Search

Denosumab is an established targeted systemic therapy for treatment of giant cell tumor of bone (GCTB). We sought to determine whether treatment response could be quantified from radiomics analysis of radiographs taken longitudinally during treatment. Pre- and post-treatment radiographs of 10 GCTB tumors from 10 patients demonstrating histologic response after treatment with denosumab were analyzed. Intensity- and texture-based radiomics features for each manually segmented tumor were calculated. Radiomics features were compared pre- and post-treatment in tumors. Mean intensity (p = 0.033) significantly increased while skewness (p = 0.028) significantly decreased after treatment. Post-treatment increases in fractal dimensions (p = 0.057) and abundance (p = 0.065) approached significance. A potential linear correlation in mean (p = 0.005; ΔMean = 0.022 * duration − 0.026) with treatment duration was observed. Radiomics analysis of plain radiographs quantifies time-dependent matrix mineralization and trabecular reconstitution that mark positive response of giant cell tumors of bone to denosumab.

Giant cell tumor of bone is a locally aggressive, rarely metastasizing neoplasm. Evidence suggests that the neoplastic cells may be osteoblastic in differentiation. Standard treatment is surgical removal, but medical therapy with denosumab, an inhibitor of receptor activator of nuclear factor-κβ ligand, has become a component of patient management in select cases. Denosumab-treated giant cell tumor of bone (DT-GCTB) shows drastic morphologic changes including the presence of abundant bone. To further determine the relationship of the neoplastic cells to osteoblast phenotype, we performed a morphologic and immunohistochemical study on a series of DT-GCTB. Cases of DT-GCTB were retrieved from surgical pathology files, available slides were reviewed, and immunohistochemistry for H3.3 G34W, SATB2, and p63 was performed. The cohort included 31 tumors from 30 patients (2:3 male:female), ages 15 to 73 years (median=36 y). The morphology of post-denosumab-treated tumors ranged from tumors composed of an abundant bone matrix with few spindle cells to spindle cell-predominant tumors. Five had focal residual classic CGTB, and 2 manifested mild nuclear atypia. The majority expressed all markers: 86.2% for H3.3 G34W, 96.7% for SATB2, and 100% for p63. All markers stained the various tumor components including spindle cells and the cells on the surface of and within the treated tumor bone matrix. Most markers were also positive in reactive-appearing woven bone adjacent to tumor: 84.6% for H3.3 G34W, 100% for SATB2, and 68% for p63. These findings suggest that denosumab treatment of giant cell tumor of bone results in osteoblastic differentiation with bone production.

Purpose Amplifications of receptor tyrosine kinases (RTKS) are therapeutic targets in multiple tumor types (e.g. HER2 in breast cancer), and amplification of the chromosome 4 segment harboring the three RTKs KIT, PDGFRA, and KDR (4q12amp) may be similarly targetable. The presence of 4q12amp has been sporadically reported in small tumor specific series but a large‐scale analysis is lacking. We assess the pan‐cancer landscape of 4q12amp and provide early clinical support for the feasibility of targeting this amplicon. Experimental Design Tumor specimens from 132,872 patients with advanced cancer were assayed with hybrid capture based comprehensive genomic profiling which assays 186–315 genes for all classes of genomic alterations, including amplifications. Baseline demographic data were abstracted, and presence of 4q12amp was defined as 6 or more copies of KIT/KDR/PDGFRA. Concurrent alterations and treatment outcomes with matched therapies were explored in a subset of cases. Results Overall 0.65% of cases harbored 4q12amp at a median copy number of 10 (range 6–344). Among cancers with >100 cases in this series, glioblastomas, angiosarcomas, and osteosarcomas were enriched for 4q12amp at 4.7%, 4.8%, and 6.4%, respectively (all p < 0.001), giving an overall sarcoma (n = 6,885) incidence of 1.9%. Among 99 pulmonary adenocarcinoma cases harboring 4q12amp, 50 (50%) lacked any other known driver of NSLCC. Four index cases plus a previously reported case on treatment with empirical TKIs monotherapy had stable disease on average exceeding 20 months. Conclusion We define 4q12amp as a significant event across the pan‐cancer landscape, comparable to known pan‐cancer targets such as NTRK and microsatellite instability, with notable enrichment in several cancers such as osteosarcoma where standard treatment is limited. The responses to available TKIs observed in index cases strongly suggest 4q12amp is a druggable oncogenic target across cancers that warrants a focused drug development strategy. Implications for Practice Coamplification of the receptor tyrosine kinases (rtks) KIT/KDR/PDGFRA (4q12amp) is present broadly across cancers (0.65%), with enrichment in osteosarcoma and gliomas. Evidence for this amplicon having an oncogenic role is the mutual exclusivity of 4q12amp to other known drivers in 50% of pulmonary adenocarcinoma cases. Furthermore, preliminary clinical evidence for driver status comes from four index cases of patients empirically treated with commercially available tyrosine kinase inhibitors with activity against KIT/KDR/PDGFRA who had stable disease for 20 months on average. The sum of these lines of evidence suggests further clinical and preclinical investigation of 4q12amp is warranted as the possible basis for a pan‐cancer drug development strategy., Matching treatment strategy to tumor biology is central to precision medicine. The co‐amplification of three distinct RTK encoding genes (KIT, KDR, and PDGFRA) on chromosome 4q12 (4q12amp) may be an oncogenic driver and thus a target for therapy. This article assesses the pan‐cancer landscape of 4q12amp and provides clinical support for the feasibility of targeting this amplicon.

Background Gene-modified autologous T cells expressing NY-ESO-1c259, an affinity-enhanced T-cell receptor (TCR) reactive against the NY-ESO-1-specific HLA-A*02-restricted peptide SLLMWITQC (NY-ESO-1 SPEAR T-cells; GSK 794), have demonstrated clinical activity in patients with advanced synovial sarcoma (SS). The factors contributing to gene-modified T-cell expansion and the changes within the tumor microenvironment (TME) following T-cell infusion remain unclear. These studies address the immunological mechanisms of response and resistance in patients with SS treated with NY-ESO-1 SPEAR T-cells. Methods Four cohorts were included to evaluate antigen expression and preconditioning on efficacy. Clinical responses were assessed by RECIST v1.1. Engineered T-cell persistence was determined by qPCR. Serum cytokines were evaluated by immunoassay. Transcriptomic analyses and immunohistochemistry were performed on tumor biopsies from patients before and after T-cell infusion. Gene-modified T-cells were detected within the TME via an RNAish assay. Results Responses across cohorts were affected by preconditioning and intra-tumoral NY-ESO-1 expression. Of the 42 patients reported (data cut-off 4June2018), 1 patient had a complete response, 14 patients had partial responses, 24 patients had stable disease, and 3 patients had progressive disease. The magnitude of gene-modified T-cell expansion shortly after infusion was associated with response in patients with high intra-tumoral NY-ESO-1 expression. Patients receiving a fludarabine-containing conditioning regimen experienced increases in serum IL-7 and IL-15. Prior to infusion, the TME exhibited minimal leukocyte infiltration; CD163+ tumor-associated macrophages (TAMs) were the dominant population. Modest increases in intra-tumoral leukocytes (≤5%) were observed in a subset of subjects at approximately 8 weeks. Beyond 8 weeks post infusion, the TME was minimally infiltrated with a TAM-dominant leukocyte infiltrate. Tumor-associated antigens and antigen presentation did not significantly change within the tumor post-T-cell infusion. Finally, NY-ESO-1 SPEAR T cells trafficked to the TME and maintained cytotoxicity in a subset of patients. Conclusions Our studies elucidate some factors that underpin response and resistance to NY-ESO-1 SPEAR T-cell therapy. From these data, we conclude that a lymphodepletion regimen containing high doses of fludarabine and cyclophosphamide is necessary for SPEAR T-cell persistence and efficacy. Furthermore, these data demonstrate that non-T-cell inflamed tumors, which are resistant to PD-1/PD-L1 inhibitors, can be treated with adoptive T-cell based immunotherapy. Trial registration ClinicalTrials.gov, NCT01343043, Registered 27 April 2011.

Despite their rarity, angiosarcomas are one of the most aggressive soft tissue sarcomas. Management can often be challenging due to their location and infiltrative nature. A multidisciplinary treatment approach is always warranted, but the recurrence remains high even for localized tumors despite multimodality treatment. In the metastatic setting, cytotoxic chemotherapies, targeted therapies, and, more recently, immunotherapy are used. The sequence of systemic therapies remains currently a topic of active investigation. Over the last couple of years, there have been significant advances in understanding angiosarcoma biology, most notably via patient-driven initiatives like the Angiosarcoma Project. The knowledge derived from such translational work has led to identifying potential biomarkers of response to treatments and exploring new therapeutic avenues. More clinical trials are underway to expand treatment options and improve patient outcomes.

Macrophages can be co-opted to contribute to neoplastic, neurologic, and inflammatory diseases. Colony-stimulating factor 1 receptor (CSF1R)-dependent macrophages and other inflammatory cells can suppress the adaptive immune system in cancer and contribute to angiogenesis, tumor growth, and metastasis. CSF1R-expressing osteoclasts mediate bone degradation in osteolytic cancers and cancers that metastasize to bone. In the rare disease tenosynovial giant cell tumor (TGCT), aberrant CSF1 expression and production driven by a gene translocation leads to the recruitment and growth of tumors formed by CSF1R-dependent inflammatory cells. Small molecules and antibodies targeting the CSF1/CSF1R axis have shown promise in the treatment of TGCT and cancer, with pexidartinib recently receiving FDA approval for treatment of TGCT. Many small-molecule kinase inhibitors of CSF1R also inhibit the closely related kinases KIT, PDGFRA, PDGFRB, and FLT3, thus CSF1R suppression may be limited by off-target activity and associated adverse events. Vimseltinib (DCC-3014) is an oral, switch control tyrosine kinase inhibitor specifically designed to selectively and potently inhibit CSF1R by exploiting unique features of the switch control region that regulates kinase conformational activation. In preclinical studies, vimseltinib durably suppressed CSF1R activity in vitro and in vivo, depleted macrophages and other CSF1R-dependent cells, and resulted in inhibition of tumor growth and bone degradation in mouse cancer models. Translationally, in a phase I clinical study, vimseltinib treatment led to modulation of biomarkers of CSF1R inhibition and reduction in tumor burden in TGCT patients.

Background Among sarcomas, which are rare cancers, many types are exceedingly rare; however, a definition of ultra-rare cancers has not been established. The problem of ultra-rare sarcomas is particularly relevant because they represent unique diseases, and their rarity poses major challenges for diagnosis, understanding disease biology, generating clinical evidence to support new drug development, and achieving formal authorization for novel therapies. Methods The Connective Tissue Oncology Society promoted a consensus effort in November 2019 to establish how to define ultra-rare sarcomas through expert consensus and epidemiologic data and to work out a comprehensive list of these diseases. The list of ultra-rare sarcomas was based on the 2020 World Health Organization classification, The incidence rates were estimated using the Information Network on Rare Cancers (RARECARENet) database and NETSARC (the French Sarcoma Network's clinical-pathologic registry). Incidence rates were further validated in collaboration with the Asian cancer registries of Japan, Korea, and Taiwan. Results It was agreed that the best criterion for a definition of ultra-rare sarcomas would be incidence. Ultra-rare sarcomas were defined as those with an incidence of approximately ≤1 per 1,000,000, to include those entities whose rarity renders them extremely difficult to conduct well powered, prospective clinical studies. On the basis of this threshold, a list of ultra-rare sarcomas was defined, which comprised 56 soft tissue sarcoma types and 21 bone sarcoma types. Conclusions Altogether, the incidence of ultra-rare sarcomas accounts for roughly 20% of all soft tissue and bone sarcomas. This confirms that the challenges inherent in ultra-rare sarcomas affect large numbers of patients.

In this report, we describe a 54-year-old male with cystic retroperitoneal sarcoma extending through the inguinal canal. Patient initially underwent inguinal hernia repair with mesh placement for suspected cord lipoma, after which he developed recurrent loculated retroperitoneal fluid collections refractory to multiple attempts at drain placement and laparotomy. Twenty-nine months after initial surgery, patient was referred to our institution on suspicion of malignancy. Pathology of resections taken during subsequent laparotomy showed foci of malignant cells interspersed throughout reactive proliferations. Follow-up immunohistochemistry confirmed high-grade sarcoma, likely atypical liposarcoma, but was unable to definitively establish subtype. Despite en bloc resection and gemcitabine/docetaxel chemotherapy, local progression continued, and patient was enrolled in clinical trials of doxorubicin with dual immune checkpoint blockade. This case suggests that sarcoma should be considered as a differential diagnosis of retroperitoneal or inguinal mass unresponsive to treatment; and highlights the difficulty of subtyping and managing cystic retroperitoneal sarcoma.

Background Zalifrelimab is a fully human monoclonal antibody against cytotoxic T-lymphocyte -associated protein 4 (CTLA-4). Preliminary data demonstrated clinical benefit and tolerability, as monotherapy, in patients with recurrent solid tumors including rare tumor types. Previously presented Phase I data reported one durable complete response in recurrent cutaneous angiosarcoma (cAS).1 Here we report additional clinical responses from an ongoing Phase 2 study of zalifrelimab monotherapy including clinical benefit in rare solid tumors. Methods In an ongoing, phase 2 study (NCT03104699), the safety and efficacy of zalifrelimab, as monotherapy, was evaluated in patients who progressed on prior anti-PD-1/L1 treatment. All patients were treated intravenously (IV) with zalifrelimab at 1 mg/kg every 3 weeks until disease progression or up to 2 years. Results Overall, 44 patients were treated and 29 patients were response-evaluable at the time of report. In patients with refractory solid tumors treated with zalifrelimab, we report a disease control rate (CR, PR, and SD) of 51.7%, objective response rate (ORR) of 10.3% (3/29), disease stabilization of 41.3% (12/29). Clinical activity was observed in five solid tumors considered rare, including; cAS (N=1), glucagonoma (N=1), chondrosarcoma (N=1), spindle-cell sarcoma (N=1) and fibroblastic sarcoma (N=1). In these rare tumors, durable partial responses of 45 and 30 weeks were observed in cAS of the scalp with lymph node metastases and glucagonoma, respectively. Both patients remain on zalifrelimab with no evidence of disease progression. Additionally, durable disease stabilization was observed in a patient with spindle-cell sarcoma. Patients with chondrosarcoma and fibroblastic sarcoma progressed on therapy. Zalifrelimab was well tolerated with the most commonly reported treatment-related adverse events including fatigue, nausea, anemia, diarrhea and vomiting, consistent with the drug class. Most events were mild or moderate and resolved with standard treatments. Conclusions Our data demonstrates the potential for Zalifrelimab to promote meaningful clinical benefit in difficult to treat tumors, including patients that progress on prior PD-1/PD-L1 therapy or chemotherapy. Notably, responses were observed in rare tumor types such as recurrent cutaneous angiosarcoma and glucagonoma. Treatment with zalifrelimab is safe and well tolerated in patients with advanced malignancies. Trial Registration NCT03104699. Reference Vaia Florou, Andrew E Rosenberg, Eric Wieder, Krishna V. Komanduri, Despina Kolonias, Mohamed Uduman, John C Castle, Jennifer S. Buell, Jonathan C. Trent and Breelyn A. Wilky Journal for Immunotherapy of Cancer 2019 7:213.

Background Relapsed and refractory sarcomas continue to have poor survival rates. The cancer stem cell (CSC) theory provides a tractable explanation for the observation that recurrences occur despite dramatic responses to upfront chemotherapy. Preclinical studies demonstrated that inhibition of the mechanistic target of rapamycin (mTOR) sensitizes the CSC population to chemotherapy. Methods Here we present the results of the Phase II portion of a Phase I/II clinical trial that aimed to overcome the chemoresistance of sarcoma CSC by combining the mTOR inhibitor temsirolimus (20 mg/m2 weekly) with the chemotherapeutic agent liposomal doxorubicin (30 mg/m2 monthly). Results Fifteen patients with relapsed/refractory sarcoma were evaluable at this recommended Phase 2 dose level. The median progression free survival was 315 days (range 27–799). Response rate, defined as stable disease or better for 60 days, was 53%. Nine of the patients had been previously treated with doxorubicin. Therapy was well tolerated. In a small number of patients, pre- and post- treatment tumor biopsies were available for assessment of ALDH expression as a marker of CSCs and showed a correlation between response and decreased ALDH expression. We also found a correlation between biopsy-proven inhibition of mTOR and response. Conclusions Our study adds to the literature supporting the addition of mTOR inhibition to chemotherapy agents for the treatment of sarcomas, and proposes that a mechanism by which mTOR inhibition enhances the efficacy of chemotherapy may be through sensitizing the chemoresistant CSC population. Further study, ideally with pre- and post-therapy assessment of ALDH expression in tumor cells, is warranted. Trial registration The trial was registered on clinicaltrials.gov (NCT00949325) on 30 July 2009. http://www.editorialmanager.com/csrj/default.aspx

Small randomized trials have not shown an overall survival (OS) difference among local treatment modalities for patients with extremity soft‐tissue sarcomas (E‐STS) but were underpowered for OS. We examine the impact of local treatment modalities on OS and sarcoma mortality (SM) using two national registries. The National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) Program were analyzed separately to identify patients with stage II‐III, high‐grade E‐STS diagnosed between 2004 and 2013 and treated with (1) amputation alone, (2) limb‐sparing surgery (LSS) alone, (3) preoperative radiation therapy (RT) and LSS, or (4) LSS and postoperative RT. Multivariable analyses (MVAs) and 1:1 matched pair analyses (MPAs) examined treatment impacts on OS (both databases) and SM (SEER only). From the NCDB and SEER, 7828 and 2937 patients were included. On MVAs, amputation was associated with inferior OS and SM. Relative to LSS alone, both preoperative RT and LSS (HR, 0.70; 95% CI: 0.62‐0.78) and LSS and postoperative RT (HR, 0.69; 95% CI: 0.63‐0.75) improved OS in NCDB analyses with confirmation by SEER. Estimated median survivals from MPA utilizing NCDB data were 7.2 years with LSS alone (95% CI: 6.5‐8.9 years) vs 9.8 years (95% CI: 9.0‐11.2 years) with LSS and postoperative RT. A MPA comparing preoperative RT and LSS to LSS alone found median survivals of 8.9 years (95% CI: 7.9‐not estimable) and 6.6 years (95% CI: 5.4‐7.8 years). Optimal high‐grade E‐STS management includes LSS with preoperative or postoperative RT as evidenced by superior OS and SM.

Immunotherapy has changed the treatment paradigm of melanoma and other malignancies. Recently, trials of checkpoint inhibition in sarcomas have been far from outstanding, although specific sarcoma subtypes appear to benefit from these novel therapies. The next steps involve combining immune checkpoint inhibition with classic cancer therapies in order to increase immunogenicity and also potentially complex immunotherapy techniques such as adoptive cell therapy. Currently, numerous clinical trials are exploring different immunotherapies in the sarcomas. Herein, we describe some of the preclinical and clinical data that have laid the groundwork for the use of immunotherapies in sarcomas, as well as the current and future studies that could make immunotherapy a therapeutic option for patients with sarcoma.

BackgroundAGEN1181 is a novel anti-CTLA-4 antibody with enhanced FcyR-dependent functionality, engineered to bind high and low binding alleles of FcyRIIIA, promoting superior T cell priming, memory responses, and depletion of intratumoral T regulatory cells. Further, AGEN1181 avoids complement recruitment, predictive of better tolerability. Here we report initial safety and efficacy findings from a phase I/Ib study of AGEN1181 as monotherapy and in combination with balstilimab (BAL; anti-PD-1).MethodsEligible patients (pts) had advanced solid tumors refractory to standard therapies. AGEN1181 was dosed Q3W (0.1–3 mg/kg) or Q6W (1–2 mg/kg) as monotherapy, or Q6W (0.1–2 mg/kg) in combination with BAL Q2W (3 mg/kg).ResultsAs of July 16th 2021, 102 pts received AGEN1181 (43 monotherapy, 59 combination). Median age, 63 years (29–83); 50.5% with ≥3 prior lines of therapy. MTD not yet reached with AGEN1181 dosing up to 3 mg/kg Q3W as monotherapy and 2 mg/kg in combination with BAL. The most common treatment-related adverse events (TRAEs) of any grade were fatigue (34.3%), diarrhea (32.4%), and nausea (19.6%) with grade ≥3 events in 21.6% (diarrhea/colitis, 11.8%, fatigue, 2.9%). Notably, no immune-related hypophysitis or pneumonitis has been observed. Discontinuation from AGEN1181 due to TRAEs occurred in 15% of pts. Grade 5 TRAEs occurred in two pts (colitis [chronic], intestinal perforation). The disease control rate in evaluable pts (completed ≥1 on-treatment scan) defined as best overall response of CR, PR, or SD ≥6 weeks was 48.1% for AGEN1181 monotherapy ≥1 mg/kg (1 CR, 3 PR, 9 SD) and 70% for combination (3 PR, 6 unconfirmed PR [uPR], 19 SD). Monotherapy responders include individual pts with MSS endometrial cancer (CR), PD-1-relapsed/refractory cervical cancer (PR), PD-1-relapsed/refractory melanoma (PR), and pancreatic cancer (PR). Enrollment is continuing in several disease expansion cohorts with combination therapy. For MSS CRC, 2 PR, 2 uPR, and 7 SD have been seen in 17 evaluable ≥1 mg/kg patients to date. In the ovarian cohort (n=6), 2 PRs and 3 SD are noted. Additional combination responders include one PR and uPR in MSS endometrial cancer, two uPRs in visceral angiosarcoma (uPRs) and one uPR in PD-1-relapsed/refractory NSCLC (uPR); the majority of the responses are recent and ongoing.ConclusionsAGEN1181 alone and in combination with BAL demonstrates favorable tolerability and compelling clinical activity, notably in poorly immunogenic tumor types and PD-1-refractory pts. These results underscore the significant potential of AGEN1181 to expand benefit of anti-CTLA-4 therapy to a broader patient population.Trial RegistrationNCT03860272Ethics ApprovalThe study obtained ethics approval at each participating center (UT Health Sciences Center at San Antonio, University of Colorado Cancer Center, St John’s Cancer Institute, and HonorHealth under WIRB Study number 1256391; USC Norris Comprehensive Cancer Center, Beth Israel Deaconess Medical Center, and MD Anderson Cancer Center, approval numbers HS19-00277, 19–132, and 140346, respectively). All patients provided written informed consent in accordance with federal, local, and institutional guidelines.

Highlights • Myoepithelial carcinoma of the vulva and epithelioid sarcoma has overlapping histological, immunohistochemical and genetic features. • Similarities between two diagnoses in aggressive vulvar cancer should be noted as a sarcoma-based chemotherapy regimen should be considered. • We recommend immediate surgical resection with bilateral superficial and deep inguinal lymph node dissections in these aggressive cancers. • Identification of SMARCB1-deficiency trials of targeted therapies such as EZH2 inhibitors which show promise in halting further progression., Introduction Myoepithelial carcinoma and proximal-type epithelioid sarcoma of the vulva are two rare malignancies with known aggressive behavior. In addition to a similar clinical course, these two disease entities also have significant histologic and pathologic overlap. Given the rarity of these malignancies, there is limited literature on the appropriate treatment regimen. Nevertheless, there is a consensus that early surgical resection is beneficial in both cases. Presentation We present a case of a patient who was initially diagnosed with myoepithelial carcinoma of the vulva with a differential later expanded to include possible epithelioid sarcoma. Discussion We demonstrate the importance in early identification of a SMARCB1 deficiency. Additionally, we suggest an appropriate treatment regimen for these patients going forward. Specifically, we encourage consideration of bilateral superficial and deep inguinal lymphadenectomies. Furthermore, sarcoma based chemotherapy regimens in the appropriate clinical setting may be beneficial in treating SMARCB1 deficient tumors. Additionally, there are now clinical trials involving EZH2 Inhibitors which may offer benefit for similar patients going forward. Conclusion This case highlights the difficulty in making a definitive diagnosis, and the importance in identifying a SMARCB1 deficiency as it will affect treatment options and may allow for enrollment in ongoing clinical trials.

Gastrointestinal stromal tumors (GISTs) are the most common GI tract mesenchymal tumors. GIST patients are optimally managed by a precision medicine approach. Herein, we discuss the latest advances in precision medicine and ongoing clinical trials relevant to GIST. Circulating tumor DNA for detection of mutational changes could replace tissue biopsies and radiographic imaging once validated. Most GISTs are KIT/PDGFRα mutated, and despite the good clinical response to imatinib, treatment is generally not curative, more often due to secondary mutations. New mechanisms to bypass this resistance by inhibiting KIT downstream pathways and by targeting multiple KIT or PDGFRα mutations are being investigated. Immunotherapy for GIST patients is in its infancy. These approaches may lead to more effective, less toxic therapies.

Gastrointestinal stromal tumors (GIST) contain tumor-infiltrating immune cells and their presence provides an opportunity and rationale for developing effective forms of immunotherapy. The types of tumor-infiltrating inflammatory cells and relevant immune checkpoint inhibitors are the focus of active investigation. The most numerous tumor-infiltrating inflammatory cells are tumor-associated macrophages (TAMs) and CD3+ T cells. Studies have shown that patients with GISTs that harbor increased numbers of CD3+ T cells have better outcomes. However, the clinical behavior of GIST has not been shown to correlate with the number of TAMs. The biological significance of other less frequent tumor-infiltrating immune cells including tumor-infiltrating neurtrophils (TINs), natural killer cells (NKs), B cells, dendritic cells (DCs) remains unclear. The immune checkpoint inhibitors CTLA-4, PD1/PDL1 and TIM3/galectin-9 are molecules that can be targeted by synthesized antibodies. Clinical and pre-clinical trials using this approach against immune checkpoint inhibitors, anti-KIT antibody and the generation of chimeric antigen receptor (CAR) T-cells have shown promising results. The treatment of GIST with immunotherapy is complex and evolving; this article reviews its current status for patients with GISTs.

Angiosarcoma is an uncommon endothelial malignancy and a highly aggressive soft tissue sarcoma. Due to its infiltrative nature, successful management of localized angiosarcoma is often challenging. Systemic chemotherapy is used in the metastatic setting and occasionally in patients with high-risk localized disease in neoadjuvant or adjuvant settings. However, responses tend to be short-lived and most patients succumb to metastatic disease. Novel therapies are needed for patients with angiosarcomas.We performed a retrospective analysis of patients with locally advanced or metastatic angiosarcoma, who were treated with checkpoint inhibitors at our institution. We collected their clinical information and outcome measurements. In one patient with achieved complete response, we analyzed circulating and infiltrating T cells within peripheral blood and tumor tissue.We have treated seven angiosarcoma (AS) patients with checkpoint inhibitors either in the context of clinical trials or off label [Pembrolizumab + Axitinib (NCT02636725; n = 1), AGEN1884, a CTLA-4 inhibitor (NCT02694822; n = 2), Pembrolizumab (n = 4)]. Five patients had cutaneous angiosarcoma, one primary breast angiosarcoma and one radiation-associated breast angiosarcoma. At 12 weeks, 5/7 patients (71%) had partial response of their lesions either on imaging and/or clinical exam and two (29%) had progressive disease. 6/7 patients are alive to date and, thus far, 3/7 patients (43%) have progressed (median 3.4 months)- one achieved partial response after pembrolizumab was switched to ongoing Nivolumab/Ipilimumab, one died of progressive disease at 31 weeks (primary breast angiosarcoma) and one was placed on pazopanib. One patient had a complete response (CR) following extended treatment with monotherapy AGEN1884. No patient experienced any ≥ grade 2 toxicities.This case series underscores the value of targeted immunotherapy in treating angiosarcoma. It also identifies genetic heterogeneity of cutaneous angiosarcomas and discusses specific genetic findings that may explain reported benefits from immunotherapy.

Background Angiosarcoma is an uncommon endothelial malignancy and a highly aggressive soft tissue sarcoma. Due to its infiltrative nature, successful management of localized angiosarcoma is often challenging. Systemic chemotherapy is used in the metastatic setting and occasionally in patients with high-risk localized disease in neoadjuvant or adjuvant settings. However, responses tend to be short-lived and most patients succumb to metastatic disease. Novel therapies are needed for patients with angiosarcomas. Methods We performed a retrospective analysis of patients with locally advanced or metastatic angiosarcoma, who were treated with checkpoint inhibitors at our institution. We collected their clinical information and outcome measurements. In one patient with achieved complete response, we analyzed circulating and infiltrating T cells within peripheral blood and tumor tissue. Results We have treated seven angiosarcoma (AS) patients with checkpoint inhibitors either in the context of clinical trials or off label [Pembrolizumab + Axitinib (NCT02636725; n = 1), AGEN1884, a CTLA-4 inhibitor (NCT02694822; n = 2), Pembrolizumab (n = 4)]. Five patients had cutaneous angiosarcoma, one primary breast angiosarcoma and one radiation-associated breast angiosarcoma. At 12 weeks, 5/7 patients (71%) had partial response of their lesions either on imaging and/or clinical exam and two (29%) had progressive disease. 6/7 patients are alive to date and, thus far, 3/7 patients (43%) have progressed (median 3.4 months)- one achieved partial response after pembrolizumab was switched to ongoing Nivolumab/Ipilimumab, one died of progressive disease at 31 weeks (primary breast angiosarcoma) and one was placed on pazopanib. One patient had a complete response (CR) following extended treatment with monotherapy AGEN1884. No patient experienced any ≥ grade 2 toxicities. Conclusions This case series underscores the value of targeted immunotherapy in treating angiosarcoma. It also identifies genetic heterogeneity of cutaneous angiosarcomas and discusses specific genetic findings that may explain reported benefits from immunotherapy.

Summary Background VEGF promotes an immunosuppressive microenvironment and contributes to immune checkpoint inhibitor resistance in cancer. We aimed to assess the activity of the VEGF receptor tyrosine-kinase inhibitor axitinib plus the anti-PD-1 immune checkpoint inhibitor pembrolizumab in patients with sarcoma. Methods This single-centre, single-arm, phase 2 trial was undertaken at a tertiary care academic medical centre in Miami, FL, USA, and participants were recruited from all over the USA and internationally. Patients were eligible if they were aged 16 years or older, and had histologically confirmed advanced or metastatic sarcomas, including alveolar soft-part sarcoma (ASPS); measurable disease with one site amenable to repeated biopsies; an ECOG performance status of 0–1; and progressive disease after previous treatment with at least one line of systemic therapy (unless no standard treatment existed or the patient declined therapy). The first five patients were enrolled in a lead-in cohort and were given axitinib 5 mg orally twice daily and pembrolizumab 200 mg intravenously for 30 min on day 8 and every 3 weeks for cycles of 6 weeks for up to 2 years. Thereafter, patients received escalating doses of axitinib (2–10 mg) plus flat dose pembrolizumab according to the schedule above. The primary endpoint was 3-month progression-free survival. All patients were evaluable for survival and safety analyses. This study is registered with ClinicalTrials.gov, number NCT02636725, and is closed to accrual. Findings Between April 19, 2016, and Feb 7, 2018, of 36 patients assessed for eligibility, 33 (92%) were enrolled and given study treatment (intention-to-treat population and safety population), 12 (36%) of whom had ASPS. With a median follow-up of 14·7 months (IQR 10·1–19·1), 3-month progression-free survival for all evaluable patients was 65·6% (95% CI 46·6–79·3). For patients with ASPS, 3-month progression-free survival was 72·7% (95% CI 37·1–90·3). The most common grade 3 or 4 treatment-related adverse events included hypertension (five [15%] of 33 patients), autoimmune toxicities (five [15%]), nausea or vomiting (two [6%]), and seizures (two [6%]). Serious treatment-related adverse events occurred in seven (21%) patients, including autoimmune colitis, transaminitis, pneumothorax, haemoptysis, seizures, and hypertriglyceridemia. There were no treatment-related deaths. Interpretation Axitinib plus pembrolizumab has manageable toxicity and preliminary activity in patients with advanced sarcomas, particularly patients with ASPS, warranting further investigation in randomised controlled trials. Funding Merck, Pfizer, American Cancer Society, and Sylvester Comprehensive Cancer Center.

PURPOSE: To determine whether MRI volumetric and image texture analysis correlates with treatment-induced biologic changes in desmoid fibromatosis (DF) earlier than conventional response criteria. MATERIALS AND METHODS: This retrospective study included 27 patients with histologically proven extra-abdominal DF who were managed with active surveillance or systemic therapy (from 2004 to 2016). MRI volumetric and image texture parameters were derived from manual tumor segmentations, and tumor signal intensity was normalized to muscle. Results were compared with objective response rates based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, World Health Organization (WHO) lesion response, volumetrics, and MRI-modified Choi criteria. Correlation coefficients (r) between image texture features and maximum tumor diameters were obtained by using a meta-analysis approach. RESULTS: The 27 included patients (mean age, 39 years; 74% women) were followed for an average of 4 years, comprising 207 distinct time-point assessments. The mean baseline tumor maximum diameter was 7.9 cm (range, 3.4–15.2 cm). Partial response (PR) rates as best response were 37%, 44%, 70%, and 81% by RECIST, WHO, volumetrics, and MRI-modified Choi criteria, respectively. Among the 10 tumors showing RECIST PR, a preceding MRI-modified Choi PR was observed in 70% (seven of 10), on average 1.3 years earlier. Multiple image texture parameters showed associations with objective measurements of tumor diameter including mean tumor-to-muscle signal ratio (r = 0.51; P = .004), median tumor-to-muscle signal ratio (r = 0.52; P = .003), energy (r = 0.48; P < .001), run entropy (r = 0.32, P = .04), and gray-level nonuniformity (r = 0.54; P ≤ .001). CONCLUSION: Volumetric signal and image texture assessment allows more comprehensive analysis of DF biologic change and may permit early prediction of DF behavior and therapeutic response. Keywords: MR Imaging, Soft Tissues/Skin, Neoplasms-Primary © RSNA, 2021

Immune checkpoint inhibitors have been widely incorporated for cancer treatment in a variety of solid and hematologic malignancies. Multiple clinical trials have demonstrated the efficacy of PD-1/PD-L1 and CTLA-4 axis inhibition in the metastatic and adjuvant settings. Due to the risks of autoimmune toxicity with these agents, stringent inclusion/exclusion criteria were employed in those initial clinical trials. These criteria led to exclusion or underrepresentation of a variety of patient populations with underlying immune dysfunction. These populations included patients with preexisting autoimmune diseases, solid organ or bone marrow transplant recipients, patients with HIV or viral hepatitis infections, patients receiving concurrent chronic steroid therapy, as well as patients who were elderly, pregnant, or had poor performance status. Thus, established guidelines on the use of immune checkpoint inhibitors in these patients are lacking, and evidence to support efficacy or toxicity are overall limited to retrospective studies and case series. Fortunately, ongoing clinical trials are now including these patients and are shedding light on whether these underrepresented populations can also safely benefit from immune checkpoint inhibitor therapies. In this review, we summarize the most clinically relevant available data on the use of checkpoint inhibitors in immunocompromised patient groups with a primary focus on safety.

2599 Background: Pembrolizumab was recently approved in tumors with TMB ≥10 mut/Mb. FSM can complement TMB in predicting ICI responses. We obtained a real-world dataset of genomic alterations from 250,813 samples to examine the distribution of TMB and FSM across a variety of malignancies. We then conducted a multi-institutional retrospective review of pts treated with ICI. Methods: Database samples were sequenced by Foundation Medicine using hybrid capture genomic profiling to evaluate all classes of genomic alterations in at least 315 genes. The clinical cohort included pts with metastatic solid malignancies who received ICI and had undergone commercial next-generation sequencing (NGS). Pts were classified into four distinct groups: TMB-L ( < 10mut/Mb)/ FS-A (absent FSM), TMB-H (≥10mut/Mb)/ FS-A, TMB-L /FS-P (present, ≥1 FSM) and TMB-H/FS-P. Progression-free survival (PFS), overall survival (OS), and response rate (RR) were compared between the groups. Results: 246,252 MSS and 4,561 MSI-High samples were segregated by histology and divided into four distinct groups based on the TMB and FSM. For the MSS cohort the distribution was: TMB-L/FS-A (N = 111,065, 45%), TMB-H/FS-A(N = 15,313, 6%), TMB-L /FS-P (N = 98,389, 40%) and TMB-H/FS-P (N = 21,485, 9%). In the ICI-treated clinical cohort, there were 230 pts in 12 histology groups; 212 had information on TMB and FSM. The most common primary sites were GI (N = 39), melanoma (N = 37), GU (N = 32) and H&N cancer (N = 21). 159 pts received single ICI and 53 dual ICI. 196 tumors were MSS, 11 MSI, and 5 unknown. Group distribution: TMB-L/FS-A 80 pts (38%), TMB-L/FS-P 57pts (27%), TMB-H/FS-A 36pts (17%), TMB-H/FS-P 39pts (18%). FS-P was associated with higher RR 23.81 vs. 12.8 % (p = 0.02). Regardless of TMB, the median PFS for FS-P vs. FS-A was 7.9 and 4.0 mo, respectively (p < 0.01). TMB-L/FS-P had superior PFS (5.1 mo) compared to TMB-L/FS-A (3.6 mo) group (p < 0.01). The 15-month PFS probability was 12% for TMB-L/FS-A vs. 38% for TMB-L/FS-P. No statistically significant difference was detected in OS between the groups. From the pan-cancer cohort, histologies with more than 40% of samples in the TBM-L/FS-P (MSS) group were: CRC, RCC, PDAC, biliary, breast, esophageal, and endometrial cancers. Additional genomic data will be presented. Conclusions: FSM are frequently found on commercial NGS testing in tumors that are MSS and TMB-L. The presence of FSM may complement TMB in predicting benefit from immunotherapy. If validated in additional cohorts, FSM presence could be utilized to identify pts that may benefit from ICI, particularly for tumors with low TMB.

11505 Background: AL3818 (Catequentinib, Anlotinib) is a novel, orally administered, small molecule tyrosine kinase inhibitor. The primary objective of this Phase 3 study is to evaluate the efficacy of AL3818 monotherapy in patients (pts) with synovial sarcoma (SS) comparing with dacarbazine in randomization setting. Methods: Patients with a diagnosis of synovial sarcoma requiring second line or further line treatment were eligible for enrollment. The regimen was a 21-day cycle with oral AL3818 administered on 14 days on and 7 days off. This phase 3 trial is randomized in 2:1 ratio of AL3818 comparing to dacarbazine with option of crossover after PD of dacarbazine treatment. Progression free survival (PFS) with Log Rank test is the primary endpoint and this trial for SS is currently completed enrolled in US and Italy. Results: Total 79 pts initiated treatment and are evaluable, 52 received AL3818 as treatment arm (T), and 27 received dacarbazine (D) as control arm (C). Arms T/C median ages were 40.5/42.0 years (range: 18-70+) and 20/16 (38.5%/59.3%) were male. Overall, PFS was 2.89 months (95% CI: 2.73 – 6.87) for AL3818 and 1.64 (95% CI: 1.45 – 2.70) for D. The PFS of study met the primary endpoint with a p-value of 0.0015 and a HR of 0.449 (95% CI: 0.270– 0.744). At the month 4, 6, and 12, the percentages of progression free patients for AL3818 were 48.1%, 42.3% and 26.9%; and for D were 14.85%, 11.1% and 3.7%. For grade 3 treatment-related adverse events, 12(23.1%) of pts experienced for AL3818 and 7(25.9%) of pts experienced for D. The most common AL3818 related grade 3 AEs were diarrhea (5.8%) and hypertension (3.8%). Conclusions: This phase III trial demonstrates improved disease control and superior progression free survival for AL3818 vs dacarbazine in advanced SS. In addition, the study further confirms the acceptable benefit-risk profile of AL3818 from the prior randomized Phase 2b soft tissue sarcoma study (NCT02449343). AL3818 is a meaningful treatment option for pts with advanced SS. Clinical trial information: NCT 03016819 Clinical trial information: NCT03016819.

Simple Summary In this position paper, we aim to summarize state-of-the-art treatments for patients with leiomyosarcomas in order to identify knowledge gaps and current unmet needs, thereby guiding the community to design innovative clinical trials and basic research and close these research gaps. This white paper arose from a leiomyosarcoma research meeting in October 2020 hosted by the National LeioMyoSarcoma Foundation (NLMSF) and Sarcoma Patients EuroNet (SPAEN). Abstract As leiomyosarcoma patients are challenged by the development of metastatic disease, effective systemic therapies are the cornerstone of outcome. However, the overall activity of the currently available conventional systemic treatments and the prognosis of patients with advanced or metastatic disease are still poor, making the treatment of this patient group challenging. Therefore, in a joint effort together with patient networks and organizations, namely Sarcoma Patients EuroNet (SPAEN), the international network of sarcoma patients organizations, and the National LeioMyoSarcoma Foundation (NLMSF) in the United States, we aim to summarize state-of-the-art treatments for leiomyosarcoma patients in order to identify knowledge gaps and current unmet needs, thereby guiding the community to design innovative clinical trials and basic research and close these research gaps. This position paper arose from a leiomyosarcoma research meeting in October 2020 hosted by the NLMSF and SPAEN.

Malignant progression of a benign or low-grade tumor in individuals with germline alteration of SMARCB1 gene is not well characterized. In a family in which two carrier children had germline SMARCB1 mutations and atypical teratoid rhabdoid tumor, we report malignant progression of a nerve sheath tumor over a 7-year period in an affected adult family member. Prompt identification of the germline SMARCB1 alteration and the resultant rhabdoid tumor predisposition syndrome can help guide genetic counseling and surveillance in affected family members.

Angiosarcomas are rare vascular neoplasms that are among the most aggressive subtypes of soft tissue sarcomas. Surgical resection is often challenging even in localized disease, as the infiltrative nature of these cancers leads to frequent local and metastatic recurrences. Cytotoxic chemotherapy, including anthracycline-based regimens and taxanes can produce significant responses in a subset of patients but durability is limited with most patients ultimately succumbing to metastatic disease. Targeted therapy with tyrosine kinase inhibitors is usually well-tolerated but prone to development of resistance. Few head-to-head trials have addressed the optimal sequence of therapies, or demonstrated conclusive benefits of one therapy over another based on clinical and etiologic factors. Novel therapies in clinical trials, including antibodies to endoglin and checkpoint inhibitors have demonstrated exciting early activity in patients with angiosarcoma. Improved understanding of the genetic heterogeneity within various angiosarcoma subtypes may identify predictive biomarkers to match patients to effective existing and future therapies. Overall, angiosarcoma patients with optimal performance status are best served in clinical trials that incorporate novel combinations of cytotoxic chemotherapy, targeted therapies, and immunotherapies.

Soft-tissue sarcomas pose diagnostic and therapeutic challenges to physicians, owing to the large number of subtypes, aggressive tumor biology, lack of consensus on management, and controversy surrounding interval and duration of surveillance scans. Advances in multidisciplinary management have improved the care of sarcoma patients, but controversy remains regarding strategies for surveillance following definitive local control. This review provides an updated, comprehensive overview of the current understanding of the risk of local recurrence of soft-tissue sarcoma, by examining the literature based on features such as histological type and grade, tumor size, and resection margin status, with the aim of helping clinicians, surgeons, and radiologists to develop a tailored approach to local imaging surveillance.

e22543 Background: Angiosarcoma (AS) is a rare endothelial malignancy with only 2–3 new cases per one million diagnosed yearly but is among the most aggressive soft tissue sarcomas. Some cutaneous angiosarcomas may have a mutational landscape similar to UV light exposed melanoma. These findings offer a rationale for the early limited evidence of checkpoint inhibitor activity in cutaneous angiosarcomas. Methods: This is a retrospective review of patients with locally advanced or metastatic angiosarcoma, who were treated with checkpoint inhibitors at our institution. Descriptive statistics were used to analyze our findings. Results: Since 2016, we have treated seven angiosarcoma patients with checkpoint inhibitors either in the context of clinical trials or off label [Pembrolizumab + Axitinib (NCT02636725; n = 1), a CTLA-4 inhibitor (NCT02694822; n = 2), Pembrolizumab (n = 4)]. Five patients had cutaneous AS, one primary breast AS and one radiation associated breast AS. The average age was 66 years old and 5/7 (71%) patients were females. All patients had received prior systemic therapies (range 1-7, mean 3) and 2/7 (29%) patients had metastatic disease at the time of treatment. The mean number of checkpoint inhibitor doses was 6. At twelve weeks, 5/7 patients (71%) had partial response, by RECIST, of their lesions either on imaging or clinical exam and two (29%) had progressive disease. 6/7 patients are alive to date and, thus far, 3/7 patients (43%) progressed (median 3.4 months)- one achieved partial response after pembrolizumab was switched to ongoing Nivolumab/Ipilimumab, one died of progressive disease at 31 weeks (primary breast AS) and one was placed on subsequent therapy. No patient experienced any toxicities more than grade 2. Conclusions: This is a single institution, retrospective review of patients with AS treated with checkpoint inhibitors, first reported in the literature. Checkpoint inhibitors may be an effective and safe treatment option for this aggressive sarcoma. Prospective clinical trials are needed to systemically study this effect.

2617 Background: ICI benefit certain patients (pts) with various malignancies and discovering biomarkers for response is an active research field. Recently, higher TMB (top 20% in each histology) based on nonsynonymous single nucleotide variants from MSK-IMPACT was shown to correlate with superior survival in a pancancer cohort. Fsindels may generate more immunogenic neoantigens and robust T cell infiltrates, thus predicting better responses to ICI. We previously demonstrated the clinical implication of fsindel in lung cancer pts on ICI. However, its value in other solid cancers has not been evaluated. Methods: Comprehensive genomic profiling (CGP) of the tumors was performed by FoundationOne to derive fsindel and TMB as previously described. Pts with advanced solid cancers who received ICI and had CGP available were included. We categorized pts into two groups; 0 fsindel (FS-) and more than 1 fsindel (FS+). Also, they were categorized into TMB high (top 20%) and TMB low (bottom 80%) within their own histology. Progression free survival (PFS) and overall survival (OS) were compared. Results: One hundred thirty-one pts excluding lung cancer were included. There were 11 histology groups: 14 soft tissue sarcomas, 19 GU, 23 GI, 23 skin, 10 HEENT, 10 RCC, 9 GYO, 6 pancreas, 5 mucosal melanoma, 4 breast, and 8 others. 74 pts received pembrolizumab, 25 nivolumab, 29 ipilimumab/nivolumab, and 3 atezolizumab. All pts had metastatic disease, mean age was 61 years and 55 (42%) were women. Among the 131 pts, 74 were FS- and 57 FS+. The presence of fsindel (FS+) was significantly correlated with overall response (p = 0.032) and clinical benefit rates (p = 0.025). TMB-high did not show any significant difference in PFS (p = 0.1) or OS (p = 0.28) when compared to the TMB low. However, in a combined model of TMB and fsindel, TMB high and FS+ patients had significantly better PFS compared to patients who had either TMB high or FS+ or neither (TMB low and FS-) (p = 0.021). Conclusions: Combined model of TMB high and fsindel (+) correlated with superior PFS in advanced solid cancer pts on ICI, in concordance with previous report for lung cancer. Validation in a larger cohort is underway.

Background: NY-ESO-1c259T-cells recognizing an NY-ESO-1 derived peptide complexed with HLA-A*02 (SPEAR T-cells) are being studied in an ongoing multi-cohort clinical trial in synovial sarcoma (NCT01343043). We compared safety, efficacy and cell persistence between two cohorts using different doses of lymphodepleting chemotherapy. Methods: There are four cohorts separated by differing antigen expression levels and lymphodepletion regimens, and this assessment compares cohorts 1 (closed) and 4 (ongoing). In both, ≥50% patient tumor cells expressed NY-ESO-1 at 2+/3+ levels by immunohistochemistry. Following apheresis, T-cells are isolated, activated, transduced to express NY-ESO-1c259T and expanded. Lymphodepletion in cohort 1 consists of fludarabine 30 mg/m2/d × 4 d and cyclophosphamide 1800 mg/m2/d × 2d, and in cohort 4 consists of fludarabine 30 mg/m2/d × 3d and cyclophosphamide 600 mg/m2/d × 3d. Target dose is 1–6 × 109 transduced cells. Disease is assessed at weeks 4, 8 and 12 and every 3 months until disease progression. Results: 12 patients were treated in cohort 1 and 14 patients in cohort 4 (as of 23Nov17). Median transduced cell dose was 3.6 × 109 cells in cohort 1 and 2.6 × 109 cells in cohort 4. Treatment-related adverse events (AEs) were observed in 100% of patients in cohort 1 and 86% in cohort 4; related serious adverse events (SAEs) were reported in 50% of cohort 1 and 14% of cohort 4. There were no fatal AEs. Overall response rate (ORR) in cohort 4 is 29% vs 50% in cohort 1, and duration of response is in cohort 4 is 16 weeks vs 31 weeks in cohort 1. The best overall response of stable is 50% in cohort 1 and 64% in cohort 4. Median peak expansion of transduced T-cells in peripheral blood in responders is lower in cohort 4 (40,137 copies/μg DNA) vs cohort 1 (106,174 copies/μg DNA). Median absolute lymphocyte counts following lymphodepletion were 1×107/L (range 0-3) in cohort 1 and 9×107/L (0-40) in cohort 4. Conclusions: The greater ORR and higher peak expansion in cohort 1 may be attributable to the dose intensity of the lymphodepleting regimen. Although related SAEs were reported in a higher proportion in cohort 1 than 4, the safety and tolerability are acceptable in both, and cell doses were similar. The data and overall benefit:risk considerations support utilizing higher doses of preconditioning chemotherapy in future trials. Citation Format: Sandra P. D'Angelo, Dejka Araujo, Brian Van Tine, George Demetri, Mihaela Dutra, John Glod, Warren Chow, Stephen Grupp, Alibiruni Abdul Razak, William Tap, Breelyn Wilky, Erin Van Winkle, Elliott Norry, Samik Basu, Karen Chagin, Malini Iyengar, Trupti Trivedi, Rafael Amado, Crystal Mackall. Comparison of pretreatment conditioning on efficacy in two cohorts of a pilot study of genetically engineered NY-ESO-1c259T-cells in patients with synovial sarcoma [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A007.

Most solitary fibrous tumors (SFTs) are cured by complete resection, but many recurrent and metastatic SFTs do not respond to treatment and are fatal. Malignant histology, defined by England's pathologic criteria, is strongly associated with recurrence, but some benign SFTs still behave aggressively. Several studies have suggested that extrathoracic SFTs have a worse prognosis. We reviewed thoracic and extrathoracic SFTs from our institution to determine if extrathoracic location is associated with recurrence, independent of malignant histology.With IRB approval, we retrieved patient pathology reports from the Johns Hopkins Surgical Pathology database between 1991 and 2011 and included 83 SFT patients in our analysis. Patient history and outcomes were obtained from the medical record and primary care physicians. Predictors of recurrence were analyzed by univariate and multivariate analysis and survival determined by the Kaplan-Meier method.Of the 83 patients, 59 had extrathoracic SFTs in neurologic (n = 24), extremity or head/neck (n = 13), or visceral/intraabdominal (n = 22) sites. A total of 74 SFTs were classified benign and 9 as malignant. Of the 14 recurrences, 13 occurred in extrathoracic SFTs; only 7 were classified as malignant. Multivariate analysis confirmed that malignant histology had the strongest association with recurrence, but extrathoracic location also independently predicted recurrence. A total of 20 benign SFTs possessed 1 or more of England's criteria but to an insufficient degree for malignant classification. These "borderline" SFTs were more likely to recur than benign SFTs without these features.Extrathoracic and "borderline" SFTs with any of England's criteria have a higher risk of recurrence.

There are few effective therapies for high-risk sarcomas. Initial chemosensitivity is often followed by relapse. In vitro, mammalian target of rapamycin (mTOR) inhibition potentiates the efficacy of chemotherapy on resistant sarcoma cells. Although sarcoma trials using mTOR inhibitors have been disappointing, these drugs were used as maintenance. We conducted a Phase I/II clinical trial to test the ability of temsirolimus to potentiate the cytotoxic effect of liposomal doxorubicin and present here the dose-finding portion of this study. Adult and pediatric patients with recurrent or refractory sarcomas were treated with increasing doses of liposomal doxorubicin and temsirolimus using a continual reassessment method for escalation, targeting a dose-limiting toxicity rate of 20%. Blood samples were drawn before and after the first dose of temsirolimus in Cycles 1 and 2 for pharmacokinetic analysis. The maximally tolerated dose combination was liposomal doxorubicin 30 mg/m(2) monthly with temsirolimus 20 mg/m(2) weekly. Hematologic toxicity was common but manageable. Dose-limiting toxicities were primarily renal. Concurrent administration of liposomal doxorubicin resulted in increased exposure to sirolimus, the active metabolite of temsirolimus. Thus, the combination of liposomal doxorubicin and temsirolimus is safe for heavily pretreated sarcoma patients. Co-administration with liposomal doxorubicin did not alter temsirolimus pharmacokinetics, but increased exposure to its active metabolite.

11539Background: GIST is the most common sarcoma of the GI tract. Management of GIST is determined by KIT, PDGFR, or other genomic alterations. Tissue diagnosis has been the mainstay of the biomark...

11579Background: Recent data (D’Angelo et al, 2018) has suggested possible benefit for a subset of sarcoma patients from immune checkpoint inhibitors (ICPI). We assessed a large sarcoma population ...

11547Background: Inhibition of programmed-death 1 (PD1) by pembrolizumab (P) produced overall response rates (ORR) of 19% in advanced STS [SARC028]. Vascular endothelial growth factor (VEGF) suppre...

3086Background: Agenus AGEN2034 is a fully-human IgG4 monoclonal antibody antagonist targeting Programmed Cell Death Protein-1 (PD-1). The objective was to assess safety, MTD, pharmacokinetic (PK) ...

Trainee exposure to clinical oncology during residency training is heterogeneous and often modest. The steep learning curve upon entry into fellowship can result in undue stress for fellows and their patients. Simulation-based training has been shown to be superior to classical didactic approaches. We have introduced several innovative simulation-based workshops into the curriculum for the Johns Hopkins Hematology/Oncology Fellowship Training Program in order to address this unmet need. During the first months of training, fellows were engaged in activities emphasizing essential clinical and procedural skills. Specific workshops included the following: (1) chemotherapy writing, (2) cadaveric and simulation-based bone marrow biopsy and intrathecal chemotherapy administration, and (3) simulation-based communication skills training. All first-year fellows in our program participated in these exercises. Pre- and post-workshop surveys were administered to assess knowledge, attitudes, and behaviors; additional distant post-workshop evaluations were disseminated to assess the durability/impact of the curricula and for program evaluation. Overall, participating fellows indicated that the workshops improved patient care and comfort with procedures and patient-centered communication. Continued implementation of these workshops was recommended for program improvement. To the best of our knowledge, ours is amongst the first oncology fellowship training programs to systematically implement simulation-based curricula into our schema for fellowship training. We hypothesize that proactively introducing fellows to these high-yield activities will translate into improved patient care and reduced stress for trainees. Additional investigation into the long-term impact of such curricula remains an area of ongoing need.

Imaging criteria for measuring the response of desmoid fibromatosis to systemic therapy are not well established. We evaluated a series of patients with desmoids who underwent systemic therapy to document magnetic resonance imaging (MRI) features associated with a positive clinical response. This Institutional Review Board-approved retrospective study included 23 patients (mean age 40.5) with 29 extra-abdominal tumors. Therapeutic regimens included cytotoxic chemotherapy (n = 19), targeted therapy (n = 3), and nonsteroid anti-inflammatory drugs (NSAIDS; n = 1). Clinical effects were categorized as progressive disease, stable, or partial response. Maximum tumor dimension (Dmax), approximate tumor volume (VTumor), and quantitative tumor T2 hyperintensity and contrast enhancement (relative to muscle) for pre- and post-treatment MRIs were compared. Three lesions progressed, 5 lesions were stable, whereas 21 showed a clinical response. Dmax decreased more in responders (mean −11.0 %) than in stable/progressive lesions (mean −3.6 and 0 % respectively, p = 0.28, ANOVA); by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) 27 out of 29 lesions were “stable,” including the 3 progressive lesions. In responders, VTumor change averaged −29.4 %, but −19.2 % and +32.5 % in stable and progressive lesions respectively (p = 0.002, ANOVA); by 3D criteria 14 out of 29 lesions showed a partial response. T2 hyperintensity decreased by 50–54 % in partial response/stable disease, but only by 10 % in progressive lesions (p = 0.049, t test). Changes in contrast enhancement ranged from −23 % to 0 %, but were not statistically significant among response groups (p = 0.37). Change in T2 hyperintensity showed a positive correlation with volumetric change (r = 0.40). Decreases in volume and T2 hyperintensity reflect the positive response of desmoid fibromatosis to systemic therapy; RECIST 1.1 criteria are not sensitive to clinically determined tumor response.

Purpose of review MRI plays a crucial role in the initial diagnosis, treatment planning, and long-term management of bone and soft tissue sarcomas. Technological advances have enabled improvements in both delineation of anatomic detail, and in functional imaging techniques that interrogate tissues at the cellular level. This bears particular relevance in sarcomas as morphological parameters alone do not necessarily correlate with treatment response and prognosis. Here, we describe recent developments in advanced MRI techniques, including chemical-shift MRI, diffusion-weighted imaging (DWI), MR spectroscopy (MRS), and dynamic contrast enhanced (DCE) MRI. Recent findings Chemical-shift MRI allows robust discrimination of marrow infiltrating neoplasms from benign red marrow. DWI reveals tumor cellularity, and aids in distinguishing benign and malignant tumors along with the assessment of treatment response. MRS is technically challenging in the musculoskeletal system, but shows promise as a means to noninvasively assess metabolic aberrations in a variety of sarcomas. DCE is particularly suited to treatment response evaluation, in which traditional size-based assessment criteria may underestimate efficacy in clinical trials. Summary Functional MRI techniques offer novel imaging biomarkers that effectively complement conventional MRI in the assessment of bone and soft tissue sarcomas at all stages of patient care.

e22521 Background: Sarcoidosis can mimic metastatic cancer. Although sarcoidosis is associated with carcinomas, there are limited data supporting its association with GIST and other sarcomas. Prior reports on cancer related sarcoidosis are inconsistent in terms of prognosis; while some reports link sarcoidosis with a favorable prognosis, others associate it with recurrence and secondary malignancies. Here we describe a series of 7 patients with diagnosis of sarcoma and sarcoidosis seen at a single sarcoma center in South Florida. Methods: Seven patients with diagnosis of both sarcoma and sarcoidosis were identified over the period of 2007 to 2016. Data of presentation, treatment, histology and outcome was tabulated for analysis. The Standardized Incidence Ratio (SIR) was calculated for the state of Florida and for our hospital catchment area. Results: Of the seven patients, 4 cases were GIST, 1 case of unclassified spindled and epithelioid cell sarcoma that coexisted with tenosynovial giant cell tumor, 1 case of uterine leiomyosarcoma, and 1 case of myxofibrosarcoma. Sarcoidosis was diagnosed before sarcoma in 3 patients, after the diagnosis of sarcoma in 3 patients and at the same time of sarcoma diagnosis in 1 patient. All cases of sarcoidosis involved the lungs. From our series, 3 patients have shown no progression of sarcoma, 1 is alive with sarcoma, 2 died due to progression of sarcoma and 1 was lost to follow up. Statistical analyses showed a SIR = 268 (95% CI 106-503), when comparing to the expected incidence in the state of Florida and SIR = 831 (95% CI 329-1562), when comparing to the expected incidence in our catchment area. Conclusions: This case series points to a statistically robust, non-random, association between Sarcoma and Sarcoidosis that has not been previously described. Our study found the lung is not only the most common site of sarcoma metastasis but also the most common site of sarcoidosis. These results infer that patients with presumed metastatic sarcoma should be considered for a biopsy to rule out a benign process such as sarcoidosis. Additionally, the presence of sarcoidosis could be associated with risk of sarcoma. The mechanism of sarcoidosis-associated sarcoma is ongoing.

3075 Background: AGEN1884 is a fully human IgG1 monoclonal antibody targeting the co-inhibitory protein cytotoxic T lymphocyte-associated protein 4 (CTLA-4). CTLA-4 blockade has been shown to augment T cell activation and proliferation, resulting in immune infiltration of the tumor and subsequent regression. Objectives: Assess the safety, maximum tolerated dose (MTD), and pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of AGEN1884 in patients (pts) with advanced and refractory malignancies using a “3+3” trial design. Methods: Eleven pts have been enrolled and treated to date. AGEN1884 was administered intravenously q3w for 4 doses and then q12w. Three (0.1, 0.3 and 1 mg/kg) of six (3, 6 and 10 mg/kg) planned dose levels have been completed. Results: Five pts were accrued at 0.1 mg/kg dose level (2 were not DLT evaluable) and three pts each at doses of 0.3 mg/kg and 1 mg/kg. Median age was 56 years (range 26–70), ECOG 0–2, with a median of 4 (range 1–8) prior therapies. No DLT events have been observed thus far. Data from 5 pts were available for PK evaluation. Half-life of AGEN1884 post first dose was 8.8 and 9.6 days for 0.3 mg/kg and 0.1 mg/kg dose levels, respectively, as measured by ELISA. As of Jan 31, 2017, pts across cohorts were followed for a median of 6 weeks (range 0-28). Six pts (54.5%) have come off study due to disease progression, while 5 (45.5 %) remain on study. One confirmed partial response (80% reduction) by RECIST criteria was seen at 0.1 mg/kg in a patient with angiosarcoma. Conclusions: AGEN1884 is safe at 0.1 and 0.3 mg/kg dose levels. Dose escalation is ongoing and updated safety and PK data will be presented. Clinical trial information: NCT02694822.

11017 Background: Previous studies noted racial/ethnic disparities in high-grade extremity soft tissue sarcoma (ESS) treatment and overall survival (OS). Retrospective series have noted worse OS for Amputation (Amp) vs limb salvage surgery (LSS) and for LSS alone vs LSS plus radiation (RT). Given superior functional outcomes, LSS is now favored over Amp when possible. This study examines racial/ethnic disparities in receipt of Amp vs LSS and impact on OS using modern data from a national registry. Methods: The National Cancer Database was used to identify patients (pts) with stage II-III, high-grade ESS diagnosed between 2004-2014 and treated definitively with 1) Amp alone, 2) LSS alone, 3) Preoperative RT [pre RT] + LSS or 4) LSS + Post-operative RT [post RT]. Multivariate analyses (MVA) utilized logistic regressions for patterns of local treatment and Cox proportional hazards regression for OS. The Kaplan-Meier method was used to estimate 5-year OS. Results: Among 12,020 pts, receipt of LSS vs Amp did not differ significantly by race, ethnicity, age, insurance status, income, or educational attainment on MVA. The rate of Amp was higher in academic centers (OR 2.42; p = .006) or integrated network programs (OR 2.30; p = .014) vs community programs and rural vs. Metro settings (OR 1.88; p = .035). Actuarial 5-year OS by treatment was Amp 43%, LSS 59%, pre RT + LSS 61%, and LSS + post RT 66% (p < .001). On MVA, OS was worse with Amp vs. LSS alone (HR 1.37; p < .001) while pre RT + LSS (HR 0.70; p < .001) and LSS + post RT (HR 0.72; p < .001) had improved OS vs LSS alone. Treatment at a comprehensive community, academic, or integrated network programs vs community program; private insurance vs none; Hispanic vs. non-Hispanic (HR 0.85, p = .048); and higher educational attainment were associated with improved OS. More comorbidities, other primary cancers, older age, and no transitions in care were associated with worse OS. Conclusions: The only racial/ethnic disparity identified when evaluating rates of Amp and OS for ESS was a small OS benefit for Hispanic pts. OS was inferior with Amp and best with LSS with either pre RT or post RT. OS was improved at non-community programs, potentially indicating a need for referral to experienced centers.

TPS3097 Background: Myxoid/round cell liposarcomas (MRCLS) account for 6-10% of soft tissue sarcomas. Although a chemosensitive tumor, metastatic MRCLS has a poor prognosis and is inevitably fatal. More effective, durable and less toxic therapies are needed. NY-ESO-1 is a cancer/testis antigen that is expressed in 80-90% of MRCLS tumors. This study will evaluate the safety and efficacy of genetically engineered affinity enhanced autologous NY-ESO-1c259T cells recognizing an NY-ESO-1 derived peptide complexed with HLA-A*02 in MRCLS. Methods: This open label phase I/II non-randomized pilot study will evaluate efficacy (overall response rate by RECIST v1.1, time to response, duration of response, progression free survival, overall survival), safety, and translational research endpoints. Patients must meet these criteria: ≥ 18 yrs old; HLA-A*02:01, *02:05 or *02:06 positive; have advanced (metastatic or inoperable) MRCLS expressing NY-ESO-1 at 2+/3+ intensity in ≥30% of tumor cells by IHC; measurable disease; prior systemic anthracycline therapy; have ECOG status 0 or 1; and adequate organ function. Initially, ten patients are planned to be enrolled, with potential to enroll an additional 5 patients. Patients who do not receive the minimum cell dose or who do not receive the T-cell infusion may be replaced. Following apheresis, the T cells are isolated and expanded with CD3/CD28 beads, transduced with a lentiviral vector containing the NY-ESO-1c259 TCR, and 1– 8 × 109 transduced T-cells are infused intravenously on Day 1 after lymphodepletion with fludarabine 30 mg/m2/day and cyclophosphamide 600 mg/m2/day on days -7 to -5. Response is assessed at 4, 8, 12 and 24 weeks, and then every 3 months until confirmation of progression of disease. On study tumor biopsies and blood samples will be evaluated to compare the pre- and post-T cell infusion immune profile for association with treatment outcome. Clinical trial information: NCT02992743.

After failure of standard therapy, few effective treatment options exist for adult patients with metastatic sarcomas, and median survival remains dismal at approximately 1 year. Pazopanib, a multitargeted tyrosine kinase inhibitor, has recently been approved for nonadipocytic soft tissue sarcomas refractory to chemotherapy. In this review, we will revisit the efficacy of pazopanib in sarcomas, and present a patient case that illustrates two of many unanswered questions: which sarcoma patients are most likely to benefit from pazopanib therapy, and what criteria are best suited to accurately detect benefit in clinical trials?Pazopanib has been tested in sarcoma patients in a phase II and phase III study, and was shown to prolong progression-free survival by 3 months relative to placebo. Although histology has been the primary stratification variable for subgroup analysis in large sarcoma trials, the PALETTE study did not demonstrate superior response within histologic cohorts. Ongoing trials seek to explore efficacy of pazopanib in previously excluded histologies, as well as include correlative studies to identify histologic and molecular biomarkers to predict patients likely to benefit.Pazopanib has been proven to provide modest benefit overall to nonadipocytic soft tissue sarcoma patients, but we have yet to identify the molecular basis for those patients who derive exceptional benefit.

Primary and metastatic malignant bone lesions result in significant pain and disability in oncology patients. Targeted bone-seeking radioisotopes including 153 Samarium ethylene-diamine-tetramethylene-phosphonic acid ( 153 Sm-EDTMP) have been shown to effectively palliate bone pain, often when external beam radiotherapy (EBRT) is not feasible. However, recent evidence also suggests 153 Sm-EDTMP has cytotoxic activity either alone or in combination with chemotherapy or EBRT. 153 Sm-EDTMP may be useful as anti-neoplastic therapy apart from pain palliation in a variety of malignancies. For prostate cancer patients, several phase I and II clinical trials have shown that combined 153 Sm-EDTMP and docetaxel-based chemotherapy can result in >50% decrease in prostate- specific antigen with manageable myelosuppression. In hematologic malignancies, 153 Sm-EDTMP produced clinical responses when combined with bortezomib in multiple myeloma. 153 Sm-EDTMP also can be used with myeloablative chemotherapy for marrow conditioning prior to stem cell transplant. In osteosarcoma, 153 Sm-EDTMP infusion delivers radiation to multiple unresectable lesions simultaneously and provides local cytotoxicity without soft tissue damage that can be combined with chemotherapy or radiation. Prior to routine incorporation of 153 Sm-EDTMP into therapeutic regimens, we must learn how to ensure optimal delivery to tumors, determine which patients are likely to benefit, improve our ability to assess clinical response in bone lesions and further evaluate the efficacy of 153 Sm-EDTMP in combination with chemotherapy, radiation and novel targeted agents.

10026 Background: There is growing interest in RNA and DNA helicases as therapeutic targets in a variety of sarcomas. We investigated the expression and function of RNA helicase DDX3 in Ewing sarco...