Introduction: Endometrial stromal sarcoma (ESS) is a rare tumor that remains a diagnostic and therapeutic challenge to physicians worldwide. The metastatic setting implies a poor prognosis, with a 5-year survival rate below 40%. Patients with advanced-stage high-grade ESS (HG-ESS) have limited therapeutic options, often involving various chemotherapy regimens. Case Presentation: This report depicts the case of a 47-year-old female diagnosed with HG-ESS. She underwent several lines of treatment starting with radiotherapy and brachytherapy, followed by multiple lines of treatment including trabectedin over several months. After retreatment with trabectedin and achieving disease stabilization for 10 months, treatment was optimized by trabectedin combined with radiotherapy, leading to stable disease that is still ongoing and lasts for over 17 months. Conclusion: Our case underscores the challenging nature of treating patients with HG-ESS and highlights the safety of long-term retrial with trabectedin, coupled with radiotherapy administration. This approach maintained a durable stable disease response in the metastatic setting.

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Symptomatic control and tumoral shrinkage is an unmet need in advanced soft-tissue sarcoma (STS) patients beyond first-line. The combination of trabectedin and radiotherapy showed activity in a recently reported clinical trial in this setting. This retrospective series aims to analyze our experience with the same regimen in the real-life setting. We retrospectively reviewed advanced sarcoma patients treated with trabectedin concomitantly with radiotherapy with palliative intent. Growth-modulation index (GMI) was calculated as a surrogate of efficacy. Forty metastatic patients were analyzed. According to RECIST, there was one (2.5%) complete response, 12 (30%) partial responses, 18 (45%) disease stabilizations, and nine (22.5%) progressions. After a median follow-up of 15 months (range 2–38), median progression-free survival (PFS) and overall survival (OS) were 7.5 months (95% CI 2.8–12.2) and 23.5 months (95% CI 1.1–45.8), respectively. Median GMI was 1.42 (range 0.19–23.76), and in 16 (53%) patients, it was >1.33. In patients with GMI >1.33, median OS was significantly longer than in those with GMI 0–1.33 (median OS 52.1 months (95% CI not reached) vs. 8.9 months (95% CI 6.3–11.6), p = 0.028). The combination of trabectedin plus radiotherapy is an active therapeutic option in patients with advanced STS, especially when tumor shrinkage for symptomatic relief is needed.

Background The capacity of inducing tumor shrinkage in advanced soft tissue sarcomas (STS) is an unmet need beyond the first-line of systemic therapy. Pivotal studies of approved drugs reported RECIST response rates below 10%. Thus, it is challenging to relieve symptoms related to tumor volume in patients progressing to anthracycline-based schemes. Besides that, the overall response rate (ORR) is an appropriate surrogate for overall survival. This phase II trial explores the combination of trabectedin (T) and concurrent radiotherapy (RT) in the metastatic setting and is supported by preclinical experiments and previous phase I trial. Methods Patients received T 1.5 mg/m2 in 24-h infusion and started RT (30 Gy, 3 Gy/day) from the end of the first T perfusion. Most relevant inclusion criteria were metastatic progressing STS, a maximum of two previous systemic lines for advanced disease with at least one previous anthracycline-based line. Neither all the lesions nor all the sites were required to be irradiated. The main endpoint was ORR by RECIST 1.1. A Simon 2-stage was used to estimate 35% ORR of interest for further investigation (α = 0.1, power 90%; P0 = 0.10). Central pathology and radiological review were mandatory. Results From 10/2017 to 11/2018, 27 patients were enrolled. Histologies were: leiomyosarcoma 7 (26%), synovial sarcoma 6 (22%), liposarcoma 4 (15%) and other 10 (37%). The median of previous lines was 2, and ECOG distribution was 0: 19 (70%) and 1: 8 (30%). With a median follow-up of 6 months (1-12), there were 9 events of progression and 3 events of death. The 6-month PFSR was 75% and the 6-month OSR was 86%. From 26 evaluable patients by RECIST, there were 15 PR (57.7%), 7 SD (26.9%) and 4 PD (15.4%). One G3 and 3 G1 pneumonitis were observed. One toxic death occurred (sepsis) being G3-4 neutropenia observed of 7 (26%) while febrile neutropenia was reported in 2 (7.4%) cases. Conclusions T concurrent with RT showed a relevant activity in progressing metastatic setting in a wide range of STS types, giving options for tumor shrinkage beyond the first-line of advanced STS. The RECIST ORR of 57.7% and 6-m PFSR of 75% confirm the synergy of T+RT. Clinical trial identification NCT02275286. Legal entity responsible for the study GEIS (Spanish Group for Research on Sarcoma). Funding GEIS, ISG (Italian Sarcoma Group), FSG (French Sarcoma Group); PharmaMar. Disclosure J. Martin Broto: Research grant / Funding (institution): EISAI; Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy: Lilly. A. Italiano: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Roche; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Inmune Design; Honoraria (self), Advisory / Consultancy: Epizyme; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Bayer; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self): Novartis; Research grant / Funding (self): Merck Serono; Research grant / Funding (self): AstraZeneca/MedImmune; Research grant / Funding (self): MSD Oncology. R.M. Alvarez Alvarez: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Honoraria (self): Pierre Fabre; Honoraria (self): Pfizer; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self): Bayer; Honoraria (self): Bristol-Myers Squibb; Research grant / Funding (self): Roche; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Peregrine Pharmaceuticals; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Merrimack; Research grant / Funding (institution): Janssen. A. Lopez Pousa: Travel / Accommodation / Expenses: PharmaMar. A. Redondo: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy: Clovis Oncology; Research grant / Funding (institution): Eisai. J. Blay: Honoraria (self), Research grant / Funding (self): PharmaMar. A. Gronchi: Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Lilly; Advisory / Consultancy, Travel / Accommodation / Expenses: Nanobiotix; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Honoraria (self): Pfizer. N. Hindi: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Novartis. All other authors have declared no conflicts of interest.

BACKGROUND:Myxoid liposarcoma (ML) exhibits a special sensitivity to trabectedin (T) and radiation therapy (RT). Preclinical data suggest a synergistic effect. We aimed to study safety, feasibility and activity of the administration of pre-operative concurrent T and RT in patients affected by localized resectable ML. METHODS:Patients received 3 cycles (C) of T in combination with RT (45 Gy) in 25 fractions (1.8 Gy/fraction). Dose Levels for T were: - 1 (1.1 mg/m2), 0 (1.3 mg/m2) and 1 (1.5 mg/m2). Primary endpoint was safety; antitumor activity was assessed by RECIST and Choi criteria. This study is registered at ClinicalTrials.gov, number NCT02275286. The phase 1 part of the study is complete and phase 2 is ongoing. FINDINGS:From February 2015 to May 2016, 14 patients (M/F 7/7), median age 36 years (range 24-70) and median tumor size 12.5 cm (range 7-17 cm), were enrolled. One dose limiting toxicity (G3 transaminitis) occurred at Level 0 and one (sepsis due to catheter infection) at Level 1. All patients completed RT. Five patients achieved PR (36%), 8 SD (57%), 1 distant PD (7%) by RECIST, while 12 achieved PR (86%), 1 SD (7%) and 1 distant PD (7%) by Choi criteria. Twelve patients underwent surgery. Median viable residual tumor was 5% (0-60). INTERPRETATION:T in combination with RT showed a favorable safety profile and antitumor activity in localized ML. T dose of 1.5 mg/m2 is the recommended dose for the phase 2 study, which is ongoing. FUNDING:This study was partially supported by Pharmamar.

11544 Background: Patients (pts) with advanced STS who require tumor shrinkage beyond first line, have very limited options since the approved drugs exhibit less than 10% of RECIST response. Trabectedin (T) had shown preclinical synergy with radiotherapy (RT). Low-dose RT concurrent with T was conducted in a phase I/II trial as a proof-of-concept of synergy. We present here data from the phase I (pulmonary metastatic cohort) Methods: Pts received T along with RT (30 Gy) in 10 fractions (3Gy/fr). Dose Levels for T were: -1 (1.1 mg/m2), 1 (1.3 mg/m2) and 2 (1.5 mg/m2). Dose level 1 was expanded for a better cardiotoxicity assessment. Dose-limiting toxicity (DLT) were defined as grade ≥3 events excluding G3/4 neutropenia lasting < 5 days, G3 transaminitis if not led to T delay and G3-4 nausea/vomiting due to inadequate prophylaxis. Primary endpoint was response rate according to RECIST Results: From 04/2015 to 06/2017, 18 pts were enrolled. Histologies were: synovial sarcoma in 10 (56%) pts, UPS in 3 (17%), myxoid liposarcoma, dedifferentiated liposarcoma, G3 NOS sarcoma, leiomyosarcoma and MPNST in 1 pts each. Median previous lines 1 (0-3). Twelve pts received T at dose level 1 and 6 pts at level 2. Overall, G 3/4 AEs were: neutropenia (8), ALT elevation (2), GGT elevation (2), anemia (2), febrile neutropenia and pneumonitis (1 each). There were two DLTs: Transient G4 ALT elevation in level 1 and G4 neutropenia ( > 5 days) in level 2. Based on central radiological review and 17 evaluable pts, 2 pts achieved CR (12%), 3 PR (18%), 6 SD (35%), 6 PD (35%). On local review, we found 2 CR (12%), 5 PR (29%), 4 SD (24%), 6 PD (35%). On the irradiated lesions, 4 CR (24%), 8 PR (47%), 4 SD (24%) and 1 PD (5%) were found. With a median FU of 18 m, median PFS was 2.83 (2.3-3.3). Thirteen pts (72%) have died, with a median OS of 8.77 m (3.6-13.9) and 12-month OS rate of 48% Conclusions: T concurrent with RT was feasible in pts with pulmonary metastatic STS regardless of histologic subtype. T at 1.5 mg/m2 is the recommended dose for phase II part. We confirmed the synergy of T+RT, with 71% of the irradiated lesions showing long-lasting dimensional responses. Clinical trial information: NCT02275286.

Background: In patients with advanced soft tissue sarcomas (STS) there is low probability to obtain tumor shrinkage with second-line drugs. That means that patients requiring volumetric response to palliative relief have few therapeutic options since active second-line drugs in STS exhibit less than 10% of RECIST response. Trabectedin (T) has shown to be synergistic with radiation therapy (RT) in preclinical experiments. Additionally, a substantial activity of T+RT has recently been reported in a phase I trial with 71% of overall response rate (ORR) in the irradiated nodules. Methods: Cases with advanced STS treated with T at standard dose of 1.5 mg/m2 24-h infusion and RT 30-39 Gy (3 Gy per fraction) were collected for this retrospective series from one sarcoma reference center. RT was started 24 h later the trabectedin initiation. ORR according to RECIST 1.1, progression free survival (PFS) and overall survival (OS) were analized. Results: Twenty patients with median age 51 (27-77) and male/female 9/11 were selected. STS subtypes were uterine and somatic leiomyosarcoma 5(25%) and 4 (20%) respectively, high grade myxoid liposarcoma 4 (20%) and non-L STS 7 (35%). All but one patient received previous systemic lines, 2 (0-6). Response assessment was, 5 (25%) PR, 9 (45%) SD and 6 (30%) PD. Considering only radiated lesions, response evaluation was as follows: PR 5 (25%), SD 13 (65%) and 2 (10%) PD. There were 8/12 minor responses. Patients with non-L sarcomas also had disease control (1 myxofibrosarcoma, 2 sarcoma NOS achieved minor responses, 1 fibrosarcoma, 1 malignant peripheral nerve sleath tumor, 1 synovial sarcoma with SD). There were not toxic deaths and only one G3 SAE (transaminitis). No dose-reductions or interruptions were registered. With a median follow-up of 11.2 mos (4.4-36), there were 11 progression and 6 death events. The median of PFS was 9.9 months (6.5-13.2 months) while the median OS has not been reached. Conclusions: T + RT have shown relevant clinical activity in advanced STS, whatever the histotype and location. In 70% of cases there was some shrinkage in radiated lesions bringing up the opportunity of better disease control. Both ORR and PFS were clearly superior with T + RT than historical results obtained with T alone. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: N. Hindi: Research funding to institution: Eisai, Novartis, PharmaMar; Travel funding: PharmaMar. J. Martin-Broto: Advisory: PharmaMar; Research funding to institution: Eisai, Novartis, PharmaMar; Travel funding: PharmaMar. All other authors have declared no conflicts of interest.

Appears in: INTED2016 Proceedings Publication year: 2016Page: 7068 (abstract only)ISBN: 978-84-608-5617-7ISSN: 2340-1079doi: 10.21125/inted.2016.0679Conference name: 10th International Technology, Education and Development ConferenceDates: 7-9 March, 2016Location: Valencia, Spain