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397784 Background: Ripretinib, a switch-control tyrosine kinase inhibitor (TKI), is indicated for patients (pts) with gastrointestinal stromal tumor (GIST) who received prior treatment with ≥3 TKIs, including imatinib. Sunitinib is approved for advanced GIST after imatinib failure. Circulating tumor DNA (ctDNA) analysis may provide insight into the efficacy of these agents in second-line advanced GIST. Here, we present exploratory baseline ctDNA results from INTRIGUE. Methods: INTRIGUE is an open-label, phase 3 study that enrolled adult pts with advanced GIST who progressed on or had intolerance to imatinib (NCT03673501). Randomization was 1:1 to ripretinib 150 mg once daily (QD) or sunitinib 50 mg QD (4 wks on/2 wks off). Baseline peripheral whole blood was analyzed by Guardant360, a 74-gene ctDNA next-generation sequencing (NGS)-based assay. Only KIT mutations are reported here. Results: Of 453 pts in the overall intent-to-treat (ITT) population, 362 (80%) samples were analyzed. ctDNA was detected in 280/362 (77%), with KIT mutations detected in 213/280 (76%). Common resistance mutations were in the KIT activation loop (AL; exons 17/18; 89/213, 42%) and ATP-binding pocket (ATP-BP; exons 13/14; 81/213, 38%). Efficacy in pts with detectable ctDNA in the KIT exon 11 and overall ITT populations was consistent with the primary analysis based on tumor data used for randomization. Pts with KIT exon 11 + 17/18 (−9/13/14) mutations had superior progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) with ripretinib vs sunitinib, whereas pts with exon 11 + 13/14 (−9/17/18) mutations had better PFS, ORR, and OS with sunitinib vs ripretinib (Table). Subgroup safety profiles were consistent with the primary analysis. Conclusions: While KIT ATP-BP mutations predicted clinical benefit from sunitinib vs ripretinib, pts harboring resistance mutations in the KIT AL derived meaningful clinical benefit from ripretinib but not sunitinib. This study demonstrates the value of ctDNA NGS-based sequencing of the complex landscape of KIT mutations to predict the clinical benefit of ripretinib or sunitinib as second-line therapy in pts with advanced GIST. Clinical trial information: NCT03673501 . [Table: see text]

11555 Background: Results of the double-blind randomized phase 2 trial (NCT01900743), showed that regorafenib (REG) is an active treatment in patients (pts) previously treated with chemotherapy for an NASTS (cohorts B-leiomyosarcoma, C-synovial sarcoma, D-other sarcoma, Mir 2016), and in pts previously treated with pazopanib (PAZ) (cohort E, Penel 2019). We now present an updated analysis of progression-free survival (PFS) in all NASTS pts to assess the heterogeneity of treatment effect according to histological subtype and prior exposure to PAZ. Methods: Pts received REG 160 mg/d, 21/28 d, or placebo (PB). Pts receiving PB were offered optional cross over in case of centrally confirmed disease progression. The primary endpoint was PFS, according to RECIST-1.1, based on full blinded central review of imaging (including a re-review for cohorts B, C and D, because first analysis was based on a partial central review in these cohorts). Overall survival (OS) was a secondary endpoint. We performed a pooled analysis of cohorts B, C, D and E, on the intent-to-treat dataset, including a multivariate analysis with interaction terms to assess the heterogeneity of treatment effect according to covariates. Results: From 06/2013 to 10/2017, 175 pts were randomized (87 REG vs 88 PB; 56, 27, 55, 37 pts in cohorts B, C, D and E, respectively). The median age was 59 yrs (range, 20-81). There were 101 women (58%). Histological subtype was leiomyosarcoma in 80 pts (LMS; 41 REG vs 39 PB; 56 in cohort B and 24 in cohort E), synovial sarcoma in 28 (SS; 13 REG vs 15 PB; 27 in cohort C and 1 in cohort E), and other sarcoma in 67 (33 REG vs 34 PB; 55 in cohort D and 12 in cohort E). The median number of prior lines of systemic treatment was 2 (range, 1-6). Overall, 43 pts had received prior PAZ (21 REG vs 22 PB). Out of 88 pts assigned to PB, 69 switched to REG after progression (79%). We confirmed a significant PFS-benefit associated with REG in multivariate analysis of the pooled study population, with a HR = 0.48 (95%CI, 0.35–0.66, p < 0.001); median PFS = 2.1 vs 1.0 months, respectively. This benefit appears significant in each histological subtype. However, we observed a borderline interaction between histological subtype and treatment effect (p = 0.09): PFS benefit appears larger in pts with SS (HR = 0.21, 0.10-0.48, p < 0.001) and other sarcoma (HR = 0.49, 0.30-0.81, p = 0.006) than in LMS (HR = 0.59, 0.37-0.93, p = 0.022). PFS benefit appears rather homogeneous across strata of pts with vs without prior exposure to PAZ (interaction test, p = 0.26). Overall, in this study, regorafenib does not show any statistically significant OS-benefit (HR = 0.77, 0.57–1.05, p = 0.10), likely due to the fact that 79% of PB pts crossed over to REG at progression. Conclusions: The present study confirms the clinical PFS benefit associated with regorafenib in all NASTS pts, regardless of prior treatment with pazopanib. Clinical trial information: NCT01900743.

11520 Background: AcSé Pembrolizumab is a Phase 2, non-randomized parallel arms, open-label, multicentric study from Unicancer investigating the efficacy and safety of pembrolizumab monotherapy in different cohorts of patients with rare cancers (NCT03012620). Here we report the results of pembrolizumab in the rare sarcoma cohort. Methods: Selected histotypes were all rare sarcomas patients (pts) (incidence < 0.2/100,000/year). Main inclusion criteria were age > 18, ECOG PS≤1 and advanced or metastatic disease resistant to standard treatment. Patients received pembrolizumab 200 mg IV as a 30-minute infusion on Day 1 of every 21-day cycle for a maximum of 2 years. The primary endpoint was the confirmed objective response rate according to RECIST v1.1 at 12 weeks. Secondary endpoints included clinical benefit rate, duration of response, progression-free survival (PFS), overall survival (OS), and safety. Five groups of pts were distinguished, namely chordoma, alveolar soft-part sarcoma (ASPS), desmoplastic small round cell tumor (DSRCT), smarca4 deficient malignant rhabdoid tumor (SMRT), and other histotypes. Results: 98 patients including 34 with chordoma, 14 ASPS, 11 SMRT, 8 DSCRT and 31 with other histotypes, were included from July 2017 to December 2020. The median number of cycles was 5 (range, 1 to 35) with 78 (79.6%) patients who discontinued the trial after a median of 4 cycles. There were 6 (7.3%) partial response (PR) at 12 weeks. The best response was CR in 1 patient (1%), PR in 14 patients (14.3%), and stable disease (SD) in 33 (33.7%). Median duration of response was 8.2 months [IQR, 4.1 to 9.0]. The occurrence of best response depended on the histotype, with 3 (8.8%) responses in chordoma, 7 (50%) in ASPS, 3 (27%) in SMRT, 1 (12.5%) in DSCRT and 1 (3.2%) in other histotypes (p = 0.0011). At the data cut off, median PFS was 2.75 months, and median OS was 19.7 months on the overall population. Outcomes differed according to the histotype group, with the 12 months PFS rates at 31.2% (chordoma), 35.7% (ASPS), 18.2% (SMRT), 0% (DSCRT) and 3.3% (other), respectively (p < 0.0001), and median PFS at 6.6 (chordoma), 7.5 (ASPS), 1.1 (SMRT), 2.1 (DSCRT) and 2.1 months (other), while 1-year OS rates were 76.6% (chordoma), 85.7% (ASPS), 36.4% (SMRT), 17.5% (DSCRT) and 42.9% (other) with median OS only reached for SMRT (2.4 months), DSRCT (10 months), and the other histotype group (7.1 months) (p = 0.004). The side effect profile of pembrolizumab was similar to other tumor type. Conclusions: Pembrolizumab is safe and well tolerate in this pop od STS pts, AcSé study reports high levels response rate and prolonged activity in selected subtypes of rare sarcomas. Clinical trial information: NCT03012620.

e23547 Background: Gemcitabine has shown clinical activity against angiosarcoma in single cases or small series, as a single agent or in combination with taxanes. We aimed to evaluate its activity in a larger, homogeneous series of pts with advanced angiosarcoma. Methods: We retrospectively reviewed the electronic medical records of consecutive adult pts with advanced angiosarcoma treated with gemcitabine(1000 mg/m2 IV days 1, 8 and 15 of a 28-days cycle) at our institutions from January 2010 to January 2021. All cases were confirmed by an expert pathologist from the French network of Sarcoma pathologists (RRePS). Response was evaluated according to RECIST 1.1, and survival was estimated using the Kaplan-Meier method. Results: Fourty-two pts [median age : 52 years (range : 25-90), median PS : 1 (range : 0-2), 36 women)] were identified. Ten (24%) had locally advanced disease; the median number of metastatic sites was 2 (range : 1-4) in the remaining 32 pts. Primary tumor site was breast/chest wall (12), face/scalp (9), heart (8), other viscera (7) or limbs (7). Eleven (26%) occurred in previously irradiated field. All pts but 4 had received prior anthracyclines (peri-operatively or in the metastatic setting) and weekly paclitaxel, and 9 (21%) had received pazopanib. Gemcitabine was given as second, third and fourth line in 7 (17%), 20 (47%) and 15 (36%) pts, respectively. Best tumor response by RECIST 1.1 was PR (16 pts, 38%), SD (10 pts, 24%) or PD (16 pts, 38%). All pts with cardiac angiosarcoma experienced a PR, as well as 4 of 10 pts with angiosarcoma arising in irradiated field and 3 of the 4 pts with CNS metastases. Median PFS was 5.4 months (95%CI : 3.1-6.5), and median OS was 9.9 months (95%CI : 6.6-13.4). Two febrile neutropenia occurred. No new safety signal was observed. Ongoing studies are exploring whether candidate biomarkers such as hENT1 expression could help predicting the benefit of gemcitabine in pts with angiosarcoma of the heart and large vessels. Conclusions: Single agent gemcitabine has clinically meaningful activity in advanced, heavily pre-treated angiosarcoma (including cardiac angiosarcoma). This series may serve as a benchmark for future clinical trials in angiosarcoma.

11528 Background: Chordoma is a rare tumor with no approved therapy. Preclinical studies have shown expression of EGFR and activated EGFR family kinases (EGFR, HER2 and HER4). Erlotinib and other anti-EGFR agents (gefitinib and cetuximab) have shown clinical activity in advanced chordoma in single case reports or small series. We aimed to evaluate the activity of erlotinib in a larger, homogeneous series of pts with advanced chordoma. Methods: We retrospectively reviewed the electronic medical records of consecutive adult pts with advanced chordoma progressive over 6 months (+/- 2 weeks, according to RECIST 1.1), treated with erlotinib (150 mg daily) at Gustave Roussy (Villejuif, France) following multidisciplinary tumor board discussion, from January 2010 to January 2021. All cases were confirmed by an expert pathologist. Response was evaluated according to RECIST 1.1, and survival was estimated using the Kaplan-Meier method. Results: Thirty-one pts [median age : 60 years (range : 32-88), median PS : 2 (range : 1-3), 30 males)] were identified. Twenty-seven (87%) had locally advanced disease; the median number of metastatic sites was 1 (range : 1-2) in the remaining 4 pts. Primary tumor site was sacral (25), lumbar (3) or cervical (3). All pts but 6 had undergone prior surgery, and 29 (94%) had undergone radiotherapy of the primary tumor. Eight pts had received previous systemic treatments (imatinib in 4, sorafenib and regorafenib in 2 each). Best tumor response by RECIST 1.1 was PR (4 pts, 13%), SD (14 pts, 45%) or PD (13 pts, 42%). Median PFS was 6.2 months (95%CI : 4.5-9.8), and median OS was 15.9 months (95%CI : 10.6-20.2). Fourteen pts (45%) remained progression-free after 1 year, and three (10%) after two years under erlotinib. Grade 3 diarrhea occurred in 4 pts (13%) and grade 3 skin rash in 13 pts (42%). Twelve pts (39%) required dose reduction to 100 mg daily due to multiple grade 2 toxicities. Ongoing studies are exploring whether candidate biomarkers such as EGFR and HER2 expression or amplification, and their mutational status could help predicting the benefit of erlotinib in pts with advanced chordoma. Conclusions: Erlotinib has clinically meaningful but unpredictable activity in advanced chordoma. Molecular profiling would probably be of high interest in this setting. This series may serve as a benchmark for future clinical trials in chordoma.

11511 Background: Pazopanib (P) was assessed prospectively in a phase 2 study in SFT resulting in a longer progression free survival (PFS) and overall survival (OS) compared to historical controls treated with chemotherapy. No statistical correlation was found between angiogenic factors and P in its pivotal phase III sarcoma trial. In the last two years, a soaring interest on the prognostic and predictive value of inflammatory indexes such as neutrophil/lymphocyte (NLR) and platelet/lymphocyte (PLR) is emerging in sarcomas. A retrospective analysis of inflammatory indexes of patients who entered the GEIS-32 (NCT02066285) trial was performed. In that trial advanced SFT patients were treated with P from front-line. Methods: All eligible patients who entered in the typical- and malignant-SFT cohort of the GEIS-32 trial were included in this analysis. To determine NLR and PLR, baseline values of platelets (10e9/L), neutrophils (10e9/L) and lymphocytes (10e9/L) were obtained from complete blood count tests. Additionally, RDW (standardized as 1 = upper value of normal range) values at baseline were also determined. The impact of NLR, PLR and RDW on OS, PFS and Choi response were analyzed by univariate and multivariate analysis. MAXSTAT was used to determine optimal cut-off points for overall survival. Metastasis free interval (MFI), mitotic count and ECOG were also analyzed, among others. Results: Sixty-seven out of 70 enrolled SFT patients, median age 63-y and 57% female, were considered for this analysis. The median follow-up from treatment initiation was 20.0 months. High standardized RDW value at baseline (cut-off 1.03) was significantly associated with worse OS [10.7 months (95% CI 3.8-17.5) vs 49.8 months (95% CI 9.4-90.2), p < 0.001] and worse PFS [8.8 months (95% CI 0.9-7.0) vs 9.8 months (7.4-12.3), p = 0.001]. High PLR (cut-off 242) significantly correlated with worse OS [10.7 months (95% CI 5.2-16.2) vs 49.8 months (95% CI 14.6-85.0), p < 0.001] and worse PFS [4.5 months (95% CI 2.0-7.0) vs 10.1 months (95% CI 6.3-13.9), p = 0.005], and high NLR (cut-off 3.78) was significantly associated with worse OS [11.7 months (95% CI 3.5-19.8) vs NA, p < 0.001] and worse PFS [4.5 months (95% CI 1.9-7.0) vs 10.8 months (95% CI 8.7-12.9), p = 0.010]. Independent variables in multivariate analysis were NLR, RDW, MFI and mitosis for PFS; while RDW and ECOG for OS (see table). Further, NLR and mitosis were independent factors for Choi progressive disease (as best response). Conclusions: High NLR and RDW values were independent biomarkers of worse outcome in advanced SFT patients treated with pazopanib.[Table: see text]

11510 Background: DF rare locally aggressive fibroblastic non-metastasizing tumor, with an unpredictable course. Its management remains challenging, there is a current shift in standard of care from large surgical resection (SR) to active surveillance (AS). Most of DF display somatic mutation of CTNNB1, with three major hotpots: S45F, T41A and S45P. The poor prognosis of S45F is a matter of debate (Timbergen et al. Ann Surg 2019). Methods: ALTITUDES (NCT02867033) is a nationwide prospective registry of DF, diagnosed from January 2016 to December 2020 and confirmed by central pathological review. CTNNB1 mutations were identified by NGS. Primary endpoint was event-free survival (including disease progression or relapse). We have selected pts managed by AS, SR or systemic treatments as front-line. Pt undergoing R2 resection and then managed by follow-up were part of AS group. Prognostic factors were assessed using univariate and multivariate Cox Model. Results: From the 630-pts enrolled in ALTITUDES, 500 (79.3%) were eligible for the present analysis. Exclusion criteria were diagnosis before 2016 in 13 pts, multiple DF in 33 pts, 39 pts without CTNNB1 mutation analysis, and 45 pts receiving other treatments. The study population included 349 females (69.8%), the median age was 40 years (range 1-89). Abdominal wall was the predominant primary site: 161 pts (32.2%). In 430 (86.0%) cases, there was a CTNNB1 mutation, including, S45F in 56 cases (11.2%). In 70 cases (14.0%), we did not identify CTNNB1 mutation. The front-line managements were AS in 361 pts (72.2%), SR with R0/R1 margins in 57 cases (11.4%) and systemic treatments in 82 pts (16.5%). The median follow-up was 23 months (Range, 0.4-55). Overall, progression or relapse occurred in 128 pts (25.6%). We observed a significant EFS-difference between treatment groups, both in univariate and multivariate analysis with, compared to AS, a better outcome in patients with SR and worse outcome in patients who had received a systemic treatment (p = 0.01 in multivariate analysis). The risk of event was significantly associated with the tumor size, with a HR = 1.46 in tumors larger than 50 mm compared to smaller tumors (95%CI, 1.01-2.10, p = 0.04). We did not observe any significant association between the CTNNB1 mutational status and the outcome: compared to patients with another mutation, the hazard ratio associated with a S45F mutation was HR = 0.84 (95%CI, 0.48-1.46, p = 0.53) in multivariate analysis. Age, gender, location (abdominal wall versus other) were not associated with EFS. Conclusions: In this large prospective study, S45F was not an independent poor prognostic factor in DF. Size and front-line treatment drive both the outcome. The understanding and prediction of natural course of DF require further studies.

11532 Background: IM is the standard first-line therapy in advanced GIST, with a median progression-free survival (PFS) of 30 months. Recent multi-kinase inhibitors (MKIs) such as nilotinib, dasatinib or masitinib have been tested as first-line therapies in phase II/III studies. This might theoretically result in increased PFS (by the addition of a new line of treatment), or in early emergence of resistance to approved MKIs. Methods: A retrospective chart review was performed in GIST pts who received investigational MKIs (in phase II/III trials) as first-line treatment, followed by IM as second line. Data on demographics, molecular profile, PFS, and overall survival (OS) were collected in two French referral centers. Results: Of 47 pts, (57% females), 22 (47%) had a KIT exon 11 mutation, one a KIT exon 9 mutation (2%), one a PDGFR D842V mutation (2%). Five patients were wild-type for KIT and PDGFR. The mutational status was unknown in 18 pts (38 %). From 2005 to 2011, 21 pts (45%) received masitinib, 18 (38%) received dasatinib and 8 pts (17%) received nilotinib. Median PFS on first-line treatment was 18.9 months [95%IC: 9.0-26.0]. Median time-to-failure (TTF) with IM was 19.7 months [95%IC: 14.8-53.4]. Median time to second relapse was 50.2 months [95%IC: 31.2-92.2]. Thirty-five patients (74.5%) were dead at the end of follow-up. The median OS from time of initial diagnosis was 5.9 years [95%IC: 4.5-8.2]. Conclusions: GIST pts who received MKIs other than IM as first-line treatment and IM as second-line had a time to second relapse longer than that observed historically with IM in first line. This suggests that using MKIs other than IM in first line does not decrease IM efficacy in second line. Further comparative studies are needed to confirm these findings, but this is encouraging to further develop studies with other MKIs in the first line setting.

11560 Background: Since 2010, presentation to a designated sarcoma tumor board and pathological review by an expert network are mandatory for sarcoma patients in France. NETSARC+ (merging the 3 initial RREPS, RESOS & NETSARC) collected prospectively all cases of reviewed sarcomas and tumors of intermediate malignancy (TIM) nationwide. We report on the incidence of subtypes according to WHO classification from 2013 to 2016. Methods: Sarcoma expert pathologists reviewed samples were all prospectively integrated in the database; the results using the latest WHO classification are presented for the years 2013 to 2016, including yearly variations. Correlation of the incidence of each histotype with dedicated published clinical trials was conducted. Results: 139 different histological subtypes are reported among the 25172 patients with sarcomas (n = 18710, 64%) or TIM (n = 6460, 36%), respectively n = 5838, n = 6153, n = 6654, and n = 6527 yearly from 2013 to 2016. Over these 4 years, the observed yearly incidence of sarcomas, TIM, and all was therefore 79.7, 24.9 and 95.1/10e6/year, above that previously reported. GIST, liposarcoma, leiomyosarcomas, undifferentiated sarcomas represented 13%, 13%, 11% and 11% of all sarcomas. Only GIST, as a single entity exceeded a yearly incidence above 10/million per year. There were respectively 30, 63 and 66 different histological subtypes of sarcomas or TIM (single entities or lumped together, e.g. MPNST, or vascular sarcomas...) with an incidence ranging from 10 to 1/10e6/year, 1-0.1/10e6 per year, or < 0.1/10e6/year respectively. The 2 later “incidence groups” included 21% of the patients. The incidence of 8 histotypes varied significantly over this 4 years. Patients with tumors with an incidence above 1/10e6 per year have significantly higher numbers of dedicated published phase III and phase II clinical trials (p < 10e-6). Conclusions: This nationwide registry of sarcoma patients with an histology reviewed by sarcoma experts shows that the incidence of sarcoma and TIM is higher than previously reported, may vary over years for some histotypes, and that tumors with an incidence < 10e6 have a much lower access to clinical trials.

TPS11568 Background: GastroIntestinal Stromal Tumors (GIST) are paradigmatic models of cancers with a driver mutation of an oncogene, in which imatinib is recommended as adjuvant therapy or treatment of locally advanced and metastatic forms. After failure of imatinib (either progression or toxicity), sunitinib and regorafenib are indicated as 2nd and 3rd lines, respectively. Beyond approved drugs, tyrosine kinase inhibitors (TKI) can bring clinical benefit because some clones remain sensitive to TKI. Lenvatinib is a broad spectrum TKI targeting KIT, RET, PDGFRA, VEGFR 1-3 and FGFR 1-4, that is approved in the treatment of differentiated thyroid carcinoma and metastatic renal cell carcinoma and hepatocellular carcinoma. Methods: This prospective, randomized, placebo-controlled, double-blinded, multicenter trial evaluates the efficacy and safety of Lenvatinib in adult GIST patients (pts) who failed at least to previous imatinib and sunitinib. Seventy-four pts will be randomly allocated in a 1:1 ratio to receive either oral lenvatinib, at a daily dose of 24mg, or its matching placebo, continuously, until progression of disease (PD) or unacceptable toxicity. Randomization will be stratified according to the number of different previous anticancer drugs (2 or > 2). The primary objective is to compare the Progression-free survival (PFS) between arms. The expected median PFS are 1.5 month in the control arm and 3.0 months in the experimental arm (HR = 0.5). Seventy one events will provide 90% power to show significant improvement in PFS, using a 2-sided log-rank test at a 10% level. Secondary endpoints include the overall survival, the objective response rate, the best overall response, the quality of life and the safety profile. Patients allocated in the placebo arm who experience PD (RECIST 1.1) may switch to active lenvatinib. Radiological endpoints will be evaluated using the RECIST 1.1. Translational objectives will be to identify blood and tumor parameters as predictive markers of lenvatinib efficacy. Recruitment has been activated in January 2020. Ten participating sites of the French Sarcoma Group will participate in the trial. Clinical trial information: NCT04193553 .

11506 Background: U-LMS and ST-LMS are rare tumors with poor prognosis when locally advanced or metastatic, and with moderate chemosensitivity. Overall response rates (ORR) given in the 1st-line setting do not exceed 50% for U-LMS and 35% for ST-LMS with a mean response duration of 3- 6 months without impact on overall survival (OS). In 2015 we reported very encouraging results of the LMS-02 study (NCT02131480) with ORR of 59.6% in U-LMS, and 39.3% in ST-LMS with manageable toxicity (Pautier; Lancet oncol 2015). Herein, we report the updated results of progression-free survival (PFS) and final results of overall survival (OS). Methods: Patients (pts) received 60 mg/m² intravenous Doxo followed by trabectedin 1.1 mg/m2 as a 3-hour infusion on Day 1 and pegfilgrastim on Day 2, repeated every 3 weeks for up to 6 cycles. Surgery for residual disease was permitted. Patients were stratified into U-LMS and ST-LMS groups. Results: Overall, 108 patients with LMS with a median age of 59 years and mostly metastatic disease (85%) were enrolled. Of those, 77 patients (71.3%) have received all 6 cycles of treatment, and 20 patients (18.5%) had metastasis resection. With a median follow-up of 7.2 years (95% CI: 6.9 - 8.2), the overall median PFS was 10.1 months (95% CI: 8.5 - 12.6), being 8.3 months (95 CI: 7.4 - 10.3) and 12.9 months (95% CI: 9.2 - 14.1) in U and ST group, respectively. Median OS was 34.4 months (95% CI: 26.9 - 42.7), being 27.5 months (95% CI: 17.9 - 38.2) in U-LMS and 38.7 months (95% CI: 31.0 - 52.9) in ST-LMS group. The median OS among the 20 pts with surgery was not reached vs 31.6 months in the population without surgery (95% IC: 23.9 - 35.4). Conclusions: The Doxo +Trab combination is an effective 1st-line therapy for pts with LMS, with promising PFS and OS results and an acceptable safety profile. Merely for comparison, the most recent results of Doxo alone in metastatic LMS, given in 1st-line setting in a phase III ANNOUNCE trial conducted during the same period, reported median PFS of 6.9 months, and median OS of 21.9 months (ASCO 2019 LBA3). Results of the LMS04 trial (NCT02997358), a randomized phase III study comparing this combination vs Doxo alone in 1st-line therapy in metastatic LMS are pending. Clinical trial information: NCT02131480 .

LBA3 Background: Dox is standard therapy in STS. In a Ph 2 trial, olaratumab (a human IgG1 antibody targeting PDGFRα) + dox improved overall survival (OS) and progression-free survival (PFS) vs dox. ANNOUNCE aimed to confirm the OS benefit in advanced STS. Methods: Adult pts with unresectable locally advanced or metastatic STS, anthracycline-naïve, and ECOG PS 0-1 were eligible. Pts were randomized 1:1 to olaratumab (20mg/kg Cycle 1, 15mg/kg subsequent cycles) or PBO on Days 1 and 8 of each 21-day cycle combined with dox (75mg/m2) on Day 1 for up to 8 cycles. After 8 cycles, pts with disease control continued olaratumab or PBO until progression or toxicity. Randomization was stratified by histology, prior systemic therapy, ECOG PS, and geographic region. Dexrazoxane use was allowed to mitigate dox-related cardiotoxicity. Primary endpoints were OS in the intent-to-treat (ITT) population and/or leiomyosarcoma (LMS) subset of the ITT population; the study was designed to be positive if either primary endpoint was met. Secondary endpoints included PFS, response/disease control rates, safety, and pharmacokinetics. Results: 509 pts were randomized: 258 in the investigational and 251 in the control arm. Baseline pt characteristics were well balanced. Dexrazoxane was received by 63.0% vs 65.1% of pts (investigational vs control arm, respectively, for all data). In the ITT population, median OS was 20.4 vs 19.8 months (m) (HR=1.05, 95% CI: 0.84-1.30; p = 0.69) and was 21.6 vs 21.9 m in LMS pts (HR=0.95, 95% CI: 0.69-1.31; p = 0.76). Median PFS was lower in the investigational arm in the ITT population (5.4 vs 6.8 m; HR=1.23, 95% CI: 1.01-1.50; p = 0.04) and in LMS pts (4.3 vs 6.9 m, HR=1.22, 95% CI: 0.92-1.63; p = 0.17). Median dox exposure was 6 vs 7 cycles. Safety was similar between arms. Olaratumab serum concentrations reached levels expected from prior trials. Additional subgroup/biomarker results will be presented. Conclusions: ANNOUNCE did not confirm that olaratumab + dox, followed by olaratumab monotherapy, improves OS over dox in pts with advanced STS. Further analyses are warranted to explore the inconsistent outcomes between the Ph 3 and Ph 2 studies. Clinical trial information: NCT02451943.

11056 Background: We previously reported that secondary resection (2Surg) improved local relapse free (LRFS) but not overall survival (OS) in a retrospective series of pts with localized STS after unplanned 1st excision. Here we investigated the impact of 2Surg specifically after a first R1 or R2 resection in the 10931 pts with STS of the limb or trunk wall included in the nationwide NETSARC database from 2010 to 2017. Methods: NETSARC (netsarc.org) is a network of 26 reference sarcoma centers with specialized multidisciplinary tumor boards (MDT), funded by the French NCI (INCa). Since 2010, presentation to an MDTB and second pathological review are mandatory for sarcoma pts. Statistics were performed with SPSS23.0. LRFS, metastasis-free survival (MFS), OS compared with the logrank test. Results: The series included 5598 (51.2%) males. Median age was 56.7. Tumor sites: 5295 (49.4%) lower limb, 3670 (33.6%) trunk wall. 1966 (18.0%) upper limb. As previously reported in the entire series, local RFS (LRFS) and RFS (p

11062 Background: EHE is a rare vascular mesenchymal tumor for which there is currently no standard for treatment particularly for metastatic disease. EHE often present metastatic evolution but metastases are not a poor prognostic factor. The aim of this study was to improve knowledge of outcome of EHE patients and see the impact of active surveillance on outcome for metastatic EHE patients. Methods: Patients with EHE treated at three centers in France were included in this retrospective cohort. Univariate analysis of prognostic factors was performed using the Cox model. Survival was estimated using the Kaplan-Meier method and long rank analysis. Results: Fifty-seven patients with EHE were collected in this analysis: 27 (47%) women and 30 (53%) men, with a median age at diagnosis of 39 years (range, 12-83). At diagnosis, 17 (29.8%) patients had a localized tumor, while 40 (70.2%) patients had synchronous metastases. The most commonly affected organs were liver (29.8%), bones (14.0%), skin, lungs and soft tissues (10.5% each). For the 17 patients with localized EHE, the median distant recurrence-free survival after resection of primary was 64.6 months, 95% CI [29.4, NA], (median follow-up of 62.7 months, range, 12.5-234.8). For the 40 patients with metastatic EHE, the median progression-free survival (PFS) was 59.0 months, 95% CI [21.3, NA], (median follow-up of 121.1 months, range, 1.0-202.0). No prognostic factor was identified for localized EHE. For metastatic EHE, age was associated with progression (p = 0.019), and presence of pleural/ascites/pericarditis effusion adversely affected overall survival (OS) (p = 0.002). An initial “wait and see” attitude was proposed to 23 patients (57.5%) while 17 patients (42.5%) were treated at diagnosis with local or systemic treatment (monotherapy or combination of chemotherapy with anthracyclin, taxane, cyclophosphamide). OS were similar in both groups of patients, 174months and 121months for chemotherapy treated patients and active surveillance patients respectively (p = 0.56). Conclusions: Presence of effusion was a significant poor prognostic factor in metastatic EHE patients. Active surveillance could be proposed for asymptomatic patients without effusion but this strategy need to be confirmed in largest or prospective randomized trials.

e14609 Background: Radiotherapy (RT) can prime an anti-tumor immune response. Unfortunately, this response rarely generates total tumor destruction and abscopal effect. When activated by RT, intratumorally (IT) administered hafnium oxide nanoparticles (NBTXR3) locally increase radiation dose deposit and tumor cell death compared to RT alone. We hypothesized that NBTXR3 + RT could enhance the anti-tumor immune response, both in mice and humans. Methods: Murine CT26 cells were injected in both flanks of immunocompetent mice. When tumor volume reached 50-120mm3, NBTXR3 (or vehicle) was injected IT in right flank tumors only, then irradiated (3x4Gy). Mice were sacrificed when tumors reached 800mm3. Alternatively, tumors were collected 3 days after last RT fraction and immune cell infiltrates analyzed by immunohistochemistry (IHC). Patients (pts) with locally advanced Soft Tissue Sarcoma (STS) (NCT02379845) received NBTXR3 + RT or RT alone. Pre- and post-treatment (biopsy and resection, respectively) tumor tissues from pts were analyzed by IHC and Digital Pathology for immune biomarkers ( > 16 pts per arm). Results: In mice, IHC analyses showed an increase of CD8+ T cells infiltrates in both flanks of mice treated with NBTXR3+RT, while this was not observed in animals treated with RT alone. Furthermore, ICH analysis of post- vs pre-treatment samples from STS pts showed a marked increase of CD8+ and PD1 biomarkers for pts treated with NBTXR3 + RT, while no differences were seen for pts treated with RT alone. Conclusions: NBTXR3 + RT markedly changes the tumor immune profile in a similar manner in mice and pts with STS. We hypothesize that this adaptive immune response could help convert a local tumor microenvironment to a “hot” phenotype and thus improve the efficacy of immune checkpoint inhibitors. These results led us to investigate the safety and systemic effect of NBTXR3 activated by stereotactic ablative RT (SABR) in combination with anti-PD-1 antibody in pts with locoregionally recurrent or metastatic (to lung or liver) Head and Neck squamous cell carcinoma HNSCC, as well as in metastatic non-small cell lung cancer (NSCLC) and liver metastasis patients [NCT03589339].

11021 Background: After we demonstrated the activity of REG in pts with advanced non-adipocytic STS (MirTLO 2016), we conducted a dedicated study in pts previously treated with PAZ+chemo. Methods: We report here the 5th cohort of a double-blind randomized phase 2 trial (NCT01900743). Pts were treated with regorafenib (160mg/d, 21/28d) or placebo (PB). Pts receiving placebo were offered optional cross-over in case of centrally confirmed disease progression. The primary endpoint was centrally-reviewed RECIST-based progression-free survival (PFS), evaluated on the intent-to-treat dataset. A total of 24 events was required to ensure a 90%-power for HR = 0.33 (median PFS, 3·6 vs 1·2 months), with a 1-sided α = 0·1. Overall survival (OS) was a secondary endpoint. Results: From 12/2015 to 10/2017, 37 pts were randomized (18 REG vs 19 PB) and included in the final analysis. The median age was 60 (36-76). There were 28 women (76%). All pts had a performance status 0 or 1. Histological subtypes included 24 leiomyosarcoma (11 vs 13, in REG and PB, respectively), 1 synovial sarcoma (REG), 12 other sarcoma (7 vs 5). All pts had previously been treated with PAZ +chemo (including doxorubicin: 19 vs 17; ifosfamide: 11 vs 3; trabectedin: 11 vs 9; and dacarbazine: 7 vs 6), with 2-6 prior lines. The median relative dose intensity of REG was 0·86, range 0·41-1. Out of 19 pts assigned to placebo, 13 switched to REG after progression. There was no reported objective response. We observed a significant benefit of REG compared to PB in terms of PFS (HR = 0·38; 95%CI, 0·19-0·76; p = 0·007; median PFS = 2·1 vs 1·1 months, respectively), and OS despite the cross-over (HR = 0·41; 95%CI, 0·17-0·98; p = 0·04; median OS = 18·6 vs 8·2 months). Before cross-over, the most common clinically significant grade 3 or higher adverse events were diarrhea (4 vs 0), dyspnea (3 vs 1), arterial hypertension (2 vs 0), hand-foot skin reaction (2 vs 0). Conclusions: The present study demonstrates that regorafenib has a clinically meaningful anti-tumor activity in pts with non-adipocytic soft tissue sarcoma pretreated by both chemotherapy and pazopanib, improving PFS and OS. Clinical trial information: NCT01900743.

11006 Background: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal malignancy of the gastrointestinal tract. Advanced GIST is treated with tyrosine kinase inhibitors (TKIs). Most patients (pts) develop resistance over time. We reported in 2013 (Van Looy CTOS) that cabozantinib (cabo), a TKI targeting KIT/MET/AXL/VEGFR, showed activity in GIST xenograft models through inhibition of tumor growth, proliferation and angiogenesis, both in imatinib-sensitive and -resistant tumors (Gebreyohannes Mol Cancer Ther 2016;15:2845-28). Cohen (Cancer Res 2015;75:2061-70) found that cabo can overcome compensatory MET signaling in GIST in vitro. EORTC 1317 assessed the safety and activity of cabo in pts who had progressed on imatinib and sunitinib. Methods: In this multi-center, open label, single arm Phase 2 study eligible metastatic GIST pts received 60 mg (freebase weight) cabo p.o./d. Primary endpoint was progression-free survival rate at wk 12, assessed by local investigator per RECIST 1.1. If at least 21 of 41 eligible and evaluable pts were progression-free at wk 12, the activity of cabo was sufficient to warrant further exploration (A’Hern one-stage design). Results: A total of 50 consenting pts were eligible and started treatment between 02/2017 and 08/2018, with 16 (32%) still continuing cabo at the database cut-off in 01/2019. The number of 3 wk treatment cycles ranges from 2-28+. Among the first 41 eligible and evaluable pts, 24 were progression-free at wk 12, satisfying the study decision rule. Among all 50 pts, 30 were progression-free at wk 12 (60%, 95% confidence interval (CI) 45-74%). A total of 7 pts achieved a confirmed partial response (PR) (14%, 95%CI 6-27%) and 33 had stable disease (SD) (66%, 95%CI 51-79%). Progression as best response was seen in 9 pts (18%, 95%CI 9-31%), one was not evaluable. Disease control (PR+SD) was achieved in 40 pts (80%, 95%CI 66-90%). Median progression-free survival was 6.0 mo (95%CI 3.6-7.7). The most common cabo-related grade ≥3 adverse events were diarrhea (74%), hand-foot syndrome (58%), fatigue (46%), hypertension (46%), weight loss (38%) and oral mucositis (28%), with 33 (66%) pts requiring dose reductions, 25 (50%) treatment interruptions and no cabo-related deaths. Conclusions: EORTC 1317 met its primary endpoint, with 24/41 pts (58.5%) being progression-free at wk 12. Results of this trial confirm preclinical data and warrant further exploration of cabo in GIST. Clinical trial information: NCT02216578.

TPS11078 Background: We have recently identified a gene expression signature so called “CINSARC” which is related with chromosomal instability and highly predictive of metastasis-free and overall survival in soft-tissue sarcoma (STS) patients. The prognostic relevance of this signature has been validated recently in an independent set of sarcomas from the Cancer Genome Atlas (TCGA) consortium. Despite optimal locoregional treatment, patients with high-risk CINSARC have a very poor outcome.However, the main issues with peri-operative chemotherapy in STS patients are the identification of patients who are more likely to benefit from this approach and the characterization of the best chemotherapy regimen. Indeed, in all clinical trials investigating peri-operative chemotherapy in STS, patients were included on the basis of classical histological criteria (grade, tumor size, deep location). The CINSARC is more discriminant than grade to evaluate the prognosis of STS patients (35% of grade 3 are low-risk CINSARC and 40% of grade are high-risk CINSARC). We hypothesize than: (1) 6 cycles of anthracyclines-ifosfamide is associated with improved outcome in comparison to 3 cycles of chemotherapy (ISG-STS 10-01) in patients with high-risk CINSARC STS; (2) Chemotherapy-free strategy is not associated with detrimental outcome in low-risk CINSARC STS. Methods: This is a multicenter phase III trial (sponsor: Institut Bergonié) which aims to evaluate the efficacy (intent-to-treat analysis) of 6 cycles of neoadjuvant doxorubicin + ifosfamide based chemotherapy+ surgery +/-radiotherapy (Arm B) in comparison with 3 cycles of neoadjuvant doxorubicin + ifosfamide based chemotherapy + surgery +/- radiotherapy (Arm A) in terms of 3-year progression-free survival (PFS) in high-risk CINSARC patients with resectable STS. Patients with low-risk CINSARC signature will be treated at investigator discretion. 334 patients will have to be recruited over 36 months in 10 centers of the French Sarcoma Group. This is the first study assessing the impact of peri-operative chemotherapy in STS based on a prognostic molecular signature. The study is open for accrual at time of submission. Clinical trial information: NCT03805022.

Purpose Aberrant mammalian target of rapamycin (mTOR) signaling is common in sarcomas and other malignancies. Drug resistance and toxicities often limit benefits of systemic chemotherapy used to treat metastatic sarcomas. This large randomized placebo-controlled phase III trial evaluated the mTOR inhibitor ridaforolimus to assess maintenance of disease control in advanced sarcomas. Patients and Methods Patients with metastatic soft tissue or bone sarcomas who achieved objective response or stable disease with prior chemotherapy were randomly assigned to receive ridaforolimus 40 mg or placebo once per day for 5 days every week. Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), best target lesion response, safety, and tolerability. Results A total of 711 patients were enrolled, and 702 received blinded study drug. Ridaforolimus treatment led to a modest, although significant, improvement in PFS per independent review compared with placebo (hazard ratio [HR], 0.72; 95% CI, 0.61 to 0.85; P = .001; median PFS, 17.7 v 14.6 weeks). Ridaforolimus induced a mean 1.3% decrease in target lesion size versus a 10.3% increase with placebo (P < .001). Median OS with ridaforolimus was 90.6 weeks versus 85.3 weeks with placebo (HR, 0.93; 95% CI, 0.78 to 1.12; P = .46). Adverse events (AEs) more common with ridaforolimus included stomatitis, infections, fatigue, thrombocytopenia, noninfectious pneumonitis, hyperglycemia, and rash. Grade ≥ 3 AEs were more common with ridaforolimus than placebo (64.1% v 25.6%). Conclusion Ridaforolimus delayed tumor progression to a small statistically significant degree in patients with metastatic sarcoma who experienced benefit with prior chemotherapy. Toxicities were observed with ridaforolimus, as expected with mTOR inhibition. These data provide a foundation on which to further improve control of sarcomas.

Purpose Desmoid tumors are mesenchymal fibroblastic/myofibroblastic proliferations with locoregional aggressiveness and high ability to recur after initial treatment. We present the results of the largest series of sporadic desmoid tumors ever published to determine the prognostic factors of these rare tumors. Patients and Methods Four hundred twenty-six patients with a desmoid tumor at diagnosis were included, and the following parameters were studied: age, sex, delay between first symptoms and diagnosis, tumor size, tumor site, previous history of surgery or trauma in the area of the primary tumor, surgical margins, and context of abdominal wall desmoids in women of child-bearing age during or shortly after pregnancy. We performed univariate and multivariate analysis for progression-free survival (PFS). Results In univariate analysis, age, tumor size, tumor site, and surgical margins (R2 v R0/R1) had a significant impact on PFS. PFS curves were not significantly different for microscopic assessment of surgical resection quality (R0 v R1). In multivariate analysis, age, tumor size, and tumor site had independent values. Three prognostic groups for PFS were defined on the basis of the number of independent unfavorable prognostic factors (0 or 1, 2, and 3). Conclusion This study clearly demonstrates that there are different prognostic subgroups of desmoid tumors that could benefit from different therapeutic strategies, including a wait-and-see policy.

11538Background: PPIs alter the PK of several oral drugs, either through a decrease in absorption due to higher GI tract pH, or the induction of efflux pumps such as ABCB1. The PK of SU is well cor...

TPS11587Background: PD-L1 is expressed in soft tissue sarcomas (STS) but PD-1 inhibition alone has limited activity. This primary resistance may partly be explained by IDO pathway activation. Epige...

11564Background: Soft tissue sarcomas (STS) are rare tumors accounting for less than 1% of human cancers. While the highest incidence of sarcomas is observed in elderly, this population is often ex...

11508Background: With the exception of a study in translocation-related STS (Kawai, 2015), T has never been compared to BSC in a study including patients (pts) with all sarcoma histotypes. The effi...

11568Background: Retroperitoneal sarcoma (RPS) are complex to treat. We previously reported that management and surgery in a reference center are independent prognostic factors for relapse free sur...

11580Background: Neo-adjuvant CT with anthracyclines plus ifosfamide (AI) is a therapeutic option in patients (pts) with marginally LASTS, aiming at a local benefit, facilitating surgery, in additi...

11548Background: This study describes clinical characteristics of a large cohort of aSTS patients (pts) and effectiveness of chemotherapy (CT) based on real world data. Methods: Multicenter retrosp...

11569Background: Options for limb-preserving surgery in locally advanced (LA) STS include chemotherapy and/or radiotherapy (RT), or ILP with tumour necrosis factor-alpha (TNFa) + melphalan, if the ...

e15149Background: Radiotherapy (RT) can prime an anti-tumor immune response. Unfortunately, this response is not sufficient to allow tumor destruction and abscopal effect (effect on a distant untre...

e23512Background: Imatinib (IM) treatment should be continued indefinitely in advanced GIST since treatment interruption is generally followed by rapid tumor progression in almost all cases, even w...

Purpose Given the importance of angiogenesis in soft tissue sarcoma (STS), pazopanib, an oral angiogenesis inhibitor that targets vascular endothelial growth factor receptor and platelet-derived growth factor receptor, was explored in patients with advanced STS. Patients and Methods Patients with intermediate- or high-grade advanced STS who were ineligible for chemotherapy or who had received no more than two prior cytotoxic agents for advanced disease, who had documented progression, who had adequate performance status, and who had good organ function were eligible. Pazopanib 800 mg was given daily. The primary end point was progression-free rate at 12 weeks (PFR12 weeks). Secondary end points were response, safety, and overall survival. Four different strata were studied: adipocytic STS, leiomyosarcomas, synovial sarcomas, and other STS types. A Simon two-stage design was applied (P1 = 40%; P0 = 20%; α = β = .1) for each stratum. Results One hundred forty-two patients were enrolled. The adipocytic STS stratum was closed after the first stage, given insufficient activity (PFR12 weeks, five [26%] of19). PFR12 weeks was 18 (44%) of 41 patients in the leiomyosarcoma cohort, 18 (49%) of 37 in the synovial sarcomas, and 16 (39%) of 41 in the other STS types. Compared with historical controls who were treated with second-line chemotherapy, progression-free and overall survivals were prolonged in the three cohorts in which the primary end point was reached. The most frequent drug-related toxicities were hypertension, fatigue, hypopigmentation, and nausea. Other toxicities included liver enzyme elevations, myelosuppression, and proteinuria, all of which were mostly grades 1 to 2. The most frequent grades 3 to 4 toxicities were hyperbilirubinemia (6.3%), hypertension (7.7%), and fatigue (7.7%). Conclusion Pazopanib is well tolerated in patients with relapsed, advanced STS and demonstrates interesting activity that warrants additional study in patients with leiomyosarcomas, synovial sarcomas, and other STS types.

Purpose Single-agent doxorubicin remains the standard treatment for advanced soft tissue sarcomas. Combining doxorubicin with standard-dose ifosfamide has not been shown to improve survival and is associated with a significantly increased toxicity; it is not known whether higher dose single-agent ifosfamide is superior to doxorubicin. Patients and Methods This randomized prospective multicenter phase III trial was designed to compare progression-free survival of patients with advanced soft tissue sarcoma receiving either regimen of standard doxorubicin 75 mg/m2 every 21 days, ifosfamide 9 g/m2 over 3 days continuous infusion, or ifosfamide 3 g/m2 per day in 3 hours over 3 days. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, and toxicity. Results The study included 326 patients. Grade 4 leukopenia, neutropenia, febrile neutropenia, and encephalopathy were more frequent in the ifosfamide arms. Progression-free survival, overall survival, and response rates were not significantly different between the three arms. An independent data monitoring committee reviewed the interim data and recommended early closure of the trial for futility (ie, no significant difference would be shown). Conclusion Single-agent doxorubicin remains the treatment of choice for patients with advanced soft tissue sarcoma.

11041 Background: A subset of metastatic GIST exhibit very long-term survival after imatinib (IM) introduction. The aim of this study was to analyse the clinico-biological characteristics of GIST pts alive > 10 years (yrs) after diagnosis (dx) of metastases (mets) and identify possible factors associated with long-term survival. Methods: Pts were identified from 2 sarcoma databases; NetSarc and ConticaGIST. Clinical data prospectively registered in the databases were supplemented with retrospective review of medical records. Results: We identified 141 pts (75 men, 66 women) with median age 54 (17-84) yrs and median ECOG 0 (0-2). Primary tumors (T) were all CD117+, and mainly gastric or intestinal (64 & 45 pts), with median size 10 (2-40) cm, CD34+ (82 pts), mitoses/50 HPF ≤ 5 (n = 36), or > 5 (n = 81). Genotype was documented in 82 (58%) pts with 73 (89%) KIT mutations (in exons 11,9 and 12 of 69, 3, and 1 pts respectively) and 9 WT KIT. 129 (91%) T were resected, 124 upfront, 5 post IM, with R0/R1/R2 resections in 61, 11, and 10 pts. Mets were mainly hepatic or peritoneal (78 & 51 respectively). 1st line TKI was given to 139 pts: 130 received IM; 88 (63%) within a clinical trial (CT), 41 (29%) had mets resection. Second, 3d and 4th line TKI were given to 81, 51 and 37 pts respectively, comprising 27, 7 and 10 from CT. Median number of TKIs was 2 (0-7), but 60 (44%) pts received only 1st line with no GIST progression within or after 10 yrs. 2 pts never received TKI but had mets resection. After median FU of 14.3 yrs (10-34.5), 104 remain alive, 37 died. Mean and Median OS from initial dx are 24 yrs (CI95% 21.6-27) and 20,8 yrs. Median PFS on TKIs are 127, 29, 21 and 22 mos on 1st, 2d, 3d and 4th line of TKI. In univariate analysis no factor is significantly associated with OS, but T size (≤ 10 vs > 10 cm) and oligometastatic disease (≤5 vs > 5 mets) are borderline significant (p = 0.056 and 0.07), and good PS (ECOG ≤ 1) at 2dline TKI initiation is associated with better PFS (p = 0.03). Conclusions: This large series of long-term ( > 10 yrs) survivors of metastatic GIST shows a high proportion of mets resection and a longer duration of PFS for TKI at any line. In this selected population, no prognostic factor is associated with long OS.

11067 Background: Sarcomas are a variety of rare connective tissue cancers. Doxorubicin and olaratumab (Ab against PDGFRA) improved survival in a recent Phase 1/2 study. Besides PDGFRA mutated gastrointestinal stroma tumor (GIST) and dermatofibrosarcoma protuberans, the role of PDGFR and the according ligands in the biology of sarcoma remain unclear. Methods: The expression levels of PDGF (A,B,C,D) and PDGFRs (A,B,L) were studied in a series of 255 sarcoma pts in localized phase using the Agilent 014850 platform. Data are available online (http://atg-sarc.sarcomabcb.org). Histologies were GIST (n = 60), myxoid liposarcoma (MLPS, n = 50), synovial sarcoma (SyS, n = 58), and sarcoma with complex genomics (SCG, n = 87). Expression levels were analyzed and tested for prognostic values for metastasis free survival (MFS) in uni- and multivariate analysis using SPSS 19.0. Results: Expression levels (ELs) of PDGFs and PDGFRs varied across histotypes: PDGFA levels were highest in SyS and lowest in MLPS (p < 0.0001). PDGFB and C levels were lower in GIST (p < 0.0001), while PDGFD ELs were similar across histological subtypes. PDGFRA ELs were highest in MLPS, while PDGFRB & L ELs were lowest in GIST and SyS (p < 0.0001 all). Complex patterns of correlation of expression between ligands and receptors were observed in each individual subtypes. PDGFA ELs above median were associated with a marginally higher risk of metastasis . Conversely, PDGFD ELs above median was associated with a reduced risk of metastasis in the whole cohort (p = 0.02). The ELs of the 3 receptors were not correlated to MFS. In multivariate analysis using Cox model on the non-GIST sarcoma cohort (histology, grade, depth, with size, PDGFA, PDGFD as continuous variables): histology, size, grade and PDGFA ELs were independent adverse prognostic factors (PF), while PDGFD ELs was a favorable PF for MFS. In the GIST cohort, testing AFIP score, PDGFA & D ELs as continuous variable, PDGFD ELs was also an independent favorable PF for MFS, in addition to AFIP score. Conclusions: The expression of PDGFs and the according receptors varies across sarcoma histological subtypes. PDGFA and D expression levels correlate independently to the risk of metastatic relapse.

11053 Background: There is a good rationale for immunotherapy in sarcoma. We report results of the first open-label multicentre phase 2 study assessing the anti-PD-1 antibody pembrolizumab in combination with metronomic cyclophosphamide (CP) in patients (pts) with advanced soft tissue sarcomas (STS) and gastro-intestinal stromal tumor (GIST). Methods: This trial included 4 cohorts of pts with advanced STS: leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS), other sarcomas (Others), and GIST. All pts received CP 50 mg BID one week on, one week off, and pembrolizumab 200mg IV q21 days. The primary endpoint encompassed non-progression and objective response at 6 months per RECIST evaluation criteria v1.1 for LMS, UPS, and Others, and 6-month non-progression for GIST. Correlative studies of immune biomarkers were planned on pt’s tumor and plasma samples. Results: Between June 2015 and July 2016, 57 pts were included, and 50 were assessable for efficacy. Three pts experienced tumor shrinkage resulting in a partial response (PR) in one of them. The 6-month non-progression rate was 0%, 0%, 14.3% (95%CI 1.8-42.8), and 11.1% (95%CI 2.8-48.3) in LMS, UPS, Others, and GIST respectively. The most frequent adverse events were grade 1 or 2 fatigue, diarrhea, anemia. The only pt who experienced PR was the only one with a PD-L1-positive staining in more than 10% of immune cells on archived tumor sample. A strong macrophage infiltration was observed in tumor samples, and these macrophages largely expressed the inhibitory enzyme Indoleamine-2,3-dioxygenase-1 (IDO1). Moreover, a significant increase of the kynurenine/tryptophane ratio was observed in pts plasma samples during study treatment (p =0.0007). Conclusions: PD-1 inhibition has limited activity in advanced STS and GIST. This primary resistance may be explained by the low percent of PD-L1 positivity in these tumors, and an immune-suppressive tumor microenvironment resulting from macrophage infiltration and IDO1 pathway activation. Further strategies assessing drugs such as CSF1-R inhibitors and/or IDO inhibitors combined with anti-PD-1/PD-L1 in selected sarcoma subtypes are warranted. Clinical trial information: NCT02406781.

11052 Background: Based on the placebo (PBO) controlled phase 2 trial (Mir, Lancet Oncol 2016), RE has shown to be an active drug in patients (pts) with leiomyosarcoma (LMS), synovial sarcoma (SS) and other non-adipocytic sarcoma (OTH), but not in liposarcoma. Pts initially allocated to PBO were allowed to cross-over to RE after progression. We here report the activity of RE after cross-over. Methods: From July 2013 to Dec 2014, 138 pts were enrolled in the non-adipocytic sarcoma cohorts (LMS, SS & OTH). After update in Dec 2016, median follow-up was 32 mo (vs 17 mo in the initial publication). Benefit of RE vs PBO in terms of progression-free survival (PFS) and overall survival (OS) from randomization was estimated by hazard ratio (HR) in Cox models. In the PBO arm, intra-patient benefit of RE after cross-over was evaluated by the growth modulation index (GMI), where PFS1=PFS with PBO before cross-over, and PFS2=PFS with RE after cross-over. The impact of timing of RE allocation (delayed after cross-over, vs early at study entry) was evaluated by comparing PFS after cross-over in PBO arm to PFS after randomization in RE arm. Results: As detailed in the table, major PFS benefit of RE vs PBO allocated by randomization was confirmed with long follow-up (HR=0.50 [95%CI 0.35-0.71] p

11024 Background: WP is an active regimen for treatment of AS pts (Ray-Coquard JCO 2015). We report here the correlative analysis conducted during a phase 2 trial assessing WP +/- B. Methods: Circulating pro/anti-angiogenic factors (FGF, PlGF, SCF, Selectin, thrombospondin, VEGF, VEGF-C) were collected at D1 and D8. Prognostic value for PFS was assessed using Cox model (biomarkers as continuous variables). We attempt to identify subgroups of pts benefiting from adding B using interaction tests (predictive factors). Results: Among the 51 pts enrolled in this trial, 45 were analyzable: 20 in Arm A (WP without B) and 25 in Arm B (with B). Median PFS was 5.5 and 6.1 months, respectively (p = 0.84). Samples were collected in 45 pts at D1 and 42 pts at D1 and 8. Baseline biomarkers were similar in both arms (excluding Selectin, significantly lower in arm A: median of 25 vs. 35 ng/mL, p = 0.03). In arm A, there was no significant difference between values at D1 and D8. In arm B, there were a significant decrease in VEGF (from a median of 0.49 to 0.08 ng/mL; p < 0.01) and selectin (from a median of 35.3 to 31.7 ng/mL; p < 0.01), and a significant increase in PlGF (from a median of 16.1 to 30.0 pg/mL; p < 0.01). In univariate analysis, factors associated with PFS were: de novo vs. radiation-induced AS (HR = 2.39 (p < 0.01), visceral vs. superficial AS (HR = 2.04; p < 0.03), VEGF-C at D1 (HR = 0.77; p < 0.03), FGF at D8 (HR = 1.17; p < 0.01), difference in FGF D8-D1 (HR = 1.24; p < 0.01), and PlGF value at D1 (HR = 1.02; p < 0.05). In multivariate analysis, factors associated with PFS were: de novo AS (HR = 2.39; p = 0.03), VEGF-C at D1 (HR = 0.73; p < 0.02) and FGF difference between D8 and D1 (HR = 1.16; p < 0.02). None of these factors were associated with benefit of adding B. Conclusions: Baseline VEGF-C levels and change in FGF were independent prognostic factors in pts with or without B. Addition of B significantly decreased the level of circulating VEGF and selectin and increased the level of circulating PlGF in AS patients. We did not identify subgroup of pts benefiting from adding of B to WP. Clinical trial information: NCT01303497.

e22504Background: Therapeutic options in adult patients with advanced or metastatic osteosarcoma (OS) are limited, and effective systemic treatments are needed in this setting. Methods: Retrospecti...

11003Background: We investigated the activity and safety of RE in doxorubicin-pretreated metastatic soft tissue sarcomas (STS). Methods: REGOSARC (NCT01900743) consisted of 4 independent cohorts of...

11013Background: Since 2009 a network of 26 reference multidisciplinary centers aiming to improve the quality of care for sarcoma patients (pts) in France was granted by the French National Cancer Institute. We report here on the results of this network on patient management after 5 years. Methods: Data of the NetSarc network database include pts characteristics, previous treatment and diagnosis procedures, medical decision, survival and progression. From Jan 2010 to Dec 2014, 13454 newly diagnosed pts were included, soft tissue and visceral representing 10427 (77%) and 3027 (23%) respectively. These represent an estimated 78% of sarcoma case in France in 5 years. Individual Netsarc enters managed a median of 325 (range 39-1529) pts in 5 years. Results: 6955 women (52%) and 6499 men (48%), with a median age of 60y (range 0-101) were included. Soft tissue and visceral represented 10427 (77%) and 3027 (23%) pts respectively. LMS (12%), GIST (8.2%), DDLPS (7.3%) and UPS (11%) were the most frequent histotype...

e22549Background: Epithelioid sarcoma (ES) is a rare soft tissue sarcoma subtype, with poor and short-term responses to conventional, doxorubicin-based chemotherapy (Jones et al, Am J Clin Oncol 20...

11050Background: Desmoid tumors (DT) are locally aggressive neoplasms, with a need for effective systemic treatment in locally advanced or progressive disease, in order to avoid the short- and long...

2515 Background: SAR405838 is an oral antagonist of HDM2 that results in p53 induction. In an ongoing Phase I study, p53 activation was demonstrated at doses that have an acceptable safety profile....

10520 Background: To report in a hypothesis-generating phase II study the activity and safety of SO in advanced chordomas. Methods: Pts received SO 800 mg/d until progression, intolerance or up to ...

LBA10502 Background: In a phase II study of pts with advanced soft tissue sarcoma, 32% and 47% of pts with LMS and ADI respectively, treated with the microtubule dynamics inhibitor eribulin achieved progression-free survival (PFS) at the 12 wk timepoint (Schöffski et al. Lancet Oncol. 2011; NCT00413192). Based on these findings, this phase III study (NCT01327885) compared overall survival (OS) in pts with advanced LMS and ADI treated with eribulin or dacarbazine. Methods: Pts aged ≥ 18 yrs with advanced high/intermediate grade LMS or dedifferentiated, myxoid, round cell or pleomorphic variants of ADI incurable by surgery and/or radiotherapy were enrolled. Pts had ECOG status ≤ 2 and had received ≥ 2 standard systemic treatment regimens including an anthracycline. Pts were randomized 1:1 to eribulin (1.4 mg/m2, IV on D1 and D8) or dacarbazine (850–1200 mg/m2, IV on D1) every 21 days until disease progression. Primary endpoint was OS. Secondary endpoints included PFS, PFS rate at Wk 12 and safety. Results: Overall, 452 pts (67% female; 79% < 65 yrs) were randomized (228 eribulin; 224 dacarbazine). Median OS for eribulin and dacarbazine was 13.5 and 11.5 months, respectively (HR = 0.768, 95% CI 0.618–0.954; P= 0.017). PFS was 2.6 months in both arms (HR = 0.877, 95% CI 0.710–1.085; P= 0.229). PFS rate at Wk 12 was 33% and 29% for eribulin and dacarbazine, respectively. In eribulin and dacarbazine arms, respectively, 26% and 14% of pts required dose reductions and 8% and 5% discontinued due to treatment-emergent adverse events (TEAEs). TEAEs were more frequent in eribulin than dacarbazine arm, including neutropenia (44% vs 24%), pyrexia (28% vs 14%), peripheral sensory neuropathy (20% vs 4%) and alopecia (35% vs. 3%); as were TEAEs of grade 3 (63% vs 53%), grade 4 (26% vs 20%), and fatal TEAEs (4% vs 1%). Thrombocytopenia was more frequent in dacarbazine than eribulin arm (28% vs 6%). Conclusions: This phase III trial of eribulin trial met its primary objective of OS benefit in pretreated pts with advanced LMS or ADI. Eribulin had a toxicity profile consistent with prior experience, with no unexpected or new safety findings. Funding Source: Eisai Inc. Clinical trial information: NCT01327885.

10506 Background: GIST is the most common mesenchymal neoplasm of the gastrointestinal tract. Imatinib followed by sunitinib then regorafenib is the usual sequence in advanced setting. P is effecti...

10523 Background: Trabectedin (T) maintenance beyond 6 cycles (cy) of treatment in responding pts with ASTS is associated with improved outcomes (Retrospective on database analysis; ASCO 2013). Her...

10563 Background: Functionalized hafnium oxide nanoparticles (NBTXR3) have been developed as selective radioenhancers, which may represent a breakthrough approach for the local treatment of solid t...

e21522 Background: Trabectedin is approved in the European Union for patients (pts) with advanced soft tissue sarcoma (STS) after failure of anthracyclines or ifosfamide. Methods: Consecutive pts w...