bluuebunny/crossref_metadata_2025_split huggingface dataset:
A double-blind placebo-controlled randomized phase II trial assessing the activity and safety of regorafenib (REG) in patients (pts) with nonadipocytic soft tissue sarcoma (STS) previously treated with pazopanib (PAZ).
Authors: Penel Nicolas , Blay Jean-Yves , Wallet Jennifer , Ray-Coquard Isabelle Laure , Le Cesne Axel , Ryckewaert Thomas , Italiano Antoine , Salas Sebastien , Delcambre Corinne , Bompas Emmanuelle , Bertucci Francois , Saada-Bouzid Esma , Chaigneau Loic , Chevreau Christine , Thery Julien , Decoupigny Emilie , Vanseymortier Marie , Le Deley Marie-Cecile , Mir Olivier 
Published: March 2020

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.
ALT-GIST: Randomized phase II trial of imatinib alternating with regorafenib versus imatinib alone for the first-line treatment of metastatic gastrointestinal stromal tumor (GIST).
Authors: Yip Desmond , Zalcberg John Raymond , Blay Jean-Yves , Eriksson Mikael , Espinoza David , Price Timothy Jay , Marreaud Sandrine , Italiano Antoine , Steeghs Neeltje , Boye Kjetil , Underhill Craig , Naher Sayeda , Oostendorp Martinus , Gebski Val , Simes John , Gelderblom Hans , Joensuu Heikki 
Published: March 2020

11023 Background: Imatinib (IM) is the standard first-line treatment for advanced GIST and regorafenib (REG) is approved for third line therapy. We studied if an alternating regimen of two tyrosine kinase inhibitors, IM and REG, delays resistance to IM and improves outcomes. Methods: ALT-GIST (NCT02365441) is a randomised non-comparative phase II trial to investigate the efficacy of an alternating regimen (ALT) of 21-25 days of IM 400mg orally daily followed by a 3-7-day gap for washout followed by 21 days of REG 160 mg orally daily and a 7-day gap for washout. The control arm was continuous IM 400mg daily. Delayed recruitment led to revised endpoints of activity and safety. To assess clinical activity, the best objective tumor response (OTR) at 9 months was deemed to be an appropriate endpoint in the revised protocol. Results: Seventy-six eligible patients (ALT 40, IM 36) enrolled from June 2015 to September 2018 were evaluable for the OTR. The patients (pts) were predominately male (n = 51, 67%). Median age was 58 (range, 24-81) in the ALT arm and 65 (range, 35-82) in the IM arm. KIT was mutated in 63, PDGFR in 2, and wildtype in 5 tumors. Relative dose intensity in the ALT arm 102% for IM and 82% for REG and was 93% in the IM arm. Median follow-up time was 19.3 months (range 6.0-40.0).The best responses to the ALT and IM treatments were similar at 9 months, 1 vs 0 pts had complete response, 23 vs 23 partial response, 15 vs 13 stable disease, and the OTR was 60% (95% CI, 45-74%) and 64% (95% CI, 48-78%), respectively. Seven (18%) pts in ALT arm and 10 (28%) in IM arm discontinued treatment due to progressive disease. Seven pts (18%) in the ALT arm stopped protocol therapy due to unacceptable toxicity, and none in the IM arm. Fifteen (38%) pts in the ALT arm and 14 (38%) in the IM arm had serious adverse events, mostly grade 3. Progression free survival (PFS) at 1 year was ALT 0.86 (95%CI:0.69,0.94) and IMI 0.83 (95% CI 0.65-0.92), p logrank = 0.57. Conclusions: There was no meaningful difference in the primary endpoint of OTR and in PFS between the groups in this first analysis of ALT-GIST, and no unexpected safety signals. The study is ongoing and other endpoints will be reported in due course. Clinical trial information: ACTRN12614000950662.
Secondary genomic alterations in Ewing sarcoma.
Authors: Uche An , Chow Warren Allen , Millis Sherri Z. 
Published: March 2020

11024 Background: Ewing sarcoma (ES) is the second most common bone cancer in children and young adults. The prognosis of recurrent or metastatic ES is poor, with a 5-year overall survival <30%. ES is characterized by translocations involving ETS transcription factors ( EWS– FLI and EWS– ERG translocations are the most common). Secondary somatic alterations in ES are infrequently described. Aberrations in fibroblast growth factor receptor 4 ( FGFR4), a receptor tyrosine kinase protein that plays an important role in cellular processes,have been shown to contribute to carcinogenesis in different types of cancer.More recently, the FGFR4-Gly388Arg (G388R) single nucleotide polymorphism (SNP), with the substitution of arginine instead of glycine in the transmembrane domain of the receptor, is found to significantly increase the risk of breast and prostate cancer. Mouse embryonic fibroblasts derived from knock-in strain of homologous FGFR4-G388R mice display a transformed phenotype, and TGFα-induced mammary carcinogenesis in this strain is significantly enhanced. The association between FGFR4 G338R SNP and ES has not been evaluated. We evaluated the frequency of FGFR4 G338R and whether comprehensive genomic profiling (CGP) might uncover additional, potentially targetable, genomic alterations (GA) in ES. Methods: Tissue from 253 patients with ES was assayed by hybrid-capture based CGP (FoundationOne Heme, next generation sequencing (NGS), analysis which includes both DNA sequencing of 406 genes and RNA sequencing of 265 genes), performed in the course of clinical care to evaluate GAs, including base substitutions, indels, amplifications, copy number alterations and gene fusions/rearrangements. Tumor mutational burden (TMB) was calculated from a minimum of 1.4 Mb sequenced DNA and reported as mutations/Mb. Microsatellite instability (MSI) status was determined by a novel algorithm analyzing 114 specific loci. Results: CGP identified several GAs in ES: TP53 (n= 50, 20%), MLL3 (n=15, 6%), MSH3 (n=14, 5%), ARID1A (n=11, 4%) and FGFR4 (n=3, 1%). FGFR4 G338R SNP was found in almost half of the patients (n=123, 49%). Conclusions: Secondary GAs in TP53, MLL3, MSH3, ARID1A and FGFR4 were found in more than one third of patients with ES (n=93, 37%). FGFR4 G388R SNP was detected in nearly half of patients, and may represent an alternative method of sarcomagenesis. Overall, the frequency of these GAs is significantly greater than previously reported. These GAs may inform the potential for targeted therapies.
Outcomes of extra-skeletal versus skeletal Ewing sarcoma patients treated with standard chemotherapy protocol.
Authors: Salah Samer , Abuhijla Fawzi Jamil , Ismaeel Taleb , Yaser Sameer , Sultan Iyad Yasin , Shehadeh Ahmad , Abelal Samer , Al-Mousa Abdelatif , Abuhijlih Ramiz 
Published: March 2020

11027 Background: Extra-skeletal ewing sarcomas (ES) are rare, and data on outcomes following standard ES chemotherapy protocols are very limited. Methods: We retrospectively collected data on skeletal and extra-skeletal ES patients who presented with localized disease from January, 2006 to June, 2018. Disease and treatment characteristics were compared between the two groups by the chi-square test. Overall survival (OS) and local recurrence free survival (LRFS) were estimated by the Kaplan-Meier method and compared by the Log-rank test. Results: A total of 120 patients were included. Twenty-nine (24%) had extra-skeletal and 91 (76%) had skeletal ES. Location was in the extremity in 51 (43%) and non-extremity in 69 (57%). For extra-skeletal ES, tumors originated from soft tissue in 23 (79%), and viscera in 6 (21%). All patients received standard vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide (VDC-IE), with a plan for local control at week 12 of the protocol. Local control was by surgery in 76 (63%) and radiotherapy in 44 (37%). At a median follow up of 38 months, there was no difference in 5-year OS between extra-skeletal and skeletal ES patients (67% and 70% respectively, p = 0.96). Patients with visceral ES had inferior 5-year OS compared to all others (soft-tissue extra-skeletal and skeletal ES); 33% vs. 72%; p = 0.013. Resectability rate was not different between extra-skeletal and skeletal ES patients (54% and 69% respectively, p= 0.11). Furthermore, among patients who underwent surgery, there was no difference between extra-skeletal and skeletal ES patients in R0 resection rate (86% and 89% respectively, p= 0.52) and poor ( < 90%) tumor necrosis rate (62% and 46% respectively, p= 0.31). However, more local recurrences (28% vs. 10%, p= 0.034) and inferior 5-year LRFS (74% vs. 83%; p = 0.042) were observed in the extra-skeletal group, although more extra-skeletal patients received adjuvant radiotherapy; 11 (73%) vs. 21 (36%), p = 0.01. Conclusions: Patients with localized extra-skeletal ES have OS outcomes that are comparable to skeletal ES treated with standard VDC-IE chemotherapy. However, extra-skeletal ES patients are at significantly higher risk of local recurrence.
Clinical characteristics of nonosteogenic, non-Ewing’s sarcoma of the bone: Experience at the Toronto Sarcoma Program.
Authors: Veitch Zachary William Neil , Ferguson Peter Charles , Griffin Anthony , Alshammari Kanan , Al-Ezzi Esmail Mutahar , Malone Eoghan Ruadh , Demicco Elizabeth , Dickson Brendan , Catton Charles N. , Chung Peter W. M. , Gupta Abha A. , Abdul Razak Albiruni Ryan , Wunder Jay 
Published: March 2020

11029 Background: Non-osteogenic sarcoma of the bone is a rare entity comprising a heterogenous group of malignant tumors. Clinical characteristics and outcome data are sparse in the literature. We evaluated the characteristics and long-term outcomes of patients (pts) with this disease. Methods: Pts with non-osteogenic sarcoma of the bone treated at the Toronto Sarcoma Program from 1987-2017 were identified from our institutional sarcoma database. Patient characteristics (ie: age, gender, tumor size, histology, grade, necrosis, tumor location), treatment modality (ie: surgical management, chemotherapy, radiotherapy), and survival information were collected. Survival was estimated by Kaplan-Meier (log-rank). Multi-variate analysis (MVA) was used to evaluate characteristics for sarcoma specific survival. Results: Of 130 pts identified, 106 had non-metastatic disease with a median age of 46 (range 18-89). Male-to-female predominance was 1.5:1. Common histologies were undifferentiated pleomorphic sarcoma (UPS; 42%), leiomyosarcoma (21%), and fibrosarcoma (11%). Tumors were generally high grade (59%) and > 5 cm in size (73%). The majority of pts received chemotherapy (68%), with Cisplatin/Doxorubicin based regimens (95%). R0 resection was achieved in 85% of cases. Survival for the entire cohort, showed a median (m)DFS of 8.13 years (95%CI:2.52-18.02), and a mOS of 11.72 (95%CI:7.00-not reached [NR]). Median sarcoma specific survival was NR, however 15- and 25-year survivals were 60.4% and 52.6% respectively. MVA demonstrated axial tumor location (HR = 13.03; p = 0.005), no chemotherapy (HR = 4.50; p = 0.017) and tumor grade (G2: HR = 36.21; p = 0.012; G3: HR = 20.30; p = 0.015) as risk factors for sarcoma specific death. Tumor size > 10cm (p = 0.085) and necrosis > 90% (p = 0.082) trended towards significance. Conclusions: Non-osteogenic sarcoma of the bone is a rare tumor entity, with a predominant UPS histology. Patient outcomes are reasonable, with measurable long-term survival. Axial tumor location, absence of chemotherapy, and high-grade disease predict for worse survival outcome. Further evaluation with larger data series is warranted to more fully understand this disease.
Multidisciplinary treatment of 99 adult osteosarcoma (OST) patients (pts) with synchronous and metachronous metastases (mets): A retrospective series of the French Sarcoma Group (FSG).
Authors: Lavit Elise , Aldea Mihaela , Isambert Nicolas , Kurtz Jean-Emannuel , Delcambre Corinne , Lebrun-Ly Valerie , Soibinet-Oudot Pauline , Chevreau Christine , Bompas Emmanuelle , Le Maignan Christine , Boudou-Rouquette Pascaline , Le Cesne Axel , Mancini Julien , Blay Jean-Yves , Duffaud Florence 
Published: March 2020

11030 Background: Treatment (trt) options for metastatic OST are scarce. Following failure of standard 1st line therapy pts who relapse present a challenging trt dilemma, and have poor prognosis. Surgical removal of all mets is essential. Currently, there are no standardized 2nd line trt options in relapsed OST. Methods: Pts were identified from 2 sarcoma databases; Netsarc and ConticaBase. Clinical data prospectively registered in the databases were supplemented with retrospective review of the medical records. Results: From January 2009 to December 2016, we identified 99 pts, in 12 FSG centers; 30 with synchronous (SC) and 69 with metachronous (MC) mets, with 62 males. Median age was 25 years (18-53). Total number of mets was 1 for 31 pts, 2-5 for 26 and > 5 for 42. Mets sites were lung, bone and other in 77, 14 and 22 pts respectively. Median time to first MC mets was 22 months (mo) (4-97). All pts except 10 with MC mets received a 1st line systemic trt for relapse, 65 a 2d-line, 38 a 3d-line, and 20 a 4th line, with 27 pts included in a clinical trial. Sixty five pts had local trt of distant mets (surgery for 54, irradiation for 5 and radioablation for 6). Eighteen pts had repeated thoracotomies (2 for 13 pts, 3 for 5, 1 for 1 pt). Nine of 10 MC mets pts (with ≤ 5mets) who never received any systemic trt had complete mets resection, 1 had mets radioablation, all were alive at last follow-up (FU). Median FU was 16.5 mo (2-132). Median progression free survival (PFS) and overall survival (OS) were 5.5 (95%CI 4-7) and 16.5 mo (95%CI 10-25) respectively. In multivariate analysis; > 5 mets, time to 1st mets < 24 mo, were negative prognostic factors on OS and PFS (p= 0.03, 0.01 and p=0.013, 0.00 respectively). Bone mets and absence of mets surgery were negative prognostic factors on OS only (with p=0.012, 0.008). Conclusions: Adult OST pts with distant mets are heterogeneous with poor prognosis. Complete surgery of distant mets remains essential. In reference sarcoma center, OST pts at relapse with > 1 mets commonly receive >1st line of systemic trt, and are included in clinical trial. Multidisciplinary trt combining complete mets local trt and systemic therapy seems to be rational.
Multi-institutional european single-arm phase II trial of pazopanib in advanced typical solitary fibrous tumors (SFT): A collaborative Spanish (GEIS), Italian (ISG), and French (FSG) sarcoma groups study.
Authors: Jurado Josefina Cruz , Dumont Sarah Naomie , Penel Nicolas , Luna Fra Pablo , Alava Enrique , Hindi Nadia , Blay Jean-Yves , Stacchiotti Silvia , Collini Paola , Redondo Andres , Bernabeu Daniel , Lopez-Pousa Antonio , Grignani Giovanni , Moura David Silva , Martinez-Trufero Javier , Terrier Philippe , Karanian Marie , Le Cesne Axel , Casali Paolo Giovanni , Martin Broto Javier 
Published: March 2020

11038 Background: SFT is a ubiquitous uncommon soft tissue sarcoma with a pronounced hemangiopericytoma-like vascular pattern, exhibiting rich VEGF (tumor and endothelial cells) and VEGFR1/2 (endothelial cells) expression. Pathologists distinguish typical SFT (T-SFT) and malignant SFT (M-SFT) based on mitosis (≤4 vs > 4), pleomorphism or necrosis. Yet, not clear boundaries are always seen between both subtypes. We have recently published a phase II trial exploring the activity of pazopanib (P) in M-SFT (Lancet Oncol Dec 2018). Here, we present the outcome of the T-SFT cohort of the same trial. Methods: Most relevant inclusion criteria were: unresectable or metastatic, T-SFT (tumor tissue from diagnostic time) confirmed by central pathology review before accrual, with evidence of STAT6 overexpression (IHC and FISH and/or NGS), ≥18 years, ECOG 0-2, progressive, measurable disease and no previous antiangiogenic agents. Main endpoint was response rate according to Choi criteria. Central radiological assessment was mandatory. P was administered at 800 mg/d continuously till progression or toxicity. Results: From June 2014 to December 2018, 34 patients were enrolled in this cohort. The median age was 64 y (31-81). At baseline, ECOG 0/1/2 was distributed as 16/15/3; whereas, locally advanced/metastatic distribution was 11 (32%) and 23 (68%) respectively. At the time of the present analysis, 24 patients were deemed eligible and evaluable for response. Response rates according to local and central assessment were PR 6 (25%), SD 15 (62%), PD 3 (12%) and PR 12 (50%), SD 11 (46%), PD 1 (4%). With a median follow-up of 21 months, the median PFS following local and central assessment were 18.4 (6.6-30.1) and 9.8 (7.5-12.2) months respectively, both were clearly superior to that previously published in M-SFT cohort (5.57 m). The median of OS was 49.8 months. High tumor burden at baseline > 116 mm, ECOG 1-2 vs 0, and PD by local or central response assessment showed significantly worse OS. Metastatic vs locally advanced patients had a similar outcome regarding OS. Conclusions: T-SFT cohort exhibited clearly longer PFS than previous reported M-SFT cohort to pazopanib treatment, and pazopanib showed to improve the historical outcome obtained with chemotherapy in advanced SFT. Clinical trial information: NCT02066285.
Survival and signals of response in advanced sarcoma patients enrolled on phase 1 trials in the era of precision oncology and novel immunotherapies.
Authors: Sen Shiraj , Hess Kenneth R. , Hong David S. , Falchook Gerald Steven , Pestana Roberto , Janku Filip , Naing Aung , Benjamin Robert S. , Patel Shreyaskumar , Meric-Bernstam Funda , Subbiah Vivek 
Published: March 2020

11063 Background: Few effective US FDA approved therapies exist for refractory, metastatic sarcomas. Many of these patients therefore enroll onto phase 1 clinical trials. Because tumor-specific outcomes are not always reported in less common cancers such as sarcomas, outcomes of sarcoma patients treated with novel immunotherapy and targeted therapy approaches remains unknown. Methods: We analyzed clinical and next generation sequencing data from all sarcoma patients treated on phase 1 trials at MD Anderson Cancer Center (MDACC) and performed logistic and Cox proportional hazards regression analyses to evaluate response rate (RR), median time to progression (mTTP), clinical benefit rate (CBR; defined as CR, PR, or SD > 6 months), and median overall survival (OS). Results: Among the 406 patients with advanced sarcomas (321 soft tissue sarcoma, 85 bone sarcomas) treated on phase 1 trials at MDACC from May 2006 to May 2018, median age was 53 (range 11-84), 48% were female, with a median 3 prior lines of therapy (range 0-9). The most commonly treated soft tissue sarcoma subtypes included leiomyosarcoma (n = 66; 16%), liposarcoma (n = 52; 13%), GIST (n = 44; 11%), UPS (n = 14; 3%), and synovial sarcoma (n = 11; 3%) and most commonly treated bone sarcomas included osteosarcoma (n = 34; 8%), chondrosarcoma (n = 28; 7%), and Ewing’s sarcoma (n = 25; 6%). RR was 7% (95% CI 5, 10), mTTP was 2.9 months (95%CI 2.6, 3.1), CBR was 24% (95% CI 20, 29), mOS was 17.2 months (95% CI 13.8, 20.8). 2 patients had a CR as best response, 1 chondrosarcoma patient treated with an anti-APO2L/Trail agent and 1 Ewing’s sarcoma patient treated with the combination of an IGF1R inhibitor plus mTOR inhibitor. 26 patients (6%) had a PR as best response using novel immunotherapies targeting PD1, PDL1 plus CCR4, CTLA4 plus KIT, and TLR7/8 and novel targeted therapies against TRK, LRRC15, cMET, mTOR, VEGF, MDM2, KIT/PDGFRA, and FGFR. Responses were seen across sarcoma subtypes - ASPS, UPS, myxoid sarcoma, liposarcoma, GIST, carcinosarcoma, clear cell sarcoma, embryonal rhabdomyosarcoma, epitheliod sarcoma, fibrious histiosarcoma, and Ewing’s sarcoma. Conclusions: Our analysis identifies a reasonable survival in heavily pretreated, metastatic refractory sarcoma patients with responses seen with novel targeted therapies and immunotherapies that are not yet US-FDA approved. Biomarker analysis is ongoing to help identify the subset of responders in our cohort. Advanced sarcoma patients should be considered for molecular profiling and early phase clinical trials.