bluuebunny/crossref_metadata_2025_split huggingface dataset:
Three versus one year of adjuvant imatinib for high-risk gastrointestinal stromal tumor (GIST): Survival analysis of a randomized trial after 10 years of follow-up.
Authors: Joensuu Heikki , Eriksson Mikael , Sundby Hall Kirsten , Reichardt Annette , Hermes Barbara , Schuette Jochen , Cameron Silke , Hohenberger Peter , Jost Philipp , Al-Batran Salah-Eddin , Lindner Lars H , Bauer Sebastian , Wardelmann Eva , Nilsson Bengt E. , Kallio Raija S. , Jaakkola Panu , Junnila Jouni , Alvegard Thor , Reichardt Peter 
Published: May 2020

11503 Background: Adjuvant imatinib improves recurrence-free survival (RFS) when administered after surgery to selected patients with operable gastrointestinal stromal tumor (GIST). It is uncertain whether overall survival (OS) improves, since imatinib improved OS in only one of the 3 large randomized trials conducted, and in this trial (the Scandinavian Sarcoma Group XVIII/German trial; SSGXVIII/AIO; NCT00116935) the statistical significance for OS remained borderline. The objective of the present analysis was to evaluate long-term OS of patients who participated in the SSGXVIII/AIO trial. Methods: SSGXVIII/AIO is an open-label, randomized (1:1), multicenter phase 3 trial. Four hundred patients who underwent macroscopically complete surgery for GIST with a high estimated risk for recurrence according to the modified National Institutes of Health Consensus Criteria were accrued between February 2004 and September 2008. Imatinib was scheduled to be administered 400 mg/day orally for either 12 months or 36 months after surgery. The patients were scheduled to be followed up for 10 years after study entry. Imaging of the abdomen was carried out periodically. The primary end point was RFS; the secondary objectives included OS and treatment safety. Results: The median follow-up time was 119 months. In the Intention-To-Treat Population 194 RFS events and 96 OS events were recorded. In the 36-month group, 5-year and 10-year RFS was 71.4% and 52.5%, and in the 12-month group, 53.0% and 41.8%, respectively (HR 0.66, 95% CI 0.49-0.87; P = .003). In the 36-month group, the 5-year and 10-year OS rates were 92.0% and 79.0%, and in the 12-month group, 85.5% and 65.3%, respectively (HR 0.55, 95% CI 0.37-0.83; P = .004). In the Efficacy Population, from which 15 patients who did not have GIST in central pathology review and 24 patients who had intra-abdominal metastases removed at surgery were excluded, 10-year OS was 81.6% in the 36-month group and 66.8% in the 12-month group (HR, 0.50, 95% CI 0.32-0.80; P = .003). No new safety signals were detected. Conclusions: About 50% of deaths can be avoided during the first decade of follow-up after surgery with 3-year imatinib treatment as compared to 1-year treatment. Clinical trial information: NCT00116935 .
A phase II multi-arm study of durvalumab and tremelimumab for advanced or metastatic sarcomas.
Authors: Somaiah Neeta , Conley Anthony Paul , Lin Heather Y. , Amini Behrang , Sabir Sharjeel H , Araujo Dejka M. , Benjamin Robert S. , Livingston J Andrew , Patel Shreyaskumar , Ratan Ravin , Ravi Vinod , Zarzour Maria Alejandra , Wang Wei-Lien , Tate Taylor , Roland Christina Lynn , Daw Najat C. , Futreal Andrew , Lazar Alexander J. , Wistuba Ignacio Ivan , Hwu Patrick 
Published: May 2020

11509 Background: The combination of durvalumab (D), (anti- PD-L1) and tremelimumab (T), (anti-CTLA-4), was evaluated to determine activity in specific sarcoma subtypes (NCT02815995). We report final results of the clinical efficacy, safety and correlatives. Methods: Pts ≥12 yrs, with advanced/metastatic sarcoma, were enrolled based on subtype: LPS, LMS, angiosarcoma (AS), UPS, synovial sarcoma, osteosarcoma, ASPS, chordoma, and other sarcomas. Pts received D 1500mg and T 75mg every 4 wks for 4 cycles followed by D alone every 4 wks for up to 12 months (mo) unless the patients experienced unacceptable toxicity or disease progression. Re-treatment was allowed if progression occurred after stopping therapy within the next 12 mo. The primary end-point was PFS at 12 wks (RECIST). Secondary objectives included safety, response rates (irRC and RECIST) and survival. Biopsies were collected at baseline and at 6 wks for flow, PD-L1, multiplex IHC staining and sequencing. Results: Baseline characteristics of the 57 pts who received treatment are listed in the Table. Median OS for all pts was 20.8 mo (95% CI: 11.7, NR), the 12-mo survival was 63% (95% CI: 52%, 78%) and the 24-mo survival was 45% (95%CI: 33%, 61%). The mPFS for all pts was 4.5 mo (95% CI: 2.8, 6.9). The PFS at 12 wks for all pts was 51% (95%CI: 37%, 63%), PFS at 12 mo was 28% (95% CI: 18%, 43%), and PFS at 24 mo was 25% (95% CI: 16%, 41%). The 12 wk PFS was lowest for the LPS cohort (6 pts) at 16% (95% CI: 1%, 52%), and highest for the ASPS cohort (10 pts) at 90% (95% CI: 47%, 99%). PRs by irRC were observed in ASPS (5/10), chordoma, (1/5), UPS (1/5), and cutaneous AS (1/1), and 14 pts completed 12 mo of therapy. 14 pts (24.6%) experienced grade ≥3 related AEs (colitis, nausea, cardiac dysfunction, thyroiditis, pneumonitis, hepatitis, myositis, anemia and fatigue). Clinical benefit correlated with tumors with an inflamed phenotype; based on higher than median density of 3 major categories of tumor infiltrating lymphocytes (TIL): CD3+, CD3+CD8+, CD3+CD8+GZB+, seen in the 36 paired biopsies. Conclusions: In addition to histology (ASPS, cutaneous AS, UPS, chordoma), a higher TIL immune score can help predict clinical benefit. Clinical trial information: NCT02815995 . [Table: see text]
Association of immune-related adverse events (irAEs) with improved clinical outcome in sarcoma patients treated with immune checkpoint blockade (ICB).
Authors: Rosenbaum Evan , Seier Kenneth , Kelly Ciara Marie , Kiesler Hannah , Martindale Moriah , Nicholls Cory , Chi Ping , Dickson Mark Andrew , Gounder Mrinal M. , Keohan Mary Louise , Movva Sujana , Nacev Benjamin , Hwang Sinchun , Qin Li-Xuan , D'Angelo Sandra P. , Tap William D. 
Published: May 2020

11510 Background: IrAEs are associated with improved clinical outcomes after treatment with ICB in select epithelial malignancies. We hypothesized that sarcoma patients (pts) treated with ICB who developed an irAE would have improved outcomes compared to pts who had no irAE. Methods: Adverse events (AEs) from 3 sarcoma-specific ICB trials (nivolumab plus NKTR-214, pembrolizumab plus epacadostat, and pembrolizumab plus T-VEC) were reviewed. AEs probably or definitely related to ICB were classified as immune- or non-immune-related by the principal investigator. Endpoints of interest included best overall response (BOR) by RECIST 1.1 (complete response [CR]/partial response [PR]), durable clinical benefit (DCB; CR/PR/stable disease [SD] ≥ 16 weeks), and progression-free survival (PFS). Outcomes were stratified by the presence or absence of ≥ 1 irAE of any grade and by grade 1-2, grade 3-4, or no irAE (three-category comparison). Results: A total of 124 pts received ICB on these studies. Median pt age was 56 (range: 13-90); 53% were male; all but one pt had a performance status of ≤ 1. BOR was PR in 12 pts, SD in 41, and PD in 69. 2 pts were not evaluable. 40 pts (32%) had ≥ 1 irAE of any grade, 6 of whom had a grade 3-4 irAE. The most common irAEs (≥ 5% of pts) were rash (15%), arthralgia (11%), myalgia (9%), pruritis (8%), and hypothyroidism (6%). The proportion of pts with a CR/PR was higher in pts with than without an irAE (18% vs. 6%, respectively; P = 0.058). A significantly higher proportion of pts with an irAE had DCB compared to those without (53% and 29%, respectively; P = 0.017). The median PFS of pts with an irAE was 16.6 months compared to 10.6 in those without (P = 0.013). The proportion of pts with a grade 3-4 irAE and a CR/PR was highest (33%) compared to pts with grade 1-2 (15%) or no irAE (6%) (P = 0.048). More pts with grade 3-4 irAE achieved DCB (67%) than grade 1-2 (50%) or no irAE (29%) (P = 0.027). Median PFS was 22.6, 15, and 10.6 weeks in the grade 3-4, grade 1-2, and no irAE groups, respectively (P = 0.047). Conclusions: Approximately one-third of advanced sarcoma pts with ICB-based immunotherapy developed an irAE. As reported previously in select carcinomas, sarcoma pts with irAEs were more likely to have clinical benefit than those without irAEs. Further research is needed to understand the mechanism behind this association and to validate these findings prospectively.
Survivin-responsive conditionally replicating adenovirus for patients with advanced sarcoma demonstrated potent and long-term efficacy and high safety in a phase I clinical trial.
Authors: Nagano Satoshi , Futagawa Toshitaka , Sumi Eriko , Ijichi Nobuhiro , Yamaguchi Munekazu , Nakajo Masanori , Hashiguchi Teruto , Takeda Yasuo , Yoshiura Takashi , Shimizu Akira , Takatani Muneo , Komiya Setsuro , Kosai Ken-ichiro 
Published: May 2020

11512 Background: Whereas one of oncolytic viruses (OVs), inducing selective tumor killing and systemic anti-tumor immunity, was approved by FDA in 2015, the best OV that more safely and efficiently treats intractable cancers has not been successfully developed. By our platform technology to efficiently construct next-generation OVs, i.e., “conditionally replicating adenoviruses (CRAs) that target and/or treat tumor cells with multiple factors” (m-CRAs), we identified that among candidates, survivin-responsive m-CRAs (Surv.m-CRAs) exhibited the most potent antitumor efficacy and cancer selectivity ( i.e., safety) in preclinical studies ( Cancer Res, 2005 et al.). Here we present the data of First-In-Human phase I clinical trial of Surv.m-CRA-1 for musculoskeletal tumors (MST). Methods: This single-arm, open label study included 9 patients with unresectable and advanced MST. Patients underwent a single intratumoral injection of either 1×10^10 viral particle (vp) (low), 1×10^11 vp (mid) or 1×10^12 vp (high). The primary endpoints were safety and tolerability. The secondary endpoints included the local control of treated tumor at one month, defined by RECIST and Choi criteria, analysis of dissemination of Surv.m-CRA-1, serum cytokine and adenoviral antibody. Long-term follow-up was done in some patients. Results: Four patients (44.4%) had grade 3 or higher adverse events, including lymphopenia, leukocytopenia and mildly elevated liver transaminase in 2, 1 and 1 patient, respectively. Virus excretions, including second peak of viremia from viral replication in tumor, were observed in 1, 2 and 3 patients of low, mid and high dose, respectively. Out of 9 patients, 5 PR, 3 SD and 1 PD by Choi, and 8 SD and 1 PD by RECIST were observed. During follow-up, another 1 and 2 patients became PR by Choi and RECIST, respectively. Of note, long-term PR (over 2 years) after a single injection of Surv.m-CRA-1 was achieved in two chordoma cases in low dose. Conclusions: Surv.m-CRA-1 was well tolerated and showed antitumor activity for prolonged periods against advanced MST. We about to start Phase I/II study of multiple injections of Surv.m-CRA-1 for advanced solid tumors in two-arms for musculoskeletal tumors and pancreatic cancer. Clinical trial information: R000026464 .
Genomic analysis of advanced malignant soft tissue tumors to suggest effect of genome-wide loss-of-heterozygosity of germline mutations/variants on anti-PD-1 immunotherapy response and survival of the patients.
Authors: Takahashi Katsuhito , Miyaji Yasutomo , Higuchi Hajime , Komohara Yoshihiro , Doi Koichi , Sano Hiroko , Aida Shinsuke , Yashima Jun , Yamamoto Hiromasa , Suzawa Ken , Takahashi Yuko , Toyooka Shinichi , Saito Ayumi , Oyama Yu , Narahara Hiroyuki , Yotsumoto Junko , Ono Yasuo , Teraoka Satoshi 
Published: May 2020

11531 Background: Malignant soft tissue tumor is a rare cancer with few therapeutic options. Although recent genomic characterization of soft tissue sarcoma revealed massive CNA and an excess of polygenic burden of pathological germline variants, their clinical and therapeutic significance remains to be understood. Methods: We recruited 155 patients with malignant soft tissue tumors (135 female and 20 male, mean age 51, 100 LMS, 19 LPS, 4 ESS, 3 UPS, 3 AS, 3 MPT, 3 GIST and others) of confirmed metastasis/recurrence. Whole exome sequencing was performed as reported in 2018ASCO. The MSI status was analyzed by PCR. Tumor immune microenvironment was assessed by immunohistochemistry. Results: Of the 595 COSMIC genes, heterozygous germline mutations/variants of the genome-wide 0-44 genes (av. 9.7/tumor) showed somatic loss-of-heterozygosity (LOH) with allele frequency of more than 70%. Patients with less than 33% LOH (n=53) in the total of somatic and LOH mutations showed improved 5-year survival rate compared with those (n=102) with more LOH (71% vs 52%, p=0.037). LMS (n=100) had higher value of LOH mutations than other tumors (n=55)(av. 55.5 vs 31.2%, p<0.001). Two patients with bone metastasis, one from liver undifferentiated sarcoma (case 1) and the other from uterine LMS (case 2) were identified as MSI-High and resultant higher TMB of 6.48 and 6.60/Mb, respectively than 1.47/Mb in av. Tumors from both cases had de novo mutations of MMR deficiency as EXO I (A153V) and WRN (S1120F) in case 1 and MSH2 (G674D) in case 2. Case 1 with pleural dissemination was treated with 5 cycles of Pembrolizumab (200mg/body, d1 q3weeks) but was progressive disease, while case 2 had no evaluable lesion after surgical removal of bone metastasis. Number of CD8+ T-cell infiltration (TIL), one of the best parameter with response to PD-1 blockade, was much higher in case 2 than in case 1 (av. 907 vs 290/mm2). Case 2 had no LOH mutations while case 1 had 37% LOH with more total mutations in tumor (16.1 vs 85.9/Mb). Higher values of LOH (av. 67 vs 19%) were clearly correlated with decreased density of CD8+TIL in tumor tissues (av. 9.6 vs 429/mm2, n=5, p=0.018). Conclusions: Our results, for the first time, suggest that in malignant soft tissue tumors, accumulation of genome-wide LOH of germline mutations/variants, from which self-antigens could be generated, may influence tumor immune microenvironment, and thus influence immunotherapy response and survival of the patients.
Long-term results of selective internal radioembolization (SIRT) to control progressive liver metastases of gastro-intestinal stromal tumors (GIST) beyond treatment with tyrosine kinase inhibitors (TKI).
Authors: Hohenberger Peter , Rathmann Nils , Buesing Karen , Menge Franka , Diehl Steffen 
Published: May 2020

11538 Background: Liver and peritoneum are the main area of metastatic spread in GIST. Liver resection does not play a role for hepatic metastases in comparison to f.e. colorectal cancer. If hepatic metastases are the only or major area of tumor progression and are resistant to available TKIs due to a missing mutation in KIT/PDGFRA/SDH ( ‘wildtype’) or after treatment with 1st/2nd/3rd/4th line therapy, interventional radioembolization with yttrium-90 (90Y) microspheres are promising treatment options, as radiation doses as high as 200Gy can be applied locally. We analyzed the long-term results of SIRT with respect to hepatic-progression-free survival (HEP-PFS) in a consecutive cohort of patients.. Methods: From 1/2008 to 1/2018, 25 pts (12f, 13m) with biopsy proven liver metastases of GIST which were the only (n = 13) or the dominant site of progression (n = 12) were treated by SIRT. Median age at GIST diagnosis had been 51.8 yrs and when receiving SIRT was 57.6yrs (range, 18–75yrs). The mutational status was ‘wildtype’ (n = 7, 2 NF-1), exon 11 (n = 7), exon 11+2nd mutation (n = 6), exon 9 (n = 3), exon 9+2ndmut (n = 1), and, exon 13 (n = 1). All patients except of two had prior TKI therapy: 1 line n = 3, 2 lines n = 11, 3-4 lines n = 9. Follow-up after SIRT was done via dynamic MRI and contrast-enhanced (CE)-CT, the median follow-up is 30.6 mos (range, 12-100mos) and all patients were followed until death. Results: The median hepatic-progression free survival (HEP-PFS) after SIRT was 17 months (range, 5-53+, 95%CI 11.8-22.1 mos). Of the patients with concomitant extrahepatic disease, the extraHEP-PFS was median 10 months. Twelve patients received next-line TKI therapy for progressive extrahepatic disease, whereas six patients required this for progressive liver metastases. When comparing the results according to the mutational status, patients with a ‘wildtype’ tumor showed a better median HEP-PFS of 19 mos (range, 12-53+, 95%CI 16.7-21.2 mos.) in comparison to KIT exon 9/11/13 mutated patients with only 14 months (range, 4-34 mos., 95%CI 6.5-21.4 mos), p < 0.11 (Wilcoxon). Conclusions: 90Y radioembolization (SIRT) offers a safe and effective treatment for patients with liver metastases of GISTs being the dominant site of tumor progression and with no drug treatment options available. In patients known to have no mutation in KIT/PDGFRA (wt, also NF-1 associated) it looks whether the results might be even more promising and SIRT could be used in early treatment lines.
Which patients with pre-treated locally advanced or metastatic sarcoma benefit most from trabectedin treatment: First results of a retrospective study of the German Interdisciplinary Sarcoma Group (GISG-14 - ReTraSarc).
Authors: Pink Daniel , Richter Adrian , Andreou Dimosthenis , Richter Stephan , Flörcken Anne , Deinzer Christoph , Kasper Bernd , Egerer Gerlinde , Ivanyi Philipp , Tuchscherer Armin , Kessler Torsten , Schuler Markus , Schmidt Christian , Bahr Jeannette , Ittermann Till , Reichardt Peter 
Published: May 2020

11554 Background: Despite the growing amount of published data regarding the outcomes of sarcoma patients treated with trabectedin, still some questions remain unanswered. The aim of the ReTraSarc trial (NCT03284320) was to evaluate the efficacy and safety of trabectedin in a large German population. Methods: Patients treated between 2007-2018 were retrospectively analyzed. All patients had histologically confirmed soft tissue (STS; n = 478) or bone (BS; n = 31) sarcoma; either metastatic (n = 468) or locally advanced (n = 41) disease, and had received at least one cycle of trabectedin. Based on follow-up data (until October 2019), progression-free survival (PFS) and overall survival (OS) after initiation of trabectedin treatment were estimated according to the Kaplan-Meier method. Results: A total of 509 patents were analyzed. Patients had a mean age of 54 years for STS and 30 years for BS-patients, and 25.4% of them aged > 65 years. Overall, 71.4% of patients had a good performance status (ECOG 0/1), and 37.7% received two prior lines, 28.3% three and 34% received > 3 prior lines of systemic treatment. Patients received a median of 3 cycles (IQR: 2-6 cycles) of trabectedin. Trabectedin resulted in an objective response rate (ORR) of 10% with a 37.4% of disease control rate (DCR). The median PFS and OS were 2.5 months (IQR: 1.4-6.1 months) and 8.2 months (IQR: 3-21 months), respectively. Significantly more patients with liposarcoma (22.1%; 95% CI: 15.2-32.2) were free from progression at 12 months after treatment as compared with patients with leiomyosarcoma (8.5%; 95% CI: 4.8-14.9). More analyses of effectiveness and safety are in progress (e.g. stratified per sarcoma subtypes or therapeutic line) and will be presented. Conclusions: The results of this real-life study, with a large number of patients and long-term follow-up, allow us to better analyze PFS and OS in sarcoma patients treated with trabectedin, given in different treatment lines and after dose modifications and/or cycle delays. Additionally, the results of this study enable us to evaluate the real-life impact of rechallenge with trabectedin in a further therapy line. Clinical trial information: NCT03284320 .
Multicenter, open-label phase II study of daily oral regorafenib for chemotherapy-refractory, metastatic and locally advanced angiosarcoma.
Authors: Agulnik Mark , Robinson Steven Ian , Okuno Scott H. , Siontis Brittany , Attia Steven , Kocherginsky Masha , Milhem Mohammed M. , Monga Varun , Chawla Sant P. , Oppelt Peter John , Hirbe Angela C. , Van Tine Brian Andrew 
Published: May 2020

11561 Background: Angiosarcoma has a particularly poor prognosis with 5-year overall survival rates of approximately 30-40%. Treatment of locally advanced and metastatic angiosarcoma is inadequate. Data strongly suggest concurrent, potent inhibition of VEGFR and Tie2 represents an attractive therapeutic strategy in angiosarcoma. Regorafenib displays potent VEGFR and Tie2 receptor inhibition and also possesses activity against additional potential targets in angiosarcoma including PDGFRs, RAF, KIT and FGFR, amongst others. Methods: A multicenter phase II study of regorafenib in patients with locally advanced or metastatic angiosarcoma was conducted through the Midwest Sarcoma Trials Partnership. Adequate performance status, organ function, measurable disease (RECIST 1.1) and 1-4 prior therapies were required. Regorafenib 160 mg PO daily was given in 28-day cycles (21 days on, 7 days off) until disease progression (PD) or unacceptable toxicity. The primary endpoint was progression-free survival (PFS), assessed at 16 weeks. Secondary endpoints include overall response rate (ORR), clinical benefit rate (CBR), OS, and safety and tolerability. A Simon 2-stage design was used. Results: After final enrollment of the second stage, a total of 31 pts were enrolled at 6 sites, 23 are evaluable for response. Median age was 65 (range 30-91); 50% were female, 67.7% had metastatic disease. PFS at 4 months is 52.2% with a median PFS and OS of 3.55 and 11.4 months. 1 confirmed CR and 2 PR, 12 SD and 8 PD were observed. ORR and CBR are 14.29 and 65.2%, respectively. No uncommon grade 3-4 adverse events were observed. 6 pts were non-evaluable due to refusal of further therapy and 2 patients progressed prior to first evaluation. Conclusions: Regorafenib was well tolerated in this study of pretreated patients with angiosarcomas and met its primary endpoint with a median PFS > 45% at 4 months. Treatment was feasible and did not reveal any previously unreported toxicities. Efficacy outcomes were complicated by early withdrawals of patients. RECIST responses were encouraging and regorafenib has a clinically meaningful 4-month PFS. Clinical trial information: NCT02048722 .