3.2 mg/m2 in combination with doxorubicin 25 mg/m2 every 3 weeks. The study combination was well-tolerated and demonstrated intriguing clinical activity.

The Synergy of 177Lu-FAPI-046 with Tyrosine Kinase Inhibitor in a Sarcoma Patient-Derived Xenograft Mouse Model

BackgroundGiven the heterogeneity and high mortality associated with metastatic soft tissue sarcoma, this study aims to evaluate the therapeutic efficacy of combining 177Lu-FAPI-46 with Pazopanib against this malignancy. MethodsPatient-derived xenograft (PDX)-bearing mice were randomly divided into three groups: the control group, the 177Lu-FAPI-46 monotherapy group, and the 177Lu-FAPI-46 combined with Pazopanib therapy group. Therapeutic efficacy was regularly monitored. ResultsThe microPET imaging showed a 0.84-fold decrease in the T/M ratio of 68Ga-FAPI-46 on day 7/8 post combination therapy, while the control group exhibited a 1.23-fold increase. Combination therapy significantly inhibited tumor proliferation, as evidenced by reduced Ki-67 and increased caspase 3 expressions. Notably, there was no significant body weight loss observed in any group. ConclusionThis study successfully demonstrated the reduction in FAP expression and suppression of tumor volume in sarcoma PDX following the combination therapy of 177Lu-FAPI-46 with Pazopanib.

Regional hyperthermia for soft tissue sarcoma – a survey on current practice, controversies and consensus among 12 European centers

Purpose To analyze the current practice of regional hyperthermia (RHT) for soft tissue sarcoma (STS) at 12 European centers to provide an overview, find consensuses and identify controversies necessary for future guidelines and clinical trials. Methods In this cross-sectional survey study, a 27-item questionnaire assessing clinical subjects and procedural details on RHT for STS was distributed to 12 European cancer centers for RHT. Results We have identified seven controversies and five consensus points. Of 12 centers, 6 offer both, RHT with chemotherapy (CTX) or with radiotherapy (RT). Two centers only offer RHT with CTX and four centers only offer RHT with RT. All 12 centers apply RHT for localized, high-risk STS of the extremities, trunk wall and retroperitoneum. However, eight centers also use RHT in metastatic STS, five in palliative STS, eight for superficial STS and six for low-grade STS. Pretherapeutic imaging for RHT treatment planning is used by 10 centers, 9 centers set 40–43 °C as the intratumoral target temperature, and all centers use skin detectors or probes in body orifices for thermometry. Discussion There is disagreement regarding the integration of RHT in contemporary interdisciplinary care of STS patients. Many clinical controversies exist that require a standardized consensus guideline and innovative study ideas. At the same time, our data has shown that existing guidelines and decades of experience with the technique of RHT have mostly standardized procedural aspects. Conclusions The provided results may serve as a basis for future guidelines and inform future clinical trials for RHT in STS patients.

Safety and efficacy of percutaneous image-guided ablation for soft tissue sarcoma metastases to the liver.

To evaluate outcomes following percutaneous image-guided ablation of soft tissue sarcoma metastases to the liver. A single-institution retrospective analysis of patients with a diagnosis of metastatic soft tissue sarcoma who underwent percutaneous image-guided ablation of hepatic metastases between January 2011 and December 2021 was performed. Patients with less than 60 days of follow-up after ablation were excluded. The primary outcome was local tumor progression-free survival (LPFS). Secondary outcomes included overall survival, liver-specific progression-free survival. and chemotherapy-free survival. Fifty-five patients who underwent percutaneous ablation for 84 metastatic liver lesions were included. The most common histopathological subtypes were leiomyosarcoma (23/55), followed by gastrointestinal stromal tumor (22/55). The median treated liver lesions was 2 (range, 1-8), whereas the median size of metastases were 1.8 cm (0.3-8.7 cm). Complete response at 2 months was achieved in 90.5% of the treated lesions. LPFS was 83% at 1 year and 80% at 2 years. Liver-specific progression-free survival was 66% at 1 year and 40% at 2 years. The overall survival at 1 and 2 years was 98% and 94%. The chemotherapy-free holiday from the start of ablation was 71.2% at 12 months. The complication rate was 3.6% (2/55); one of the complications was Common Terminology Criteria for Adverse Events grade 3 or higher. LPFS subgroup analysis for leiomyosarcoma versus gastrointestinal stromal tumor suggests histology-agnostic outcomes (2 years, 89% vs 82%, p=.35). Percutaneous image-guided liver ablation of soft tissue sarcoma metastases is safe and efficacious.

First-Line Anlotinib Treatment for Soft Tissue Sarcoma in Chemotherapy-Ineligible Patients: An Open-label, Single-arm, Phase 2 Clinical Trial.

Standard treatment for patients with unresectable locally advanced or metastatic soft-tissue sarcoma (LA/M STS) is chemotherapy based on anthracyclines, but patient tolerance of chemotherapy is limited. The present trial (NCT03792542) investigated the use of anlotinib as first-line treatment for patients with advanced STS, in particular liposarcoma (LPS). Eligible patients were previously untreated, pathologically confirmed, unresectable LA/M STS cases. Anlotinib was given orally at a dose of 12 mg once daily from day 1 to day 14 every 3 weeks until disease progression or intolerable adverse events (AEs) occurred. The primary endpoint was progression-free survival (PFS) and the secondary endpoints overall survival (OS), the objective response rate and the disease control rate (DCR). The safety profile was also evaluated. Forty patients were enrolled from April 2019 to Jun 2022 and are included in the intention-to-treat analysis. The median PFS was 6.83 months [95% confidence interval (CI): 4.17-8.71] and the median OS 27.40 months (95% CI: 16.43-not evaluable); 1 patient reached partial response and 26 attained stable disease, with a DCR of 67.5% (27/40). Median PFS and OS times for LPS patients were 8.71 and 16.23 months, respectively. Ten (25.0%) patients had treatment-related AEs ≥ grade 3, with in particular a higher incidence of hypertension (15.0%) and proteinuria (7.5%). The findings suggest a potential benefit in employing front-line anlotinib to treat patients with STS, who are not eligible for cytotoxic chemotherapy. Of note, the clinical outcomes for the LPS subgroup of patients were encouraging.

Abstract 1880: Ecubectedin and PM54 demonstrate antitumor activity in patient-derived xenograft models of soft tissue sarcoma

Abstract Objective: Soft tissue sarcoma (STS) is a heterogenous group of rare, malignant tumors arising from mesenchymal tissue. Doxorubicin (DOX)-based chemotherapy is the standard for advanced or metastatic STS, despite low response rates and poor disease control. We explored the antitumor activity of two novel compounds, ecubectedin (ECU; PM14) and PM54 (PharmaMar), in two patient-derived xenograft (PDX) models of STS, leiomyosarcoma (LMS) and CIC-rearranged sarcoma (CRS). Mode of action of ECU and PM54 is similar to lurbinectedin (LUR), inhibiting oncogenic transcription by eviction of oncogenic transcription factors from gene promotors’ recognition sequences, while inducing the generation of double strand breaks through DNA adduct formation. Methods: Female NMRI nu/nu mice (n=104) were transplanted bilaterally with STS PDX: UZLX-STS134 (CRS) and UZLX-STS22_2 (LMS). Xenografted mice were randomized to six treatment groups: 1) vehicle (VEH) (5% dextrose) 5 mL/kg once weekly (QW) intravenously (IV); 2) DOX 5 mg/kg QW IV; 3) trabectedin (TRA) 0.15 mg/kg QW IV; 4) LUR 0.18 mg/kg QW IV; 5) ECU 1.2 mg/kg QW IV; 6) PM54 1.2 mg/kg QW IV. Treatment lasted 16 days and antitumor activity was assessed by tumor volume (TV) analysis, histopathology and western blot. The Mann-Whitney U test was used to compare groups, the Wilcoxon test to compare to baseline. Results: ECU and PM54 caused TV shrinkage in UZLX-STS134, while TV in other groups grew significantly on day 16 (Table 1). VEH treatment led to the largest TV increase on day 16, compared to any treatment. PM54 treatment showed TV stabilization in UZLX-STS22_2, and significantly smaller tumors than VEH and TRA treated tumors (p<0.05 and p<0.01, respectively). Histopathological evaluation corroborate the results from the relative TV analysis. Conclusion: Novel drugs exhibit promising results in the PDX models tested, supporting ongoing exploration in additional PDX models of synovial sarcoma and dedifferentiated liposarcoma. Table 1: TV change on day 16 versus baseline, and comparison of proliferative and apoptotic activity Tumor volume change Proliferative activity (pHH3) Apoptotic activity (cPARP) Subtypes UZLX-STS134 UZLX-STS22_2 UZLX-STS134 UZLX-STS22_2 UZLX-STS134 UZLX-STS22_2 VEH(5 ML/kg) 387%*** 349%** n/a n/a n/a n/a DOX (5 mg/kg/QW IV) 177%*** 243%** ↓*** ↓ ↑** ↑ TRA(0.15 mg/kg/QW IV) 230%** 254%*** ↓** ↓** ↑** ↑*** LUR(0.18 mg/kg/QW IV) 202%** 232%** ↓*** ↓*** ↑*** ↑** ECU(1.2 mg/kg/QW IV) 41%*** 181%** ↓*** ↓*** ↑*** ↑*** PM54 (1.2 mg/kg/QW IV) 76%*** 162% ↓*** ↓*** ↑*** ↑ Citation Format: Daniël Gorgels, Agnieszka Wozniak, Chao-Chi Wang, Pablo M. Avilés, Maria J. Guillen, Carmen Cuevas, Patrick Schöffski. Ecubectedin and PM54 demonstrate antitumor activity in patient-derived xenograft models of soft tissue sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1880.

Combining nanoparticle albumin-bound paclitaxel with camrelizumab in advanced soft tissue sarcoma: activity, safety, and future perspectives.

Background: It is still uncertain whether Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) and programmed cell death protein 1 (PD-1) inhibitor have synergistic effects on metastatic soft tissue sarcomas (STSs). The purpose of this study was to evaluate the safety and activity of nab-paclitaxel plus camrelizumab (a PD-1 inhibitor) in patients with advanced STS who had previously failed chemotherapy. Methods: In this single-center, open-label, single-arm phase II clinical trial, patients with advanced (unresectable or metastatic) STS who had previously failed chemotherapy received up to six cycles of nab-paclitaxel plus camrelizumab, whereas camrelizumab treatment was continued for up to 1 year. The median progression-free survival (PFS), objective response rate (ORR) and safety were collected and evaluated. Results: This trial included 40 patients (28 men and 12 women). The overall ORR was 22.5%, and the median PFS was 1.65months (95% confidence interval [CI], 1.3-2.0months). Patients with epithelioid sarcoma demonstrated a longer PFS compared with those with other histological subtypes (2.3months vs. 1.5months, respectively); however, this difference was not significant. Patients who had received only one line of previous chemotherapy had a significantly longer PFS compared with those who had undergone two or more lines of previous chemotherapy (2.8months vs. 1.3months, respectively, p = 0.046). In terms of safety, the toxicity of this combination therapy is mild and no serious adverse events have occurred. Conclusion: Nab-paclitaxel plus camrelizumab exhibited modest activity and mild toxicity in treating epithelioid sarcoma, angiosarcoma, and fibrosarcoma. The overall effectiveness of this treatment regimen for advanced STS is relatively low. Further research on combining nab-paclitaxel with effective drugs, including chemotherapy and targeted agents, for these specific STS subtypes is needed.

Durvalumab plus pazopanib combination in patients with advanced soft tissue sarcomas: a phase II trial

We aimed to determine the activity of the anti-VEGF receptor tyrosine-kinase inhibitor, pazopanib, combined with the anti-PD-L1 inhibitor, durvalumab, in metastatic and/or recurrent soft tissue sarcoma (STS). In this single-arm phase 2 trial (NCT03798106), treatment consisted of pazopanib 800 mg orally once a day and durvalumab 1500 mg once every 3 weeks. Primary outcome was overall response rate (ORR) and secondary outcomes included progression-free survival (PFS), overall survival, disease control rate, immune-related response criteria, and safety. The ORR was 30.4% and the trial met the pre-specified endpoint. The median PFS was 7.7 months (95% confidence interval: 5.7–10.4). The common treatment-related adverse events of grades 3–4 included neutropenia (9 [19.1%]), elevated aspartate aminotransferase (7 [14.9%]), alanine aminotransferase (5 [10.6%]), and thrombocytopenia (4 [8.5%]). In a prespecified transcriptomic analysis, the B lineage signature was a significant key determinant of overall response (P = 0.014). In situ analysis also showed that tumours with high CD20+ B cell infiltration and vessel density had a longer PFS (P = 6.5 × 10−4) than those with low B cell infiltration and vessel density, as well as better response (50% vs 12%, P = 0.019). CD20+ B cell infiltration was identified as the only independent predictor of PFS via multivariate analysis. Durvalumab combined with pazopanib demonstrated promising efficacy in an unselected STS cohort, with a manageable toxicity profile.

Cardiac Morbidity and Mortality in Patients with Sarcoma: A Population-Based Study.

Soft tissue sarcoma (STS) is a rare malignancy that affects soft tissues. It encompasses various subtypes and requires different treatment strategies. Doxorubicin is a commonly used anthracycline in the management of localized and metastatic STS. However, high doses of doxorubicin are associated with cardiotoxicity, which can significantly impact patients' long-term outcomes. This study aimed to evaluate doxorubicin's effect on cardiac function in patients with sarcoma and to correlate the frequency of cardiotoxicity with potential risk factors. A retrospective analysis was conducted on patients with sarcoma who were treated with doxorubicin between 2016 and 2022 at King Abdulaziz Medical City in Saudi Arabia. Patient demographic information, comorbidities, cardiac measurements, laboratory values, systemic therapy, and treatment outcomes were collected from electronic medical records. A statistical analysis was performed to assess the association between cardiotoxicity and various factors. A total of 133 patients were included in the study, with a median age of 30 years. Cardiotoxicity was observed in 9% of the patients. Female patients had a significantly higher risk of developing cardiotoxicity. Patients with a higher Eastern Cooperative Oncology Group (ECOG) performance status and lower troponin I levels also had an increased risk of cardiotoxicity. However, there was no significant association between cardiotoxicity and the number of chemotherapy cycles, total cumulative dose of doxorubicin, or history of radiation. Furthermore, patients with cardiotoxicity had a higher risk of mortality. The overall survival of the patients was 18 months. Doxorubicin-associated cardiotoxicity is a concern for patients with sarcoma. Female patients and patients with a higher ECOG performance status are at an increased risk of developing cardiotoxicity. Careful monitoring and risk assessment are crucial for mitigating the adverse effects of doxorubicin treatment in patients with sarcoma. Future studies are warranted to validate these findings and explore preventive strategies for doxorubicin-induced cardiotoxicity in patients with sarcoma.

Chemotherapy With Eribulin Following Potentially Curative Surgery in Patients With Localized Liposarcoma.

Soft tissue sarcomas are rare and heterogenous malignancies with high recurrence rates following resection and a poor prognosis in advanced stages. Eribulin is used in metastatic soft tissue sarcoma patients, who have failed first line chemotherapy and has been approved for patients with pretreated advanced liposarcoma (LPS) in the United States and Europe following the publication of data of a phase III trial. In addition, no data are available for eribulin as postoperative treatment after potentially curative surgery. We, thus, retrospectively evaluated efficacy and tolerability of adjuvant eribulin in patients with LPS not suitable for intensive chemotherapy in the routine clinical setting. In this retrospective single center analysis, efficacy and safety of eribulin were retrospectively evaluated in five high risk LPS patients. Eribulin as treatment was administered to five patients with LPS following surgical resection. Median progression-free survival and overall survival were 12.3 months and 44.3 months, respectively. Toxicity was generally manageable, and grade 3+4 events were rare. Postoperative eribulin may be feasible in selected high risk LPS patients, who are not candidates for intensive chemotherapy regimens. Further prospective trials, however, are needed.

LTX-315 and adoptive cell therapy using tumor-infiltrating lymphocytes generate tumor specific T cells in patients with metastatic soft tissue sarcoma

ABSTRACTLTX-315 is an oncolytic peptide that elicits both local and systemic immune responses upon intratumoral injection. In the present pilot trial, we treated patients with metastatic soft tissue sarcoma with the combination of LTX-315 and adoptive T-cell therapy using in vitro expanded tumor-infiltrating lymphocytes. Six heavily pretreated patients were included in the trial and treated with LTX-315 of which four patients proceeded to adoptive T-cell therapy. Overall, the treatment was considered safe with only expected and manageable toxicity. The best overall clinical response was stable disease for 208 days, and in this patient, we detected tumor-reactive T cells in the blood that lasted until disease progression. In three patients T-cell reactivity against in silico predicted neoantigens was demonstrated. Additionally, de novo T-cell clones were generated and expanded in the blood following LTX-315 injections. In conclusion, this pilot study provides proof that it is feasible to combine LTX-315 and adoptive T-cell therapy, and that this treatment can induce systemic immune responses that resulted in stabilization of the disease in sarcoma patients with otherwise progressive disease. Further optimization of the treatment protocol is warranted to increase clinical activity. ClinicalTrials.gov Identifier: NCT03725605

Sex-dependent Prognosis of Patients with Advanced Soft Tissue Sarcoma.

To examine whether overall survival (OS) differs for male and female patients with advanced soft-tissue sarcoma (STS). The study included patients from Kaiser Permanente Northern California and Stanford Cancer Center with grade 2 and 3 locally advanced or metastatic STS whose tumor underwent next-generation sequencing. We used Cox regression modeling to examine association of sex and OS adjusting for other important factors. Among 388 eligible patients, 174 had leiomyosarcoma (LMS), 136 had undifferentiated pleomorphic sarcoma (UPS), and 78 had liposarcoma. OS for male versus female patients appeared to be slightly better among the full cohort [HR = 0.89; 95% confidence interval (CI), 0.66-1.20]; this association appeared to be stronger among the subsets of patients with LMS (HR = 0.76; 95% CI, 0.39-1.49) or liposarcoma (HR = 0.74; 95% CI, 0.32-1.70). Better OS for male versus female patients was also observed among all molecular subgroups except mutRB1 and mutATRX, especially among patients whose tumor retained wtTP53 (HR = 0.73; 95% CI, 0.44-1.18), wtCDKN2A (HR = 0.85; 95% CI, 0.59-1.23), wtRB1 (HR = 0.73; 95% CI, 0.51-1.04), and among patients whose tumor had mutPTEN (HR = 0.37; 95% CI, 0.09-1.62). OS also appeared to be better for males in the MSK-IMPACT and TCGA datasets. A fairly consistent pattern of apparent better OS for males across histologic and molecular subgroups of STS was observed. If confirmed, our results could have implications for clinical practice for prognostic stratification and possibly treatment tailoring as well as for future clinical trials design.

Toll-Like Receptor 4 Agonist Injection With Concurrent Radiotherapy in Patients With Metastatic Soft Tissue Sarcoma

Metastatic soft tissue sarcomas (STSs) have limited systemic therapy options, and immunomodulation has not yet meaningfully improved outcomes. Intratumoral (IT) injection of the toll-like receptor 4 (TLR4) agonist glycopyranosyl lipid A in stable-emulsion formulation (GLA-SE) has been studied as immunotherapy in other contexts. To evaluate the safety, efficacy, and immunomodulatory effects of IT GLA-SE with concurrent radiotherapy in patients with metastatic STS with injectable lesions. This phase 1 nonrandomized controlled trial of patients with STS was performed at a single academic sarcoma specialty center from November 17, 2014, to March 16, 2016. Data analysis was performed from August 2016 to September 2022. Two doses of IT GLA-SE (5 μg and 10 μg for 8 weekly doses) were tested for safety in combination with concurrent radiotherapy of the injected lesion. Primary end points were safety and tolerability. Secondary and exploratory end points included local response rates as well as measurement of antitumor immunity with immunohistochemistry and T-cell receptor (TCR) sequencing of tumor-infiltrating and circulating lymphocytes. Twelve patients (median [range] age, 65 [34-78] years; 8 [67%] female) were treated across the 2 dose cohorts. Intratumoral GLA-SE was well tolerated, with only 1 patient (8%) experiencing a grade 2 adverse event. All patients achieved local control of the injected lesion after 8 doses, with 1 patient having complete regression (mean regression, -25%; range, -100% to 4%). In patients with durable local response, there were detectable increases in tumor-infiltrating lymphocytes. In 1 patient (target lesion -39% at 259 days of follow-up), TCR sequencing revealed expansion of preexisting and de novo clonotypes, with convergence of numerous rearrangements coding for the same binding sequence (suggestive of clonal convergence to antitumor targets). Single-cell sequencing identified these same expanded TCR clones in peripheral blood after treatment; these T cells had markedly enhanced Tbet expression, suggesting TH1 phenotype. In this nonrandomized controlled trial, IT GLA-SE with concurrent radiotherapy was well tolerated and provided more durable local control than radiotherapy alone. Patients with durable local response demonstrated enhanced IT T-cell clonal expansion, with matched expansion of these clonotypes in the circulation. Additional studies evaluating synergism of IT GLA-SE and radiotherapy with systemic immune modulation are warranted. ClinicalTrials.gov Identifier: NCT02180698.

Impact of Consolidative Radiation on Overall and Progression-Free Survival in Pediatric, Adolescent, and Young Adult Metastatic Bone and Soft Tissue Sarcoma

To determine the association between consolidative radiation (RT) and survival in children, adolescents, and young adults with metastatic sarcoma. Eligibility criteria included patients aged ≤39 years with newly diagnosed metastatic bone or soft tissue sarcoma who completed local control of the primary tumor without disease progression. Consolidative RT was defined as RT to all known sites of metastatic disease. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). The least absolute shrinkage and selection operator Cox provided adjusted estimates. To account for immortal time bias, consolidative RT was used as a time-varying covariate in a time dependent Cox model. Distant failure was estimated using the Fine-Gray model. Patients (n=85) had a median age at diagnosis of 14.8 years. Most common histology was Ewing Sarcoma (45.9%) followed by rhabdomyosarcoma (40.0%). Receipt of consolidative RT was associated with Ewing Sarcoma (P < .001) and local control modality as those who underwent local control with surgery and RT compared with surgery alone were more likely to be treated with consolidative RT (P=.034). Consolidative RT was independently associated with improved OS (hazard ratio [HR], 0.41; 95% CI, 0.17-0.98; P=.045) and improved PFS (HR, 0.37; 95% CI, 0.16-0.88; P=.024) after adjusting for confounding variables and immortal time bias. Patients treated with consolidative RT also experienced a lower risk of distant failure (HR, 0.33; 95% CI, 0.17-0.64; P=.001). In an independent data set of patients with metachronous progression (n=36), consolidative RT remained independently associated with improved OS. Consolidative RT was independently associated with improved OS and PFS and decreased risk of distant failure in child, adolescent, and young adult patients with metastatic sarcoma. Future work should evaluate biomarkers to optimize patient selection, timing, and dose for consolidative RT.

1952P Efficacy and safety of utidelone in previously treated patients with advanced or metastatic soft tissue sarcomas (HX-SARC02): A prospective, single-arm, phase II study

1952P Efficacy and safety of utidelone in previously treated patients with advanced or metastatic soft tissue sarcomas (HX-SARC02): A prospective, single-arm, phase II study

LBA90 A randomized phase II study of durvalumab and tremelimumab compared to doxorubicin in patients with advanced or metastatic soft tissue sarcoma (MEDISARC, AIO-STS-0415)

LBA90 A randomized phase II study of durvalumab and tremelimumab compared to doxorubicin in patients with advanced or metastatic soft tissue sarcoma (MEDISARC, AIO-STS-0415)

LBA91 TOMAS2: A randomized phase II study from the Italian Sarcoma Group (ISG) of trabectedin plus olaparib (T+O) or trabectedin (T) in advanced, metastatic, or unresectable soft tissue sarcomas (STS) after failure of standard treatments

LBA91 TOMAS2: A randomized phase II study from the Italian Sarcoma Group (ISG) of trabectedin plus olaparib (T+O) or trabectedin (T) in advanced, metastatic, or unresectable soft tissue sarcomas (STS) after failure of standard treatments

Impact of Consolidative Radiation on Overall and Progression Free Survival in Pediatric, Adolescent and Young Adult Metastatic Sarcoma

To determine the association between consolidative radiation and survival in pediatric, adolescent, and young adult (AYA) metastatic sarcoma MATERIALS/METHODS: Eligible patients included those diagnosed with metastatic bone or soft tissue sarcoma at ≤39 years of age. Patients whose cancer progressed prior to the time of local control were excluded. Consolidative radiation (RT) was defined as RT to all sites of metastatic disease. Kaplan Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Cox proportional hazards was used to account for confounding variables. To adjust for immortal time bias (ITB), end of local control was chosen as a landmark time. Patients (n = 77) had a median age at diagnosis of 14.5 years (range: 1.7-29.7 years). The most common histology was Ewing sarcoma (49%), followed by rhabdomyosarcoma (30%). Median follow up was 28.5 months, without significant difference between patients treated with and without consolidative RT (23.7 vs. 21.5 months, p = 0.270). Median time to completion of consolidative RT from diagnosis was 8.5 months. Ewing sarcoma was more likely to be treated with consolidative RT compared to other histologies (p<0.001). Consolidative RT was associated with improved OS (2yr OS: 81.9% vs. 57.9%, p = 0.009) and PFS (2yr PFS: 71.2% vs. 30%, p = 0.001). On multivariate analysis, after accounting for age, histology, number, and type of metastases (lung, bone or other), consolidative RT remained independently associated with improved OS (hazard ratio (HR):0.36, 95% confidence interval [CI]: 0.17, 0.78, p = 0.010) and improved PFS (HR = 0.34, 95% CI = 0.16, 0.73, p = 0.006). The OS benefit for consolidative RT persisted after adjusting for ITB (1yr OS post-local control: 80.9% vs. 89.7%, p = 0.016). The effect of consolidative RT was validated in a dataset consisting of patients who were diagnosed with localized disease but had metastatic progression (n = 30). In this metachronous population, consolidative RT remained independently associated with improved OS (HR = 0.11, 95% CI = 0.03, 0.51, p = 0.004) after accounting for age. ConsolidativeRT was independently associated with improved OS and PFS in pediatric and AYA patients with metastatic sarcoma at diagnosis. The OS benefit extended to those who underwent consolidative RT for metastatic progression. Future work should evaluate biomarkers to optimize patient selection and timing and dose of consolidative RT.

Hypofractionated Accelerated Radiation Dose-Painting (HARD) vs. Standard Radiotherapy for Unresected Soft-Tissue Sarcoma

Conventionally fractionated radiotherapy (CFRT) offers modest local control (LC) for unresected soft tissue sarcoma (STS). Although STS has a low α/β (∼2 - 6) that may benefit from a hypofractionated radiotherapy regimen, it is often limited due to the toxicity risk to surrounding organs. A simultaneous integrated boost to gross disease (2.5 - 3 Gy/fraction), with lower doses to the intermediate and low risk target volume, may offer a safe isotoxic dose escalation approach. We hypothesize that this hypofractionated accelerated radiotherapy dose-painting (HARD) will improve local control compared to CFRT. We performed a single institution retrospective analysis of patients who received external beam radiotherapy with definitive intent (≥50 Gy) for unresected STS. CFRT was defined as 1.8 - 2 Gy/fraction (Gy/fx). HARD regimens consisted of 60 - 66 Gy at 3 Gy/fx or 70 Gy at 2.5 Gy/fx to gross disease, with 1.8 - 2.4 Gy/fx to intermediate and low risk regions. All anatomical sites and histologies were included. Local control (LC) was defined from date of current diagnosis, estimated by Kaplan-Meier methods via log-rank tests or Cox regression for univariate analysis (UVA), when appropriate. Cox regression multivariate analysis (MVA) included regimen, biological effective dose (α/β 6; BED6), lesion size, age, and grade. We identified 77 patients with primary and metastatic STS treated with HARD (n = 40) or CFRT (n = 37) between 1990 and 2022, with a median follow up of 24 months in surviving patients. The mean dose for CFRT and HARD are 56.8 Gy (50 - 77.4 Gy) and 64.9 Gy (60 - 70 Gy), respectively. HARD was comprised of 65% for 3 Gy/fx and 35% for 2.5 Gy/fx regimens. At the time of RT, grade 3 (69%) and extremity (39%) tumors were the most common. Tumor histology was very heterogenous across both cohorts, with undifferentiated pleomorphic sarcoma being the most common for HARD (33%) and CFRT (19%). HARD was more often utilized in stage IV patients (55% vs. 19%, p = 0.001) and had a higher mean BED6 (96 vs. 74.2 Gy, p < 0.001) than CFRT, but without differences in age (67 vs. 59 years), tumor size (8 vs. 10 cm), concurrent chemotherapy (35% vs. 30%), Karnofsky performance status (86 vs. 85), follow-up (19 vs. 28 months), and grade (all p > 0.1). On UVA, there was a LC benefit associated with higher BED6 (HR 0.94, 95% CI 0.9 - 0.98, p = 0.002) and the HARD regimen (2-year LC 95% vs. 62%, p < 0.001). On MVA, only HARD (HR 0.07, 95% CI 0.006 - 0.729, p = 0.027) was independently associated with LC. Although the HARD regimen and higher BED6 were both associated with significant improvement in LC, only the HARD regimen independently associated with a local control benefit for unresected STS. These results suggest biologic dose-intensification exploiting the low α/β of STS with an isotoxic hypofractionated regimen may be a favorable strategy for unresectable STS. Future prospective studies are necessary to validate these findings.

Metabolic Clues to Bile Acid Patterns and Prolonged Survival in Patients with Metastatic Soft-Tissue Sarcoma Treated with Trabectedin.

Metastatic soft-tissue sarcomas (mSTS) encompass a highly heterogeneous group of rare tumours characterized by different clinical behaviours and outcomes. Currently, prognostic factors for mSTS are very limited, posing significant challenges in predicting patient survival. Within a cohort of 39 mSTS patients undergoing trabectedin treatment, it was remarkable to find one patient who underwent 73 cycles of trabectedin achieving an unforeseen clinical outcome. To identify contributing factors to her exceptional long-term survival, we have explored circulation metabolomics and biohumoral biomarkers to uncover a potential distinct host biochemical phenotype. The long-term survival patient compared with the other mSTS patients exhibited a distinctive metabolic profile characterized by remarkably higher levels of ursodeoxycholic acid (UDCA) derivatives and vitamin D and lower levels of lithocholic acid (LCA) derivatives, as well as reduced levels of inflammatory C-Reactive Protein 4 (C-RP4) biomarker. Despite its exploratory nature, this study reveals a potential association between specific bile acid metabolic profiles and mSTS patients' prognosis. Enhanced clinical understanding of the interplay between bile acid metabolism and disease progression could pave the way for new targeted therapeutic interventions which may improve the overall survival of mSTS patients.