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Soft tissue sarcomas (STS) are a rare, heterogeneous group of solid tumors in need of improved therapeutic options. First-line chemotherapy is considered the current standard of care for patients with advanced, symptomatic STS, but the median survival is only 8 to 12 months. Efforts to increase response rates by using combination or dose-dense regimens have largely failed to improve patient outcomes. However, increasing evidence supports the use of specific treatments for certain histological subtypes of STS, and novel therapies, including tyrosine kinase and mammalian target of rapamycin inhibitors, are currently under active investigation. In addition, novel treatment approaches (such as maintenance therapy) designed to prolong the duration of response to chemotherapy and delay disease progression are being explored. This article provides an overview of current systemic therapies for patients with advanced STS and discusses ongoing efforts designed to improve patient outcomes through the use of novel therapeutic agents and treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Approximately half of patients with localised, high-risk soft tissue sarcoma of the extremity develop metastases. We aimed to assess whether the addition of pembrolizumab to preoperative radiotherapy and surgery would improve disease-free survival., Methods: We completed an open-label, randomised clinical trial in patients with grade 2 or 3, stage III undifferentiated pleomorphic sarcoma or dedifferentiated or pleomorphic liposarcoma of the extremity and limb girdle. Patients were enrolled at 20 academic institutions in Australia, Canada, Italy, and the USA. Patients were randomly assigned to preoperative radiotherapy then surgery (control group) or preoperative pembrolizumab with radiotherapy (initiated 1-14 days after the first dose of pembrolizumab) then surgery and postoperative pembrolizumab (experimental group). Pembrolizumab (200 mg intravenously every 3 weeks) was administered as three neoadjuvant cycles (before, during, and after radiotherapy) and 14 or less adjuvant cycles. Primary endpoint was disease-free survival. This study is registered with ClincialTrials.gov (NCT03092323)., Findings: Between Nov 18, 2017, and Nov 14, 2023, 143 participants were randomly assigned to treatment. A modified intention-to-treat analysis of 127 patients with median follow-up of 43 months showed that the experimental group (n=64) had significantly longer disease-free survival than the control group (n=63; log-rank one-sided p=0·035; hazard ratio [HR] 0·61; 90% CI 0·39-0·96). The 2-year disease-free survival increased by 15% with addition of pembrolizumab: 52% (90% CI 42-64) and 67% (90% CI 58-78) for the control and experimental groups, respectively. Disease-free survival was similarly improved with pembrolizumab for the intention-to-treat patient population (HR 0·61 [90% CI 0·39-0·95]). Grade 3 or higher adverse events occurred more frequently in the experimental group (56%) than the control group (31%)., Interpretation: Addition of pembrolizumab to preoperative radiotherapy and surgery improves disease-free survival for patients with stage III undifferentiated pleomorphic sarcoma and pleomorphic or dedifferentiated liposarcoma of the extremity, which establishes a promising new treatment option for these patients., Funding: Stand Up to Cancer and Merck Sharp & Dohme., Competing Interests: Declaration of interests YMM reports leadership roles in ASTRO and NRG Oncology and an honorarium from the University of Wisconsin–Madison. YMM, KVB, KJW, and DGK report grant funding from Stand Up to Cancer (Merck Catalyst Program) to the institution to support this study. KVB reports funding from SARC and the National Cancer Institute. AMH reports grant funding paid to Australia and New Zealand Sarcoma Association from the GPA Andrew Ursini Charitable Fund to support sample shipment to the USA and grant funding paid from Cancer Australia to Australia and New Zealand Sarcoma Association for clinical research team support for this study in Australia. YMM, AMH, SMS, and CFM report royalties from UpToDate for authorship contributions. AMH reports payment for participating on an advisory board for Teli. SMS reports grant funding from TRACON, Adaptimmune, and GlaxoSmithKline (GSK) to the institution; travel support from the National Comprehensive Cancer Network; and payment for participation in an advisory board for BioAtla. AJW reports a leadership role on the Board of Directors for SARC. VM reports grant funding from Rising Tide Foundation for Cancer Research; honoraria for presentations from Association of Northern California Oncologists and Gundersen Health System; participation in an advisory board for Forma Therapeutics; and funding to the institution from Amgen, Prelude Therapeutics, Jazz Pharmaceuticals, Astex Pharma, Oblato Therapeutics, Orbus Therapeutics, and Novartis. SA reports grant funding to the institution from SARC, Merck, TRACON, Bayer, Novartis, Lilly, Karyopharm, Epizyme, Blueprint, Genmab, CBA Pharma, Philogen, Gradilis, Deciphera, Takeda, Incyte, Springworks, Adaptimmune, Advenchen, Bavarian Nordic, BTG Pharmaceuticals, PTC Therapeutics, GSK, Forma Therapeutics, Ayala Pharma, Trillium, Boehringer Ingelheim, Salarius, Theseus, Monopar, C4 Therapeutics, Inhibrx, Noxopharm, Rain Therapeutics, Shanghai Pharma, PharmaMar, Cogen, and Jazz Therapeutics. SA reports grant funding to himself from Guardant. EC reports consulting fees from Sonata Therapeutics, Adaptimmune, Epizyme, and Bayer; and participation in advisory boards for Adaptimmune and Pfizer. DIP reports honoraria for presentations to Bayer. BAVT reports grant funding from Polaris; a patent on ALEXT3102; a patent on the use of ME1 as a biomarker; licences from Accuronix Therapeutics; consulting fees from Cytokinetics, Bayer, Deciphera Pharmaceuticals, Daiichi Sankyo, EcoR1, Advenchen, Putnam, Salarius Pharmaceuticals, Boxer Capital, Acuta Capital Partners, Aadi Bioscience, Race Oncology, Kronos Bio, Sonata Therapeutics, and Hinge Bio; honoraria for presentations from Iterion Therapeutics, and Total Health Conference; travel support from Adaptimmune, Advenchen Laboratories, Polaris, and Kronos Bio; participation in advisory boards for Apexigen, Daiichi Sankyo, Epizyme, Bayer US Medical Affairs Oncology, PTC Therapeutics, Asdi Biosciences, Boehringer Ingelheim, Agenus, Regeneron Pharmaceuticals, Curis; and an unpaid role on the safety monitoring board for Polaris. GT reports receiving payment for participating on an advisory board for Servier and consulting fees from Daiichi Sankyo. BC reports funding paid to the institution by SARC for support of this study; grant funding for clinical trial support paid to the institution by Bristol Myers Squibb, Macrogenics, Karyopharm Therapeutics, Infinity Pharmaceuticals, Advenchen Laboratories, Xencor, Compugen, Iovance, RAPT Therapeutics, IDEAYA Biosciences, Ascentage, Atreca, Replimune, Instil Bio, Adagene, TriSalus Life Sciences, Kinnate, PTC Therapeutics, Xilio Therapeutics, Kezar Life Sciences, and Immunocore; payment for participation on advisory boards at Novartis, Delcath, Instil Bio, Replimune, Atreca, Regeneron, and Treeline Biosciences; and payment for participation on the data monitoring committee for SpringWorks Therapeutics. AG reports funding to the institution from PharmaMar and Nanobiotix; consulting fees from Novartis, Pfizer, Bayer, Lilly, PharmaMar, SpringWorks, and Boehringer Ingelheim; honoraria for presentations from PharmaMar and Deciphera; travel support from PharmaMar; and leadership roles as the International Representative on the Executive Council of the Society of Surgical Oncology, a member of the Board of Directors of the European Society of Surgical Oncology, and a member of the Board of Directors of the Italian Sarcoma Group. CFM reports consulting fees for participating on advisory boards for Deciphera, Daiichi Sankyo, and Aadi Bioscience. MAD reports funding to the institution from Eli Lilly, Sumitomo Pharma, and Aadi Bioscience. LED reports funding from SARC to the institution to support this study; funding to the institution for clinical trial activities from Salarius, Inhibrx, BioAtla, Adaptimmune, GSK, SpringWorks, Epizyme, BTG Pharmaceuticals, Eisai, and Novartis; consulting fees from GLG Expert Network and Guidepoint Expert Network; educational payment from SpringWorks; payment for participating on advisory boards for Daiichi Sankyo, Inhibrx, Regeneron, and SpringWorks; leadership role on the scientific steering committee for SARC; leadership role on the scientific advisory board for the Osteosarcoma Institute; and a former leadership role on the Northwest Sarcoma Foundation Board of Directors. BEB reports consulting fees from Daiichi Sankyo, Deciphera, and Musculoskeletal Transplant Foundation; participation on a data safety monitoring board for PARITY Trial and SAFETY trial; and serving as a member of the Executive Board for the Musculoskeletal Tumor Society. RFR reports funding to the institution for clinical trial support from Aadi Bioscience, Adaptimmune, AROG, Ayala, BioAtla, Blueprint, Cogent, Daiichi-Sankyo, Deciphera, GlaxoSmithKline, InhibRx, NanoCarrier, Oncternal, PTC Therapeutics, SARC, SpringWorks, TRACON, and Trillium; consulting fees from Aadi Bioscience, Adaptimmune, Bayer, Blueprint, Boehringer Ingelheim, Daiichi-Sankyo, Deciphera, GSK, NanoCarrier, and SpringWorks; honoraria for lectures from SpringWorks; travel support for advisory board participation for Deciphera; leadership role as co-chair of the ECOG-ACRIN Sarcoma Working Group; medical writing assistance from Prescott Medical Communications Group with financial support from SpringWorks Therapeutics; and spouse ownership in Limbguard. DGK reports funding from MSD through the Merck Investigator Studies Program to the institution to support this study; and grant funding to the institution from Bristol Myers Squibb, Varian Medical Systems, the National Institutes of Health, and the Department of Defense. DGK has a licence for an imaging device through Lumicell; patents through Lumicell and XRad Therapeutics; membership on the scientific advisory board of Lumicell; membership on the independent data monitoring committee for the clinical trial SARCO; previous leadership role as the Councillor in Medicine on the Board of Directors of the International Association for Radiation Research; and holding stock in XRad Therapeutics and Lumicell. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Introduction: Desmoid tumors (DTs) are rare, fibroblastic cell proliferations that can exhibit locally aggressive behavior but lack metastatic potential. Initial management has traditionally involved upfront resection; however, contemporary guidelines and expert panels have increasingly advocated for prioritizing active surveillance strategies., Methods: A single-institution, retrospective chart review identified all patients diagnosed with a primary DT at any site from 2007 to 2020. The primary outcome was the initial management strategy over time. Secondary outcomes included treatment-free survival (TFS) and time to treatment (TTT) for those undergoing active surveillance, as well as recurrence-free survival (RFS) and time to recurrence for those undergoing resection., Results: Overall, 103 patients were included, with 68% female and a median follow-up of 44 months [24-74]. The most common tumor locations included the abdominal wall (27%), intra-abdominal/mesenteric (25%), chest wall (19%), and extremity (10%). Initial management included resection (60%), systemic therapy (20%), active surveillance (18%), and cryoablation (2%). Rates of surgical resection significantly decreased (p < 0.001) over time, from 69.6% prior to 2018 to 29.2% after 2018. For those treated with upfront resection, 5-year RFS was 41.2%, and for patients undergoing initial active surveillance, TFS was 66.7% at 2 years, with a median TTT of 4 months [4-10]., Conclusions: This single-institution cohort at a tertiary medical center spanning over a decade demonstrates the transition to active surveillance for initial management of DTs, and highlights salient metrics in the era of surveillance. This trend mirrors recommended treatment strategies by expert panels and consensus guidelines., (© 2024. Society of Surgical Oncology.)

CIC-rearranged sarcomas comprise a group of exceptionally aggressive round-cell sarcomas. These tumors most commonly demonstrate CIC::DUX4 fusion and show similar histopathology to Ewing sarcomas, though lesions mimicking vascular neoplasms have recently been described. Here, we describe a case of a patient with CIC::DUX4 fusion sarcoma identified using RNA-based molecular testing who was initially diagnosed with an endothelial neoplasm. The tumor showed extensive vasoformative growth, complete WT1 negativity, and global positive staining for ERG, CD31, and DUX4 by immunohistochemistry. Methylation testing of the tumor clustered more closely with angiosarcomas than with CIC-rearranged sarcomas. Our findings suggest that CIC::DUX4 fused neoplasms may demonstrate a more diverse phenotypic range than previously appreciated and offer evidence that both molecular and immunohistochemical studies are needed for accurate diagnosis., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: Ewing Sarcoma (ES), a rare cancer with a pathognomonic translocation resulting in the Ewing sarcoma gene (EWS)::FLI1 oncoprotein, has a poor prognosis in the relapsed/refractory (R/R) setting. Tokalas (TK)216 was designed to bind EWS::FLI1 proteins directly, disrupt protein-protein interactions, and inhibit transcription factor function. TK216 plus vincristine showed synergistic activity in preclinical tumor models. To our knowledge, we report the results of a first-in-class, first-in-human phase I/II trial of TK216 in R/R ES., Patients and Methods: TK216 was administered intravenously as a continuous infusion to patients with R/R ES in 11 cohorts. The dosing duration of 7 days was later extended to 10, 14, and 28 days. Vincristine could be added on day 1 after cycle 2, per investigators' choice. The trial used a 3 + 3 design with an expansion cohort at the recommended phase II dose (RP2D)., Results: A total of 85 patients with a median age of 27 years (range, 11-77) were enrolled. The maximum tolerated dose for the 14-day infusion of TK216, 200 mg/m 2 once daily, was determined in cohort 9 and selected as the RP2D. The median previous number of systemic therapies regimens was three (range, 1-10). The most frequent-related adverse events in patients treated at the RP2D included neutropenia (44.7%), anemia (29.4%), leukopenia (29.4%), febrile neutropenia (15.3%), thrombocytopenia (11.8%), and infections (17.6%). In cohorts 9 and 10, two patients had a complete response, one had a partial response, and 14 had stable disease; the 6-month progression-free survival was 11.9%. There were no responses among the eight patients in cohort 11., Conclusion: TK216 administered as 14-day continuous infusion with or without vincristine was well tolerated and showed limited activity at the RP2D in R/R ES.

Purpose: Loddo et al. (Br J Cancer 100:959-70, 2009) established the prognostic significance of cell cycle markers and "Cell-Cycle Phenotypes" in breast carcinoma. This study aims to 1) identify prognostic cell-cycle markers in sarcoma, and 2) assess the prognostic potential of specific cell-cycle phenotypes in sarcoma., Methods: Tissue samples from 128 soft tissue sarcomas were stained for four cell cycle-specific markers: Mcm2, Geminin, Plk1, and H3S10ph. Only primary soft tissue tumors (liposarcoma, leiomyosarcoma, synovial sarcoma, and undifferentiated pleomorphic sarcoma) were included in the analysis. Any tumor coming from a recurrent or metastatic lesion were excluded from the analysis. Three cell-cycle phenotypes (I, II, III) were derived from marker expression patterns. Prognostic significance was evaluated in a subset of primary soft tissue sarcomas using Cox regression for survival analysis., Results: Compared to phenotype I, the phenotype III tumors had a decreased 5-year overall survival (HR 6.81 [2.36-19.61]; p =  < 0.001), 5-year disease-free survival (HR 1.07 (1.02-1.18); p = 0.004), and 5-year metastasis-free survival (HR 4.34 [1.58-11.93]; p = 0.004). High expression of Plk1 was associated with decreased 5-year overall survival (HR: 4.04 CI [1.21-6.67; p = 0.02) and 5-year metastasis-free survival (HR: 2.91 CI [1.15-7.37]; p = 0.03). Geminin was also found to have a decreased 5-year overall survival (HR:2.84 CI [1.21-6.67]; p = 0.02). No statistical difference in prognostication were noted between phenotypes and the AJCC system., Conclusions: We identified three unique sarcoma cell cycle phenotypes that have prognostic significance. This performs similarly to the AJCC staging system., (© 2024. The Author(s).)

Purpose: Epithelioid hemangioendothelioma (EHE) is a rare vascular cancer with pathogenic TAZ-CAMTA1 (calmodulinbinding transcription activator 1) operating as an oncogenic driver through activation of the MAPK pathway. Trametinib is an inhibitor of MEK, a critical kinase in the MAPK pathway. We sought to evaluate the effect of trametinib in patients with EHE., Patients and Methods: A phase 2 trial of trametinib was conducted in patients with locally advanced or metastatic EHE. Eligibility requirements included evidence of tumor progression or presence of EHE-related pain requiring opiates for management before enrollment. The primary endpoint was objective response rate (ORR) as per RECIST1.1 in cases with TAZ- CAMTA1 confirmed by fusion-FISH. Secondary objectives were to estimate ORR for all patients, median progression-free survival (PFS), 2-year overall survival (OS) rate, patient safety, and change in patient-reported global health and pain scores per PROMIS questionnaires., Results: 44 patients enrolled and 42 started trametinib. TAZ- CAMTA1 was detected in 27 tumor samples. TheORRwas 3.7%[95% confidence interval (CI), 0.094-19.0], median PFS was 10.4 months (95%CI, 7.1-NA), and 2-year OS rate was 33.3%(95%CI, 19.1-58.2) in the target population. Median pain intensity and interference scores improved significantly after 4 weeks of trametinib in patients using opiates. Common adverse events related to trametinib were rash, fatigue, nausea/vomiting, diarrhea/constipation, alopecia, and edema; one grade 5 ARDS/pneumonitis was related to trametinib., Conclusions: Trametinib was associated with reduction in EHE-related pain and median PFS of more than 6 months, providing palliative benefit in patients with advanced EHE, but the trial did not meet the ORR goal. See related commentary by Van Tine and Haarberg, p. 4552., (©2024 American Association for Cancer Research.)

Dedifferentiated liposarcoma (DDLPS) is a malignant mesenchymal neoplasm in desperate need of novel therapeutic approaches. Often occurring in conjunction with well-differentiated liposarcoma (WDLPS), DDLPS can behave more aggressively and exhibits a significant risk for developing recurrence or metastatic disease when compared to its well-differentiated counterpart. A multidisciplinary approach is critically important, particularly for patients with localized disease, as disease presentations are often complex, and the management of patients has become increasingly nuanced as treatment approaches have become more refined. Expert pathology review and appropriate application of diagnostic molecular techniques are key components of DDLPS diagnosis and also reflect an improved understanding of the underlying pathogenesis of the disease. Systemic therapies remain limited for DDLPS, but novel therapies targeting important underlying molecular drivers have resulted in ongoing clinical trials aiming to improve outcomes for patients with advanced disease. In recognition of the increased activity and interest within the DDLPS field, a multidisciplinary group of nationally recognized experts in medical oncology, surgical oncology, radiation oncology, and pathology was convened to summarize key insights. This position paper highlights important points from the meeting and provides evidence-based recommendations for practicing clinicians., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The purpose of this study was to determine if dual-energy CT (DECT) vital iodine tumor burden (ViTB), a direct assessment of tumor vascularity, allows reliable response assessment in patients with GIST compared to established CT criteria such as RECIST1.1 and modified Choi (mChoi). From 03/2014 to 12/2019, 138 patients (64 years [32-94 years]) with biopsy proven GIST were entered in this prospective, multi-center trial. All patients were treated with tyrosine kinase inhibitors (TKI) and underwent pre-treatment and follow-up DECT examinations for a minimum of 24 months. Response assessment was performed according to RECIST1.1, mChoi, vascular tumor burden (VTB) and DECT ViTB. A change in therapy management could be because of imaging (RECIST1.1 or mChoi) and/or clinical progression. The DECT ViTB criteria had the highest discrimination ability for progression-free survival (PFS) of all criteria in both first line and second line and thereafter treatment, and was significantly superior to RECIST1.1 and mChoi (p < .034). Both, the mChoi and DECT ViTB criteria demonstrated a significantly early median time-to-progression (both delta 2.5 months; both p < .036). Multivariable analysis revealed 6 variables associated with shorter overall survival: secondary mutation (HR = 4.62), polymetastatic disease (HR = 3.02), metastatic second line and thereafter treatment (HR = 2.33), shorter PFS determined by the DECT ViTB criteria (HR = 1.72), multiple organ metastases (HR = 1.51) and lower age (HR = 1.04). DECT ViTB is a reliable response criteria and provides additional value for assessing TKI treatment in GIST patients. A significant superior response discrimination ability for median PFS was observed, including non-responders at first follow-up and patients developing resistance while on therapy., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Ewing sarcoma (ES) is a malignant tumor of bone and soft tissue that most often occurs in children, adolescents, and young adults. Debate and controversy remain in the management of relapsed/refractory ES (RR-ES). The authors leveraged the expertise assembled by the National Ewing Sarcoma Tumor Board, a multidisciplinary virtual tumor board that meets monthly to discuss challenging cases of ES. In this review, they focus on select topics that apply to the management of patients with RR-ES. The specific topics covered include the initial approach of such patients and discussion of the goals of care, the role of molecular testing, chemotherapy regimens and novel agents to consider, the role of maintenance therapy, and the use of high-dose chemotherapy with autologous stem cell rescue. The data referenced are often limited to subgroup analyses and/or compiled from multiple sources. Although not intended to replace the clinical judgement of treating physicians, these guidelines are intended to support clinicians and provide some clarity and recommendations for the management of patients with RR-ES. PLAIN LANGUAGE SUMMARY: Ewing sarcoma (ES) is a bone and soft tissue cancer that most often occurs in teenagers and young adults. This article uses the experience of the National Ewing Sarcoma Tumor Board, a multi-institution, multidisciplinary virtual tumor board that meets monthly to discuss challenging cases of ES and to address questions related to the treatment of patients with relapsed ES. Although not intended to replace the clinical judgement of treating physicians and limited by available data, these consensus recommendations will support clinicians who treat patients with this challenging malignancy, made even more difficult when it recurs., (© 2024 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Malignant phyllodes tumors (MPT) are rare fibroepithelial breast cancers with no known effective systemic therapy; metastatic progression portends a dismal prognosis. We sought to describe the genomic landscape of MPTs through genomic profiling and immunotherapeutic biomarker analysis., Materials and Methods: Cases of sequenced MPT were identified from a Clinical Laboratory Improvement Amendments-certified, College of American Pathologists-accredited laboratory (Foundation Medicine). All cases underwent genomic profiling using adaptor ligation-based, next-generation sequencing assay of 324 genes. Tumor agnostic immunotherapy biomarkers, microsatellite instability, tumor mutational burden (TMB), and programmed death-ligand 1 (PD-L1) expression were evaluated. Fisher's Exact Tests and analysis of variance were used to test for differences between groups and for continuous variables as appropriate., Results: Of 135 MPT cases identified; 94 (69.6%) were localized/locally recurrent and 41 (30.4%) were metastatic. Median age was 54 years (range 14-86). The median TMB was 2.5 mut/Mb and 3 were TMB-high (≥10 mut/Mb). 21.4% were PD-L1+ via Dako 22C3 assay (CPS ≥1). Most commonly altered genes included TERT-promoter (69.7%), CDKN2A (45.9%), TP53 (37.8%), NF1 (35.6%), CDKN2B (33.3%), MED12 (28.9%), MTAP (27.7%), KMT2D (22.2%), PIK3CA (20.0%), PTEN (18.5%), and RB1 (18.5%). Several tumors harboring genomic alterations with US Food and Drug Administration-approved indications in other tumor types were found including NF1, PIK3CA, EGFR Exon 19/20 insertions, and BRAF V600E mutations., Conclusions: In the largest genomic evaluation of MPT to date, multiple clinically actionable mutations were found. Routine sequencing of metastatic MPT may provide additional information to guide treatment decisions and clinical trial enrollment., (© The Author(s) 2024. Published by Oxford University Press.)

Introduction: Nirogacestat is a targeted gamma secretase inhibitor approved in the United States for adults with progressing desmoid tumors. In the phase 3 DeFi study (NCT03785964) of nirogacestat, ovarian toxicity (OT) was identified as a safety signal among females of reproductive potential (FORP). This analysis further describes the incidence, presentation, and resolution of OT., Methods: Patients were randomized to twice-daily oral nirogacestat (150 mg) or placebo, taken in continuous 28-day cycles. Investigator-identified OT in FORP was based on abnormal reproductive hormone values or perimenopausal symptoms (or both). Adverse event follow-up was conducted to assess OT resolution. Post hoc analyses included return of menstruation and return of follicle-stimulating hormone (FSH) to within normal limits (WNL) (≤20.4 mIU/mL)., Results: Of 92 randomized females, 73 in the safety population were FORP (n = 36 nirogacestat, n = 37 placebo). OT was identified in 75% (27 of 36) receiving nirogacestat and 0% (0 of 37) receiving placebo. As of October 24, 2022, investigators reported OT resolution in 78% (21 of 27) of patients, with median OT duration of 19.1 weeks. Off-treatment resolution was reported in all 11 patients (100%) who stopped nirogacestat treatment; of these, all nine with available menstruation information experienced return of menstruation and eight had FSH WNL at last reported assessment. Resolution was reported in 10 of 14 (71%) while on nirogacestat; of these, all 10 experienced return of menstruation and seven had FSH WNL. Two patients were lost to follow-up., Conclusion: Most FORP treated with nirogacestat experienced OT, with the majority resolving, including all who stopped treatment, suggesting that OT is transient., (© 2024 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. nab -Sirolimus is approved in the United States for the treatment of metastatic or locally advanced malignant perivascular epithelioid cell tumor (PEComa) on the basis of the primary analysis results of the phase II Advanced Malignant Perivascular Epithelioid Cell Tumors (AMPECT) trial (ClinicalTrials.gov identifier: NCT02494570). Results from the primary analysis were previously published; however, the median duration of response (mDOR) had not been reached at that time. Here, 3 years after the primary analysis, we report final efficacy and safety data (data cutoff: April 29, 2022). At study completion, the confirmed overall response rate (by independent radiologist review using RECIST v1.1) was 38.7% (95% CI, 21.8 to 57.8), with an additional converted confirmed complete response (n = 2). Median progression-free survival remained the same at 10.6 months (95% CI, 5.5 to 41.2). The mDOR was reached at 39.7 months (95% CI, 6.5 to not reached [NR]), and the median overall survival at completion was 53.1 months (95% CI, 22.2 to NR). The most common treatment-related adverse events (TRAEs) were stomatitis (82.4%) and fatigue and rash (each 61.8%). No new or unexpected adverse events occurred, and no grade ≥4 TRAEs were reported. These results highlight the long-term clinical benefit of nab- sirolimus in patients with advanced malignant PEComa, with a DOR of >3 years.

Ewing sarcoma (ES) is a malignant tumor of bone and soft tissue that most often occurs in adolescents and young adults. Despite an international coordinated approach, several nuances, discrepancies, and debates remain in defining the standard of care for treating ES. In this review, the authors leverage the expertise assembled by formation of the National Ewing Sarcoma Tumor Board, a multi-institution, multidisciplinary virtual tumor board that meets monthly to discuss complicated and challenging cases of ES. This report is focused on select topics that apply to the management of patients with newly diagnosed ES. The specific topics covered include indications for bone marrow aspirate and biopsy for initial evaluation compared with fluorodeoxyglucose-positron emission tomography, the role of interval compressed chemotherapy in patients aged 18 years and older, the role of adding ifosfamide/etoposide to vincristine/doxorubicin/cyclophosphamide for patients with metastatic disease, the data on and role of high-dose chemotherapy with autologous stem cell transplantation, maintenance therapy, and whole-lung irradiation. The data referenced are often limited to subgroup analyses and/or compiled from multiple sources. Although not intended to replace the clinical judgement of treating physicians, the guidelines are intended to provide clarity and recommendations for the upfront management of patients with ES. PLAIN LANGUAGE SUMMARY: Ewing sarcoma is a malignant tumor of bone and soft tissue that most often occurs in adolescents and young adults. For this review, the authors used the experience of the National Ewing Sarcoma Tumor Board, a multi-institution, multidisciplinary virtual tumor board that meets monthly to discuss complicated and challenging cases of Ewing sarcoma. Although not intended to replace the clinical judgement of treating physicians, the guidelines will focus on the development of consensus statements for the upfront management of patients with Ewing sarcoma., (© 2023 American Cancer Society.)

Background: Alveolar soft part sarcoma (ASPS) is a rare soft-tissue sarcoma with a poor prognosis and no established therapy. Recently, encouraging responses to immune checkpoint inhibitors have been reported., Methods: We conducted an investigator-initiated, multicenter, single-group, phase 2 study of the anti-programmed death ligand 1 (PD-L1) agent atezolizumab in adult and pediatric patients with advanced ASPS. Atezolizumab was administered intravenously at a dose of 1200 mg (in patients ≥18 years of age) or 15 mg per kilogram of body weight with a 1200-mg cap (in patients <18 years of age) once every 21 days. Study end points included objective response, duration of response, and progression-free survival according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, as well as pharmacodynamic biomarkers of multistep drug action., Results: A total of 52 patients were evaluated. An objective response was observed in 19 of 52 patients (37%), with 1 complete response and 18 partial responses. The median time to response was 3.6 months (range, 2.1 to 19.1), the median duration of response was 24.7 months (range, 4.1 to 55.8), and the median progression-free survival was 20.8 months. Seven patients took a treatment break after 2 years of treatment, and their responses were maintained through the data-cutoff date. No treatment-related grade 4 or 5 adverse events were recorded. Responses were noted despite variable baseline expression of programmed death 1 and PD-L1., Conclusions: Atezolizumab was effective at inducing sustained responses in approximately one third of patients with advanced ASPS. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03141684.)., (Copyright © 2023 Massachusetts Medical Society.)

Bone sarcomas are rare heterogeneous tumors that affect patients of all ages including children, adolescent young adults, and older adults. They include many aggressive subtypes and patient groups with poor outcomes, poor access to clinical trials, and lack of defined standard therapeutic strategies. Conventional chondrosarcoma remains a surgical disease, with no defined role for cytotoxic therapy and no approved targeted systemic therapies. Here, we discuss promising novel targets and strategies undergoing evaluation in clinical trials. Multiagent chemotherapy has greatly improved outcomes for patients with Ewing sarcoma (ES) and osteosarcoma, but management of those with high-risk or recurrent disease remains challenging and controversial. We describe the impact of international collaborative trials, such as the rEECur study, that aim to define optimal treatment strategies for those with recurrent, refractory ES, and evidence for high-dose chemotherapy with stem-cell support. We also discuss current and emerging strategies for other small round cell sarcomas, such as CIC -rearranged, BCOR -rearranged tumors, and the evaluation of emerging novel therapeutics and trial designs that may offer a new paradigm to improve survival in these aggressive tumors with notoriously bad (to the bone) outcomes.

Introduction: Soft tissue and bone sarcomas are a heterogeneous group of malignancies, each with a unique biology and clinical course. As our understanding of individual sarcoma subtypes and their molecular landscapes increases, predictive biomarkers are emerging to improve patient selection for chemotherapies, targeted therapies, and immunotherapy approaches., Areas Covered: This review highlights predictive biomarkers rooted in molecular mechanisms of sarcoma biology, focusing on cell cycle regulation, DNA damage repair, and immune microenvironment interactions. We review CDK4/6 inhibitor predictive biomarkers, including CDKN2A loss, ATRX status, MDM2 levels, and Rb1 status. We discuss homologous recombination deficiency (HRD) biomarkers that predict vulnerability to DNA damage repair (DDR) pathway inhibitors, such as molecular signatures and functional HRD markers. We describe tertiary lymphoid structures and suppressive myeloid cells in the sarcoma immune microenvironment that may influence immunotherapy efficacy., Expert Opinion: While predictive biomarkers are not routinely used in sarcoma clinical practice currently, emerging biomarkers are being developed alongside clinical advancements. Novel therapies and predictive biomarkers will be essential for individualizing future approaches to sarcoma management and improving patient outcomes.

Background: Desmoid tumors are rare, locally aggressive, highly recurrent soft-tissue tumors without approved treatments., Methods: We conducted a phase 3, international, double-blind, randomized, placebo-controlled trial of nirogacestat in adults with progressing desmoid tumors according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were assigned in a 1:1 ratio to receive the oral γ-secretase inhibitor nirogacestat (150 mg) or placebo twice daily. The primary end point was progression-free survival., Results: From May 2019 through August 2020, a total of 70 patients were assigned to receive nirogacestat and 72 to receive placebo. Nirogacestat had a significant progression-free survival benefit over placebo (hazard ratio for disease progression or death, 0.29; 95% confidence interval, 0.15 to 0.55; P<0.001); the likelihood of being event-free at 2 years was 76% with nirogacestat and 44% with placebo. Between-group differences in progression-free survival were consistent across prespecified subgroups. The percentage of patients who had an objective response was significantly higher with nirogacestat than with placebo (41% vs. 8%; P<0.001), with a median time to response of 5.6 months and 11.1 months, respectively; the percentage of patients with a complete response was 7% and 0%, respectively. Significant between-group differences in secondary patient-reported outcomes, including pain, symptom burden, physical or role functioning, and health-related quality of life, were observed (P≤0.01). Frequent adverse events with nirogacestat included diarrhea (in 84% of the patients), nausea (in 54%), fatigue (in 51%), hypophosphatemia (in 42%), and maculopapular rash (in 32%); 95% of adverse events were of grade 1 or 2. Among women of childbearing potential receiving nirogacestat, 27 of 36 (75%) had adverse events consistent with ovarian dysfunction, which resolved in 20 women (74%)., Conclusions: Nirogacestat was associated with significant benefits with respect to progression-free survival, objective response, pain, symptom burden, physical functioning, role functioning, and health-related quality of life in adults with progressing desmoid tumors. Adverse events with nirogacestat were frequent but mostly low grade. (Funded by SpringWorks Therapeutics; DeFi ClinicalTrials.gov number, NCT03785964.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Regorafenib is one of several FDA-approved cancer therapies targeting multiple tyrosine kinases. However, there are few subtype-specific data regarding kinase inhibitor activity in sarcomas. We report results of a single arm, phase II trial of regorafenib in advanced Ewing family sarcomas., Methods: Patients with metastatic Ewing family sarcomas (age ≥ 18, ECOG 0-2, good organ function) who had received at least one line of therapy and experienced progression within 6 months of registration were eligible. Prior kinase inhibitors were not allowed. The initial dose of regorafenib was 160 mg oral days 1-21 of a 28-day cycle. The primary endpoint was estimating progression-free rate (PFR) at 8 weeks employing RECIST 1.1., Results: Thirty patients (median age, 32 years; 33% women [10 patients]; bone primary, 40%; extraskeletal primary, 60%) enrolled at 14 sites. The most common grade 3 or higher toxicities were hypophosphatemia (5 grade 3, 1 grade 4), hypertension (2 grade 3), elevated ALT (2 grade 3). Sixteen patients required dose reductions, most often for hypophosphatemia (n = 7 reductions in 6 patients); two stopped regorafenib for toxicity. There was one death unrelated to treatment in the 30-day post-study period. Median progression-free survival (PFS) was 14.8 weeks (95% CI 7.3-15.9); PFR at 8 weeks by Kaplan-Meier analysis was 63% (95% CI 46-81%). The RECIST 1.1 response rate was 10%. Median OS was 53 weeks (95% CI 37-106 weeks)., Conclusions: Regorafenib has modest activity in the Ewing family sarcomas. Toxicity was similar to that seen in approval studies., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Gastrointestinal stromal tumors (GIST) are the most common type of soft tissue sarcoma that occur throughout the gastrointestinal tract. Most of these tumors are caused by oncogenic activating mutations in the KIT or PDGFRA genes. The NCCN Guidelines for GIST provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with these tumors. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised systemic therapy options for unresectable, progressive, or metastatic GIST based on mutational status, and updated recommendations for the management of GIST that develop resistance to specific tyrosine kinase inhibitors.

Background: NC-6300 is a novel epirubicin (EPI) drug conjugated polymeric micelle developed using cutting-edge micellar nanoparticle technology. The nanoparticle epirubicin conjugates EPI to a polymer via a pH-sensitive linker which enables the selective EPI release into tumor. Tumor activity was observed in a monotherapy phase Ib trial, where two of two patients with angiosarcoma achieved a partial response. To further explore the activity of NC-6300 in angiosarcoma, an expansion cohort was undertaken., Methods: Ten patients with angiosarcoma were enrolled in the expansion cohort. Patients were dosed using the recommended dose of 150 mg/m2 intravenously (IV) once every 3 weeks. The primary endpoint was progression-free survival., Results: The most common adverse events (AEs) of any grade, regardless of the causal relationship with NC-6300, were neutropenia (90%), fatigue, and thrombocytopenia (60% each) and nausea (50%). The most common grades 3 and 4 AEs were neutropenia (80%), thrombocytopenia (40%), and anemia and leukopenia (20% each). The median progression-free survival (mPFS) for all subjects was 5.4 months. The mPFS was 3.8 months in subjects with prior anthracycline treatment and 8.2 months in subjects without prior anthracycline treatment., Conclusion: NC-6300 was well tolerated, showing promising activity in angiosarcoma patients without prior anthracycline treatment. NC-6300 warrants further investigation (ClinicalTrials.gov Identifier: NCT03168061)., (© The Author(s) 2022. Published by Oxford University Press.)

Desmoid tumors (DTs) are rare soft tissue mesenchymal neoplasms that may be associated with impairments, disfigurement, morbidity, and (rarely) mortality. DT disease course can be unpredictable. Most DTs are sporadic, harboring somatic mutations in the gene that encodes for β-catenin, whereas DTs occurring in patients with familial adenomatous polyposis have germline mutations in the APC gene, which encodes for a protein regulator of β-catenin. Pathology review by an expert soft tissue pathologist is critical in making a diagnosis. Magnetic resonance imaging is preferred for most anatomic locations. Surgery, once the standard of care for initial treatment of DT, is associated with a significant risk of recurrence as well as avoidable morbidity because spontaneous regressions are known to occur without treatment. Consequently, active surveillance in conjunction with pain management is now recommended for most patients. Systemic medical treatment of DT has evolved beyond the use of hormone therapy, which is no longer routinely recommended. Current options for medical management include tyrosine kinase inhibitors as well as more conventional cytotoxic chemotherapy (e.g., anthracycline-based or methotrexate-based regimens). A newer class of agents, γ-secretase inhibitors, appears promising, including in patients who fail other therapies, but confirmation in Phase 3 trials is needed. In summary, DTs present challenges to physicians in diagnosis and prognosis, as well as in determining treatment initiation, type, duration, and sequence. Accordingly, evaluation by a multidisciplinary team with expertise in DT and patient-tailored management are essential. As management strategies continue to evolve, further studies will help clarify these issues and optimize outcomes for patients., (© 2022 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Purpose: Antitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents., Methods: SEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of study treatment were included for safety analysis (ClinicalTrials.gov identifier: NCT02606461)., Results: Two hundred eighty-five patients were enrolled (selinexor, n = 188; placebo, n = 97). PFS was significantly longer with selinexor versus placebo: hazard ratio (HR) 0.70 (95% CI, 0.52 to 0.95; one-sided P = .011; medians 2.8 v 2.1 months), as was time to next treatment: HR 0.50 (95% CI, 0.37 to 0.66; one-sided P < .0001; medians 5.8 v 3.2 months). With crossover, no difference was observed in overall survival. The most common treatment-emergent adverse events of any grade versus grade 3 or 4 with selinexor were nausea (151 [80.7%] v 11 [5.9]), decreased appetite (113 [60.4%] v 14 [7.5%]), and fatigue (96 [51.3%] v 12 [6.4%]). Four (2.1%) and three (3.1%) patients died in the selinexor and placebo arms, respectively. Exploratory RNA sequencing analysis identified that the absence of CALB1 expression was associated with longer PFS with selinexor compared with placebo (median 6.9 v 2.2 months; HR, 0.19; P = .001)., Conclusion: Patients with advanced, refractory DD-LPS showed improved PFS and time to next treatment with selinexor compared with placebo. Supportive care and dose reductions mitigated side effects of selinexor. Prospective validation of CALB1 expression as a predictive biomarker for selinexor in DD-LPS is warranted.

Soft tissue sarcomas (STS) are rare malignancies of mesenchymal cell origin that display a heterogenous mix of clinical and pathologic characteristics. STS can develop from fat, muscle, nerves, blood vessels, and other connective tissues. The evaluation and treatment of patients with STS requires a multidisciplinary team with demonstrated expertise in the management of these tumors. The complete NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Soft Tissue Sarcoma provide recommendations for the diagnosis, evaluation, and treatment of extremity/superficial trunk/head and neck STS, as well as retroperitoneal/intra-abdominal STS, desmoid tumors, and rhabdomyosarcoma. This portion of the NCCN Guidelines discusses general principles for the diagnosis and treatment of retroperitoneal/intra-abdominal STS, outlines treatment recommendations, and reviews the evidence to support the guidelines recommendations.

ARST1321, a trial of patients with advanced soft tissue sarcoma, was the first National Clinical Trials Network study codeveloped by pediatric and adult consortia with two treatment cohorts. We report on the findings of a survey to identify barriers to enrolling adolescent and young adult patients (15-39 years) onto the nonchemotherapy arm. The survey response rate was 31% with a 70% completion rate. Common identified reasons for low accrual in order of decreasing frequency included insufficient funding, lack of study awareness or interest, competing trials, toxicity concerns, philosophical differences in the therapy backbone, and regulatory and infrastructure barriers. Clinical Trials.gov ID: NCT02180867.

Purpose: CMB305 is a heterologous prime-boost vaccination regimen created to prime NY-ESO-1-specific CD8 T-cell populations and then activate the immune response with a potent TLR-4 agonist. This open-label randomized phase II trial was designed to investigate the efficacy and safety of adding the CMB305 regimen to atezolizumab (anti-programmed death ligand-1 therapy) in comparison with atezolizumab alone in patients with synovial sarcoma or myxoid liposarcoma., Patients and Methods: Patients with locally advanced, relapsed, or metastatic synovial sarcoma or myxoid liposarcoma (any grade) were randomly assigned to receive CMB305 with atezolizumab (experimental arm) or atezolizumab alone (control arm). The primary end points were progression-free survival (PFS) and overall survival (OS) analyzed using the Kaplan-Meier method. Safety and immune responses were assessed., Results: A total of 89 patients were enrolled; 55.1% had received ≥ 2 prior lines of chemotherapy. Median PFS was 2.6 months and 1.6 months in the combination and control arms, respectively (hazard ratio, 0.9; 95% CI, 0.6 to 1.3). Median OS was 18 months in both treatment arms. Patients treated with combination therapy had a significantly higher rate of treatment-induced NY-ESO-1-specific T cells ( P = .01) and NY-ESO-1-specific antibody responses ( P < .0001). In a post hoc analysis of all dosed patients, OS was longer (36 months) in the subset who developed anti-NY-ESO-1 T-cell immune response (hazard ratio, 0.3; P = .02)., Conclusion: Although the combination of CMB305 and atezolizumab did not result in significant increases in PFS or OS compared with atezolizumab alone, some patients demonstrated evidence of an anti-NY-ESO-1 immune response and appeared to fare better by imaging than those without such an immune response. Combining prime-boost vaccines such as CMB305 with anti-programmed death ligand-1 therapies merits further evaluation in other clinical contexts., Competing Interests: Sant P. ChawlaStock and Other Ownership Interests: AADi, Cellestia Biotech, Immix BioPharmaHonoraria: Amgen, Roche, GlaxoSmithKline, Threshold Pharmaceuticals, CytRx Corporation, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, SARC: Sarcoma Alliance for Research through Collaboration, Janssen, Advenchen Laboratories, Bayer, InhibRx, NKMax, TymeConsulting or Advisory Role: Amgen, Roche, GlaxoSmithKline, Threshold Pharmaceuticals, CytRx Corporation, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, SARC: Sarcoma Alliance for Research through Collaboration, Janssen, Advenchen Laboratories, Bayer, NKMax, InhibRxSpeakers' Bureau: Amgen, Roche, GlaxoSmithKline, Threshold Pharmaceuticals, CytRx Corporation, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, SARC: Sarcoma Alliance for Research through Collaboration, JanssenResearch Funding: Amgen, Roche, GlaxoSmithKline, Threshold Pharmaceuticals, CytRx Corporation, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, SARC: Sarcoma Alliance for Research through Collaboration, Janssen, Advenchen Laboratories, Bayer, InhibRx, NKMax Brian A. Van TineLeadership: PolarisConsulting or Advisory Role: EMD Serono, Novartis, Epizyme, Daiihi Sankyo, Pfizer, Adaptimmune, Bayer, GlaxoSmithKline, Lilly, Cytokinetics, Apexigen, Deciphera Pharmaceuticals, Immune Design, ADRxSpeakers' Bureau: Novartis, Lilly, Adaptimmune, GlaxoSmithKlineResearch Funding: Pfizer, Merck, TRACON Pharma, GlaxoSmithKlinePatents, Royalties, Other Intellectual Property: Patent on the use of ME1 as a biomarker, Patent on ALEXT3102, Accuronix Therapeutics—Licensing agreement. Sigma-2 Receptor Ligands and Therapeutic Uses Therefor (006766), Modular Platform for Targeted Therapeutic Delivery (006755), Sigma-2 Receptor Ligand Drug Conjugates as Antitumor Compounds, Methods of synthesis and Uses Thereof (014229)Expert Testimony: Health AdvancesTravel, Accommodations, Expenses: Adaptimmune, Advenchen Laboratories, GlaxoSmithKline, Lilly Seth M. PollackConsulting or Advisory Role: GlaxoSmithKline, Daichii Sankyo, Apexigen, T-KnifeResearch Funding: Merck, EMD Serono, Incyte Kristen N. GanjooConsulting or Advisory Role: Daiichi Sankyo, Foundation Medicine, Deciphera Anthony D. EliasStock and Other Ownership Interests: AbbVie, Merck, Gilead Sciences, Allergan, Pfizer, Abbott Laboratories, Amgen, Bristol Myers Squibb, United Health Group, Align Oncology, Illumina, Exact Sciences, Lilly, Agilent, Cigna, Alexion Pharmaceuticals, BiogenerixConsulting or Advisory Role: Ayala PharmaceuticalsResearch Funding: Medivation, Astellas Pharma, Genentech, Deciphera, Xencor, Infinity Pharmaceuticals, Karyopharm Therapeutics, TopAlliance BioSciences Inc, Fosun Orinove, BioAtlaUncompensated Relationships: Seiyax Richard F. RiedelEmployment: LimbguardLeadership: LimbguardStock and Other Ownership Interests: LimbguardConsulting or Advisory Role: Daiichi Sankyo, Loxo, Ignyta, Bayer, NanoCarrier, Deciphera, SpringWorks Therapeutics, Blueprint MedicinesResearch Funding: TRACON Pharma, Bayer, Karyopharm Therapeutics, Immune Design, AADi, Plexxikon, Arog, Lilly, Daiichi Sankyo, Ignyta, Roche/Genentech, NanoCarrier, GlaxoSmithKline, SpringWorks Therapeutics, Blueprint Medicines, Epizyme, PhilogenPatents, Royalties, Other Intellectual Property: PandoNet—LimbguardTravel, Accommodations, Expenses: Daiichi Sankyo, Ignyta, NanoCarrier Steven AttiaResearch Funding: AB Science, TRACON Pharma, Bayer, Novartis, Lilly, Immune Design, Karyopharm Therapeutics, Epizyme, Blueprint Medicines, Genmab, CBA Pharma, Desmoid Tumor Research Foundation, Merck, Philogen, Gradalis, Deciphera, Takeda, Incyte, SpringWorks Therapeutics, Adaptimmune, Advenchen Laboratories, Bavarian Nordic, BTG, PTC Therapeutics, GlaxoSmithKline, FORMA Therapeutics Edwin ChoyResearch Funding: Novartis, Amgen, AstraZeneca, Mirati Therapeutics, Exelixis, Iterion Therapeutics, Immune Design, Lilly, AdaptimmuneOpen Payments Link: https://openpaymentsdata.cms.gov/physician/584027 Mark AgulnikConsulting or Advisory Role: Lilly, Adaptimmune, Regeneron, AstraZenecaSpeakers' Bureau: Bristol Myers Squibb, Bayer, DecipheraResearch Funding: Exelixis Margaret von MehrenConsulting or Advisory Role: Deciphera, ExelixisResearch Funding: ArQule, Novartis, Blueprint Medicines, Deciphera, Gradalis, Springworks Therapeutics, Lilly, Arog, Genmab, ASCOTravel, Accommodations, Expenses: Deciphera Pharmaceuticals, NCCNOther Relationship: NCCN Vicki L. KeedyConsulting or Advisory Role: Karyopharm Therapeutics, Daiichi Sankyo/LillyResearch Funding: MedPacto, Plexxikon, Daiichi Sankyo, Lilly, Immune Design, GlaxoSmithKline, TRACON Pharma, Advenchen Laboratories, Adaptimmune, Deciphera, SpringWorks Therapeutics Tony PhilipConsulting or Advisory Role: Foundation Medicine, Daiichi Sankyo/Astra Zeneca, Deciphera G. Chet BohacEmployment: MacrogenicsStock and Other Ownership Interests: Amgen, Macrogenics Sergey YurasovEmployment: Immune Design, Nuvation BioLeadership: Immune DesignStock and Other Ownership Interests: Nuvation Bio Adam YakovichStock and Other Ownership Interests: Replimune, Karyopharm TherapeuticsConsulting or Advisory Role: Merck Hailing LuEmployment: SeagenStock and Other Ownership Interests: Seagen Michael ChenEmployment: Sanamo Therapeutics, Immune DesignStock and Other Ownership Interests: Sangmo Robert G. MakiConsulting or Advisory Role: Bayer, Karyopharm Therapeutics, Deciphera, TRACON PharmaResearch Funding: Regeneron, Daiichi, Bayer, SpringWorks TherapeuticsPatents, Royalties, Other Intellectual Property: UpToDate: I write and edit chapters for their online textbookTravel, Accommodations, Expenses: TRACON Pharma, SpringWorks TherapeuticsOpen Payments Link: https://openpaymentsdata.cms.gov/physician/205679/summaryNo other potential conflicts of interest were reported.

BACKGROUND. CT-based criteria for assessing the gastrointestinal stromal tumor (GIST) response to tyrosine kinase inhibitor (TKI) therapy are limited in part because tumor attenuation is influenced by treatment-related changes including hemorrhage and calcification. The iodine concentration may be less impacted by such changes. OBJECTIVE. The purpose of this study was to determine whether the dual-energy CT (DECT) vital iodine tumor burden (TB) allows improved differentiation between treatment responders and nonresponders among patients with metastatic GIST who are undergoing TKI therapy compared with established CT and PET/CT criteria. METHODS. An anthropomorphic phantom with spherical inserts mimicking GIST lesions of varying iodine concentrations and having nonenhancing central necrotic cores underwent DECT to determine a threshold iodine concentration. Forty patients (25 women and 15 men; median age, 57 years) who were treated with TKI for metastatic GIST were retrospectively evaluated. Patients underwent baseline and follow-up DECT and FDG PET/CT. Response assessment was performed using RECIST 1.1, modified Choi (mChoi) criteria, vascular tumor burden (VTB) criteria, DECT vital iodine TB criteria, and European Organization for Research and Treatment of Cancer (EORTC) PET criteria. DECT vital iodine TB criteria used the same percentage changes as RECIST 1.1 response categories. Progression-free survival was compared between responders and nonresponders for each response criterion by use of Cox proportional hazard ratios and Harrell C-indexes (i.e., concordance indexes). RESULTS. The phantom experiment identified a threshold of 0.5 mg/mL to differentiate vital from nonvital tissue. With use of the DECT vital iodine TB, median progression-free survival was significantly different between responders and nonresponders (623 vs 104 days; p < .001).. For nonresponders versus responders, the hazard ratio for disease progression for DECT vital iodine TB was 6.9 versus 7.6 for EORTC PET criteria, 3.3 for VTB criteria, 2.3 for RECIST 1.1, and 2.1 for mChoi criteria. The C-index was 0.74 for EORTC PET criteria, 0.73 for DECT vital iodine TB criteria, 0.67 for VTB criteria, 0.61 for RECIST 1.1, and 0.58 for mChoi criteria. The C-index was significantly greater for DECT vital iodine TB criteria than for RECIST 1.1 ( p = .02) and mChoi criteria ( p = .002), but it was not different from that for VTB and EORTC PET criteria ( p > .05). CONCLUSION. DECT vital iodine TB criteria showed performance comparable to that of EORTC PET criteria and outperformed RECIST 1.1 and mChoi criteria for response assessment of metastatic GIST treated with TKI therapy. CLINICAL IMPACT. DECT vital iodine TB could help guide early management decisions in patients receiving TKI therapy.

Purpose: Malignant perivascular epithelioid cell tumor (PEComa) is a rare aggressive sarcoma, with no approved treatment. To our knowledge, this phase II, single-arm, registration trial is the first prospective clinical trial in this disease, investigating the safety and efficacy of the mammalian target of rapamycin inhibitor nab -sirolimus (AMPECT, NCT02494570)., Patients and Methods: Patients with malignant PEComa were treated with nab -sirolimus 100 mg/m 2 intravenously once weekly for 2 weeks in 3-week cycles. The primary end point was objective response rate evaluated by independent radiology review. Key secondary end points included duration of response, progression-free survival, and safety. A key exploratory end point was tumor biomarker analysis., Results: Thirty-four patients were treated (safety evaluable), and 31 were evaluable for efficacy. The overall response rate was 39% (12 of 31; 95% CI, 22 to 58) with one complete and 11 partial responses, 52% (16 of 31) of patients had stable disease, and 10% (3 of 31) had progressive disease. Responses were of rapid onset (67% by week 6) and durable. Median duration of response was not reached after a median follow-up for response of 2.5 years, with 7 of 12 responders with treatment ongoing (range, 5.6-47.2+ months). Twenty-five of 31 patients had tumor mutation profiling: 8 of 9 (89%) patients with a TSC2 mutation achieved a confirmed response versus 2 of 16 (13%) without TSC2 mutation ( P < .001). The median progression-free survival was 10.6 months (95% CI, 5.5 months to not reached), and the median overall survival was 40.8 months (95% CI, 22.2 months to not reached). Most treatment-related adverse events were grade 1 or 2 and were manageable for long-term treatment. No grade ≥ 4 treatment-related events occurred., Conclusion: nab -Sirolimus is active in patients with malignant PEComa. The response rate, durability of response, disease control rate, and safety profile support that nab -sirolimus represents an important new treatment option for this disease., Competing Interests: Andrew J. WagnerHonoraria: DecipheraConsulting or Advisory Role: Lilly, Five Prime Therapeutics, Daiichi Sankyo, Deciphera, Nanocarrier, MundipharmaResearch Funding: Lilly, Plexxikon, Daiichi Sankyo, Karyopharm Therapeutics, Aadi Bioscience, Deciphera Vinod RaviStock and Other Ownership Interests: TRACON Pharma, Merck, AstraZeneca, Pfizer, Moderna TherapeuticsConsulting or Advisory Role: Daiichi SankyoResearch Funding: Novartis, TRACON Pharma, Aadi Bioscience, AthenexTravel, Accommodations, Expenses: Daiichi Sankyo Richard F. RiedelEmployment: LimbguardLeadership: LimbguardStock and Other Ownership Interests: LimbguardConsulting or Advisory Role: Daiichi Sankyo, Loxo, Ignyta, Bayer, Nanocarrier, Deciphera, SpringWorks Therapeutics, Blueprint MedicinesResearch Funding: TRACON Pharma, Bayer, Karyopharm Therapeutics, Immune Design, Aadi Bioscience, Plexxikon, Arog, Lilly, Daiichi Sankyo, Ignyta, Roche/Genetech, NanoCarrier, GlaxoSmithKline, SpringWorks Therapeutics, Blueprint Medicines, Epizyme, PhilogenPatents, Royalties, Other Intellectual Property: PandoNet - LimbguardTravel, Accommodations, Expenses: Daiichi Sankyo, Ignyta, NanoCarrier Kristen GanjooConsulting or Advisory Role: Daiichi Sankyo, Foundation Medicine, Deciphera Brian A. Van TineLeadership: PolarisHonoraria: Bionest Partners (Healthcare Consulting Firm), Horizon CME, Research to Practice, Daiichi Sankyo, Pfizer, Adaptimmune, Bayer, GlaxoSmithKline, Lilly, Cytokinetics, Apexigen, Deciphera Pharmaceuticals, Immune Design, ADRx, Ayala Pharmaceuticals, Intellisphere LLCSpeaker’s Bureau: Novartis, Lilly, Adaptimmune, GlaxoSmithKlineConsulting or Advisory Role: EMD Serono, Novartis, Epizyme,Research Funding: Pfizer, Merck, TRACON Pharma, GlaxoSmithKlinePatents, Royalties, Other Intellectual Property: Patent on the use of ME1 as a biomarker, Patent on ALEXT3102, Accuronix Therapeutics-Licensing agreement, Sigma-Receptor Ligands and Therapeutic uses therefor (006766), Modular Platform for Targeted Therapeutics Delivery (006755), Sigma-2 Receptor Ligand Drug Conjugates as Antitumor Compounds, Methods of synthesis and uses thereof (014229)Expert Testimony: Health AdvancesTravel, Accommodations, Expenses: Advenchen Laboratories, GlaxoSmithKline, Lilly Rashmi ChughConsulting or Advisory Role: Ipsen, Deciphera, EpizymeResearch Funding: Novartis, Morphotek, MabVax, Epizyme, Aadi Bioscience, Advenchen Laboratories, Plexxikon, Mundipharma, SpringWorks Therapeutics, GlaxoSmithKline, Medivation, Qilu Puget Sound Biotherapeutics, AstraZeneca, JanssenPatents, Royalties, Other Intellectual Property: Wolters KluwerExpert Testimony: DOPF, LLC, Meyers Law, LLCTravel, Accommodations, Expenses: SpringWorks Therapeutics Lee CranmerConsulting or Advisory Role: Daiichi SankyoResearch Funding: Aadi Bioscience, Advenchen Laboratories, Lilly, Exelixis, Iterion Therapeutics, Philogen, CBA Research, Astellas Pharma Erlinda M. GordonStock and Other Ownership Interests: Counterpoint Biomedica, Delta NextGene, LLCResearch Funding: Bristol Myers SquibbPatents, Royalties, Other Intellectual Property: Coinventor of patents on targeting pharmaceutical agents to injured tissues Jason L. HornickConsulting or Advisory Role: Aadi Bioscience, TRACON Pharma Berta GrigorianEmployment: Aadi BioscienceStock and Other Ownership Interests: Aadi Bioscience Anita N. SchmidEmployment: Aadi BioscienceStock and Other Ownership Interests: Aadi Bioscience Shihe HouEmployment: Aadi BioscienceStock and Other Ownership Interests: Aadi Bioscience, Bristol Myers Squibb/Celgene Katherine HarrisConsulting or Advisory Role: Aadi Bioscience David J. KwiatkowskiConsulting or Advisory Role: Genetech/Roche, Novartis, Aadi BioscienceResearch Funding: Aadi Bioscience, Revolution Medicines, Genetech/Roche Neil P. DesaiEmployment: Aadi BioscienceLeadership: Aadi BioscienceStock and Other Ownership Interests: Aadi BioscienceResearch Funding: Aadi BiosciencePatents, Royalties, Other Intellectual Property: I hold patents as an employee of Aadi BioscienceTravel, Accommodations, Expenses: Aadi Bioscience Mark A. DicksonConsulting or Advisory Role: CelgeneResearch Funding: Lilly, Aadi BioscienceNo other potential conflicts of interest were reported.

Objective: Compare health-related quality of life (HRQoL) of selinexor versus placebo in patients with dedifferentiated liposarcoma. Materials & methods: HRQoL was assessed at baseline and day 1 of each cycle using the European Organization for Research and Treatment of Cancer 30-item core quality of life questionnaire. Results were reported from baseline to day 169 (where exposure to treatment was maximized while maintaining adequate sample size). Results: Pain scores worsened for placebo versus selinexor across all postbaseline visits, although differences in HRQoL at some visits were not significant. Other domains did not exhibit significant differences between arms; however, scores in both arms deteriorated over time. Conclusion: Patients treated with selinexor reported lower rates and slower worsening of pain compared with patients who received placebo.

Background: Avapritinib, a novel inhibitor of KIT/PDGFRA, is approved in the U.S. for the treatment of adults with PDGFRA exon 18-mutant unresectable or metastatic gastrointestinal stromal tumors (U/M GISTs). We assessed the safety of avapritinib and provide evidence-based guidance on management of avapritinib-associated adverse events (AEs), including cognitive effects and intracranial bleeding., Materials and Methods: We performed a post hoc analysis of data from a two-part, single-arm dose escalation/expansion phase I study (NAVIGATOR; NCT02508532) in patients with U/M GISTs treated with oral avapritinib 30-600 mg once daily. The primary endpoints were safety and tolerability; the impact of dose modification (interruption and/or reduction) on progression-free survival (PFS) was a secondary endpoint. Efficacy analyses were limited to patients who started avapritinib at 300 mg (approved dose)., Results: Of 250 patients enrolled in the study, 74.0% presented with KIT mutation and 24.8% presented with PDGFRA exon 18-mutation; 66.8% started avapritinib at 300 mg. The most common treatment-related AEs (any grade) were nausea (59.2%), fatigue (50.0%), periorbital edema (42.0%), anemia (39.2%), diarrhea (36.0%), vomiting (36.0%), and increased lacrimation (30.8%). No treatment-related deaths occurred. Among 167 patients starting on 300 mg avapritinib, all-cause cognitive effects rate (grade 1-2) was 37.0% in all patients and 52.0% in patients ≥65 years. Cognitive effects improved to a lower grade more quickly with dose modification (1.3-3.1 weeks) than without (4.9-7.6 weeks). Median PFS was 11.4 months with dose modification and 7.2 months without., Conclusion: Tolerability-guided dose modification of avapritinib is an effective strategy for managing AEs in patients with GISTs., Implications for Practice: Early recognition of adverse events and tailored dose modification appear to be effective approaches for managing treatment-related adverse events and maintaining patients on avapritinib. Dose reduction does not appear to result in reduced efficacy. Patients' cognitive function should be assessed at baseline and monitored carefully throughout treatment with avapritinib for the onset of cognitive adverse events. Dose interruption is recommended at the first sign of any cognitive effect, including grade 1 events., (© 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Liposarcomas are a common subfamily of soft tissue sarcoma with several subtypes recognized by the World Health Organization: atypical lipomatous tumors (ALT)/well-differentiated liposarcoma (WDLPS), dedifferentiated liposarcoma (DDLPS), myxoid liposarcoma (MLPS), pleomorphic liposarcoma (PLPS), and myxoid pleomorphic liposarcoma (MPLPS). Despite shared adipocytic features among liposarcomas, the clinical approach to each subtype differs based on histology, location, clinical behavior, and specific oncogenic drivers. In this review, we highlight subtype-specific molecular features with the potential to generate novel therapies. We discuss recent clinical trials investigating the use of preoperative radiation therapy for retroperitoneal liposarcoma, chemotherapy, small molecule inhibitors, and innovative immunotherapy approaches and describe how we incorporate these advancements into the management of liposarcoma., Competing Interests: Richard F. Riedel has received institutional clinical research support from Aadi, AROG, Blueprint, Daiichi Sankyo, Deciphera, GlaxoSmithKline, Karyopharm, Ignyta, Immune Design, Lilly, NanoCarrier, Novartis, Oncternal, Plexxikon, Roche, Springworks, Threshold, and TRACON. He has served as a consultant or advisor for Bayer, Blueprint, Daiichi Sankyo, Deciphera, Eisai, EMD Serono, Janssen, Lilly, Loxo, NanoCarrier, and Springworks. Candace L. Haddox declares that she has no competing interests.No competing interests were disclosed.No competing interests were disclosed., (Copyright: © 2020 Haddox CL et al.)

The NCCN Guidelines for Soft Tissue Sarcoma provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with soft tissue sarcomas. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including the development of a separate and distinct guideline for gastrointestinal stromal tumors (GISTs); reconception of the management of desmoid tumors; inclusion of further recommendations for the diagnosis and management of extremity/body wall, head/neck sarcomas, and retroperitoneal sarcomas; modification and addition of systemic therapy regimens for sarcoma subtypes; and revision of the principles of radiation therapy for soft tissue sarcomas.

Lessons Learned: The results from the liposarcoma cohort of SARC024 confirm previously published data and do not support the routine use of regorafenib in this patient population. Continued exploration of novel therapies, including combination approaches, is warranted for a patient population in whom limited treatment options exist., Background: Regorafenib is a multitargeted kinase inhibitor with a kinase profile overlapping, but distinct from, pazopanib, an agent approved for recurrent and metastatic non-gastrointestinal stromal tumor (GIST), non-adipocytic soft tissue sarcoma. We conducted a randomized, phase II study of regorafenib versus placebo in refractory liposarcoma patients., Methods: Patients with advanced or metastatic, treatment-refractory liposarcoma were randomized 1:1 to receive regorafenib 160 mg or placebo once daily (3 weeks on, 1 week off). Patients with well-differentiated liposarcoma only were excluded. Crossover for placebo was allowed upon progression. The primary endpoint was progression-free survival (PFS), according to RECIST version 1.1., Results: Forty-eight subjects with liposarcoma (34 dedifferentiated, 12 myxoid/round cell, 2 pleomorphic) were enrolled. Median PFS was 1.87 (95% confidence interval [CI], 0.92-3.67) months for regorafenib versus 2.07 (95% CI, 1.64-3.44) months for placebo; stratified hazard ratio [HR], 0.85 (95% CI, 0.46, 1.58), p = .62. No responses were seen on regorafenib. One PR was observed on placebo. Median overall survival was 6.46 (95% CI, 4.16-23.48) months for regorafenib and 4.89 (95% CI, 3.02-9.77) months for placebo, stratified HR, 0.66 (95% CI, 0.31-1.40), p = .28). Treatment-related adverse events were similar to the known safety profile of regorafenib., Conclusion: Regorafenib did not appear to improve PFS in treatment-refractory liposarcoma. No new significant safety signals were observed., (© 2020 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Purpose: NC-6300 is a novel nanoparticle formulation of epirubicin that has a pH-sensitive linker conjugated to epirubicin. It exhibits selective tumor accumulation owing to enhanced permeability and retention effect. We conducted a phase 1b trial to determine MTD and recommended phase II dose (RP2D) of NC-6300 monotherapy in advanced, metastatic, or unresectable solid tumors, including soft-tissue sarcomas., Patients and Methods: This phase 1b dose-escalation trial of NC-6300 monotherapy employed a Bayesian continuous reassessment method design. NC-6300 was administered on day 1 of every 21-day cycle, with epirubicin-equivalent dose increments from 125 to 215 mg/m 2 . Safety, efficacy, quality of life, and pharmacokinetic profile of NC-6300 monotherapy were evaluated., Results: Twenty-nine subjects (16 male) were enrolled: 17 with soft-tissue sarcoma, one with osteosarcoma, and 11 with other solid tumors. Observed dose-limiting toxicities included thrombocytopenia, stomatitis, lung infection, and febrile neutropenia. The most common grade 3/4 adverse events were neutropenia (59%), anemia (24%), thrombocytopenia (24%), and febrile neutropenia (21%). MTD and RP2D were determined to be 185 mg/m 2 and 150 mg/m 2 , respectively. The objective response rate in the evaluable population was 11%. Partial response was observed in angiosarcoma and endometrial stromal sarcoma. A dose-dependent increase was observed in both total and released epirubicin concentrations., Conclusions: NC-6300 was well tolerated with a manageable side effect profile, despite the MTD and RP2D being higher than conventional epirubicin doses. A signal of preliminary activity was observed in angiosarcoma. NC-6300 warrants further investigation in patients with advanced solid tumors, including sarcoma., (©2020 American Association for Cancer Research.)

BACKGROUND After a hospital stay, many older adults rely on their caregivers for assistance at home. Empirical evidence demonstrates that caregiver support programs in hospital-to-home transitions are associated with favorable caregiver and patient outcomes. We tested the feasibility of implementing the Duke Elder Family/Caregiver Training (DEFT) program in an academic medical center. METHODS: We recruited adult caregivers of homebound patients who were aged 55 years or older from Duke University Hospital in Durham, North Carolina. Caregivers attended a face-to-face caregiver training and received two telephone checks after hospital discharge with DEFT services ending at 14 days of hospital discharge. We used a one-item survey to measure overall DEFT satisfaction. We also monitored 30-day readmissions of patients whose caregivers completed the DEFT program. RESULTS: The DEFT Center received 104 consult orders in six months. Of these, 61 agreed to participate but nine caregivers were unable to schedule the DEFT training and three decided to eventually withdraw from participation. Forty-nine caregivers received the DEFT training, 12 of whom were ineligible to continue because of change in patients' disposition plan. Of the remaining 37 caregivers, 15 completed the full program and reported high satisfaction; one patient was readmitted within 30 days of discharge. LIMITATIONS: The DEFT implementation was based on academic-medical partnership and relied on electronic medical records for consult and documentation. Replicability and generalizability of findings are limited to settings with similar capabilities and resources. CONCLUSION: The implementation of a caregiver training and support program in an academic medical center was feasible and was associated with favorable preliminary outcomes., (©2020 by the North Carolina Institute of Medicine and The Duke Endowment. All rights reserved.)

Purpose: We recently reported a 17.5% objective RECIST 1.1 response rate in a phase II study of pembrolizumab in patients with advanced sarcoma (SARC028). The majority of responses occurred in undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLPS). We sought to determine whether we can identify immune features that correlate with clinical outcomes from tumor tissues obtained pre- and on-treatment., Patients and Methods: Pretreatment ( n = 78) and 8-week on-treatment ( n = 68) tumor biopsies were stained for PD-L1 and multiplex immunofluorescence panels. The density of positive cells was quantified to determine associations with anti-PD-1 response., Results: Patients that responded to pembrolizumab were more likely to have higher densities of activated T cells (CD8 + CD3 + PD-1 + ) and increased percentage of tumor-associated macrophages (TAM) expressing PD-L1 pre-treatment compared with non-responders. Pre-treatment tumors from responders also exhibited higher densities of effector memory cytotoxic T cells and regulatory T cells compared with non-responders. In addition, higher density of cytotoxic tumor-infiltrating T cells at baseline correlated with a better progression-free survival (PFS)., Conclusions: We show that quantitative assessments of CD8 + CD3 + PD-1 + T cells, percentage of TAMs expressing PD-L1, and other T-cell densities correlate with sarcoma response to pembrolizumab and improved PFS. Our findings support that multiple cell types present at the start of treatment may enhance tumor regression following anti-PD-1 therapy in specific advanced sarcomas. Efforts to confirm the activity of pembrolizumab in an expansion cohort of patients with UPS/DDLPS are underway., (©2020 American Association for Cancer Research.)

Purpose: SARC024 is a phase II clinical trial of the multikinase inhibitor regorafenib in specific sarcoma subtypes, including advanced osteosarcoma. We hypothesized that regorafenib would improve progression-free survival (PFS) in patients with sarcoma and report the results of the osteosarcoma cohort., Patients and Methods: This trial enrolled patients with progressive metastatic osteosarcoma with measurable disease by RECIST who had received at least one prior line of therapy. Patients were randomly assigned at a ratio of one to one to regorafenib or placebo. Crossover was allowed at time of disease progression. PFS was the primary end point of the study, which was powered to detect a difference of at least 3 months in median PFS., Results: Forty-two patients from 12 centers were enrolled between September 2014 and May 2018. Median age was 37 years (range, 18 to 76 years). Patients had received an average of 2.3 prior therapy regimens. Ten patients receiving placebo crossed over to active drug at time of progression. Study enrollment was stopped early, after a data safety monitoring committee review. Median PFS was significantly improved with regorafenib versus placebo: 3.6 months (95% CI, 2.0 to 7.6 months) versus 1.7 months (95% CI, 1.2 to 1.8 months), respectively (hazard ratio, 0.42; 95% CI, 0.21 to 0.85; P = .017). In the context of the crossover design, there was no statistically significant difference in overall survival. Fourteen (64%) of 22 patients initially randomly assigned to regorafenib experienced grade 3 to 4 events attributed to treatment, including one grade 4 colonic perforation., Conclusion: The study met its primary end point, demonstrating activity of regorafenib in patients with progressive metastatic osteosarcoma. No new safety signals were observed. Regorafenib should be considered a treatment option for patients with relapsed metastatic osteosarcoma.

Background: Evidence increasingly supports the integration of specialist palliative care (PC) into routine cancer care. A novel, fully integrated PC and medical oncology inpatient service was developed at Duke University Hospital in 2011., Objective: To assess the impact of PC integration on health care utilization among hospitalized cancer patients before hospice enrollment., Methods: Retrospective cohort study. Patients in the solid tumor inpatient unit who were discharged to hospice between September 1, 2009, and June 30, 2010 (pre-PC integration), and September 1, 2011, to June 30, 2012 (postintegration). Cohorts were compared on the following outcomes from their final hospitalization before hospice enrollment: intensive care unit days, invasive procedures, subspecialty consultations, radiographic studies, hospital length of stay, and use of chemotherapy or radiation. Cohort differences were examined with descriptive statistics and nonparametric tests., Results: Two hundred ninety-six patients were included in the analysis (133 pre-PC integration; 163 post-PC integration). Patient characteristics were similar between cohorts. Health care utilization was relatively low in both groups, although 26% and 24% were receiving chemotherapy at the time of admission or during hospitalization in the pre- and post-PC integration cohorts, respectively, and 6.8% in each cohort spent time in an intensive care unit. We found no significant differences in utilization between cohorts., Discussion: PC integration into an inpatient solid tumor service may not impact health care utilization during the final hospitalization before discharge to hospice. This likely reflects the greater benefits of integrating PC farther upstream from the terminal hospitalization, if one hopes to meaningfully impact utilization near the end of life.

Purpose: This study addressed the experiences of older caregivers of cancer patients in the 2 weeks following a hospital discharge. It sought to understand the challenges they face in providing supportive care to patients at home., Methods: Qualitative descriptive interviews with a narrative approach were conducted with each caregiver at 1 and 2 weeks following the patient's discharge from the hospital. A thematic analysis approach was used to identify the themes that emerged from the caregiver interviews., Results: Caregivers were primarily Caucasian (77%), were mostly 68 years of age or older (62%), and were primarily caring for a spouse (69%). Three key themes emerged from the qualitative analysis: caregiver and patient wellness are connected, caregivers' struggle with control issues, and challenges in communication with health professionals., Conclusions: These findings highlight psychosocial changes that caregivers experience over the 2-week time period following hospital discharge. Implications include the need to identify interventions to better prepare caregivers for the post-discharge period.

Background: Desmoid tumors (also referred to as aggressive fibromatosis) are connective tissue neoplasms that can arise in any anatomical location and infiltrate the mesentery, neurovascular structures, and visceral organs. There is no standard of care., Methods: In this double-blind, phase 3 trial, we randomly assigned 87 patients with progressive, symptomatic, or recurrent desmoid tumors to receive either sorafenib (400-mg tablet once daily) or matching placebo. Crossover to the sorafenib group was permitted for patients in the placebo group who had disease progression. The primary end point was investigator-assessed progression-free survival; rates of objective response and adverse events were also evaluated., Results: With a median follow-up of 27.2 months, the 2-year progression-free survival rate was 81% (95% confidence interval [CI], 69 to 96) in the sorafenib group and 36% (95% CI, 22 to 57) in the placebo group (hazard ratio for progression or death, 0.13; 95% CI, 0.05 to 0.31; P<0.001). Before crossover, the objective response rate was 33% (95% CI, 20 to 48) in the sorafenib group and 20% (95% CI, 8 to 38) in the placebo group. The median time to an objective response among patients who had a response was 9.6 months (interquartile range, 6.6 to 16.7) in the sorafenib group and 13.3 months (interquartile range, 11.2 to 31.1) in the placebo group. The objective responses are ongoing. Among patients who received sorafenib, the most frequently reported adverse events were grade 1 or 2 events of rash (73%), fatigue (67%), hypertension (55%), and diarrhea (51%)., Conclusions: Among patients with progressive, refractory, or symptomatic desmoid tumors, sorafenib significantly prolonged progression-free survival and induced durable responses. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT02066181 .).

Synovial sarcoma (SS) is an aggressive malignancy which accounts for approximately 5⁻10% of all soft-tissue sarcomas. SS has pathologic and genomic characteristics that define it as a distinct subtype of soft tissue sarcoma (STS). STS subtypes continue to be recognized as distinct entities with specific characteristics, including differential chemo-sensitivity. The objective of this study was to conduct a descriptive review of current data on survival outcomes of systemic anti-cancer therapy specific to SS. A systematic literature review was conducted, using a custom search strategy to search EMBASE, Medline and CENTRAL for clinical trials and observational studies reporting overall survival (OS), progression-free survival (PFS) and/or response for cohorts of at least 50 SS patients. We identified 28 studies meeting these criteria, 25 of which were retrospective studies. Only three prospective studies were identified. Survival reports varied widely between studies based on the population, in particular on the disease stage, and reporting was heterogeneous in terms of the time points reported on. For patients with localized disease, reports of five-year PFS ranged from 26% to 80.7% and five-year OS from 40% to 90.7%, whereas five-year OS for patients with metastatic disease was very low at around 10%; and in one case, 0% was reported. Only four of the included publications reported outcomes by type of systemic anti-cancer therapy received. Our study draws attention to the fact that additional prospective studies to better define the most appropriate treatment for SS in all stages and lines of therapy are still needed.

Soft tissue sarcomas (STS) are heterogeneous, mesenchymal malignancies with variable biologic behavior. The primary management for localized STS is surgical resection, which may be combined with neoadjuvant or adjuvant radiation therapy to increase the probability of achieving local control. Many patients with large, high-grade STS develop metastatic disease. Several clinical trials of immune checkpoint blockade for STS have produced promising responses in patients with metastatic disease. In this review, recent and ongoing clinical trials of immune checkpoint inhibition for STS are discussed. The authors explain the rationale for immune checkpoint inhibition and radiation therapy and highlight new studies testing this combination in the neoadjuvant setting for patients with high-risk STS. In addition, they describe novel combinations of immunotherapy with targeted therapies and chemotherapies being tested in the metastatic setting and discuss how these combinations have the potential to be integrated into adjuvant therapy in the future., (© 2018 American Cancer Society.)