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Affinity-optimized T cell receptors can enhance the potency of adoptive T cell therapy. Afamitresgene autoleucel (afami-cel) is a human leukocyte antigen-restricted autologous T cell therapy targeting melanoma-associated antigen A4 (MAGE-A4), a cancer/testis antigen expressed at varying levels in multiple solid tumors. We conducted a multicenter, dose-escalation, phase 1 trial in patients with relapsed/refractory metastatic solid tumors expressing MAGE-A4, including synovial sarcoma (SS), ovarian cancer and head and neck cancer (NCT03132922). The primary endpoint was safety, and the secondary efficacy endpoints included overall response rate (ORR) and duration of response. All patients (N = 38, nine tumor types) experienced Grade ≥3 hematologic toxicities; 55% of patients (90% Grade ≤2) experienced cytokine release syndrome. ORR (all partial response) was 24% (9/38), 7/16 (44%) for SS and 2/22 (9%) for all other cancers. Median duration of response was 25.6 weeks (95% confidence interval (CI): 12.286, not reached) and 28.1 weeks (95% CI: 12.286, not reached) overall and for SS, respectively. Exploratory analyses showed that afami-cel infiltrates tumors, has an interferon-γ-driven mechanism of action and triggers adaptive immune responses. In addition, afami-cel has an acceptable benefit–risk profile, with early and durable responses, especially in patients with metastatic SS. Although the small trial size limits conclusions that can be drawn, the results warrant further testing in larger studies.

This is a case of a 71-year-old man who had multiple synchronous retroperitoneal liposarcoma (LPS) foci composed of both well-differentiated and dedifferentiated histologies. In addressing this, the patient underwent a margin negative resection of a 11.8×8.8 cm right-sided dedifferentiated LPS requiring pancreaticoduodenectomy; however, a 13.1×7.2 cm left-sided well-differentiated LPS (WDLPS) was not resected due to its involvement of the proximal mesenteric vessels. The patient’s postoperative course was complicated by grade B postoperative pancreatic fistula involving the anatomical territory of the residual WDLPS. Over the next 12 months, serial CT scans demonstrated a stepwise reduction in size of the WDLPS until it completely regressed. The authors hypothesise that enzymes shed from the pancreatic fistula initiated the autodigestion and subsequent necrosis of the WDLPS with associated tumour regression.

PURPOSE: Treatment-related adverse events associated with systemic anticancer therapy (SACT) can deter patients with sarcoma from completing treatment. With self-monitoring, patients may be better empowered to self-advocate for improved symptom management. We hypothesized that by incorporating journaling, a structured form of self-monitoring, care team communication, and symptom management would improve. We thus designed a prospective randomized trial exploring journaling as a therapeutic adjuvant for symptom management ( NCT03258892 ). METHODS: Participants with sarcoma initiating SACT were randomly assigned to receive either a symptom management journal at the start of SACT or after completing two cycles of SACT. Symptom journals were designed jointly by a cancer patient focus group and by education experts. Journals were reviewed with clinical staff at each visit. Participant responses were obtained through questionnaires. Patient call volume was obtained through the electronic health record. RESULTS: Of 64 participants consented for the trial, 53 were evaluable for analysis. Fifty-five percent of participants reported that the journal was at least moderately useful. These participants were more likely to report improved communication scores ( P = .027), symptom management ( P = .011), and quality of life (QOL) ( P = .019). Participants who received the journal early were less likely to report a decrease in QOL as compared with the late journal group ( P = .757 v P = .035). CONCLUSION: To our knowledge, this is the first prospective randomized trial evaluating the use of structured journaling as a low-cost means to improve treatment-related adverse event management and QOL in patients with sarcoma undergoing SACT. These promising results will need to be confirmed by additional studies.

Carcinosarcomas of mediastinum are rare and only few well-documented cases are available in the literature. We report a detailed description of mediastinal carcinosarcoma with unique clinical manifestations and immunohistochemical and molecular profiles. A 44-year-old female with an enlarging anterior mediastinal mass was found to have a positive pregnancy test. Thoracoscopic biopsy revealed that the mass represented a carcinosarcoma with adenocarcinoma and chondrosarcoma components. The tumor focally expressed beta-HCG by immunohistochemistry and had KRAS G12A missense mutation by next generation sequencing. The case documents a rare presentation of carcinosarcoma within the mediastinum with uncommon paraneoplastic syndrome and genetic profile. Awareness of these unusual clinical and pathological manifestations of the tumor will help in reaching correct diagnosis and proper management of such patients.

PURPOSE Comprehensive genomic profiling (CGP) of sarcomas is rapidly being integrated into routine clinical care to help refine diagnosis and prognosis and determine treatment. However, little is known about barriers to successful CGP or its clinical utility in sarcoma. We set out to determine whether CGP alters physician treatment decision-making, and whether sarcoma subtypes influence the frequency of successful technical performance of CGP. METHODS A single-institution study evaluated profiling outcomes of 392 samples from patients with sarcoma, using a commercially available CGP panel. Of this group, 34 patients were evaluated prospectively (Decision Impact Trial) to evaluate the utility of CGP in physician decision-making. All cases were retrospectively analyzed to identify causes of CGP failure. RESULTS CGP successfully interrogated 75.3% (n = 295 of 392) of patients with sarcoma. Bone sarcomas had lower passing rates at 65.3% (n = 32 of 49) compared with soft tissue sarcomas at 76.7% (n = 263 of 343; P = .0008). Biopsy location also correlated with profiling efficiency. Bone biopsy specimens had a 52.8% (n = 19 of 36) passing rate versus lung (61.1%; n = 33 of 54) and abdomen (80.1%; n = 109 of 136) specimens. CGP altered physician treatment selection in 25% of evaluable patients (n = 7 of 28) and was associated with improved progression-free survival. CONCLUSION To our knowledge, this is the largest technical evaluation of the performance of CGP in sarcoma. CGP was effectively performed in the vast majority of sarcoma samples and altered physician treatment selection. Tumor location and tissue subtype were key determinants of profiling success and associated with preanalytic variables that affect DNA and RNA quality. These results support standardized biopsy collection protocols to improve profiling outcomes.

The molecular findings in Ewing sarcoma have greatly expanded in recent years. Furthermore, this is particularly true for the subset termed “Ewing-like” undifferentiated round cell sarcomas in which new translocations have been reported since the fourth edition of the WHO Classification of Tumours of Soft Tissue and Bone. Amid this expanding genetic landscape, we report a case of extraskeletal undifferentiated round cell “Ewing-like” sarcoma in a 27-year-old female. The patient presented with a large lung mass accompanied on staging imaging by deposits suspicious for metastatic disease in the humerus, calvarium, and lymph nodes of the neck and chest. Biopsy of the lung mass revealed a densely packed monotonous proliferation of round, uniform neoplastic cells with scant cytoplasm. By immunohistochemistry, the tumor cells were diffusely positive for CD99, synaptophysin, TLE1, EMA, and MUC4 and negative for FLI1, PAX7, AE1/3, S100, SOX10, WT1, p63, desmin, and HMB45. Fluorescence in situ hybridization demonstrated rearrangement of the EWSR1 gene. Next-generation sequencing based assay revealed an EWSR1-CREB3L1 fusion. Taken together, the histomorphologic and molecular findings were considered consistent with an undifferentiated round cell sarcoma with an EWSR1-CREB3L1 fusion. Although described in entities such as sclerosing epithelioid fibrosarcoma, low-grade fibromyxoid sarcoma, and small cell osteosarcoma, this has not been previously described in undifferentiated round cell (“Ewing-like”) sarcoma. This finding adds to the growing list of undifferentiated round cell sarcomas with Ewing-like morphologic phenotype–associated fusion genes and may contribute to further defining and characterizing the different subset of tumors in the Ewing family of tumors.

Background Sarcomas constitute a heterogeneous group of tumors with different clinical behaviors and variable responses to systemic therapies. Recent immunotherapy studies with PD1 inhibitors (PD1i) show promising results with use in certain soft-tissue sarcomas; however, the clinical and molecular features that best predict response to PD1i remain unclear. Methods Demographic, imaging, histologic, and genetic sequencing data was collected for sarcoma patients who received nivolumab or pembrolizumab (PD1i) treatment at our institution between January 1st 2015 and April 23rd 2018. The primary objective was to determine progression-free survival (PFS) in patients with advanced sarcomas receiving PD1i. Secondary objectives included determining overall survival (OS) and assessment of characteristics associated with response to PD1i. Fifty-six patients who were treated with PD1i therapy met inclusion criteria for this study. Results Partial response towards PD1i treatment was seen in 3 in 26 evaluable patients, but no complete responses were observed (overall response rate 11.5%). Within this group of patients, the 90 day PFS was found to be 48.8%. In patients in whom PD1 expression was known, there was a statistically significant positive correlation between expression of PD1 and longer PFS and OS rates. Patients that were treated with more than four cycles of PD1i therapy were also more likely to have a greater OS. Conclusions This study suggests activity of PD1i in a pretreated cohort of advanced sarcoma patients, particularly for the subset of patients with PD1 positive tumors. Our results highlight the importance of further research to better target the optimal patient population and markers of response.

Interdigitating dendritic cell sarcoma (IDCS) is an extremely rare cancer of dendritic cell origin that lacks a standardized treatment approach. Here, we performed genomic characterization of metastatic IDCS through whole exome sequencing (WES) of tumor tissues procured from a patient who underwent research autopsy. WES was also performed on a treatment-naïve tumor biopsy sample obtained from prior surgical resection. Our analyses revealed ultra-hypermutation, defined as >100 mutations per megabase, in this patient's cancer, which was further characterized by the presence of three distinct mutational signatures including UV radiation and APOBEC signatures. To characterize clonal heterogeneity, we used the bioinformatics tool Canopy to leverage single nucleotide and copy number variants to catalog six subclones across various metastatic tumors. Truncal alterations, defined as being present in all clonal tumor cell populations, in this patient's cancer include point mutations in TP53 and CDKN2A and amplifications of c-KIT and APOBEC3A-H, which are likely driver mutations. In summary, we have performed genomic characterization evaluating tumor mutational burden (TMB) and heterogeneity in a patient with metastatic IDCS. Despite ultra-hypermutation, this patient's cancer was not responsive to treatment with PD-1 inhibition. Our results underscore the importance of characterizing clonal heterogeneity in TMB-high cancers.

11523 Background: Desmoid tumors are known to have increased nuclear β-catenin levels. Tegavivint selectively disrupts the interaction of β-catenin and TBL1/ TBLR1, resulting in specific degradation of nuclear β-catenin. The primary objectives of this study were to determine the maximum tolerated dose (MTD), safety, and preliminary efficacy of tegavivint in patients (pts) with desmoid tumors. Methods: This study ( NCT03459469) utilized an accelerated dose escalation schema for the first two dose levels followed by a 3+3 design to determine the MTD/recommended phase 2 dose (RP2D) of tegavivint, followed by a dose expansion phase. The study included adult pts with sporadic desmoid tumors that were progressive (20% increase in tumor volume, recurrent in one year from surgery, or symptomatic), unresectable, and measurable via WHO criteria. Tegavivint was administered IV weekly (three weeks on, one week off) up to two years. Results: 24 pts were enrolled. Dose escalation enrolled 17 pts in six dose levels from 0.5 - 5 mg/kg. In dose expansion, 7 additional pts were enrolled. Dose expansion cohort also included 6 pts in dose escalation that were escalated to RP2D and 3 pts treated at RP2D in dose escalation (n = 16 total). Median age was 43 years (18-66). Median time from diagnosis was 3.1 years with median of one prior systemic treatment (range 0-6). Median time on study was 9.4 months; 3 pts remain on study at data cut-off. No dose-limiting toxicities were observed; MTD was not determined. RP2D was declared at 5 mg/kg based on pharmacologically relevant plasma concentrations and preliminary efficacy. Trough plasma concentrations (Cmin) exceeded in vitro IC50 efficacy estimates at 4 mg/kg and 5 mg/kg. Median half-life was 38 hours supporting once weekly administration. Treatment-related adverse events (TRAEs) occurring in ≥20% of pts included fatigue (71%), headache (38%), nausea (33%), constipation (21%), decreased appetite (21%), and dysgeusia (21%), mostly Grade 1-2. Grade 3 TRAEs of hypophosphatemia, stomatitis, increased ALT, diarrhea, and headache occurred in 5 separate pts. There were no grade 4-5 adverse events (AEs). One serious AE of Grade 2 extravasation occurred. Objective response rate (ORR) of 17% across all dose levels and 25% at RP2D (WHO and RECIST criteria) were observed. Median duration of response was 8.1 months (range 6 to 11.8 months) with all responses ongoing. The 9-month progression free survival rate was 76% (95% CI: 54 - 90%) among all pts and 79% (95% CI: 51 – 93%) among those treated at RP2D. Patient reported outcomes and correlative science will be included in the presentation. Conclusions: Tegavivint is well tolerated with mostly Grade 1/2 AEs and no serious toxicity associated with WNT inhibition. The ORR of 25% at the RP2D warrants continued development of tegavivint in desmoid tumors. Clinical trial information: NCT03459469.

11500 Background: Lete-cel is an autologous T-cell therapy targeting NY-ESO-1 tumors using a genetically modified, high-affinity T-cell receptor. MRCLS is a sarcoma with poor response to current immunotherapy approaches and limited treatment options. The cancer testis antigen NY-ESO-1 is expressed in 80‒90% of MRCLS tumors, making this a promising target. This report summaries the primary efficacy and safety results of a pilot study of lete-cel in patients (pts) with advanced or metastatic MRCLS. Methods: This is an open label, study of lete-cel in pts with advanced or metastatic MRCLS following reduced-dose (Cohort 1 [C1]; 30 mg/m2 fludarabine [flu] x 3d + 600 mg/m2 cyclophosphamide [cy] x 3d) or standard dose (Cohort 2 [C2]; 30 mg/m2 flu x 4d + 900 mg/m2 cy x 3d) lymphodepletion (LD). Key eligibility criteria were: age ≥18 y; HLA-A*02:01; A*02:05, or A*02:06; advanced or metastatic NY-ESO-1+ MRCLS (≥30% of cells 2+/3+ by IHC); prior anthracycline treatment, and measurable disease. The transduced T cell dose range was 1– 8 × 109. Response was assessed at weeks 4, 8, 12, 24, then every 3 months (mo) until disease progression, death, or withdrawal. Investigator-assessed (IA) ORR by RECIST v1.1 was the primary efficacy endpoint. Secondary endpoints included safety, independently assessed ORR by RECIST v1.1, time to response (TTR), duration of response (DOR), progression-free survival (PFS). Overall survival (OS) was an exploratory endpoint. Results: 23 pts enrolled from March 2017 to February 2020. The median age was 47.0 yrs (range 33 to 72). 20 pts were dosed with T cells, 10 in each cohort with a median transduced T cell dose of 4.6 x 109. 8 of 20 pts (40%) had 1 line of prior therapy, 6 pts (30%) had 2 lines, and 6 pts (30%) had ≥3 lines. The median follow-up was 5.6 (C1) and 12.9 (C2) mo. In C1 the IA ORR was 20%, with best response (BR) of partial response (PR) in 2 pts and BR of stable disease (SD) in 8 pts. The median TTR was 1.9 mo, median DOR was 5.3 mo (95% CI: 1.9-8.7), and median PFS was 5.4 mo (95% CI: 2.0-11.5). In C2 the IA ORR was 40%, with BR of PR in 4 pts and BR of SD in 5 pts. The median TTR was 1.9 mo, median DOR was 7.5 mo (95% CI: 6.0-NE), and median PFS was 8.7mo (95% CI: 0.9-NE). OS is not yet mature. All pts experienced at least 1 treatment-emergent adverse event (TEAE). 55% of pts experienced serious TEAEs. 90% of pts had Gr ≥3 TE neutropenia, with 83% probability of resolution of initial Gr ≥3 occurrence by Day 30. Cytokine release syndrome occurred in 80% of pts, of which 25% were Gr 3, with 1st onset within 5d of infusion and median duration 7.5d. No Graft-vs-host disease, immune effector cell–associated neurotoxicity syndrome, Guillain-Barré Syndrome were reported. Conclusions: Treatment with a single dose of lete-cel showed anti-tumor activity, including response and long median PFS with an acceptable safety profile in pts with advanced and metastatic MRCLS. Clinical trial information: NCT02992743.

11578 Background: Despite immunotherapy’s promise in oncology, its use for sarcoma remains challenging. There are no sarcoma-specific biomarkers for immune checkpoint inhibitors (ICI). Previously, we reported our institutional experience highlighting ICI activity in 29 patients with sarcoma. In this updated study, we further explore responses to ICI based on ICI regimen and other covariates to identify significant clinical factors in sarcoma outcomes. Methods: Patients in the Ohio State University Sarcoma clinics were enrolled in the Sarcoma Retrospective ICI database from January 1, 2015 through November 1, 2021. Data included treatment regimen (single agent ICI or ICI+combination) along with covariates: stage, age, gender, histology, change in neutrophil-to-lymphocyte ratio (NLR), number of cycles of ICI and immune-related adverse events (irAE). ICI+combination was further categorized into ICI+chemotherapy, ICI+radiation, ICI+surgery or ICI+multiple (more than 2 modalities). Statistical analysis included log rank tests and proportional hazard regression. The primary objective was to evaluate overall survival (OS) and progression-free survival (PFS). Results: One hundred and thirty-five patients met inclusion criteria. We demonstrated improved OS in patients treated with ICI+combination (p = 0.014, median 64 weeks), but no effect on PFS (p = 0.471, median 31 weeks). Whether patients had received single agent or combination ICI, those who received more than 3 cycles of ICI had an improved OS and PFS (p < 0.05 for both). Patients who received single-agent ICI and whose change in NLR was less than 5 had an improved OS (p = 0.002); this was not seen in patients who received ICI+combination therapy (p = 0.441). Patients who had a documented irAE of dermatitis had improved OS but only in the ICI+combination cohort (p = 0.021). There were no differences in OS based on age, gender, histology or sub-categories of ICI+combination. This was not the case for PFS; patients who received any ICI regimen and were younger than 70 had a worse PFS (p = 0.036). Patients who developed an irAE, specifically colitis (p = 0.009), hepatitis (p = 0.048) and dermatitis (p = 0.003) had an improved PFS. There were no differences in PFS based on ICI regimen (or sub-categories of ICI+combination), gender, histology, change in NLR or grade of irAE. Our ICI cohort results are consistent with historical data from our previous study. Further, irAEs are similar to historical data. Conclusions: This retrospective study demonstrates that ICI+combination therapy can improve OS in sarcoma. This is consistent with our prior results of ICI in sarcoma. Benefits in OS/PFS were seen in patients who received more than 3 cycles of ICI and developed certain irAE. These results can direct the optimal duration of ICI therapy. Those with decreased change in NLR also had improved OS, demonstrating a potential prognostic biomarker. Further studies are needed to validate our findings.

Background: Alveolar soft part sarcoma (ASPS) is a rare soft-tissue sarcoma with a propensity for early hematogenous dissemination to the lungs and frequent brain metastasis. The development of lung metastasis almost invariably precedes intracranial involvement. There are no previously reported cases in which a patient was synchronously diagnosed with ASPS and multiple brain metastasis without lung involvement. Case Description: A 29-year-old gentleman was found to have three intracranial lesions following the onset of generalized seizures. Staging studies identified a soft-tissue mass in the left thigh and an adjacent femoral lesion. Biopsy of the soft-tissue mass was consistent with ASPS. The patient then underwent neoadjuvant stereotactic radiotherapy to all three brain lesions, followed by en bloc resection of the dominant lesion. The patient was then started on a programmed death-ligand 1 (PD-L1) inhibitor. Subsequent surgical resection of the primary lesion and femur metastasis demonstrates a histopathologic complete response of the bony metastasis and partial response of the primary lesion. At present, the patient has received 14 cycles of atezolizumab without recurrence of the primary or bony lesions and the irradiated intracranial disease has remained stable without recurrence of the resected dominant lesion. Conclusion: While intracranial involvement is relatively common in ASPS, a case with multiple, synchronously diagnosed brain metastasis without concurrent lung metastasis has not been described. The presented case discusses the safety and efficacy of aggressive management of intracranial disease in the setting of atezolizumab. Prospective evaluation of the efficacy of checkpoint inhibitors and the prognostic value of PD-L1 expression in ASPS with brain metastasis are necessary.

Trial Information Click here to access other published clinical trials. 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.

Inflammatory myofibroblastic tumors (IMTs) are soft tissue neoplasms with rare metastatic potential. Approximately half of IMTs are positive for an ALK rearrangement, and ALK inhibitors have been used successfully in the treatment of IMTs with a variety of ALK fusions. This report describes a 21-year-old woman with an aggressive, metastatic IMT with a novel NUMA1-ALK fusion that showed a dramatic response to the ALK inhibitors crizotinib and alectinib. To our knowledge, this report provides the first published description of an IMT with a NUMA1-ALK fusion. The patient's aggressive IMT responded favorably to crizotinib and alectinib, suggesting that ALK inhibitors may be effective in IMT with NUMA1-ALK fusions. We review published reports of ALK-driven IMTs that have received ALK inhibitor therapy and suggest characteristics that may be associated with favorable response to treatment. We also discuss the strengths and limitations of immunohistochemistry, fluorescence in situ hybridization, and next-generation sequencing in the diagnosis and management of IMTs.

BackgroundThis is an open label pilot study (NCT02992743) on letetresgene autoleucel (lete-cel; GSK3377794), an NY-ESO-1-specific autologous CD4+ and CD8+ T cells expressing a high affinity T-cell receptor which recognizes the NY-ESO-1 antigen epitope in complex with specific HLA- alleles A*02, which exhibited anti-tumor activity and manageable safety profiles in patients with advanced MRCLS based on interim analysis (IA) data.1 Lymphodepletion has been shown to enhance the expansion, persistence, and homing of therapeutically infused T-cells, thereby potentiating therapeutic efficacy against malignant diseases.2 Initial T-cell kinetics data from this study demonstrated that lymphodepletion regimen (LDR)-B robustly depleted lymphocytes at infusion and was trended with higher peak cell expansion (Cmax) vs. LDR-A. The peak expansion was significantly associated with weight-normalized transduced cell dose and trended with response.1 Here, we will be discussing additional cell kinetics data and other exploratory biomarker correlates of response.MethodsPatients with advanced MRCLS were enrolled to 2 cohorts and received either planned A (N=10) or B (N=10) LDRs prior to lete-cel infusion (table 1). Response was assessed per RECIST v1.1. Transduced cell kinetics were measured by quantitative PCR of transgene vector copies in DNA from peripheral blood mononuclear cells (PBMCs). Serum cytokines (Meso Scale Discovery immunoassay) as pharmacodynamic (PD) markers of response and their association with T cell kinetics will be discussed. Phenotypic characterization of the cell product (pre- and post- infusion) via Flow cytometry using Cytek Aurora (23 color panel), to help understand correlation of response with engineered cell product attributes, will be presented. Potential biomarker correlates of clinical response were tested using generalized linear models.ResultsFive out of 6 responders with available lab data exhibited robust lymphocyte depletion at infusion (0–25 cell/µL) and high Cmax (>50,000 vector copies/µg gDNA) with LDR. Only 6/14 non-responders exhibited low lymphocytes counts at infusion and high Cmax. LDR-B also induced strong depletion of monocytes at infusion (p=0.03) vs. LDR-A, but depletion of monocytes did not show association with response. Higher Cmax was correlated with exposure (AUC0–28d) (Adj. R2=0.606). AUC0–28d was a better predictor of response in patients receiving LDR-B (p=0.0182), with AUC0–28d trending towards predicting response in the LDR-A cohort. AUC0–28d was associated with tumor volume reduction (p=0.0569).Abstract 391 Table 1ConclusionsExposure–response analysis of this study reveals that efficacy appears to be driven by weight-normalized transduced cell dose and LDR via AUC0–28d. Higher AUC0–28d was correlated with Cmax and maximum tumor volume reduction.AcknowledgementsThis study (208469; NCT02992743) was funded by GlaxoSmithKline.Trial RegistrationNCT02992743ReferencesD’Angelo SP, et al. J Clin Oncol 2021;39:15_suppl:11521.Bechman, Maher. Expert Opin Biol Ther 2021;21(5):627–637.Ethics ApprovalThis study was approved by institutional review boards (IRB) at the six participating sites.

11541 Background: Sarcoma is a heterogeneous group of malignant tumors that consist of distinct histological and molecular subtypes, each with unique features. Despite immunotherapy’s promise in many cancers, immunotherapeutic approaches for sarcoma have had variable response rates. Evaluating the tumor microbiome is a promising new approach that aims to improve our understanding of the immunogenicity of sarcoma subtypes, leading to improved treatment options and better clinical outcomes. Methods: We utilized The Cancer Genome Atlas (TCGA) and Genome Tissue Expression (GTEx) database to obtain RNA sequencing (RNAseq) data to identify microbes in sarcoma samples (all subtypes available). Due to the large number of sarcoma subtypes, we focused on three groups: dedifferentiated liposarcoma (DDLPS), leiomyosarcoma (LMS) and “other,” representing all other sarcoma subtypes. We utilized ExoTIC, “Exogenous sequences in Tumors and Immune cells,” a tool recently developed by Dr. Daniel Spakowicz and Dr. Xaiokui Mo. ExoTIC takes raw RNAseq reads and carefully aligns to both human and non-human reference genomes to identify low-abundance microbes. Models of association were analyzed based on each of the three groups as well as all the samples: “All” group. We performed Cox proportional hazards regression to identify the microbes associated with overall survival (OS). Results: We evaluated 97 LMS, 56 DDLPS and 100 “other” RNAseq samples (Table). ExoTIC identified 1304 microbes, of which 431 were statistically associated with OS in the “All” group. Of these, 50 microbes were statistically associated only with DDLPS, 54 only with LMS (e.g., Candida dubliniensis, Mycobacterium avium, Streptococcus sp. Z15), and 46 with “other.” The presence of no organism was associated with improved survival. Median hazard ratios were largest in DDLPS (2.3), followed by “other” (2.1) and LMS (1.9). Only 18 microbes were found in the DDLPS, LMS and “All” groups, including Bacillus sp., Streptococcus lutetiensis, Clostridium tetani, and Pseudomonas sp. LTJR-52. Each was negatively correlated with survival with a median hazard ratio of 2.5. Conclusions: We found a specific relationship between microbial presence and histological sarcoma subtype (DDLPS, LMS), which also statistically correlated with OS. Assessing individual characteristics of a sarcoma histological subtype with its particular microenvironment (e.g., microbes) can lead to personalized treatment insights and improvements in outcomes. Our future research will consist of validating and correlation of the microbial profile of sarcoma subtypes with clinical outcomes retrospectively and prospectively. [Table: see text]

11521 Background: Cancer testis antigen NY-ESO-1 is expressed in multiple tumor types, including 80‒90% of MRCLS [1,2]. Overall response rates (ORRs) to MRCLS treatment are low (1L, 2 fludarabine [flu] x 3d + 600 mg/m2 cyclophosphamide [cy] x 3d) or high-dose (Cohort 2 [C2]; 30 mg/m2 flu x 4d + 900 mg/m2 cy x 3d; initiated based on C1 data) LD. Key eligibility: age ≥18 y; HLA-A*02:01; A*02:05, or A*02:06; advanced high-grade NY-ESO-1+ MRCLS (≥30% of cells 2+/3+ by IHC); prior anthracycline; measurable disease; specified washouts; and active/chronic/intercurrent illness restrictions. Stages include screening, leukapheresis, lete-cel manufacture, LD, lete-cel infusion (1– 8 × 109 transduced T cells), follow-up. Response is assessed at wk 4, 8, 12, and 24, then every 3 mo to disease progression/death/withdrawal. The primary efficacy endpoint is investigator-assessed ORR by RECIST v1.1. In C1 (n=10 patients [pts]), lete-cel was well tolerated and linked with 2 confirmed partial responses (PR; ORR, 20%) and stable disease (SD) in 8 pts. Planned interim analysis for C2, shown here, was done once all 10 treated pts had ≥3 post-baseline disease assessments or progressed/died/withdrew. Efficacy data will be correlated with transduced cell kinetics and pharmacodynamics marker profiles. Results: Durable (1.0–7.8 mo) PR (4/10 pts [ORR, 40%]; 2 ongoing) and prolonged (2.7–10.6 mo) SD (5/10 pts; 3 ongoing) with tumor regression were observed. Treatment-emergent cytopenias occurred in all pts. All experienced T-cell related cytokine release syndrome (5 serious adverse events; 30% Grade 3), with onset ≤5d of infusion and median duration 7.5d. Graft-vs-host disease, immune effector cell–associated neurotoxicity syndrome, pancytopenia, or aplastic anemia were not reported. Conclusions: A single lete-cel infusion after high LD showed antitumor activity in advanced MRCLS and a manageable safety profile consistent with other lete-cel studies. The trial is active but no longer recruiting (NCT02992743). MRCLS is included in a separate, ongoing lete-cel study (NCT03967223). References: 1. D’Angelo SP, et al. J Clin Oncol 2018;36:15_suppl, 3005. 2. Pollack SM, et al. Cancer Med 2020;9(13):4593–602. 3. D’Angelo SP, et al. J Immunother Cancer 2020;8:P298. Funding: GSK (208469; NCT02992743). Editorial support was provided by Eithne Maguire, PhD, of Fishawack Indicia, part of Fishawack Health, and funded by GSK. Clinical trial information: NCT02992743.

TPS2661 Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T-cell therapy using a genetically modified T-cell receptor (TCR) to improve recognition of cancer cells expressing NY-ESO-1/LAGE-1a. Next generation NY-ESO-1 TCR T-cell therapies, such as GSK3901961 and GSK3845097, integrate added genetic modifications to enhance anticancer activity. GSK3901961 co-expresses the CD8α chain to stabilize TCR-human leukocyte A (HLA) class I interactions on CD4+ T cells, improving T-cell persistence and helper functions such as Type 1 T-helper antitumor responses. GSK3845097 co-expresses a dominant negative transforming growth factor-β (TGF-β) type II receptor to reduce TGF-β pathway activation and maintain T-cell proliferation, cytokine production, and cytotoxicity in the tumor microenvironment. A first-time-in-human master protocol (NCT04526509) will evaluate safety, tolerability, and recommended phase 2 dose (RP2D) of these and possible subsequent therapies. Substudy 1 will assess GSK3901961 in patients (pts) with advanced non-small cell lung cancer (NSCLC) or synovial sarcoma (SS). Substudy 2 will assess GSK3845097 in pts with advanced SS. Methods: Each substudy includes a dose confirmation stage to assess RP2D and a dose expansion stage. Key inclusion criteria are age ≥18 y; measurable disease per RECIST v1.1; HLA-A*02:01, A*02:05, or A*02:06 positivity; NY-ESO-1/LAGE-1a tumor expression; advanced (metastatic/unresectable) SS with t(X;18) translocation and anthracycline-based therapy receipt/completion/intolerance (SS only); and Stage IV NSCLC, receipt of ≥1 prior line(s) of standard of care (SOC) therapy including programmed death receptor- or ligand-1 inhibitors, and SOC chemotherapy receipt/intolerance (Substudy 1 only). Key exclusion criteria are prior malignancy that is not in complete remission or clinically significant systemic illness; prior receipt of gene/NY-ESO-1–specific therapy or allogenic stem cell/solid organ transplant; central nervous system metastases (SS only); and actionable genetic aberration and receipt/failure of ≥3 systemic therapy lines (Substudy 1 only). Primary endpoints are safety (adverse events) and tolerability (dose-limiting toxicities). Secondary endpoints include investigator-assessed overall response rate, duration of response, and maximum expansion/persistence and phenotype of infiltrating transduced T cells. Exploratory endpoints include laboratory parameters, overall survival, and anti-GSK3901961 or -GSK3845097 titers as applicable. Analyses will be descriptive. The substudies are enrolling. Funding: GSK (209012; NCT04526509). Editorial support was provided by Eithne Maguire, PhD, of Fishawack Indicia, part of Fishawack Health; funded by GSK. Previously presented at AACR 2021 (CT219). Clinical trial information: NCT04526509.

Background and Objectives The purpose of this study was to determine the pattern and timing of major wound complications (MWCs) in patients at our institution who received multimodality treatment for lower extremity soft tissue sarcoma (LE-STS) and to evaluate the impact of MWCs on tumor control and patient outcomes. Methods The medical records of 102 LE-STS patients treated with limb-sparing surgery and radiation therapy were reviewed. MWCs were defined as secondary operations with anesthesia, seroma/hematoma aspiration, admission for IV antibiotics, or persistent deep packing. Results MWCs occurred in 22% of patients, with 45% of events occurring >120 days after resection. On multivariate analysis, preoperative external beam radiation therapy (EBRT) (OR 4.29, 95% CI 1.06–17.40, P = 0.042) and skin graft placement (OR 6.39, 95% CI 1.37–29.84, P = 0.018) were found to be independent predictors of MWCs. MWC occurrence did not predict for chronic toxicity and did not impact tumor control or survival. Conclusions A considerable proportion of MWCs occur >120 days from surgical resection with preoperative EBRT and skin graft placement independent predictors for MWCs. While an additional source of morbidity, MWC occurrence did not impact tumor control, nor did it predict for chronic toxicity. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

Background Patients with metastatic or locally aggressive cutaneous squamous-cell carcinoma (cSCC) have historically had limited and noneffective treatment options. The mainstay treatment has been surgery, which can be disfiguring and may not be technically feasible for larger lesions. Patients and Methods A retrospective review of 18 patients treated with nivolumab (n = 17) or pembrolizumab (n = 1) anti–programmed cell death protein 1 (PD-1) inhibitors for metastatic or locally advanced cSCC from March 2015 to present was performed. Results Three patients had metastatic disease, 5 patients had locally aggressive plus regional nodal disease, 8 patients had locally advanced disease, and 2 had multifocal skin disease. Seventeen patients had undergone at least 1 surgery, 12 also had received radiotherapy, 8 had disease that had failed to respond to other systemic treatments, and 2 had chronic lymphocytic leukemia. Of 18 patients treated, 14 had dramatic responses with improvement in clinical symptoms and impressive tumor reduction with equally impressive duration. Objectively, 4 patients had complete response, 10 had partial response, 3 had stable disease, and 1 patient had progression of disease. Three patients died, 1 from an ischemic cerebrovascular incident possibly related to treatment, 1 likely not related to neither treatment nor disease, and 1 due to disease progression. Therapy was otherwise well tolerated, and 10 patients currently continue to receive the therapy. Thirteen patients continue to have stable or no new disease at a median time of 12 months since the start of treatment. Conclusion PD-1 blocking agents may provide clinically meaningful and palliative therapy for patients with aggressive cSCC who are not surgical candidates.

Objective. Thyroid disease has been reported among the endocrinopathies that can occur after treatment with ipilimumab. Graves’ disease, however, has been rarely reported with this medication. Here we report a case of Graves’ disease diagnosed after initiation of ipilimumab in a patient with melanoma.Methods. We present the clinical presentation and management course of this patient followed by a related literature review.Results. A 67-year-old male with metastatic melanoma was started on ipilimumab. He developed hyperthyroidism after two doses of ipilimumab. The cause of hyperthyroidism was determined to be Graves’ disease. Ipilimumab was held and the patient was started on methimazole with return to euthyroid status. Ipilimumab was resumed and the patient continued methimazole during the course of ipilimumab therapy, with controlled hyperthyroidism. Restaging studies following four cycles of ipilimumab showed complete response in the lungs, with residual melanoma in the neck. The patient then underwent total thyroidectomy and left neck dissection as a definitive treatment for both hyperthyroidism and residual melanoma.Conclusion. Graves’ disease can develop after starting ipilimumab and methimazole can be an effective treatment. For patients whose hyperthyroidism is well-controlled on methimazole, ipilimumab may be resumed with close monitoring.

11511 Background: In the open-label multicenter phase II study, A091401, nivolumab (N) and nivolumab+ipilimumab (N+I) demonstrated a confirmed response rate (RR) of 5% and 16%, respectively in patients (pts) with advanced sarcoma (D’Angelo SP et al Lancet Oncology 2018). Responses occurred in undifferentiated pleomorphic sarcoma (UPS), myxofibrosarcoma, leiomyosarcoma, sarcoma not otherwise specified and alveolar soft part sarcoma. Here, we report efficacy of N and N+I, in each of 3 expansion cohorts [gastrointestinal stromal tumor (GIST), UPS and dedifferentiated liposarcoma (DDLS)]. Methods: Pts refractory to ≥ 1 regimen(s) were randomized (non-comparative) to receive either N [N (3 mg/kg q2W)] or N+I [N (3 mg/kg Q3W x4, then Q2W) plus I (3 mg/kg q3W x4)]. The primary endpoint was 6 month confirmed RR (RECIST v1.1). For UPS and DDLS, 2 confirmed responses in the 1st 12 evaluable pts was needed (85% power, 1-sided alpha=0.15, 5 v 25% RR). For GIST, a confirmed response in the 1st 9 evaluable pts expanded enrollment to 24 (80% power, 1-sided alpha=0.10, 5 v 20% RR). Other endpoints: adverse events (AEs, TRAEs), progression-free and overall survival (PFS, OS), and correlatives. Results: See table. Clinical trial information: NCT02500797 . Conclusions: Neither N or N+I lead to confirmed responses in GIST. In DDLS and UPS, the primary response endpoint was met with N+I but not with N alone (RR 14% for N+I vs. 7% and 8% for N alone). For the GIST cohort TRAE was higher with N+I, holding enrollment as required per protocol. There remains a pressing need to determine genomic and clinical biomarkers of response, resistance and toxicity. Correlative analyses (whole exome sequencing, multiplex IHC and RNAseq) are in progress. Support: U10CA180821, U10CA180882; ClinicalTrials.gov Identifier: NCT02500797. [Table: see text]

102 Background: MAGE-A4 is a cancer/testis antigen with expression in many solid tumors promoting cell growth by preventing cell cycle arrest and apoptosis. This study (NCT03132922) evaluated safety and efficacy of SPEAR T-cells directed against the MAGE-A4 peptide expressed in 9 tumor types. Methods: This Phase I dose-escalation, expansion trial evaluated patients (pt) who were HLA-A*02 positive with advanced cancers that expressed the MAGE-A4 protein. Autologous T-cells from eligible patients were isolated, transduced with a lentiviral vector containing the MAGE-A4c1032 TCR, and expanded. Prior to ADP-A2M4 infusion, pts received a lymphodepletion regimen of cyclophosphamide and fludarabine. Cohorts 1, 2, 3, and expansion were to receive transduced cell doses of up to: 0.12 × 109, 1.2 × 109, 6 × 109, and 10 x 109, respectively. Results: As of 23 October 2019, 9 pts were treated in dose escalation with no DLTs; 25 pts were treated in expansion. Median age was 56.5 yr (range: 31-78). All pts received prior chemotherapy. Most common ( > 30%) AEs ≥Grade 3 were lymphopenia, leukopenia, neutropenia, anemia, thrombocytopenia, and febrile neutropenia. Two pts had trial-related deaths (aplastic anemia and CVA) leading to modification of the lymphodepletion regimen and eligibility criteria. In Cohort 3/expansion (28 pts), Best Overall Response was PR (7), SD (11), PD (5), non-evaluable (5). All PRs, at the time of data cut-off, were in patients with synovial sarcoma. Transduced T-cells were detectable in all patients. Tumor infiltration of SPEAR T-cells was detectable in several cohort 3/expansion pts. Conclusions: The Phase I single agent ADP-A2M4 trial will complete enrollment shortly and updated data will be presented. ADP-A2M4 shows promising efficacy and a manageable safety profile at a dose range of 1.2 – 10 × 109. Clinical activity in various tumors has led to a separate on-going low dose radiation sub-study of this trial, a Phase II trial in sarcoma (SPEARHEAD-1, NCT04044768), and a Phase I trial (SURPASS, NCT04044859) with ADP-A2M4CD8, a next-generation SPEAR T-cell targeting MAGE-A4. Clinical trial information: NCT03132922.

11562 Background: Soft tissue sarcoma (STS) is a heterogeneous malignancy of connective tissue. Although mTOR is implicated in STS pathogenesis, clinical activity from mTORC1 inhibitors is modest. M, a potent selective mTORC1/mTORC2 inhibitor, was more effective in STS preclinical models than inhibitors of mTORC1, IGF1R and mTORC1+IGF1R, owing to more complete suppression of PI3K/AKT/mTOR and abrogation of feedback AKT activation. P, an oral multikinase inhibitor, is approved for non-adipocytic STS and often used after progression (PD) on chemotherapy. In phase 1, the RP2D of M was 30 mg weekly. A091304 was to evaluate M as a novel targeted therapy for STS. Methods: In A091304, pts were randomized 1:1 to M 30 mg weekly or P 800 mg daily. Eligibility required Eastern Cooperative Oncology Group PS ≤ 1, progression on ≥ 1 prior chemotherapy and specific STS subtypes (cohort 1: UPS; 2: LMS; 3: MPNST, SS). Crossover to M was allowed after PD on P. 1° endpoint was progression-free survival (PFS). Assuming median PFS of P was 4.6 months (mo), 98 pts yielded 80% power to detect a hazard ratio of 0.66 favoring M [1-sided test, alpha = 0.15] and including 1 planned futility analysis. 2° endpoints were response rate, clinical benefit rate (CBR) at 4 mo and safety. After 4 of the first 12 pts randomized to P experienced ≥ grade (gr) 3 toxicity, the study was amended to begin at P 400 mg, allowing titration to 800 per investigator discretion. Results: After protocol amendment, 114 pt underwent randomization (M: 56, P: 58), and 111 initiated treatment. Median PFS was 2 mo for M and 2.1 mo for P (HR = 1.47; 1-sided 85% upper confidence boundary = 1.85), with 2 partial responses in each arm. CBR was 5.4% for M and 13.8% for P. Median OS was 10.7 mo for M and 13.9 mo for P (HR = 1.41; 95% CI 0.80-2.49). 26/43 pt with PD on P crossed over to M. Median PFS after crossover was 1.8 mo (95% CI 1.5-3.5). Gr 3 drug-related adverse events (AEs) occurred in 36% on M and 41% on P; gr 4 toxicity was rare. AEs were consistent with known effects of M and P. Conclusions: P at 400 mg daily (allowing escalation to 800 mg per investigator discretion) demonstrated a shorter PFS as compared prior randomized studies with P. Despite this, M failed to demonstrate superior clinical activity as compared to P at the interim analysis. Further work will examine activity within histology-specific cohorts and evaluate available tissue samples for evidence of pharmacodynamic activity. Support: U10CA180821, U10CA180882, U10CA180888, UG1CA233324 (SWOG); https://acknowledgments.alliancefound.org . Clinical trial information: NCT02601209 .

e23538 Background: There are currently no informatics tools that are capable of providing complex clinical decision support using real-world outcomes (RWO) for patients with sarcoma. Although existing nomograms can provide prognostic scores based on clinical or genomics features, they typically are static and lack the ability to compare outcomes for patients managed with alternative treatment strategies. To address this need, we present STEP, a Sarcoma Treatment Efficacy Portal, a web-based tool designed for real-time exploration and visualization of patient data with the potential to be integrated into clinical decision workflows during outpatient visits. Methods: At The Ohio State University, clinical histories and omics data for sarcoma patients are captured in our prospective Sarcoma Registry (NCT0267796). STEP is an interactive web-based tool built in R/Shiny and supported by a pipeline written Python that processes, transforms, and caches clinical data extracted from the Sarcoma Registry in near real-time. Protected health information (PHI) is stored on a secure HIPAA compliant server behind the hospital firewall and migrated to a secure, deidentified staging database. Results: The STEP system is powered by detailed treatment specific data elements that are continuously abstracted for over 400 patients with bone and soft tissue sarcoma. This consists of manually annotated clinical histories in addition to nearly 10 million discrete data points are pulled from the EHR (labs, ICD-9/10 codes, medications, omics data). Importantly, STEP includes a cohort builder which allows users to define a treatment group of interest though any number of variables including tumor histology, chemotherapy, and omic features of interest. For any predefined cohort, STEP can provide information on overall survival and response to a variety of treatments. It also provides sorting mechanisms for identifying candidate treatments. A secure web interface allows a simple integration into a busy clinic flow. Conclusions: STEP provides a first in class, convenient, clinician friendly platform for delivering access to real-time, real-world treatment outcomes (RWO) in patients with a diagnosis of bone or soft tissue sarcoma. Additional usability testing is forthcoming.

e23547 Background: Given the rare nature of sarcoma cancers and the sometimes severe treatment-related effects of chemotherapy, many patients with sarcoma face quality of life issues during treatment. Unplanned hospital admission and emergency room (ER) visits can occur from uncontrolled symptoms and ultimately delay treatment regimens and negatively impact quality of life. The PROMIS Global Health v1.2 (PROMIS-10) surveys are validated tools to assess patients’ physical and mental well-being at the time of the survey. We sought to evaluate the correlation between PROMIS-10 scores and adverse outcomes of interest, including unplanned admissions/ED visits and patient mortality. Methods: All patients currently seen in the Sarcoma Clinics at Ohio State University routinely complete the PROMIS-10 survey at each clinic visit. For this pilot study, we collected the raw and normalized t-scores for PROMIS-10 surveys for all patients consented to The Ohio State University Sarcoma Registry (OSU-14242) from 6/1/2018 to 11/20/2019. We also collected data on unplanned hospital admission/ED visits and mortality data for each patient. Results: A total of 864 surveys for 112 patients were collected for the study period. The median number of surveys answered per patient was 6. Mean global physical t-scores (43.7 ± 8.5) and mental t-scores (47.9 ± 9.2) were lower than reference scores for the general US population (p < 0.001). 109 of 112 patients experienced an unplanned admission or ED visit during the study, with a total of 270 such encounters during the study period. PROMIS-10 scores were slightly but significantly lower for patients experiencing an admission or ED visit within 30 days of taking the survey (physical: 41.9 vs 44.1, p = 0.006; mental: 46.4 vs 48.2, p = 0.035). A total of 26 patients died during the study period; surveys completed prior to death were consistent with a greater level of physical and mental distress, with the median physical t-score = 34.9 (range: 23.5 – 50.8) and mental t-score = 43.5 (range: 33.8 – 67.6). Conclusions: We showed that we are able to obtain worthwhile data to objectively evaluate patients’ physical and mental well-being through survey data during cancer treatment. We are currently performing additional confirmatory analysis of the predictive value of the PROMIS-10 survey for adverse events and for treatment-related complications.

Therapeutic agents targeting the PD-1/PD-L1 axis have shown durable clinical responses in patients with various cancer types. Although objective responses are common, intrapatient heterogeneous responses have been described, and the mechanism for the different organ responses remains unknown. We present a series of patients in whom a lack of response was noted solely in the adrenal glands. This is the first case series describing 3 patients with heterogeneous patterns of response to pembrolizumab with progression of adrenal metastatic disease despite objective response (complete or partial response) in all other sites of metastatic disease. Two patients, one with melanoma and one with uterine carcinosarcoma, underwent robotic adrenalectomy for enlarging adrenal metastases. An additional patient with melanoma underwent laparotomy with attempted resection, but infiltration of the adrenal tumor into the inferior vena cava prohibited safe excision. This report provides additional insight into the heterogeneous patterns of disease response to anti-PD-1 therapy, highlighting the adrenal gland as a potential sanctuary site for this immunotherapy. These cases display the potential benefit of early surgical resection in this scenario and the pitfalls of delaying referral to a surgeon for assessment of operative intervention.

Background This study (NCT03132922) evaluates safety, tolerability, and antitumor activity of ADP-A2M4, genetically engineered autologous specific peptide enhanced affinity receptor (SPEAR) T-cells directed towards a MAGE-A4 peptide expressed in the context of HLA-A*02. Here, we report on a subset of patients (pts) with synovial sarcoma (SS). Methods In this first-in-human T-cell dose-escalation study, pts who are HLA-A*02+ (excluding *02:05, *02:07), have inoperable or metastatic MAGE-A4+ disease, and meet entry criteria are eligible for treatment. Following apheresis, T-cells are isolated, transduced with MAGE-A4c1032TCR, and expanded. The lymphodepletion chemotherapy increased in intensity as the study progressed, with max dose of 30mg/m2/d fludarabine x 4 d and 1800mg/m2/d cyclophosphamide x 2 d. During dose escalation, 3 pts with various tumor types received 0.1x109 (±20%), 1x109 (range: 0.5 – 1.2 × 109), or 5x109 (range: 1.2 – 6 × 109) transduced cells and were monitored for dose-limiting toxicities (DLTs). During expansion, 30 pts (not only SS) will be treated with 1.2 – 10x109 transduced cells. Disease is assessed per RECIST by CT/MRI at wk 6, 12, 18, and 24, and every 3mo for 2yr, then every 6mo or until progression. Correlative studies will investigate transduced cell persistence, phenotype, and function, and serum and tumor microenvironment factors. Results No DLTs were reported. ADP-A2M4 was well tolerated, with adverse events consistent with chemotherapy or other immunotherapies. 10 pts with SS have been treated in cohort 3 and the expansion phase (30Apr19). Median T-cell dose was 9.7x109 (4.49 - 9.98x109). 8 pts have post-baseline tumor assessments. There are 3 confirmed partial responses (PR) (-86%, -44%, -54), and 1 unconfirmed PR (-31%) at wk 6. Best response was stable disease in 3 pts (-27% and -15%, ongoing, and +12%, progressed) and progressive disease in 1. 2 pts have yet to be assessed. Ex vivo analysis of transduced cells from peripheral blood and tumor showed cells were cytolytic and activated in an antigen-specific manner. Conclusions ADP-A2M4 induced clinical responses in pts with SS. Transduced T-cells expand upon exposure to antigen and are functional. Updated data from this ongoing study will be presented. Clinical trial identification NCT03132922, First posted on April 28, 2017. Editorial acknowledgement Debra Brocksmith, MB ChB, PhD, of Envision Pharma Group; contracted by Adaptimmune. Legal entity responsible for the study Adaptimmune. Funding Adaptimmune. Disclosure B.A. Van Tine: Research grant / Funding (self): Pfizer; Research grant / Funding (self): Tracon; Research grant / Funding (self): Merck; Advisory / Consultancy: Epizyme; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy: CytRX; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy: Immune Design; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Plexxicon; Advisory / Consultancy: Adaptimmune; Speaker Bureau / Expert testimony: Caris. M.O. Butler: Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Merck; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self): Roche; Advisory / Consultancy: Adaptimmune; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: GSK; Advisory / Consultancy: Immunocore; Advisory / Consultancy: Immunovaccine; Research grant / Funding (institution): Takara Bio. M.L. Johnson: Research grant / Funding (institution): BerGenBio; Research grant / Funding (institution): Lilly; Research grant / Funding (institution), Travel / Accommodation / Expenses: EMD Serono; Research grant / Funding (institution): Janssen; Advisory / Consultancy, Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): Genmab; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Additional travel from: Astellas, AstraZeneca, Boehringer Ingelheim, Clovis, Daiichi Sankyo, Bristol-Myers Squibb, Exelixis, Incyte, Merck, Sysmex Inostics, Vapotherm: Genentech; Research grant / Funding (institution): Stemcentrix; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Checkpoint Therapeutics; Research grant / Funding (institution): Array Biopharma; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Apexigen; Research grant / Funding (institution), Travel / Accommodation / Expenses: AbbVie; Research grant / Funding (institution): Tarveda; Research grant / Funding (institution): Adaptimmune; Research grant / Funding (institution), Additional advisory for: Gelgene, Boehringer Ingelheim, Sanofi, LOXO, Calithera, Merck, Araxes Pharma, Mersana Therapeutics, BeiGene, Incyte, Guardant Health, Bristol-Myers Squibb, Ribon Therapeutics: Syndax; Research grant / Funding (institution), Additional grant funding from: Boehringer Ingelheim, Sanofi, Hengrui Therapuetics INC, Merck, Daiichi-Sankyo, Lycera, G1 Therapeutics, Dynavax, LOXO, Cytomx, BeiGene, Birdie, Corvus, Incyte, Genocea, Gritstone, Amgen, Bristol-Myers Squibb, Kadmon, Clovis, Acerta, OncoMed, Guardant Health, Takeda, Shattuck Labs, GSK: Neovia. J. Clarke: Research grant / Funding (self): MedPacto; Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Eli Lilly; Research grant / Funding (self): Genentech; Research grant / Funding (self): Spectrum; Research grant / Funding (self): Adaptimmune; Research grant / Funding (self): Bayer; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Moderna; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck; Advisory / Consultancy, Speaker Bureau / Expert testimony: Guardant; Advisory / Consultancy: AstraZeneca. D. Liebner: Advisory / Consultancy: Foundation Medicine; Advisory / Consultancy: Blueprint Medicines. K. Odunsi: Research grant / Funding (self): ITeos Therapeutics. A.J. Olszanski: Advisory / Consultancy, Research grant / Funding (self): Bristol-Myers Squibb; Advisory / Consultancy: Merck; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Array; Advisory / Consultancy, Research grant / Funding (self): EMD Serono; Advisory / Consultancy: Iovance; Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (self): Alkermes; Research grant / Funding (self): Adaptimmune; Research grant / Funding (self): Astellas; Research grant / Funding (self): Boston Biomedical; Research grant / Funding (self): Checkmate Pharmaceutics; Research grant / Funding (self): GSK; Research grant / Funding (self): Immunocore; Research grant / Funding (self): Intensity Therapeutics; Research grant / Funding (self): Kartos; Research grant / Funding (self): Kura; Research grant / Funding (self): Oncoceutics; Research grant / Funding (self): Targovax. S. Basu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Adaptimmune. F. Brophy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Adaptimmune. T. Holdich: Shareholder / Stockholder / Stock options, Full / Part-time employment: Adaptimmune. T. Trivedi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Adaptimmune. R.G. Amado: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Adaptimmune. D.S. Hong: Research grant / Funding (self): AbbVie; Advisory / Consultancy, Research grant / Funding (self): Adaptimmune; Research grant / Funding (self): Amgen; Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Bayer; Research grant / Funding (self): Bristol-Myers Squibb; Research grant / Funding (self): Daiichi-Sankyo; Research grant / Funding (self): Eisai; Research grant / Funding (self): Fate Therapeutics; Advisory / Consultancy, Research grant / Funding (self): Genentech; Research grant / Funding (self), Travel / Accommodation / Expenses: Genmab; Research grant / Funding (self): Ignyta; Advisory / Consultancy, Research grant / Funding (self): Infinity; Research grant / Funding (self): Kite; Research grant / Funding (self): Kyowa; Research grant / Funding (self): Lilly; Research grant / Funding (self), Travel / Accommodation / Expenses: LOXO; Research grant / Funding (self): MedImmune; Research grant / Funding (self): Merck; Research grant / Funding (self), Additional grant funding from: miRNA, Molecular Templates, Mologen, NCI-CTEP, Novartics, Pfizer, Seattle Genetics, Takeda. Additional advisory consulting for: Alpha Insights, Axiom, Baxter, GLG, Group H, Guidepoint Global, Merrimack, Medscape, Numab, Pfizer, Seattle Genetics, Takeda, Trieza Therapeutics, WebMD; Travel support from MiRNA, AACR, ASCO, SITC; ownership interests in Molecular Match, OncoResponse, Presagia Inc: Mirati. All other authors have declared no conflicts of interest.

High-dose interleukin-2 (IL-2) is an available treatment option for patients with metastatic melanoma or renal cell carcinoma, and is associated with sustained complete and partial responses in a subset of patients. IL-2, however, is not devoid of toxicities, most of which involve the cardiovascular system and manifest as hypotension, arrhythmias, and cardiomyopathy. This report describes an unusual presentation of takotsubo cardiomyopathy in a postmenopausal woman receiving high-dose IL-2 for metastatic melanoma.

Inflammatory myofibroblastic tumors (IMTs) are soft tissue neoplasms with rare metastatic potential. Approximately half of IMTs are positive for an

Optimal treatment of metastases to the central nervous system (CNS) in patients with malignant melanoma remains a clinical challenge. In particular, for patients with BRAF-mutant melanoma and CNS metastases, much remains unknown about the safety and efficacy of the novel BRAF-targeted agents when administered in close sequence with radiation. We report two cases of rapid development of CNS radiation necrosis in patients with metastatic melanoma treated with the BRAF inhibitor, vemurafenib, closely sequenced with stereotactic radiosurgery or fractionated stereotactic radiation therapy. In the absence of prospective safety data from clinical trials, we advise vigilance in monitoring patients with BRAF-mutant melanoma whose treatment plan includes CNS radiation and vemurafenib and caution when assessing treatment response within the CNS in these patients.

Soft tissue sarcomas (STS) are diverse tumors with heterogenous alterations. Platforms to detect circulating tumor DNA (ctDNA) have rapidly increased in popularity as they may avoid invasive biopsy morbidity. However, ctDNA profiling concordance with standard solid tumor comprehensive genomic profiling (CGP) is poorly characterized. Here, we report the outcomes of a single-institution experience comparing mutational results from commercial ctDNA and solid tumor CGP in advanced STS subjects. We identified STS subjects who had undergone solid tumor based CGP in four distinct cohorts: Dedifferentiated liposarcoma (DDLPS), leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS), and gastrointestinal stromal tumor (GIST). Subjects with radiographically measurable tumor were profiled using a commercial ctDNA CGP panel. Overlapping genes/exons on both biopsy panels were analyzed. Twenty-four subjects completed both ctDNA and solid tumor CGP. ctDNA was detected in 18/24 subjects. Subject level concordance rates in all overlapping genes were: LMS = 4/6, UPS = 2/6, DDLPS = 1/6, GIST = 0/6. Copy number alterations were notably poorly concordant. For subjects with short variant alterations and detectable tumor fractions, concordance with solid tumor CGP was 76% (13/17). LMS subjects had the highest median tumor fraction and concordance. No correlation was seen between tumor fraction or radiographic tumor volume largely driven by low estimated tumor fraction. A limitation of the study is that only targeted sequencing was performed. However, given the poor concordance in commonly altered genes, ctDNA panels in sarcoma cannot be broadly applied. Further, more extensive studies will need to be performed.

Key Points Question Can next-generation sequencing reveal rationale for the dichotomous biological activity of epithelioid hemangioendothelioma (EHE) while illuminating potentially actionable alterations? Findings In a cross-sectional study of next-generation sequencing results collected from 49 participants diagnosed with EHE, more than half of patients with EHE profiled exhibited pathogenic genomic variants in addition to the WWTR1-CAMTA1 fusion, with 18.4% of participants exhibiting a potentially targetable variant. Participants with stage III/IV EHE were more likely to exhibit a secondary pathogenic variant. Meaning Next-generation sequencing may identify secondary genomic variants that are associated with EHE aggressiveness; additionally, these variants may represent potential therapeutic targets., This cross-sectional study characterizes secondary genomic alterations in patients with epithelioid hemangioendothelioma and their association with clinical outcomes., Importance Epithelioid hemangioendothelioma (EHE) is a rare, malignant vascular sarcoma characterized in most cases by a WWTR1-CAMTA1 fusion. The clinical course of EHE exhibits a dual nature. The condition is often indolent but can rapidly grow and metastasize unpredictably. No biomarkers to date are available to predict this phenotype. The hypothesis of this study was that better defining the genomic landscape of EHE using next-generation sequencing could offer additional therapies and insight into clinical outcomes. Objective To characterize secondary EHE genomic alterations and their association with clinical outcomes. Design, Setting, and Participants Multicenter, cross-sectional, retrospective study of next-generation sequencing results collected from participants diagnosed with EHE. Data were abstracted between May 1, 2013, and May 31, 2019. This analysis was conducted from January through June 2019. Summary genomic data were provided by commercial genomic testing companies. Main Outcomes and Measures Presence or absence of secondary pathogenic genomic variants and their association with disease stage and clinical features. Results A total of 49 participants with EHE were assessed for the presence or absence of secondary genomic variants. Of these, 32 (65.3%) were female; the mean (SD) age at diagnosis was 49.9 (18.3) years (range, 11-81 years). In all, 46 participants (93.9%) had confirmed WWTR1-CAMTA1 fusion; 26 participants (57.1%) exhibited a pathogenic genomic variant secondary to the WWTR1-CAMTA1 fusion; and 9 participants (18.4%) exhibited potentially targetable genomic variants. Commonly altered genes included CDKN2A/B, RB1, APC, and FANCA. Participants older than 45 years at diagnosis had an increased prevalence of secondary genomic variants that was not statistically significant (65.6% vs 38.5%; difference, 27.1%; 95% CI, −3.5% to 58.0%; P = .16) and were more likely to have a clinically targetable variant (28.1% vs 0%; difference, 28.1%; 95% CI, 11.2%-40.2%; P = .03). In 14 participants with clinical data available, those with stage III/IV EHE were more likely to exhibit a secondary pathogenic genomic variant (80% vs 0%; difference, 80%; 95% CI, 55.2%-100%; P = .006). Participants with stage III/IV EHE were diagnosed at an older age (mean [SD] age, 54.6 [14.1] years vs 31.7 [16.0] years; P = .05) and had elevated WWTR1-CAMTA1 fusion expression that was not statistically significant (mean [SD] expression, 677 [706] copies vs 231 [213] copies; P = .20). Conclusions and Relevance Although EHE exhibits few secondary genomic variants, presence of key secondary variants may be prognostic for aggressive EHE. Further research is needed to confirm this finding and determine whether more intensive upfront treatment is necessary for these patients.

11045 Background: Epithelioid hemangioendothelioma (EHE) is a rare vascular sarcoma characterized by the WWTR1- CAMTA1 fusion ( WC-F) in a majority of cases. EHE demonstrates a biphasic clinical course; remaining indolent for many years before suddenly demonstrating aggressive progression. Cell cycle mutations have been previously noted to account for some secondary alterations; however, little is known regarding the chronicity of these secondary alterations or their clinical implications. Here we present the largest assessment of secondary genomic variants and their clinical import. Methods: Comprehensive genomic profiling from 45 WC-F positive EHE patients (pts) were provided by Foundation Medicine (FMI). 8 of these 45 pts were treated at The Ohio State University (OSU) and were evaluated retrospectively through chart review. Known deleterious alterations, variants of unknown significance (VUS), and genomic copy quantification for the WC-F was included in our analysis. Targetable gene variants were defined by OncoKB. Chi-square and student’s t-tests were used as appropriate. Results: Genomic copy number of the WC-F best fit a log-normal distribution (range: 13-2,131 copies). 20 pts (44%) did not exhibit any secondary genomic variants. The most commonly altered genes included: CDKN2A/B (7 variants), RB1 (3 variants), and ATRX (3 variants). Commonly identified pathways included: cell cycle (9 pts, 20.0%), epigenetic modulators (7 pts, 15.6%), and DNA damage repair (7 pts, 15.6%). Eight pts exhibited targetable gene variants (18%) as defined by OncoKB. Subjects ≥50 years of age exhibited a greater proportion of clinically targetable variants (27.6% vs 0%; p = 0.02). Pts with a secondary genomic variant exhibited elevated WC-F copy numbers (p < 0.001). OSU pts with aggressive EHE were more likely to have a second genomic variant (80% vs 0%; p = 0.03) when compared to indolent EHE, with trends toward higher WC-F copy numbers (809±315 vs 207±147; p = 0.2) and older age at diagnosis (59.5±5.5 vs 36.7±8.8; p = 0.1). Conclusions: In this study, secondary genomic variants in WC-F driven EHE are more common in older patients ( > 50 yo). Further, the presence of secondary genomic variants is associated with an aggressive phenotype and may drive poor prognosis. Prospective research is needed to confirm these findings.

Background: One of the significant obstacles in the development of clinically relevant microarray-derived biomarkers and classifiers is tissue heterogeneity. Physical cell separation techniques, such as cell sorting and laser-capture microdissection, can enrich samples for cell types of interest, but are costly, labor intensive and can limit investigation of important interactions between different cell types. Results: We developed a new computational approach, called microarray microdissection with analysis of differences (MMAD), which performs microdissection in silico. Notably, MMAD (i) allows for simultaneous estimation of cell fractions and gene expression profiles of contributing cell types, (ii) adjusts for microarray normalization bias, (iii) uses the corrected Akaike information criterion during model optimization to minimize overfitting and (iv) provides mechanisms for comparing gene expression and cell fractions between samples in different classes. Computational microdissection of simulated and experimental tissue mixture datasets showed tight correlations between predicted and measured gene expression of pure tissues as well as tight correlations between reported and estimated cell fraction for each of the individual cell types. In simulation studies, MMAD showed superior ability to detect differentially expressed genes in mixed tissue samples when compared with standard metrics, including both significance analysis of microarrays and cell type-specific significance analysis of microarrays. Conclusions: We have developed a new computational tool called MMAD, which is capable of performing robust tissue microdissection in silico, and which can improve the detection of differentially expressed genes. MMAD software as implemented in MATLAB is publically available for download at http://sourceforge.net/projects/mmad/. Contact: david.liebner@gmail.com Supplementary Information: Supplementary data are available at Bioinformatics online.

Purpose We performed a phase 1 study to determine the maximum tolerable dose and safety of ipilimumab with stereotactic radiosurgery (SRS) or whole brain radiation therapy (WBRT) in patients with brain metastases from melanoma. Methods and Materials Based on the intracranial disease burden, patients underwent WBRT (arm A) or SRS (arm B). The ipilimumab starting dose was 3 mg/kg every 3 weeks, starting on day 3 of WBRT or 2 days after SRS. The ipilimumab dose was escalated to 10 mg/kg using a 2-stage, 3+3 design. The primary endpoint was to determine the maximum tolerable dose of ipilimumab combined with radiation therapy. The secondary endpoints were overall survival, intracranial and extracranial control, progression-free survival, and toxicity. The ClinicalTrials.gov registration number is NCT01703507 . Results The characteristics of the 16 patients enrolled between 2011 and 2014 were mean age, 60 years; median number of brain metastases, 2 (range 1->10); and number with EC disease, 13 (81%). Treatment included WBRT (n=5), SRS (n=11), and ipilimumab 3 mg/kg (n=7) or 10 mg/kg (n=9). The median follow-up was 8 months (arm A) and 10.5 months (arm B). A total of 21 grade 1 to 2 neurotoxic effects occurred, with no dose-limiting toxicities. One patient experienced grade 3 neurotoxicity before ipilimumab administration. Ten additional grade 3 toxicities were reported, with gastrointestinal toxicities (n=5; 31%) the most common. No patient developed grade 4 or 5 toxicity. The median progression-free survival and overall survival in arm A was 2.5 months and 8 months and in arm B was 2.1 months and not reached, respectively. Conclusions Concurrent ipilimumab 10 mg/kg with SRS is safe. The WBRT arm was closed early because of slow accrual but demonstrated safety with ipilimumab 3 mg/kg. No patient experienced dose-limiting toxicity. Larger studies, including those with combination checkpoint inhibitor therapy and SRS, are warranted.

Chemotherapy has been used as a single-modality treatment or as part of combined-modality therapy in metastatic or locally advanced thyroid cancer when other conventional treatments (e.g., surgery and radiation therapy) have failed. Recent developments in the understanding of the molecular pathogenesis of thyroid cancer have allowed for more targeted investigations, but cytotoxic chemotherapy remains an important part of the armamentarium, particularly for anaplastic and relatively undifferentiated thyroid cancers. Numerous reports on the use of chemotherapy in a variety of thyroid cancers have been published, but only a few controlled clinical trials compare the efficacy of different drug regimens. We outline both conventional cytotoxic chemotherapeutic agents and novel targeted agents below.

Anaplastic thyroid cancers (ATC) account for roughly 2.2 % of all thyroid cancers in the USA (Hossain et al. J Clin Oncol 28(15s):abstr 5588, 2010) and are believed to arise from differentiated thyroid cancers (DTC) via the accumulation of genetic abnormalities that result in dedifferentiation and an aggressive phenotype (Wiseman et al. J Clin Oncol 24(18s):abstr 5556, 2006). Unfortunately, ATC is usually advanced at the time of diagnosis, with approximately 76–79 % of all patients having disease extending beyond the thyroid/neck at the time of presentation (Hossain et al. J Clin Oncol 28(15s):abstr 5588, 2010; Chen et al. Am J Clin Oncol 31(5):460–4, 2008). In the vast majority of patients, surgery alone has been associated with poor outcomes, leading to investigation into additional therapeutic options.

Medullary thyroid cancer is a malignancy of the parafollicular thyroid C cells, accounting for 2–8 % of all thyroid cancers Early detection and surgery offer the only possibility of cure, and patients with localized disease are typically treated with surgical resection with or without adjuvant external beam radiation therapy. However, despite aggressive surgical therapy, nearly 50 % of patients with a palpable neck mass who are diagnosed with localized medullary thyroid cancer will subsequently recur. In patients with unresectable disease, the clinical course is often protracted. Chemotherapeutic options for the patient with unresectable or metastatic disease are discussed below.

Molecular studies have led to an increased appreciation for the heterogeneity of thyroid neoplasms, and recent work has outlined the importance of hereditary predisposition, somatic mutation, epigenetic modulation, and tumor microenvironment and their contributions to tumor histology, clinical presentation, and prognosis. Preclinical data has supported the role of several new targets in the advanced thyroid cancer, which are summarized in Table 105.1. Clinical trials in advanced thyroid cancer are outlined in Table 105.2. Selected targets are discussed below.

e23570Background: Endoglin (CD105) is an essential angiogenic receptor expressed on Angiosarcoma (AS) tumor cells and vessels that is upregulated following hypoxia and promotes resistance to VEGF i...