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Correctly diagnosing a rare childhood cancer such as sarcoma can be critical to assigning the correct treatment regimen. With a finite number of pathologists worldwide specializing in pediatric/young adult sarcoma histopathology, access to expert differential diagnosis early in case assessment is limited for many global regions. The lack of highly-trained sarcoma pathologists is especially pronounced in low to middle-income countries, where pathology expertise may be limited despite a similar rate of sarcoma incidence. To address this issue in part, we developed a deep learning convolutional neural network (CNN)-based differential diagnosis system to act as a pre-pathologist screening tool that quantifies diagnosis likelihood amongst trained soft-tissue sarcoma subtypes based on whole histopathology tissue slides. The CNN model is trained on a cohort of 424 centrally-reviewed histopathology tissue slides of alveolar rhabdomyosarcoma, embryonal rhabdomyosarcoma and clear-cell sarcoma tumors, all initially diagnosed at the originating institution and subsequently validated by central review. This CNN model was able to accurately classify the withheld testing cohort with resulting receiver operating characteristic (ROC) area under curve (AUC) values above 0.889 for all tested sarcoma subtypes. We subsequently used the CNN model to classify an externally-sourced cohort of human alveolar and embryonal rhabdomyosarcoma samples and a cohort of 318 histopathology tissue sections from genetically engineered mouse models of rhabdomyosarcoma. Finally, we investigated the overall robustness of the trained CNN model with respect to histopathological variations such as anaplasia, and classification outcomes on histopathology slides from untrained disease models. Overall positive results from our validation studies coupled with the limited worldwide availability of sarcoma pathology expertise suggests the potential of machine learning to assist local pathologists in quickly narrowing the differential diagnosis of sarcoma subtype in children, adolescents, and young adults.

Background: Dedifferentiated chondrosarcoma (DDCS) is a rare subset of chondrosarcoma. It is an aggressive neoplasm characterized by a high rate of recurrent and metastatic disease with overall poor outcomes. Systemic therapy is often used to treat DDCS; however, the optimal regimen and timing are not well defined, with current guidelines recommending following osteosarcoma protocols. Methods: We conducted a multi-institutional retrospective analysis of clinical characteristics and outcomes of patients with DDCS. Between 1 January 2004 and 1 January 2022, the databases from five academic sarcoma centers were reviewed. Patient and tumor factors, including age, sex, tumor size, site, location, the treatments rendered, and survival outcomes, were collected. Results: Seventy-four patients were identified and included in the analysis. Most patients presented with localized disease. Surgical resection was the mainstay of therapy. Chemotherapy was used predominantly in the metastatic setting. Partial responses were low (n = 4; 9%) and occurred upon treatment with doxorubicin with cisplatin or ifosfamide and single-agent pembrolizumab. For all other regimens, stable disease was the best response. Prolonged stable disease occurred with the use of pazopanib and immune checkpoint inhibitors. Conclusions: DDCS has poor outcomes and conventional chemotherapy has limited benefit. Future studies should focus on defining the possible role of molecularly targeted therapies and immunotherapy in the treatment of DDCS.

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

Background: In ultra-rare sarcomas (URS) the conduction of prospective, randomized trials is challenging. Data from retrospective observational studies (ROS) may represent the best evidence available. ROS implicit limitations led to poor acceptance by the scientific community and regulatory authorities. In this context, an expert panel from the Connective Tissue Oncology Society (CTOS), agreed on the need to establish a set of minimum requirements for conducting high-quality ROS on the activity of systemic therapies in URS. Methods: Representatives from > 25 worldwide sarcoma reference centres met in November 2020 and identified a list of topics summarizing the main issues encountered in ROS on URS. An online survey on these topics was distributed to the panel; results were summarized by descriptive statistics and discussed during a second meeting (November 2021). Results: Topics identified by the panel included the use of ROS results as external control data, the criteria for contributing centers selection, modalities for ensuring a correct pathological diagnosis and radiologic assessment, consistency of surveillance policies across centers, study end-points, risk of data duplication, results publication. Based on the answers to the survey (55 of 62 invited experts) and discussion the panel agreed on 18 statements summarizing principles of recommended practice. Conclusions: These recommendations will be disseminated by CTOS across the sarcoma community and incorporated in future ROS on URS, to maximize their quality and favor their use as control data when results from prospective studies are unavailable. These recommendations could help the optimal conduction of ROS also in other rare tumors.

BackgroundOX40 is a costimulatory receptor upregulated on antigen-activated T cells and constitutively expressed on regulatory T cells (Tregs). INCAGN01949, a fully human immunoglobulin G1κ anti-OX40 agonist monoclonal antibody, was designed to promote tumor-specific immunity by effector T-cell activation and Fcγ receptor-mediated Treg depletion. This first-in-human study was conducted to determine the safety, tolerability, and preliminary efficacy of INCAGN01949.MethodsPhase I/II, open-label, non-randomized, dose-escalation and dose-expansion study conducted in patients with advanced or metastatic solid tumors. Patients received INCAGN01949 monotherapy (7–1400 mg) in 14-day cycles while deriving benefit. Safety measures, clinical activity, pharmacokinetics, and pharmacodynamic effects were assessed and summarized with descriptive statistics.ResultsEighty-seven patients were enrolled; most common tumor types were colorectal (17.2%), ovarian (8.0%), and non-small cell lung (6.9%) cancers. Patients received a median three (range 1–9) prior therapies, including immunotherapy in 24 patients (27.6%). Maximum tolerated dose was not reached; one patient (1.1%) receiving 350 mg dose reported dose-limiting toxicity of grade 3 colitis. Treatment-related adverse events were reported in 45 patients (51.7%), with fatigue (16 (18.4%)), rash (6 (6.9%)), and diarrhea (6 (6.9%)) being most frequent. One patient (1.1%) with metastatic gallbladder cancer achieved a partial response (duration of 6.3 months), and 23 patients (26.4%) achieved stable disease (lasting >6 months in one patient). OX40 receptor occupancy was maintained over 90% among all patients receiving doses of ≥200 mg, while no treatment-emergent antidrug antibodies were detected across all dose levels. Pharmacodynamic results demonstrated that treatment with INCAGN01949 did not enhance proliferation or activation of T cells in peripheral blood or reduce circulating Tregs, and analyses of tumor biopsies did not demonstrate any consistent increase in effector T-cell infiltration or function, or decrease in infiltrating Tregs.ConclusionNo safety concerns were observed with INCAGN01949 monotherapy in patients with metastatic or advanced solid tumors. However, tumor responses and pharmacodynamic effects on T cells in peripheral blood and post-therapy tumor biopsies were limited. Studies evaluating INCAGN01949 in combination with other therapies are needed to further evaluate the potential of OX40 agonism as a therapeutic approach in patients with advanced solid tumors.Trial registration numberNCT02923349.

Highlights • Cutaneous angiosarcoma has poor outcomes with no standardized treatment regimen. • Paclitaxel-based chemoRT (CRT) was compared to other therapies at two US institutions. • Similar oncologic outcomes and improved survival with paclitaxel CRT. • Paclitaxel CRT + surgery provided best oncologic outcomes and survival. • Paclitaxel CRT + surgery regimen now being studied in a prospective phase II trial., Introduction We compared clinical outcomes in patients with cutaneous angiosarcoma receiving concurrent paclitaxel-based chemoradiotherapy (CRT) vs. other modalities (Non-CRT). Materials and methods Patients with non-metastatic cutaneous angiosarcoma diagnosed from 1998 to 2018 at two institutions were identified. In the CRT cohort, paclitaxel 80 mg/m2 weekly was given for up to 12 weeks and patients received radiotherapy (RT) during the final 6 weeks of chemotherapy. The RT dose was 50–50.4 Gy delivered in 1.8–2 Gy per fraction with an optional post-operative boost of 10–16 Gy. Kaplan-Meier and log-rank statistics were used to compare the outcomes between the two groups. P 60 years (100% vs. 60%, p 5 cm (68.2% vs 54.3%, p = 0.023). The median follow-up was 25.8 (1.5–155.2) months. There was no significant difference in 2-year local control (LC), distant control (DC), or progression-free survival (PFS) between the two groups. The 2-year overall survival (OS) was significantly higher for the CRT cohort (94.1% vs. 71.6%, p = 0.033). Amongst the subset of patients in the CRT cohort who received trimodality therapy, the 2-year LC, DC, PFS, and OS was 68.6%, 100%, 68.6%, and 100%, respectively. Conclusion The use of concurrent paclitaxel CRT demonstrates promising outcomes. Given these results, we are currently evaluating the safety and efficacy of this regimen in prospective, phase 2 trial (NCT 03921008).

Plant-soil feedbacks may determine the long-term success of introduced species. Here we examined plant-soil feedbacks of a globally invasive shrub, Cytisus scoparius (hereafter Cytisus), which associates with multiple guilds of microbial mutualists and dominates harvested Douglas-fir forests in the Pacific Northwest. We studied Cytisus root nodulation, mycorrhizal colonization, and growth in two greenhouse experiments. First, we compared invaded to uninvaded field soils. Then we did a soil conditioning experiment with Cytisus (in both invaded and uninvaded field soil) compared to soil conditioned by Douglas-fir. Cytisus grown in invaded soils had 67% more root nodules and 72% more AMF colonization than uninvaded soil. Conditioning uninvaded soil with Cytisus increased root nodules by 14% and mycorrhizal colonization by 55%, compared to Douglas-fir conditioned soil. Despite the increased abundance of mutualists, Cytisus grown in Cytisus-conditioned soils were 41% smaller than in uninvaded soil. Cytisus increased the abundance of its microbial mutualists in soils, but overall plant-soil feedback was still negative, likely driven by soilborne pathogens, nutrient depletion, and/ or reduced benefits of mutualists. Our results do not support the idea that the high densities reached by Cytisus in its invaded range are caused by positive plant-soil feedbacks.

Background Greater than one-half of patients with melanoma who are treated with antibodies blocking programmed cell death protein 1 receptor (anti-PD-1) experience disease progression. The objective of the current study was to identify prognostic factors and outcomes in patients with metastatic melanoma that progressed while they were receiving anti-PD-1 therapy. Methods The authors evaluated 383 consecutively treated patients who received anti-PD-1 for advanced melanoma between 2009 and 2019. Patient and disease characteristics at baseline and at the time of progression, subsequent therapies, objective response rate (ORR), overall survival, and progression-free survival were assessed. Results Of 383 patients, 247 experienced disease progression. The median survival after progression was 6.8 months. There was no difference in survival noted after disease progression based on primary tumor subtype, receipt of prior therapy, or therapy type. However, significantly improved survival after disease progression correlated with clinical features at the time of progression, including normal lactate dehydrogenase, more favorable metastatic stage (American Joint Committee on Cancer eighth edition stage IV M1a vs M1b, M1c, or M1d), mutation status (NRAS or treatment-naive BRAF V600 vs BRAF/NRAS wild-type or treatment-experienced BRAF-mutant), decreasing tumor bulk, and progression at solely existing lesions. After progression, approximately 54.3% of patients received additional systemic therapy. A total of 41 patients received BRAF/MEK inhibition (ORR of 58.6%, including 70.4% for BRAF/MEK-naive patients), 30 patients received ipilimumab (ORR of 0%), and 11 patients received ipilimumab plus nivolumab (ORR of 27.3%). Conclusions The current study identified prognostic factors in advanced melanoma for patients who experienced disease progression while receiving anti-PD-1, including lactate dehydrogenase, stage of disease, site of disease progression, tumor size, and mutation status.

Background: Perivascular epithelioid cell neoplasms (PEComas) are a diverse family of mesenchymal tumors with myomelanocytic differentiation that disproportionately affect women and can be associated with tuberous sclerosis (TS). Although mTOR inhibition is widely used as first-line treatment, it is unclear what genomic alterations exist in these tumors and how they influence the response to therapy. Methods: This was a multicenter study conducted at five sites within the US. The data were collected from 1 January 2004 to 31 January 2021. We conducted a retrospective analysis to identify PEComa patients with next-generation sequencing (NGS) data and compared outcomes based on mutations. Results: No significant differences in survival were identified between TSC-1 and TSC-2 mutated PEComa or TSC-1/-2 versus other mutations. No significant difference was seen in progression-free survival (PFS) after first-line therapy between mTOR inhibition versus other systemic therapies. Conclusions: We were unable to detect differences in survival based on genomic alterations or PFS between mTOR inhibition versus other systemic therapies. Future studies should seek to identify other drivers of TSC-1/-2 silencing that could predict response to mTOR inhibition.

Background: Patients with sarcoma often require individualized treatment strategies and are likely to receive aggressive immunosuppressive therapies, which may place them at higher risk for severe COVID-19. We aimed to describe demographics, risk factors, and outcomes for patients with sarcoma and COVID-19. Methods: We performed a retrospective cohort study of patients with sarcoma and COVID-19 reported to the COVID-19 and Cancer Consortium (CCC19) registry (NCT04354701) from 17 March 2020 to 30 September 2021. Demographics, sarcoma histologic type, treatments, and COVID-19 outcomes were analyzed. Results: of 281 patients, 49% (n = 139) were hospitalized, 33% (n = 93) received supplemental oxygen, 11% (n = 31) were admitted to the ICU, and 6% (n = 16) received mechanical ventilation. A total of 23 (8%) died within 30 days of COVID-19 diagnosis and 44 (16%) died overall at the time of analysis. When evaluated by sarcoma subtype, patients with bone sarcoma and COVID-19 had a higher mortality rate than patients from a matched SEER cohort (13.5% vs 4.4%). Older age, poor performance status, recent systemic anti-cancer therapy, and lung metastases all contributed to higher COVID-19 severity. Conclusions: Patients with sarcoma have high rates of severe COVID-19 and those with bone sarcoma may have the greatest risk of death.

Opinion statementLeiomyosarcoma is one of the most common subtypes of soft tissue sarcomas accounting for approximately 20% of sarcomas. As leiomyosarcoma patients frequently develop metastatic disease, effective systemic therapies are needed to improve clinical outcomes. The overall activity of the currently available conventional systemic therapies and the prognosis of patients with advanced and/or metastatic disease are poor. As such, the treatment of this patient population remains challenging. As a result, there is a clear unmet medical need, and designing and performing meaningful clinical studies are of utmost importance to improve the prognosis of this patient group. Therefore, the aim of this review is to briefly summarize state-of-the-art treatments for leiomyosarcoma patients and to describe trial characteristics needed for informative clinical studies.

BACKGROUND Anti-programmed death protein 1 (anti-PD-1) agents have transformed the treatment of advanced melanoma and other cancers, but the rates of steroid-refractory toxicities and health care utilization are not well described. This study assessed these endpoints in patients with melanoma treated with anti-PD-1 with or without ipilimumab. METHODS This study retrospectively evaluated 344 patients with metastatic melanoma treated with anti-PD-1 or a combination of ipilimumab and nivolumab at Vanderbilt University Medical Center from 2009 to 2018. The incidence, types, grades, management, and outcomes of immune-related adverse events (irAEs) and hospitalizations for irAEs and disease progression were assessed. RESULTS Patients on combination therapy were more likely to develop irAEs than those on monotherapy (72% vs 37%; P

Cytotoxic chemotherapy has been the backbone of medical oncology for nearly a century for multiple cancer types. However, when treating advanced or metastatic disease toxicity, side effects, and acquired resistance often limit the duration of therapy. While randomized control trials have traditionally served as the proving ground for first and subsequent line therapies, rare tumor subtypes including soft tumor sarcoma (STS) provide unique challenges for developing robust treatment data. By developing human based in vitro models, we can investigate potential therapeutic mechanisms for STS. Fibrosarcoma is one distinct histologic STS subtype that relies heavily on anthracycline treatment in the first line setting, however, there are limited options once resistance develops. Anthracyclines, including doxorubicin, exert their effect through a variety of mechanisms including reactive oxygen species, DNA-adduct formation, and inhibiting topoisomerase II, histone eviction, calcium and iron homeostasis, and ceramide overproduction. However, there have also been multiple mechanisms of doxorubicin resistance including disruption of cell membrane, alteration of cell surface molecules, inactivation of drugs, gene amplification, activating alternative signaling pathways, and affecting cellular repair mechanisms. In order to investigate the role of anthracycline resistance in fibrosarcoma lines we acquired two human derived fibrosarcoma lines SW684 and HT-1080 from American Type Culture Collection (ATCC). Characterization of HT-1080 using publicly available datasets demonstrated that TP53, CDK2NA and NF1 serve as major driver mutations while SW684 relies on NRAS and IDH1 mutations. We further characterized these cell lines in vitro and noted that HT-1080 has a quick doubling time of 16 hours while SW684 has a doubling time of 91 hours. Additionally, after doxorubicin treatment, we found that HT-1080 is sensitive with an IC50 of 5.594 nanomolar while SW684 is relatively doxorubicin resistant with an IC50 of 28.915 micromolar. While proliferative rate may play a role in the sensitivities of these cell lines further characterization of the mechanism leading to doxorubicin resistance is needed. To that end, we are using a CRISPR-Cas9 approach for further genome wide screening of these fibrosarcoma lines in the presence of doxorubicin. Exploring the genetic mechanisms that result in development of doxorubicin resistance may reveal novel, targetable mechanisms expanding treatment durability in this rare STS. Citation Format: Rodney Dixon Dorand, Donna Dang, Elizabeth J. Davis, Ben Ho Park. Investigating doxorubicin resistance in fibrosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3974.

3012 Background: Ataxia telangiectasia and Rad3 related (ATR) is activated in response to replication stress from topoisomerase 1 inhibitors. Selective ATR inhibition with berzosertib potentiates the efficacy of irinotecan in colorectal mouse xenograft models. We hypothesized that berzosertib in combination with irinotecan is well tolerated, modulates the DNA damage repair response to irinotecan, and the combination is associated with clinical activity. Methods: This phase I study utilized a modified Storer’s up and down dose escalation design. Dose Levels (DLs) combined berzosertib 60 to 270 mg/m2 with irinotecan 180 mg/m2, every 2 weeks in a 4-week cycle. The primary endpoint was identification of the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Activity, pharmacokinetics (PK), and pharmacodynamics (PD) were secondary endpoints. The identification of molecular subpopulations sensitized to the combination was exploratory. Results: Between July 2016 and July 2021, 51 patients (pts) enrolled, of whom 50 received treatment. Pts most commonly had colorectal cancer (CRC, 39%), pancreatic cancer (24%), small cell lung cancer (SCLC, 6%) and non-small cell lung cancer (6%). The median number of prior lines of therapy was 4 (range, 2 to 11). In Stage I, 1 of 3 evaluable pts experienced dose-limiting toxicity (DLT) of grade 3 lung infection at DL3 (berzosertib 180 mg/m2 - irinotecan 180 mg/m2), and Stage II was initiated enrolling cohorts of 5 pts. In Stage II, 4 of the first 11 pts treated at DL4 (berzosertib 270 mg/m2 - irinotecan 180 mg/m2) were unable to complete the DLT evaluation period due to clinically significant toxicity not meeting DLT criteria: grade 2 diarrhea (1 pt), grade 3 diarrhea (1 pt), and grade 3 neutrophil decrease (2 pts). The protocol was amended to limit dose escalation beyond DL4. At DL4, 1 of 21 evaluable pts experienced DLT (grade 4 febrile neutropenia). Most common treatment-related grade ≥ 3 toxicities were neutrophil decrease (34%), lymphocyte decrease (30%), WBC decrease (28%), anemia (20%), diarrhea (16%), fatigue (8%) and hypokalemia (8%). 2 partial responses were observed, occurring in pts with pancreatic cancer and ATM alterations: 32% decrease in an ATM E11828/ATM K1109* tumor lasting 15.3 months and 68% decrease in an ATM R3008H/germline ATM R1882* tumor ongoing at 11 months. An additional pt with ATM S214fs*40 mutant colorectal cancer (CRC) experienced a 26% decrease lasting 7.5 months. Conclusions: Berzosertib 270 mg/m2 - irinotecan 180 mg/m2 was declared the RP2D. The combination is associated with manageable side effects and promising disease activity in ATM mutant solid tumors. PK and PD studies are in process. Tumor biopsy studies are planned in a 15 pt dose expansion cohort at DL4, enrolling pts with CRC, pancreatic cancer, SCLC and DNA damage repair deficient tumors. Clinical trial information: NCT02595931.

11581 Background: Desmoid tumors (DT) or aggressive fibromatosis are rare growths of fibroblastic connective tissue that can be locally aggressive but without metastatic potential. Most cases are sporadic, but 5-20% of cases are associated with Familial adenomatous polyposis (FAP). Despite numerous systemic options, optimal choice is unclear, and there is a paucity of studies comparing efficacy based on tumor site. Liposomal doxorubicin (LD) can be an appealing option for DT patients (pts) given its favorable schedule and toxicity profile. In this study, we compared outcomes in pts with intra-abdominal (IA) and extra-abdominal (EA) DT who received LD. Methods: We identified pts with DT who were treated with LD between 1/2010 - and 2/2022 at two sarcoma centers. Tumor and pt characteristics and outcomes were clinically (symptom improvement) and radiologically (RECIST 1.1) assessed. Results: 40 pts with DT treated with LD were identified; 58% female and 42% male. Pt characteristics and outcomes are summarized in Table 1. Primary tumor site was IA in 21 (53%) pts. FAP was present more commonly in pts with IA vs EA DT, 8/21 (43%) and 4/19 (21%), respectively. In the IA cohort, LD was given as first (15/21, 71%), second (10%) or third (19%) line therapy. LD was used more commonly as a later line in the EA cohort with 16%, 52%, 16%, and 16% receiving it in first, second, third, and fourth lines, respectively. 37 pts were evaluable for response. Response rate in the IA cohort treated in first-line was 50% (8 of 16) and 10 of 12 evaluable pts had symptomatic improvement. No first-line responses were seen in the EA cohort. As later lines of therapy, 7/12 pts had disease control in the second line, 6/8 pts in the third line, and 1/2 pts in the fourth line with LD in the IA cohort. 1 patient had fourth line response to LD in the EA cohort. Disease control rate with LD was 72.5% across all pts. Reasons for early discontinuation of LD included progression or lack of symptom improvement (20%), allergic reaction (12.5%), adverse effects (7.5%), or infection (2.5%). No acute or long-term cardiotoxicity was reported. 2 pts had no signs of recurrence or symptoms at follow-up, 33 pts were alive with symptomatic DT, 1 patient died from disease, and 3 were lost to follow-up. Conclusions: In our study, LD provided tumor response, disease control, and symptomatic improvement regardless of location or prior therapy, with responses most frequently seen in IA DT in first line setting. Further studies should include comparison of efficacy, adverse effects, and patient-reported outcomes while accounting for tumor location and line of therapy. [Table: see text]

TPS11595 Background: CCS of the soft tissues is a rare and aggressive subtype of sarcoma that often starts in the tendons of the arms or legs. It is molecularly characterized by t(12;22)(q13;q12) translocation, resulting in EWSR1-ATF1 or EWSR1-CREB1 gene fusion. Despite reports of occasional responses to systemic therapies, currently available therapies have shown limited efficacy in advanced CCS. Therefore, there is a significant unmet medical need for more active agents in CCS. Devimistat is a stable intermediate of a lipoate analog that inhibits pyruvate dehydrogenase and α-ketoglutarate dehydrogenase enzymes of the tricarboxylic acid (TCA) cycle preferentially within the mitochondria of cancer cells. Devimistat induces autophagy in cancer cells. In a metastatic mouse model of CCS, treatment with devimistat in combination with chloroquine significantly suppressed tumor growth (Egawa et al, 2018). Based on this data, we hypothesized that inhibition of autophagy with HCQ may sensitize cancer cells to devimistat with increased efficacy and acceptable toxicity. Given its expected synergy, we have initiated a single-arm phase I/II prospective, multicenter, open-label, non-randomized study to evaluate maximally tolerated dose (MTD), safety, and efficacy of devimistat in combination with HCQ in patients with R/R CCS. Methods: In the phase 1 portion of the study, patients with R/R CCS and other fusion-positive R/R sarcomas will be enrolled and a standard 3+3 design will be followed to evaluate toxicity, MTD, and recommended phase 2 dose. There will be two patient groups based on weight, and dose escalation will be conducted separately for each group. Starting dose of HCQ will be 5mg/kg PO BID for patients < 45 kg and 200 mg PO BID for patients ≥45 kg on days 1 through 5 of every 28 days. The first dose of HCQ each day will be followed 2 hours later by 1,000 mg/m2 devimistat (for patients < 45 kg) and 2,000 mg/m2 of devimistat (for patients ≥ 45 kg) administered over 2 hours. A maximum of 36 patients will be enrolled for the phase I portion, 18 for each patient group. In the phase 2 portion of the study, only relapsed or refractory CCS patients will be enrolled, and the response rate will be determined using RECIST 1.1. In phase 2, pharmacokinetics, duration of response, clinical benefit rate, progression-free survival, overall survival, safety, and patient-reported outcomes will also be assessed. This portion of the study will utilize Simon’s admissible two-stage design with 29 patients. This study started enrolling participants in November 2021 and has dosed six patients to date. The first two dose-escalation cohorts for patients ≥45 kg have been completed without DLT and the third dose level will be opening shortly. Clinical trial information: NCT04593758.

10511 Background: Sarcomas are rare and diverse malignancies with a subset developing in the context of heritable cancer predisposition syndromes. Data surrounding the frequency of inheritance and patient/genomic findings are limited. We aimed to describe the characteristics of patients with sarcoma referred for clinical genetic testing and to determine the prevalence of pathogenic/likely pathogenic germline variants (PGV/LPGV). Methods: We performed retrospective chart reviews of patients with sarcoma referred to Michigan Medicine Cancer Genetics Clinic between 12/2006 and 1/2020 and Vanderbilt Hereditary Cancer Clinic between 1/2005 and 1/2019. Reviewers obtained medical/family history, cancer phenotype, and results of germline genetic testing. Descriptive analyses were performed to assess the prevalence of germline variants classified as pathogenic/likely pathogenic according to American College of Medical Genetics criteria. Associations with clinical factors were tested for using Fisher’s exact test or Wilcoxon rank-sum test. Results: One-hundred sixteen patients with sarcoma underwent genetic evaluation during a 15-year period. Mean age at time of visit was 46 years (SD, 17.6 years; range, 1-80 years). Sixty-nine patients (59%) were female. The most common reasons for referral were personal history of multiple malignancies (n = 69, 59.4%), first degree relative (FDR) with malignancy (n = 67, 57.7%) and young age at diagnosis (age ≤ 18, n = 18, 15.5%). Forty-eight patients (41.4%) had both a history of multiple malignancies and a FDR with a malignancy. Eight patients had a FDR with sarcoma (6.9%). Of the 110 patients who underwent germline testing, 53 patients (48.2%) had a PGV/LPGV. Identified germline variants and frequencies are listed in the Table. There was no statistical significance between young age at diagnosis, history of personal malignancies, FDR with sarcoma, FDR with one or more malignancies, or multiple FDRs with malignancy and presence of a PGV/LPGV. Conclusions: In this multicenter study, approximately half of patients with sarcoma referred for cancer genetic testing had a PGV/LPGV associated with hereditary predisposition to cancer. There was no identified positive predictive factor for germline variants. Though TP53 was the most common, over 20 genetic variants were identified, supporting the consideration of multigene panel testing. Our study is limited to patients who were both referred to and attended genetic evaluation. Yet, the high frequency of pathogenic germline variants observed highlights the necessity for further investigation of the prevalence of and predictive factors for germline mutations in all sarcoma patients. Identified germline variants. [Table: see text]

e23500 Background: Sarcomas are a rare and heterogenous group of malignancies comprised of > 150 histologic subtypes. Adamantinoma-like Ewing sarcoma (ALES) is a rare, small round blue cell tumor that represents a variant of Ewing sarcoma (EWS). First described 20 years ago, ALES harbors a EWS subset defining EWS-related translocation; however, ALES has a complex epithelial differentiation component defining it as a distinct clinical entity. Most ALES cases arise in the head and neck, but it has also been reported in the extremities and thorax. Given the rarity of ALES, there is a paucity of literature to guide treatment and describe outcomes. Methods: We performed a retrospective review (January 1, 2010-January 1, 2022) at two sarcoma centers in the United States and identified 4 cases of ALES. Tumor and patient characteristics were described, and patient outcomes were assessed. Results: Four patients were identified. 3 (75%) were male. Median age at diagnosis was 37 years (range 23-57). Primary site of ALES was head and neck (50%) and thorax (50%). Median tumor size was 4 cm (2.7-5.5 cm). All patients underwent resection of their primary tumor, and two (50%)received adjuvant radiation therapy. All pts received/are receiving adjuvant chemotherapy. 75% of patients were treated with Vincristine, Doxorubicin, and Cyclophosphane (VDC) alternating with Ifosfamide & Etoposide (IE) for 12-14 cycles. One patient received 4 cycles of adjuvant carboplatin and etoposide and radiation after an initial diagnosis of basaloid carcinoma but recurred 47 months later and diagnosed at ALES at that time. That patient underwent re-resection followed by adjuvant chemotherapy with Vincristine, Doxorubicin, and Ifosfamide (VAI). Median follow-up from initial diagnosis was 25 months (3-39 months). All patients are alive with no evidence of disease. Conclusions: Similar to treatment of EWS, a multidisciplinary strategy is paramount. VDC/IE is a reasonable treatment strategy. Further multicenter collaboration is essential to define clinical characterization of this rare sarcoma subtype and to guide treatment particularly in the relapsed or refractory setting.[Table: see text]

e23562 Background: Ifosfamide, an alkylating agent used commonly in both hematologic and solid tumor malignancies, carries a notable risk for neurotoxicity/encephalopathy. Ifosfamide is available as both a reconstituted powder formulation and a solution for injection. Literature has shown that there may be higher rates of ifosfamide neurotoxicity/encephalopathy (INT/E) with the solution compared to the reconstituted powder. The primary objective of this study was to compare the rates of neurotoxicity/encephalopathy in association with the two available pharmaceutical formulations of ifosfamide. Methods: We performed a retrospective study of adult patients receiving at least one dose of either available pharmaceutical formulation of ifosfamide. The primary outcome was the incidence of formulation-associated INT/E. Secondary outcomes included additional risk factors for development of INT/E. Results: Of 218 patients evaluated, 212 were included in the study with 56 patients receiving the reconstituted powder formulation and 156 patients receiving the solution for injection formulation of ifosfamide. Baseline characteristics were similar between the two groups, including dose of ifosfamide received, use of INT/E prophylaxis, and renal and hepatic function. INT/E occurred in 4 patients (7.1%) receiving the reconstituted powder formulation vs 32 patients (20.5%) receiving the solution for injection (p = 0.022) Evaluation and analysis of additional risk factors for development of INT/E are ongoing, including the impact of baseline demographics, ifosfamide dosing, renal and hepatic function, and concomitant medications. Conclusions: In this study, hematology/oncology patients who were treated with ifosfamide had significantly lower rates of INT/E with the reconstituted powder formulation compared to the solution for injection. Further analysis regarding additional risk factors for INT/E development is ongoing.[Table: see text]

11528 Background: Chondrosarcoma is one of the most common bone malignancies in adults, and the third most common in pediatric patients (pts). The most prevalent subtype, conventional chondrosarcoma, is a slow growing tumor that is historically known to be refractory to chemotherapy. Anecdotal reports indicated a role for anti-PD-(L)1 in the treatment of this disease. This is the first prospective report on the efficacy of the PD-L1-targeting agent, atezolizumab, in this rare disease. Methods: Patients (pts) ages 2 and older with unresectable grade 2 or 3 conventional chondrosarcoma were eligible. No prior anti-PD-(L)1 treatment was allowed, otherwise pts were eligible irrespective of prior therapies as long as protocol-specified washout period requirements were met. Pts received atezolizumab 1200 mg (15 mg/kg with 1200 mg cap in pediatric pts) once every 21 days. Imaging was carried out at end of cycle 3, and then every two cycles. Research biopsies were collected from adult pts prior to C1D1, prior to C3D1, and at progression. Immuno-pharmacodynamic (IO-PD) studies were performed on paired tumor samples and circulating immune cells to help elucidate signaling pathways mediating the immune response, with focus on subsets of effector cells in the tumor microenvironment. Results: A total of 9 pts (7 males, 2 females) were enrolled in 6 centers across the US and Canada. Six pts were Caucasian/White, 1 Asian, 1 Hispanic, and 1 unknown. Median age was 49 years (42-72). No objective responses were seen. Three pts (33%) experienced disease stability (SD) per RECIST 1.1, for a median duration of 21 weeks as of data cutoff (January 2022). A patient with SD remains on active treatment (tx) for 35 weeks. Three patients had no tx-related adverse events (AEs). Six pts (67%) experienced at least one tx-related AE. Two patients experienced > G2 AEs, but only one was considered tx-related (lymphopenia). Immune-related AEs were all G1/2 and included hepatitis (2), hypothyroidism (1), hyperthyroidism (1), and maculopapular rash (1). IO-PD studies are ongoing and will be reported at the conference if available. Conclusions: Atezolizumab was well-tolerated but demonstrated limited activity in this cohort of pts with few treatment options. Ongoing IO-PD studies will provide insight into atezolizumab’s effect upon immune cell content and activation in the tumor microenvironment that will help design future immunotherapy trials in this disease and other sarcoma types. The study was funded by NCI Contract HHSN261201500003I. Clinical trial information: NCT04458922.

BACKGROUND: Over the past two decades, studies have demonstrated that lung ultrasound is useful in diagnosing alveolar interstitial syndrome, which is seen in patients with decompensated congestive heart failure (CHF). METHODS: We studied medical students performing lung ultrasound on patients admitted to the hospital with a presumed diagnosis of decompensated CHF in a prospective convenience observation study. Two ultrasound fellowship–trained emergency medicine attendings independently reviewed the lung ultrasounds at a later date, blinded to the students’ interpretation and other clinical information, to confirm ultrasound findings and assess for inter‐rater reliability of the lung ultrasound using intraclass correlation coefficients (ICCs). RESULTS: Thirty‐six patients were enrolled in the study resulting in 653 unique lung zones scanned. The zones were imaged and classified as being normal (B‐lines < 3) or pathologic (B‐lines ≥ 3). The novice scanners’ interpretation was compared to expert reviews using ICCs. The ICC was 0.88, with a 95% confidence interval of 0.87 to 0.90, for all lung zones scanned. CONCLUSION: There was almost perfect agreement between novice practitioners and experts when determining the presence of pathologic B‐lines in individual patients.

High-dose interleukin-2 (HD IL-2) was approved in the 1990s after demonstrating durable complete responses (CRs) in some patients with metastatic melanoma (mM) and metastatic renal cell carcinoma (mRCC). Patients who achieve this level of disease control have also demonstrated improved survival compared with patients who progress, but limited data are available describing the long-term course. The aim of this study was to better characterize long-term survival following successful HD IL-2 treatment in patients with no subsequent systemic therapy. Eleven HD IL-2 treatment centers identified patients with survival ≥5 years after HD IL-2, with no subsequent systemic therapy. Survival was evaluated from the date of IL-2 treatment to June 2017. Treatment courses consisted of 2 1-week cycles of HD IL-2. Patients were treated with HD IL-2 alone, or HD IL-2 followed by local therapy to achieve maximal response. 100 patients are reported: 54 patients with mM and 46 patients with mRCC. Progression-free survival (PFS) after HD IL-2 ranges from 5+ years to 30+ years, with a median follow-up of 10+ years. 27 mRCC and 32 mM are alive ≥10 years after IL-2. Thus, a small subset of patients with mM and mRCC achieve long-term PFS (≥5 years) after treatment with HD IL-2 as their only systemic therapy. The ability of HD IL-2 therapy to induce prolonged PFS should be a major consideration in studies of new immunotherapy combinations for mM and mRCC.

When the COVID-19 pandemic began, formal frameworks to collect data about affected patients were lacking. The COVID-19 and Cancer Consortium (CCC19) was formed to collect granular data on patients with cancer and COVID-19 at scale and as rapidly as possible. CCC19 has grown from five initial institutions to 125 institutions with >400 collaborators. More than 5,000 cases with complete baseline data have been accrued. Future directions include increased electronic health record integration for direct data ingestion, expansion to additional domestic and international sites, more intentional patient involvement, and granular analyses of still-unanswered questions related to cancer subtypes and treatments.

BACKGROUND: Older adults (aged ≥70 years) are at increased risk of severe disease and death if they develop COVID-19 and are therefore a priority for immunisation should an efficacious vaccine be developed. Immunogenicity of vaccines is often worse in older adults as a result of immunosenescence. We have reported the immunogenicity of a novel chimpanzee adenovirus-vectored vaccine, ChAdOx1 nCoV-19, in young adults, and now describe the safety and immunogenicity of this vaccine in a wider range of participants, including adults aged 70 years and older. METHODS: In this report of the phase 2 component of a single-blind, randomised, controlled, phase 2/3 trial (COV002), healthy adults aged 18 years and older were enrolled at two UK clinical research facilities, in an age-escalation manner, into 18-55 years, 56-69 years, and 70 years and older immunogenicity subgroups. Participants were eligible if they did not have severe or uncontrolled medical comorbidities or a high frailty score (if aged ≥65 years). First, participants were recruited to a low-dose cohort, and within each age group, participants were randomly assigned to receive either intramuscular ChAdOx1 nCoV-19 (2·2 × 1010 virus particles) or a control vaccine, MenACWY, using block randomisation and stratified by age and dose group and study site, using the following ratios: in the 18-55 years group, 1:1 to either two doses of ChAdOx1 nCoV-19 or two doses of MenACWY; in the 56-69 years group, 3:1:3:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY; and in the 70 years and older, 5:1:5:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY. Prime-booster regimens were given 28 days apart. Participants were then recruited to the standard-dose cohort (3·5-6·5 × 1010 virus particles of ChAdOx1 nCoV-19) and the same randomisation procedures were followed, except the 18-55 years group was assigned in a 5:1 ratio to two doses of ChAdOx1 nCoV-19 or two doses of MenACWY. Participants and investigators, but not staff administering the vaccine, were masked to vaccine allocation. The specific objectives of this report were to assess the safety and humoral and cellular immunogenicity of a single-dose and two-dose schedule in adults older than 55 years. Humoral responses at baseline and after each vaccination until 1 year after the booster were assessed using an in-house standardised ELISA, a multiplex immunoassay, and a live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) microneutralisation assay (MNA80). Cellular responses were assessed using an ex-vivo IFN-γ enzyme-linked immunospot assay. The coprimary outcomes of the trial were efficacy, as measured by the number of cases of symptomatic, virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were by group allocation in participants who received the vaccine. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. This study is ongoing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137. FINDINGS: Between May 30 and Aug 8, 2020, 560 participants were enrolled: 160 aged 18-55 years (100 assigned to ChAdOx1 nCoV-19, 60 assigned to MenACWY), 160 aged 56-69 years (120 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY), and 240 aged 70 years and older (200 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY). Seven participants did not receive the boost dose of their assigned two-dose regimen, one participant received the incorrect vaccine, and three were excluded from immunogenicity analyses due to incorrectly labelled samples. 280 (50%) of 552 analysable participants were female. Local and systemic reactions were more common in participants given ChAdOx1 nCoV-19 than in those given the control vaccine, and similar in nature to those previously reported (injection-site pain, feeling feverish, muscle ache, headache), but were less common in older adults (aged ≥56 years) than younger adults. In those receiving two standard doses of ChAdOx1 nCoV-19, after the prime vaccination local reactions were reported in 43 (88%) of 49 participants in the 18-55 years group, 22 (73%) of 30 in the 56-69 years group, and 30 (61%) of 49 in the 70 years and older group, and systemic reactions in 42 (86%) participants in the 18-55 years group, 23 (77%) in the 56-69 years group, and 32 (65%) in the 70 years and older group. As of Oct 26, 2020, 13 serious adverse events occurred during the study period, none of which were considered to be related to either study vaccine. In participants who received two doses of vaccine, median anti-spike SARS-CoV-2 IgG responses 28 days after the boost dose were similar across the three age cohorts (standard-dose groups: 18-55 years, 20 713 arbitrary units [AU]/mL [IQR 13 898-33 550], n=39; 56-69 years, 16 170 AU/mL [10 233-40 353], n=26; and ≥70 years 17 561 AU/mL [9705-37 796], n=47; p=0·68). Neutralising antibody titres after a boost dose were similar across all age groups (median MNA80 at day 42 in the standard-dose groups: 18-55 years, 193 [IQR 113-238], n=39; 56-69 years, 144 [119-347], n=20; and ≥70 years, 161 [73-323], n=47; p=0·40). By 14 days after the boost dose, 208 (>99%) of 209 boosted participants had neutralising antibody responses. T-cell responses peaked at day 14 after a single standard dose of ChAdOx1 nCoV-19 (18-55 years: median 1187 spot-forming cells [SFCs] per million peripheral blood mononuclear cells [IQR 841-2428], n=24; 56-69 years: 797 SFCs [383-1817], n=29; and ≥70 years: 977 SFCs [458-1914], n=48). INTERPRETATION: ChAdOx1 nCoV-19 appears to be better tolerated in older adults than in younger adults and has similar immunogenicity across all age groups after a boost dose. Further assessment of the efficacy of this vaccine is warranted in all age groups and individuals with comorbidities. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca.

Background Anti-programmed death-1 (anti-PD-1) therapies have improved long-term survival across many advanced cancers. However, chronic immune-related adverse events (irAEs) are not well-defined. We sought to determine the incidence, time-course, spectrum, and predictors of chronic irAEs arising from adjuvant anti-PD-1. Methods In this retrospective cohort, we analyzed patients from 8 academic medical centers with stage III-IV melanoma treated with anti-PD-1 in the adjuvant setting. Acute and chronic (persisting at least 3 months after therapy cessation) irAEs were characterized by type, time-course, management, and incidence. Results Among 387 patients, most were male (60.7%) with a median age of 63 years, had cutaneous primaries (85.8%), BRAF/NRAS WT (51.2%), and resected stage IIIb (33.1%) or IIIc (39.5%) melanomas. Median overall survival and relapse-free survival (RFS) were not reached. 359 patients (93.0%) were alive at median follow-up of 529 days. Patients with acute (p Conclusions Chronic irAEs to anti-PD-1 were more common than previously recognized and frequently persisted even with prolonged follow-up, although most were low-grade. The risks of chronic toxic effects should be integrated into treatment decision making. Ethics Approval This study was approved by the Vanderbilt Institutional Review Board

BackgroundImmune checkpoint inhibitors (ICIs) have transformed treatment for melanoma, but identifying reliable biomarkers of response and effective modifiable lifestyle factors has been challenging. Obesity has been correlated with improved responses to ICI, although the association of body composition measures (muscle, fat, etc) with outcomes remains unknown.MethodsWe performed body composition analysis using Slice-o-matic software on pretreatment CT scans to quantify skeletal muscle index (SMI=skeletal muscle area/height2), skeletal muscle density (SMD), skeletal muscle gauge (SMG=SMI × SMD), and total adipose tissue index (TATI=subcutaneous adipose tissue area + visceral adipose tissue area/height2) of each patient at the third lumbar vertebrae. We then correlated these measures to response, progression-free survival (PFS), overall survival (OS), and toxicity.ResultsAmong 287 patients treated with ICI, body mass index was not associated with clinical benefit or toxicity. In univariable analyses, patients with sarcopenic obesity had inferior PFS (HR 1.4, p=0.04). On multivariable analyses, high TATI was associated with inferior PFS (HR 1.7, p=0.04), which was particularly strong in women (HR 2.1, p=0.03). Patients with intermediate TATI and high SMG had the best outcomes, whereas those with low SMG/high TATI had inferior PFS and OS (p=0.02 for both PFS and OS).ConclusionsBody composition analysis identified several features that correlated with improved clinical outcomes, although the associations were modest. As with other studies, we identified sex-specific associations that warrant further study.

Introduction. Inadvertent excision of a soft tissue sarcoma during hernia surgery is a preventable clinical scenario that leads to unnecessary patient morbidity. Prior series are few, which only include male patients with little focus on prevention. The purpose of this study is to report the presenting features and outcomes of both male and female patients who underwent inadvertent inguinal sarcoma excision during hernia surgery. Methods. A retrospective analysis of a single sarcoma referral center identified 33 patients who were referred for definitive treatment. Patients were divided into three clinically relevant groups based on intraoperative diagnosis, sex, and location of the mass relative to the inguinal ligament. T-tests and Fisher’s exact tests were performed to compare continuous and categorical variables, respectively. Kaplan–Meier modeling was performed to assess sarcoma-specific survival. Results. Females were younger (47 years vs. 61 years, p = 0.003 ) and had smaller sarcomas (6.7 cm vs. 11 cm, p = 0.012 ) compared to males. Only two sarcomas (2/33, 6%) were p = 0.885 ). Mean follow-up was 75 months (range 5–212). Conclusion. This is the second largest study regarding inadvertent inguinal sarcoma excision and the first to include females. When a suspected hernia is >4 cm, irreducible, firm, and is growing, especially in females, consider obtaining preoperative advanced three-dimensional imaging (CT or MRI) that can differentiate a neoplasm from a hernia.

578 Background: GSK-3β overexpression is associated with worse prognosis and chemotherapy resistance in PDAC. GSK-3β inhibition reverses chemotherapy-resistance by inhibiting chemotherapy-induced, ATR-mediated, DNA damage response. 9-ING-41 has significant anti-tumor activity through apoptosis induction, anti-fibrotic activity and NK/T-cell effector stimulation. We hypothesized that 9-ING-41 in combination with GnP chemotherapy would lead to anti-tumor activity, with improved tumor responses in patients with advanced PDAC in the first line setting. Methods: Primary endpoint is disease control rate (DCR). DCR = confirmed complete response (CR), partial response (PR), or stable disease (SD) ≥ 16 weeks (wks). Secondary endpoints are safety and ORR (overall response rates). Eligibility: Advanced PDAC, ECOG PS 0-2, no prior therapy in the metastatic setting and no systemic therapy in prior 6 months. Pts received 9-ING-41 15mg/kg IV twice-weekly with G 1,000 mg/m2 and nP 125 mg/m2 on days 1,8,15 of a 28-day cycle. Simon 2-Stage Design for DCR of 65% and null hypothesis of 50% (historical control), 80% power and 2 sided-significance level of.05. Up to 23 fully evaluable pts planned for stage 1 and if ≥ 12 evaluable patients achieve a DCR 37 additional pts will be enrolled on a second stage or a randomized study commenced. Results: As of Sept 27, 2021, 42 pts enrolled. Median age: 67. 24 females, 18 males. 38 pts with metastatic and 4 with locally advanced disease. Prior adjuvant therapy: 4 pts each FOLFIRINOX and gemcitabine-based. No 9-ING-41-attributable SAEs to date. 9-ING-41 attributed AEs: visual disturbance: 24 (75%) G1/2, 1 (3%) G3; infusion reactions 9 (28%) G1/2. Chemotherapy-related AEs: anemia 13 (40%) G1/2, 1 (3%) G3; neutropenia 2 (6%) G1/2, 13 (40%) G3/4; thrombocytopenia 9 (28%) G1/2, 2 (6%) G3/4; diarrhea 8 (25%) G1/2, 4 (13%) G3; fatigue 9 (28%) G1/2, 3 (9%) G3; nausea/vomiting 24 (75%) G1/2, 1 (3%) G3; constipation 9 (28%) G1/2; febrile neutropenia 5 (16%) G3/4. In 21 pts currently evaluable for response, DCR was 62% and ORR 43%. There were 2 confirmed CRs, 6 confirmed and 1 unconfirmed PRs, 4 SD and 8 disease progressions were observed. Amongst responder’s median duration of response has not yet been reached. Conclusions: 9-ING-41 plus GnP demonstrated encouraging clinical activity but chemotherapy-related AEs were significant. Based on efficacy data to date, including confirmed CRs, we have commenced a randomized phase 2 study, evaluating 9-ING-41 plus GnP vs Gn P alone. Enrollment to the randomized study is now open (NCT03678883). Clinical trial information: NCT03678883.

Melanoma is one of the most highly mutated malignancies, largely as a function of its generation through ultraviolet light and other mutational processes. The wide array of mutations in both "driver" and "passenger" genes can present a confusing array of data for practitioners, particularly within the context of the recent revolutions in targeted and immune therapy. Although mutations in BRAF V600 clearly confer sensitivity to BRAF and mitogen-activated protein kinase kinase (MEK) inhibitors, the clinical implications of most other mutations are less often discussed and understood. In this review, we provide an overview of the high-frequency genomic alterations and their prognostic and therapeutic relevance in melanoma.

Soft-tissue sarcoma (STS) is a heterogeneous group of tumors that arise from mesenchymal tissue. The prognosis of metastatic STS is poor with a life expectancy of 12–18 months. The mainstay of treatment is chemotherapy with an anthracycline. The addition of other chemotherapeutic agents to an anthracycline has been studied with limited success in improving outcomes for STS patients. Olaratumab is a fully human IgG1 monoclonal antibody that binds to platelet-derived growth factor receptor α (PDGFR-α) preventing binding of its ligands and receptor activation. This drug recently received the US Food and Drug Administration’s accelerated approval for the treatment of advanced STS when combined with doxorubicin. This approval was based upon an improvement in overall survival of patients receiving the combination of doxorubicin and olaratumab compared to those receiving doxo-rubicin alone. In this review, we have analyzed the available literature on the development of olaratumab, its clinical utility, and its place in therapy. Based on early-phase clinical trials, olaratumab appears to be a promising agent for the treatment of STS.

// Elizabeth J. Davis 1 , Yi-Mi Wu 2 , Dan Robinson 2 , Scott M. Schuetze 1 , Laurence H. Baker 1 , Jyoti Athanikar 2 , Xuhong Cao 2 , Lakshmi P. Kunju 2 , Arul M. Chinnaiyan 2 , Rashmi Chugh 1 1 Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA 2 Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA Correspondence to: Rashmi Chugh, email: rashmim@umich.edu Keywords: extraskeletal myxoid chondrosarcoma, next generation sequencing, EWSR1-NR4A3 Received: July 29, 2016 Accepted: January 09, 2017 Published: February 21, 2017 ABSTRACT Extraskeletal myxoid chondrosarcoma (EMC) is an indolent translocation-associated soft tissue sarcoma with a high propensity for metastases. Using a clinical sequencing approach, we genomically profiled patients with metastatic EMC to elucidate the molecular biology and identify potentially actionable mutations. We also evaluated potential predictive factors of benefit to sunitinib, a multi-targeted tyrosine kinase inhibitor with reported activity in a subset of EMC patients. Between January 31, 2012 and April 15, 2016, six patients with EMC participated in the clinical sequencing research study. High quality DNA and RNA was isolated and matched normal samples underwent comprehensive next generation sequencing (whole or OncoSeq capture exome of tumor and normal, tumor PolyA+ and capture transcriptome). The expression levels of sunitinib targeted-kinases were measured by transcriptome sequencing for KDR, PDGFRA/B, KIT, RET, FLT1, and FLT4 . The previously reported EWSR1-NR4A3 translocation was identified in all patient tumors; however, other recurring genomic abnormalities were not detected. RET expression was significantly greater in patients with EMC relative to other types of sarcomas except for liposarcoma (p

BRAF and MEK inhibitors are highly active in the setting of BRAFV600 mutant melanoma. Rarely, patients without previous testing present with fulminant progression necessitating emergent treatment prior to BRAF testing results. The safety and efficacy of empiric treatment in this setting is unclear. Herein, we present two patients treated with empiric BRAF and MEK inhibitors, resulting in dramatic clinical improvement in one patient later found to have a BRAF mutation, and lack of improvement (but no accelerated progression) in a patient lacking this mutation. Empiric BRAF and MEK inhibitor treatment should not be routinely pursued but may be given safely in rare, emergent situations.

Immune checkpoint inhibitors (ICIs) have improved outcomes for patients with cancer but related hematologic toxicities have been poorly described. Using VigiBase, the World Health Organization's pharmacovigilance database of individual case safety reports of adverse drug reactions, this study aimed to identify such cases of hematologic toxicities., Immune checkpoint inhibitors have improved outcomes for patients with numerous hematological and solid cancers. Hematologic toxicities have been described, but the spectrum, timing, and clinical presentation of these complications are not well understood. We used the World Health Organization's pharmacovigilance database of individual‐case‐safety‐reports (ICSRs) of adverse drug reactions, VigiBase, to identify cases of hematologic toxicities complicating immune checkpoint inhibitor therapy. We identified 168 ICSRs of immune thrombocytopenic purpura (ITP), hemolytic anemia (HA), hemophagocytic lymphohistiocytosis, aplastic anemia, and pure red cell aplasia in 164 ICSRs. ITP (n = 68) and HA (n = 57) were the most common of these toxicities and occurred concomitantly in four patients. These events occurred early on treatment (median 40 days) and were associated with fatal outcome in 12% of cases. Ipilimumab‐based therapy (monotherapy or combination with anti‐programmed death‐1 [PD‐1]) was associated with earlier onset (median 23 vs. 47.5 days, p = .006) than anti‐PD‐1/programmed death ligand‐1 monotherapy. Reporting of hematologic toxicities has increased over the past 2 years (98 cases between January 2017 and March 2018 vs. 70 cases before 2017), possibly because of increased use of checkpoint inhibitors and improved recognition of toxicities. Future studies should evaluate incidence of hematologic toxicities, elucidate risk factors, and determine the most effective treatment algorithms. Key Points. Immune‐mediated hematologic toxicities are a potential side effect of immune checkpoint inhibitors (ICIs).Providers should monitor complete blood counts during treatment with ICIs.Corticosteroids are the mainstay of treatment for immune‐mediated hematologic toxicities.Further research is needed to define patient‐specific risk factors and optimal management strategies for hematologic toxicities.

11523 Background: Sarcoma pts often receive aggressive, highly immunosuppressive therapy and may be at high risk for severe COVID-19. Demographics, outcomes and risk factors for pts with sarcoma and COVID-19 are unknown. We aimed to describe the course of COVID-19 in sarcoma pts and to identify factors associated with adverse outcomes. Methods: The COVID-19 and Cancer Consortium (NCT04354701) is an international registry of pts with cancer and COVID-19. Adult pts (≥18 years old) with a diagnosis of sarcoma and laboratory confirmed SARS-CoV-2 were included from 50 participating institutions. Data including demographics, sarcoma diagnosis and treatment, and course of COVID-19 infection were analyzed. Primary outcome was the composite rate of hospitalization or death at 30 days from COVID-19 diagnosis. Secondary outcomes were 30 day all-cause mortality, rate of hospitalization, O2 need, and ICU admission. Descriptive statistics and univariate Fisher tests are reported. Results: From March 17, 2020 to February 6, 2021, N=204 pts were included. Median follow up was 42 days. Median age was 58 years (IQR 43-67). 97 (48%) were male. 30 (15%) had ECOG performance status ≥2. 104 (51%) received cancer treatment, including surgery or radiation, within 3 months of COVID-19 diagnosis. 153 (75%) had active cancer, of whom 34 (22%) had lung metastases. 100 (49%) pts met the composite primary endpoint; 96 (47%) were hospitalized and 18 (9%) died within 30 days from COVID-19 diagnosis. 64 (31%) required oxygen, and 16 (8%) required ICU admission. Primary endpoint rates were similar for pts who received cytotoxic chemotherapy (38/58, 66%) or targeted therapy (16/28, 57%). Pts with higher rates of the primary endpoint included patients ≥60 years old (59% vs 40%, OR 2.04, 95% CI 1.12-3.74, p=0.016), pts with ECOG PS ≥2 vs 0-1 (90% vs 41%, OR 12.2, 95% CI 3.44-66.8, p

11559 Background: The feasibility and utility of wearable devices is unknown in sarcoma patients (pts). Objective assessment of activity level, body composition, and PROs facilitate understanding of the tolerability and toxicity of cancer treatment. Methods: From 6/11-10/12/2020, we enrolled sarcoma pts receiving systemic therapy to a prospective study evaluating activity levels and sleep via a Fitbit Charge 3, body composition with the Inbody 570, and PROs using NIH PROMIS short forms (fatigue, pain, physical function, and sleep disturbance), the Generalized Anxiety Disorder Scale, and the Patient Health Questionnaire Depression Scale. Time on study was 12-16 weeks depending upon treatment. The Fitbit was worn continuously. Body composition and PROs were assessed every 3-4 weeks. Feasibility was defined as successful device wearing and data syncing. Data was collected through a cloud-based application, Fitabase. Results: 22 pts were approached and enrolled. Two pts did not complete the first study assessment due to disease progression and were excluded from analysis. 50% of pts were female. 90% of pts were white. Median age was 47 yrs (range 20-81). The most common histologies were Ewing sarcoma and leiomyosarcoma. 89.5% (17/19) of pts wore the Fibit for >3 weeks; median time was 68 days (5-112). 95% (19/20) of pts were able to sync data. Median step count was 2614 steps (376-19806). High step counts, defined as greater than the median, were associated with improved sleep (p=0.14) and physical function (p=0.22), and decreased pain (p=0.15), but these associations were not statistically significant. Low step counts, defined as lower than the median, were associated with skeletal muscle mass loss (p=0.22), but this was not statistically significant. Conclusions: Incorporating a fitness tracker is feasible in sarcoma pts receiving systemic therapy. It provides longitudinal, objective evaluation of activity levels and sleep patterns. Correlation of activity level with sleep, body composition, and PROs was limited due to small numbers; however, a larger prospective pilot study is ongoing.[Table: see text]

11503 Background: EHE is a rare vascular cancer arising in liver, lung, soft tissue and bone. The natural history of metastatic disease varies considerably from indolent growth over years to rapid growth with fatal outcome in months. Treatment of patients (pts) with metastatic EHE with antiangiogenic therapy induces tumor response in a minority of pts, and median PFS is 6-12 months. TAZ-CAMTA1 translocation results in activation of MAPK pathway and is an oncogenic driver in EHE. We sought to evaluate the effect of MEK inhibition using trametinib in pts with unresectable EHE. Methods: A phase 2 trial of trametinib 2 mg daily was conducted in pts with EHE though the Experimental Therapeutics Clinical Trials Network supported by NCI in collaboration with SARC. Additional support was provided by the EHE Rare Cancer Charity and the EHE Foundation. Pts had to have evidence of objective tumor progression or EHE-related pain requiring narcotics for relief prior to enrollment. Presence of TAZ-CAMTA1 translocation was analyzed by fusion-FISH after enrollment. Primary trial endpoint was objective response rate (ORR) per RECIST1.1 with at least 1 objective response required in the 1st 13 pts to expand enrollment to 27. The trial was amended after stage 1 to continue enrollment to 27 pts with TAZ-CAMTA1 detected by FISH with goal of >4 objective responses in this group. Secondary objectives were PFS and OS rates, safety and change in pt-reported global health and pain scores per PROMIS questionnaires. Results: 43 pts were enrolled between 6/2017 – 9/2020 across 10 sites and 41 started therapy. TAZ-CAMTA1 fusion was detected in 26, not detected in 7, test failed in 5 and was not performed due to insufficient tumor in 5. Median pt age was 54 (range 22-81 yrs) and 11 were >65 yrs; 25 were female; ECOG was 0 in 23, 1 in 16 and 2 in 3 pts. Most pts experienced reduction in tumor size. ORR per RECIST was 7% (3/41); in pts with TAZ-CAMTA1 detected, the ORR was 0% (0/26). Mean pain intensity and interference scores had a statistically significant improvement and global quality of life scores did not statistically change after 4 weeks of therapy. 17 pts remained on treatment > 6 months and 7 > 12 months. 25 pts stopped trametinib due to EHE progression, 6 died during treatment, 6 withdrew from treatment, 3 stopped drug due to adverse event and 1 is on treatment. The most common AEs related to trametinib were rash, fatigue, nausea/vomiting, diarrhea, alopecia and edema; Grade >3 AEs included anemia, dyspnea, hypoxia, hypotension, syncope and dermatitis. Conclusions: To our knowledge, this is the largest prospective clinical study focused on pts with EHE. Although the trial did not meet the ORR goal, stable disease > 6 months was seen in 40% of pts, and EHE-related pain improved on treatment. Trametinib was associated with expected cutaneous and GI adverse effects. Additional pt-reported outcomes and biomarkers of inflammation are undergoing analysis. Clinical trial information: NCT03148275.

Importance Agents targeting programmed cell death 1 (PD-1)/PD ligand 1 (PD-L1) improve long-term survival across many advanced cancers and are now used as adjuvant therapy for resected stage III and IV melanomas. The incidence and spectrum of chronic immune-related adverse events (irAEs) have not been well defined. Objective To determine the incidence, time course, spectrum, and associations of chronic irAEs arising from adjuvant anti-PD-1 therapy. Design, setting, and participants This retrospective multicenter cohort study was conducted between 2015 and 2020 across 8 academic medical centers in the United States and Australia. Patients with stage III to IV melanomas treated with anti-PD-1 in the adjuvant setting were included. Main outcomes and measures Incidence, types, and time course of chronic irAEs (defined as irAEs persisting at least 12 weeks after therapy cessation). Results Among 387 patients, the median (range) age was 63 (17-88) years, and 235 (60.7%) were male. Of these patients, 267 (69.0%) had any acute irAE, defined as those arising during treatment with anti-PD-1, including 52 (19.5%) with grades 3 through 5 events; 1 patient each had fatal myocarditis and neurotoxicity. Chronic irAEs, defined as those that persisted beyond 12 weeks of anti-PD-1 discontinuation, developed in 167 (43.2%) patients, of which most (n = 161; 96.4%) were mild (grade 1 or 2) and most persisted until last available follow-up (n = 143; 85.6%). Endocrinopathies (73 of 88; 83.0%), arthritis (22 of 45; 48.9%), xerostomia (9 of 17; 52.9%), neurotoxicities (11 of 15; 73.3%), and ocular events (5 of 8; 62.5%) were particularly likely to become chronic. In contrast, irAEs affecting visceral organs (liver, colon, lungs, kidneys) had much lower rates of becoming chronic irAEs; for example, colitis became chronic in 6 of 44 (13.6%) cases, of which 4 of 6 (66.7%) resolved with prolonged follow-up. Age, gender, time of onset, and need for steroids were not associated with the likelihood of chronicity of irAEs. Conclusion and relevance In this multicenter cohort study, chronic irAEs associated with anti-PD-1 therapy appear to be more common than previously recognized and frequently persisted even with prolonged follow-up, although most were low grade. The risks of chronic irAEs should be integrated into treatment decision-making.

Purpose:Antibodies blocking programmed death-1 receptor (anti-PD-1) produce durable responses in patients with metastatic melanoma, although >50% of patients ultimately experience disease progression. We aimed to identify prognostic factors and outcomes to subsequent therapies in patients with metastatic melanoma that progressed on anti-PD-1. Materials and methods:We evaluated 383 patients who received anti-PD-1 (alone or in combination with ipilimumab [ipi]) for advanced melanoma between 2009 and 2019. Patient and disease characteristics at baseline and progression, factors correlating with survival after progression (SaP), subsequent therapies, objective response rate (ORR), overall survival (OS), and progression free survival (PFS) were assessed. Results:Of 383 patients, 247 experienced progression. At progression, most patients were stage IV M1c (49.0%), symptomatic from their disease (66.8%), and had progression at both new and existing lesions (39.3%). The median SaP was 206 days. There was no difference in SaP based on primary tumor subtype (cutaneous vs. non-cutaneous), receipt of prior therapy, prior ipi, or therapy type (anti-PD-1 vs. combination). However, significantly improved SaP correlated with clinical features at progression, including normal LDH (p2-5cm, >5-8cm, and >8cm respectively; p Conclusions:We identified multiple clinical factors that correlated with SaP in patients with melanoma progressing on anti-PD-1. Further, we identified improved outcomes for subsequent BRAFi/MEKi or ipi + nivolumab vs. ipi alone. Finally, we identified a subgroup of patients with long-term SaP, potentially explaining the gap between PFS and OS demonstrated in many anti-PD-1 trials. Citation Format: James R. Patrinely, Laura X. Wang, Elizabeth J. Davis, Douglas B. Johnson. Outcomes after progression of disease with anti-PD-1/PDL1 therapy for advanced melanoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3154.

Importance Immune checkpoint inhibitors (ICIs) are now a mainstay of cancer treatment. Although rare, fulminant and fatal toxic effects may complicate these otherwise transformative therapies; characterizing these events requires integration of global data. Objective To determine the spectrum, timing, and clinical features of fatal ICI-associated toxic effects. Design, Setting, and Participants We retrospectively queried a World Health Organization (WHO) pharmacovigilance database (Vigilyze) comprising more than 16 000 000 adverse drug reactions, and records from 7 academic centers. We performed a meta-analysis of published trials of anti–programmed death-1/ligand-1 (PD-1/PD-L1) and anti–cytotoxic T lymphocyte antigen-4 (CTLA-4) to evaluate their incidence using data from large academic medical centers, global WHO pharmacovigilance data, and all published ICI clinical trials of patients with cancer treated with ICIs internationally. Exposures Anti–CTLA-4 (ipilimumab or tremelimumab), anti–PD-1 (nivolumab, pembrolizumab), or anti–PD-L1 (atezolizumab, avelumab, durvalumab). Main Outcomes and Measures Timing, spectrum, outcomes, and incidence of ICI-associated toxic effects. Results Internationally, 613 fatal ICI toxic events were reported from 2009 through January 2018 in Vigilyze. The spectrum differed widely between regimens: in a total of 193 anti–CTLA-4 deaths, most were usually from colitis (135 [70%]), whereas anti–PD-1/PD-L1–related fatalities were often from pneumonitis (333 [35%]), hepatitis (115 [22%]), and neurotoxic effects (50 [15%]). Combination PD-1/CTLA-4 deaths were frequently from colitis (32 [37%]) and myocarditis (22 [25%]). Fatal toxic effects typically occurred early after therapy initiation for combination therapy, anti–PD-1, and ipilimumab monotherapy (median 14.5, 40, and 40 days, respectively). Myocarditis had the highest fatality rate (52 [39.7%] of 131 reported cases), whereas endocrine events and colitis had only 2% to 5% reported fatalities; 10% to 17% of other organ-system toxic effects reported had fatal outcomes. Retrospective review of 3545 patients treated with ICIs from 7 academic centers revealed 0.6% fatality rates; cardiac and neurologic events were especially prominent (43%). Median time from symptom onset to death was 32 days. A meta-analysis of 112 trials involving 19 217 patients showed toxicity-related fatality rates of 0.36% (anti–PD-1), 0.38% (anti–PD-L1), 1.08% (anti–CTLA-4), and 1.23% (PD-1/PD-L1 plus CTLA-4). Conclusions and Relevance In the largest evaluation of fatal ICI-associated toxic effects published to date to our knowledge, we observed early onset of death with varied causes and frequencies depending on therapeutic regimen. Clinicians across disciplines should be aware of these uncommon lethal complications.

Contains fulltext : 200321.pdf (Publisher’s version ) (Open Access) The outcome for patients with unresectable or metastatic soft tissue sarcoma remains poor with few treatment options. Synovial sarcoma is a rare type of sarcoma, predominantly affecting adolescents and young adults. Following failure of first-line anthracycline-based chemotherapy, several salvage options are available. We reviewed the safety and efficacy of gemcitabine/docetaxel chemotherapy in two tertiary oncology centres. We identified patients treated with gemcitabine/docetaxel between 2004 and 2016 in a UK and a US oncology centre using retrospective pharmacy and medical records. Treatment response, toxicity and outcome data were collected. Twenty one patients were treated with gemcitabine/docetaxel, the majority as a second- or third-line treatment for metastatic disease. The response rate was 5% with a median progression-free survival of 2 months (95% CI 1.3-3.7). Toxicities reported were as expected for this chemotherapy combination. Treatment was not discontinued due to toxicity. Gemcitabine/docetaxel chemotherapy shows little efficacy in synovial sarcoma and should not be offered to this patient group outside a clinical trial context.

Immune checkpoint inhibitors, particularly those targeting PD-1/PD-L1, produce durable responses in a subset of patients across cancer types. Although often well-tolerated, these agents can induce a broad spectrum of autoimmune-like complications that may affect any organ system. Treatment of these toxicities primarily consists of immune suppression with corticosteroids and other agents. This review will briefly discuss the mechanisms of immune-related adverse events (irAEs), overview the clinical and pathologic features of major toxicities caused by PD-1/PD-L1 blockade, and review their management.

Chordomas and chondrosarcomas that cannot be controlled by local therapies are a pressing medical challenge because the efficacy of available systemic therapy is limited and unproven. Cytotoxic chemotherapy has no established role in the treatment of recurrent and/or metastatic chordoma and conventional chondrosarcoma. Molecularly targeted agents, notably multi-tyrosine kinase inhibitors, have shown some promise in case series and in phase II clinical trials in chordoma but require randomized, controlled study to prove efficacy. Additional strategies using emerging findings on the underlying pathogenesis of these tumors are being identified and developed. In the early evaluation of drug activity in chondrosarcoma and chordoma, alternate surrogate measures of tumor response using multiparameter (e.g., tumor size and density) or functional (e.g., fluorodeoxyglucose [FDG] uptake) criteria may be superior to the current response evaluation criteria in solid tumors (RECIST). Confirmation of drug efficacy in these very rare tumors will require randomized, comparative trials conducted with national or international collaboration.