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Purpose: Most patients with gastrointestinal stromal tumor (GIST) have activating mutations in KIT/PDGFRA and are initially responsive to tyrosine kinase inhibitors (TKI). The acquisition of secondary mutations leads to refractory/relapsed disease. This study reports the results of an analysis from the phase III INVICTUS study (NCT03353753) characterizing the genomic heterogeneity of tumors from patients with advanced GIST and evaluating ripretinib efficacy across KIT/PDGFRA mutation subgroups. Patients and Methods: Tumor tissue and liquid biopsy samples that captured circulating tumor DNA were collected prior to study enrollment and sequenced using next-generation sequencing. Subgroups were determined by KIT/PDGFRA mutations and correlation of clinical outcomes and KIT/PDGFRA mutational status was assessed. Results: Overall, 129 patients enrolled (ripretinib 150 mg once daily, n = 85; placebo, n = 44). The most common primary mutation subgroup detected by combined tissue and liquid biopsies were in KIT exon 11 (ripretinib, 61.2%; placebo, 77.3%) and KIT exon 9 (ripretinib, 18.8%; placebo, 15.9%). Patients receiving ripretinib demonstrated progression-free survival (PFS) benefit versus placebo regardless of mutation status (HR 0.16) and in all assessed subgroups in Kaplan–Meier PFS analysis (exon 11, P < 0.0001; exon 9, P = 0.0023; exon 13, P < 0.0001; exon 17, P < 0.0001). Among patients with wild-type KIT/PDGFRA by tumor tissue, PFS ranged from 2 to 23 months for ripretinib versus 0.9 to 10.1 months for placebo. Conclusions: Ripretinib provided clinically meaningful activity across mutation subgroups in patients with advanced GIST, demonstrating that ripretinib inhibits a broad range of KIT/PDGFRA mutations in patients with advanced GIST who were previously treated with three or more TKIs.

Background Leiomyosarcoma is a malignant mesenchymal tumor of cells of smooth muscle lineage arising commonly in retroperitoneum, uterus, large veins, and the limbs. The genetics of leiomyosarcomas are complex and there is very limited understanding of common driver mutations. Circulating tumor DNA (ctDNA) offers a rapid and noninvasive method of next-generation sequencing (NGS) that could be used for diagnosis, therapy, and detection of recurrence. Methods ctDNA testing was performed using Guardant360, which detects single nucleotide variants, amplifications, fusions, and specific insertion/deletion mutations in 73 genes using NGS. Results Of 73 patients, 59 were found to have one or more cancer-associated genomic alteration. Forty-five (76%) were female with a median age of 63 (range, 38–87) years. All samples were designated metastatic. The most common alterations were detected in Tp53 (65%), BRAF (13%), CCNE (13%), EGFR (12%), PIK3CA (12%), FGFR1 (10%), RB1(10%), KIT (8%), and PDGFRA (8%). Some of the other alterations included RAF1, ERBB2, MET, PTEN TERT, APC, and NOTCH1. Potentially targetable mutations, by Food and Drug Administration–approved or clinical trials, were found in 24 (40%) of the 73 patients. Four patients (5%) were found to have incidental germline TP53 mutations. Conclusion NGS of ctDNA allows identification of genomic alterations in plasma from patients with leiomyosarcoma. Unfortunately, there is limited activity of current targeted agents in leiomyosarcomas. These results suggest opportunities to develop therapy against TP53, cell cycle, and kinase signaling pathways. Further validation and prospective evaluation is warranted to investigate the clinical utility of ctDNA for patients with leiomyosarcoma.

Simple Summary Angiosarcomas (AS) are rare, highly aggressive sarcomas with limited therapeutic options. Genomic sequencing techniques have identified recurrent genetic abnormalities. Nevertheless, the association of these findings with etiology, site of origin, prognosis, and therapeutic implications is not well understood. We analyzed Next Generation Sequencing (NGS) and Whole Transcriptome Sequencing (WTS) data in a cohort of 143 AS cases. We identified distinct genomic biology according to the AS primary site. Head and neck AS cases primarily have Immunotherapy (IO) response markers and mutations in TP53 and POT1. On the other hand, breast AS is enriched for cell cycle alterations, predominately MYC amplification. Additionally, a microenvironment with abundant immune cells is present in a minority of cases but distributed evenly among primary sites. Our findings can facilitate the design and optimization of therapeutic strategies for AS according to its biology at different primary sites. Abstract We performed a retrospective analysis of angiosarcoma (AS) genomic biomarkers and their associations with the site of origin in a cohort of 143 cases. Primary sites were head and neck (31%), breast (22%), extremity (11%), viscera (20%), skin at other locations (8%), and unknown (9%). All cases had Next Generation Sequencing (NGS) data with a 592 gene panel, and 53 cases had Whole Exome Sequencing (WES) data, which we used to study the microenvironment phenotype. The immunotherapy (IO) response biomarkers Tumor Mutation Burden (TMB), Microsatellite Instability (MSI), and PD-L1 status were the most frequently encountered alteration, present in 36.4% of the cohort and 65% of head and neck AS (H/N-AS) (p < 0.0001). In H/N-AS, TMB-High was seen in 63.4% of cases (p < 0.0001) and PDL-1 positivity in 33% of cases. The most common genetic alterations were TP53 (29%), MYC amplification (23%), ARID1A (17%), POT1 (16%), and ATRX (13%). H/N-AS cases had predominantly mutations in TP53 (50.0%, p = 0.0004), POT1 (40.5%, p < 0.0001), and ARID1A (33.3%, p = 0.5875). In breast AS, leading alterations were MYC amplification (63.3%, p < 0.0001), HRAS (16.1%, p = 0.0377), and PIK3CA (16.1%, p = 0.2352). At other sites, conclusions are difficult to generate due to the small number of cases. A microenvironment with a high immune signature, previously associated with IO response, was evenly distributed in 13% of the cases at different primary sites. Our findings can facilitate the design and optimization of therapeutic strategies for AS.

BACKGROUND Studies suggest that surgical breast augmentation with implants is a risk factor for breast desmoid tumors. The statistical strength of this correlation is unknown, as evidence is limited to anecdotal reports. METHODS Patients with breast desmoid tumors and a history of breast implants seen at a single center between 2000 and 2021 were identified via radiology, breast, and sarcoma databases. The standardized incidence ratio (SIR) was calculated to assess the correlation between breast desmoid tumors and breast implants. The cases were pooled with published cases for analyses. Progression-free survival curves and hazard ratios were estimated using the Kaplan-Meier method and Cox proportional-hazards modeling. RESULTS Fourteen patients from one institution and 66 cases in the literature were identified. All patients were female, and the mean age was 38 years old (range 20-66). 63 patients (82%) underwent resection, 9 (12%) received chemotherapy, 3 (4%) received sorafenib, 11 (14%) received hormonal therapy, and 3 (4%) underwent active surveillance. After resection, the 2-year recurrence-free survival rate was 77% (95% CI 65%-89%). The recurrence risk was lower for resection with no residual tumor (R0) compared to microscopic (R1) or macroscopic (R2) residual tumor (HR: 0.15; 95% CI 0.02-0.8; p

Background We performed a randomized phase 3 study of trabectedin versus dacarbazine in previously‐treated patients with liposarcoma/leiomyosarcoma (LPS/LMS). Methods Patients were randomized 2:1 to trabectedin (n = 384) or dacarbazine (n = 193) administered intravenously every 3 weeks. The primary objective was overall survival (OS). Secondary objectives were progression‐free survival, objective response rate, safety, and patient‐reported outcomes, all previously reported and demonstrating superior disease control with trabectedin. Results of the final OS analysis in preplanned subgroups of patients with LPS/LMS are presented. Results At the time of the final OS analysis, 577 patients had been assigned randomly, including 423 (73%) with LMS and 154 (27%) with LPS. The median duration of treatment exposure was higher in the trabectedin arm compared with the dacarbazine arm (4 vs 2 cycles), as was the proportion of patients receiving an extended number of therapy courses (≥6 cycles: 42% vs 22%). This pattern was consistent across histological subgroups: the median number of treatment cycles (4 vs 2 for both subgroups) and proportion of patients with ≥6 treatment cycles (LMS, 43% vs 24%; LPS, 40% vs 16%). Despite improved disease control by trabectedin, no improvement in OS was observed; the final median OS for trabectedin versus dacarbazine was 13.7 versus 13.1 months (P = .49). Sensitivity analyses of OS suggest confounding by post‐study anticancer therapies, which were utilized in most patients in both treatment arms (71% vs 69%, respectively). Conclusion The final OS results demonstrated comparable survival between LPS/LMS patients receiving trabectedin or dacarbazine, which is consistent with the interim analysis results. Both LPS and LMS demonstrated improved disease control with trabectedin., A final analysis of overall survival demonstrates comparable results between patients with liposarcoma/leiomyosarcoma receiving trabectedin or dacarbazine, which is consistent with interim analysis results. Both liposarcoma and leiomyosarcoma show improved disease control with trabectedin.

11548 Background: Alterations in DNA damage response (DDR) pathways contribute to genomic instability and malignant progression and have been shown to be of clinical significance in several carcinomas and solid tumors. While some studies have identified ostensibly pathogenic variations in known and novel cancer genes with implications for sarcoma risk and treatment opportunities, there is limited information regarding the role of DDR pathway alterations in sarcoma. We identified a gene alteration in ERCC2, a gene that codes for a DNA helicase in the nucleotide excision repair pathway, in a patient with multiply relapsed epithelioid sarcoma (ES), prompting an investigation of DDR pathway alterations in sarcoma samples using a global next-generation sequencing (NGS) platform. Methods: Sarcoma patient samples (N = 5310), representing 38 pediatric and adult histologic subtypes, underwent NGS of DNA (592 gene panel or whole exome) and RNA (whole transcriptome sequencing, N = 3612) at a CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ). A threshold of 10 mut/Mb was used to identify high tumor mutational burden (TMB-H). IHC was performed for PD-L1 (SP142; 2+|5% = positive). Homologous recombination deficiency (HRD) scores were calculated as a composite of loss of heterozygosity, telomeric allelic imbalance, and large-scale transitions, using a positive threshold of 42 (N = 2138). HRD score association with biomarker status was evaluated overall and in sarcoma subtypes. Results: A pathogenic DDR pathway mutation was noted in 842 (15.9%) of the total samples. ATRX was by far the most commonly altered DDR gene (10% of all samples), with mutations observed across 25 sarcoma subtypes (11 subtypes with > 10% mutation rate: leiomyosarcoma [LMS], perivascular epithelioid cell tumor [PEComa], pleomorphic sarcoma [PLSARC], uterine sarcoma [OUSARC], osteosarcoma, spindle cell sarcoma, angiosarcoma, mesenchymal chondrosarcoma, sarcoma NOS, fibrosarcoma and ES). CHEK2, ATM, and MUTYH mutations were observed in 1-2% of sarcoma samples. More than 20 histologic subtypes showed distinct gene signatures with mutations occurring in > 3% of the samples investigated. ERCC2 was mutated in 3% of ES and 6.5% in PEComa. Median HRD scores ranged between 20-58 across sarcoma subtypes. High rates of deficient HRD (HRDd ≥ 42) were observed in PLSARC (83.2%), OUSARC (73.7%), and dedifferentiated chondrosarcoma (71.4%), while low rates of HRDd were observed in Ewing sarcoma (0%) and clear cell sarcoma (10%). In the overall cohort, ERCC2, ATRX and BRCA2 were significantly associated with increased HRD scores (p = 0.01). Conclusions:DDR pathway alterations are present in numerous histologic subtypes of sarcoma. A more comprehensive analysis of individual histologic subtypes is in progress. Further research will evaluate the clinical implications of these known and novel mutations to guide risk stratification and potential therapeutic options.

e23534 Background: Many systemic treatment options are described for desmoid tumors, including hormonal therapies, non-steroidal anti-inflammatory drugs, cytotoxic chemotherapeutic agents, and most recently, tyrosine kinase inhibitors. Although many options are described, randomized data is scarce. The lack of comparative studies precludes a definitive sequence of the existing systemic treatments in the management of desmoid tumors. Here we retrospectively compare sorafenib with cytotoxic chemotherapy to generate objective data to guide treatment choice. Methods: We analyzed all patients with desmoid tumors treated with doxorubicin, dacarbazine, vinblastine, vinorelbine, methotrexate, or sorafenib in the first-line setting at a single center from 2000-2021. The primary endpoint was investigator-assessed progression-free survival. The secondary endpoint was the rate of toxic effects recorded accordingly to the Common Terminology Criteria for Adverse Events. We calculated progression-free survival (PFS) using the Kaplan-Meier method with Log-Rank Test to estimate the 95% confidence interval. Results: 79 patients ultimately received systemic therapies. Median follow-up was 5.6 years (0 to 7.9), 69% were women, and median age at diagnosis was 37 (range 5-77). Regarding race and ethnicity, 74% were White, 26%, Black and 45%, Latino. The tumor was in the lower extremity in 21 (27%) cases, trunk in 18 (23%) cases, abdominal wall in 13 (16%), intra-abdomen in 9 (11%), upper extremity in 7 (9%), head-neck in 7 (9%) and breast in 4 (5%). Surgery before systemic treatment was used in 20 (25%) patients. The regiments used were sorafenib (n = 32), doxorubicin with dacarbazine (n = 13), liposomal doxorubicin (n = 11), methotrexate with vinblastine (n = 11), methotrexate with vinorelbine (n = 8) and methotrexate monotherapy (n = 1). The 2-year progression-free survival rate was 80% (95% confidence interval [CI], 0.64 to 0.96) in the cytotoxic chemotherapy group and 66% (95% CI, 0.46 to 0.86) in the sorafenib group (P = 0.06). The most frequently reported adverse events on the cytotoxic group were grade 1 or 2 events of nausea (25%) and rash (15%), and on sorafenib were grade 1 or 2 events of palmar-plantar erythrodysesthesia (40%) and fatigue (25%). There were no treatment-related deaths reported. Conclusions: There was no statistical difference between the analyzed treatments, although there was a trend toward lower progression rates with cytotoxic therapy.

e23508 Background: Bone sarcomas account for about 5% of cancers in adolescents and young adults (AYA). Outcomes in this population are consistently inferior than children. It is poorly understood whether this is related to the tumor biology or the therapeutic approach. In addition, regimens used in AYAs are heterogeneous due to poor tolerance of pediatric regimens and lack of clinical trials specific to this population. We sought to study the therapeutic regimes and outcomes of AYA bone sarcoma patients (pts) to understand the optimal therapeutic approach better. Methods: From our institutional database, we extracted data of pts with the diagnosis of “osteosarcoma” (OS) and “Ewing sarcoma” (ES) in the AYA (15-39 yo) population from 2011-21. We included only pts with efficacy documented to different regimens. Descriptive statistics were used for patient demographics, presentation, regimens, and outcomes (Table). Objective response rate (ORR) was defined as the number of patients achieving a partial or complete response. Relapse rate (RR) was calculated for the pts that progressed after undergoing definitive curative intent treatment. Survival comparison between groups was made using the Kaplan Meier method and Log Rank Test. We used Fisher's exact test to compare differences in ORR between treatment groups. Results: We identified 30 ES and 44 OS pts. For both ES and OS, Kaplan Meier survival analysis showed no difference in presentation adjusted overall survival between treatment groups; ( x2 .351, p .55) for ES and ( x2 1.94 p .378) for OS. Importantly, in OS, ORR difference between Adria/IVCis and Adria/IACis was statistically significant ( p .0188). Conclusions: Our study shows the heterogeneity in first-line treatment strategies for AYA pts with bone sarcomas. For ES, response rates for VAC/IE and VAI were similar. In the OS cohort, we found ORR for Adria/IACis was 81% which was statistically different to pts receiving Adria/IVCis (ORR 30%). However, we saw relapses in 43% of pts treated with Adria/IACis. This indicates that the intra-arterial approach could be helpful for limb preservation but suggests the need for intense adjuvant chemotherapy to prevent relapses. There were no statistically significant differences in the survival outcomes of AYA bone sarcoma pts treated with pediatric versus adult regimens.[Table: see text]

11580 Background: Synovial sarcomas (SS) harbor a specific, balanced, reciprocal translocation t(X;18) leading to the oncogenic SS18-SSX fusion. Defective DNA damage response (DDR) is a hallmark of cancer leading to genomic instability and is associated with chemosensitivity. Efforts have been made to identify a genetic signature that predicts SS progression, treatment response, and survival in order to identify more accessible and effective treatments. This investigation explores the role of DDR in pathogenesis of SS. Methods: Patients with the diagnosis of SS from 2013 to 2021 within the Caris Life Science database were included in the study. A combination of NGS of DNA and RNA at a CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ) was performed on archival tumors. Homologous recombination deficiency (HRD) scores were calculated as a composite of loss of heterozygosity, telomeric allelic imbalance, and large-scale transitions, using a positive threshold of 42. This study was approved by the University of Miami (UM)-Sylvester IRB and all the data collected was de-identified. Results: A total of 120 patients were identified with 49 of these patients from UM-Sylvester. Mean age of diagnosis on the sample was 46 years old (range of 15-86) and 45.8% were female. Among the 49 patients from UM-Sylvester, mean age was 60 years old (range of 35-84), 28 patients had a gene alteration identified (57%) and 6 of them a homologous recombination deficiency (HRD) gene (12%). A total of 63 different genes were identified with the most common TP53 (49%), LOH (12.2%), ATRX (10.2%) and RB1 (6.1%). Other HRD genes identified were MLH1 (4%) and CHEK2 (4%). There was no correlation identified between the age (15-65 vs elderly ⩾ 65 years) or the gender (female vs male) and the presence of a mutated DDR (p = 0.615; p = 0.091 respectively). Within the entire Caris database (N = 120), we identified 11 patients (N = 120, 9%) whose tumor tested positive for any DDR gene alteration. The most common were ATM (2.6%), followed by ATRX (1.6%) and CHEK2 (0.9%). The median HRD score was 22 within the sample. Conclusions: We report here the most common genes altered on molecular profile for a large cohort of SS samples. The prevalence of predicted pathogenic DDR gene mutation carriers in our cohort (9%) suggests that constitutional defects in this pathway may be associated with SS. We found higher rates of positive DDR on the UM-Sylvester cohort, and this could be associated with specifics of our population, given high frequency of Hispanic patients. Work is ongoing to associate our findings with race, ethnicity, survival and response to treatments. Work is ongoing to associate our findings with race, ethnicity, survival and response to treatments. These correlations will be reported in the final abstract. Cytotoxic therapy remains gold standard for metastatic SS, but better understanding of the molecular profile can pave way for further options, including targeted therapy and immunotherapy.

e23543 Background: Desmoid tumors are locally invasive mesenchymal neoplasms of fibroblastic origin arising in deep soft tissue. Despite a rare incidence of 2.4-4.3 per one million and an inability to metastasize, desmoid tumors can cause significant morbidity by invading surrounding structures, causing pain, anatomic deformities, and, in some cases, death. Due to the high post-excision recurrence rate (21-29%) and frequent spontaneous regression or stabilization (50-88%), active surveillance is the first-line treatment for desmoid tumors. Most therapeutic agents only achieve tumor stability and response rates of 10-30%. As such, a large subset of patients face disease progression without an effective therapeutic option. In this context, percutaneous cryoablation arises as a novel treatment for desmoid tumors. This retrospective chart review case series aims to describe the effectiveness of cryoablation in the treatment of desmoid tumors. Methods: We retrospectively reviewed medical records of patients with a pathologically confirmed desmoid tumor who received computed tomography (CT) guided percutaneous cryoablation at a single academic hospital between 2010 and 2021. We defined objective response rate (ORR) as the percentage of patients who have partial or complete response to cryoablation. Disease progression (PD), Stable Disease (SD), Partial Response (PR), and Complete Response (CR) were defined per mRECIST criteria. Results: We identified nine patients (8 female, mean age 33) with desmoid tumors who underwent percutaneous cryoablation. The most common tumor location was the abdominal wall (n = 5,) and the median longer axis tumor size was 9.5 cm (range: 4.5-16 cm). Seven patients received previous systemic treatments. Sorafenib (n = 6) was the most common systemic therapeutic option, followed by methotrexate/vinblastine, Adriamycin/dacarbazine, tamoxifen, nirogacestat, and sulindac. Before cryoablation, six of the seven patients receiving systematic therapies had PD; one had SD. After cryoablation, seven underwent post-cryoablation imaging. Mean time to initial post-op follow-up was 38.85 days (range: 22-60 days). Six patients achieved PR (66.67%), one patient maintained SD (11.11%), and two (22.22%) were lost to follow-up. Two patients with PR regressed to SD two and three months after initial post-cryoablation imaging, respectively, and one with SD improved to PR after eleven months. As such, ORR was 71.43% (95% CI: 0.352 to 1.08). Conclusions: Our data support cryoablation as an effective therapy for decreasing tumor burden in multi-treatment resistant desmoid tumor patients. Although larger studies are needed to assess efficacy and safety, with an ORR of over 70% and a disease control rate of over 75%, cryoablation demonstrates promising results without the toxicity of systemic therapy and thus may be an effective strategy for multi-treatment resistant desmoid tumors.

e23526 Background: Pathological complete response (pCR) to preoperative treatment has been reported as a prognostic factor for survival in the soft tissue sarcoma (STS) population. pCR evaluation has been demonstrated in breast and head and neck cancers widely associated with improved outcomes, including overall survival (OS). The assessment to pathological response is not easily subject to variability, can be globally equitable, and has the potential to serve as a surrogate endpoint for research and survival outcomes. Methods: This is a retrospective, single institution study. The inclusion criteria were: patients with STS diagnosed between 2011–2021, s/p neoadjuvant treatment, and pCR (defined as necrosis rate on surgical specimen ≥ 90%). This study was approved by the University of Miami-Sylvester IRB. Results: We identified a total of 39 patients that met our inclusion criteria. 43% of the population were women. Mean age at diagnosis was 59 years old (range 20-84). 90% of the population remains alive, with mean overall survival of 6.6 years. Disease recurrence (local and distant) was present only in 11 patients (28%) and 4 of these patients (36.3%) progressed to death. Median progression free survival (PFS) was 42.5 months (95% CI 33.9-53.1). 34% of the cohort had the myxofibrosarcoma histology, and this group had mean OS of 7.2 years and mean PFS of 5.8 years. 20% of the myxofibrosarcoma patients developed metastatic disease versus 21% among patient with different histology (p = 0.89). Among the neoadjuvant treatments delivered, 93% of the patients received a combination of chemotherapy and radiation. The most common neoadjuvant chemotherapy regimen was the combination of Doxorubicin with Ifosfamide (66% of the patients) and their mean OS was 6.2 years vs 2.9 for the other regimens (p = 0.08). Among patients that received neoadjuvant chemotherapy, the median number of preoperative cycles was 4 (SD = 1.1). The median time from the start of chemotherapy to surgery was 5 months (SD = 1.4 months). Conclusions: Treatment induced pathologic necrosis has been proven as a predictor of survival in patients with STS in multiple studies. Interestingly, the most common histology present was myxofibrosarcoma, suggesting a good response to neoadjuvant treatment in this group with a lower rate of metastatic disease after pCR, when compared to the literature (35%). Chemotherapy associated with radiation in the neoadjuvant setting was the most common treatment and Doxorubicin with Ifosfamide was associated with a longer OS. The rate of necrosis after surgery has been shown to be a prognostic factor for STS, therefore there is a need to evaluate which associated factors lead to pCR. Further research with the evaluation of the molecular profiling of STS with pCR is underwork to better understand the mechanisms behind treatment responses.

11539 Background: Ripretinib is a novel switch-control TKI that broadly inhibits KIT and PDGFRA kinase signaling. In INVICTUS (NCT03353753), a randomized, double-blind, placebo (PBO)-controlled trial of ripretinib in ≥4th-line advanced GIST, ripretinib reduced the risk of disease progression or death by 85% vs PBO with a favorable overall safety profile. Common ( > 20%) adverse events (AEs) included, but were not limited to, alopecia and PPES. Exploratory analyses evaluated the impact of alopecia and PPES on quality of life (QoL). Methods: Patients (pts) with advanced GIST previously treated with at least imatinib, sunitinib, and regorafenib were randomized (2:1) to ripretinib 150 mg QD or PBO. AEs were graded using CTCAE v4 and PROs collected using EQ-5D-5L (EQ5D) and EORTC QLQ-C30 (C30). Repeated measures (RM) models assessed the impact of alopecia and PPES on 5 PROs (EQ5D visual analogue scale; and C30 physical functioning, role functioning, and the overall health and overall QoL questions) within the ripretinib arm. Fixed effects were sex, alopecia/PPES, and ECOG scores at baseline. Results: 128/129 randomized pts received treatment (85 ripretinib 150 mg QD; 43 PBO). Alopecia, regardless of causality, occurred in 44 (51.8%) on ripretinib (34 [40.0%] grade 1; 10 [11.8%] grade 2) and 2 (4.7%) on PBO (both grade 1). PPES occurred in 18 (21.2%) on ripretinib (11 [12.9%] grade 1; 7 [8.2%] grade 2); none on PBO. The median times in days to first occurrence and worst severity grade with ripretinib were 57.0 and 62.5 for alopecia; 56.5 and 57.0 for PPES. The RM models showed a slight trend towards improvement in PRO score over time for pts with alopecia; the only association reaching a P-value of < 0.05 was between alopecia and increased overall QoL. None of the associations between PPES and PRO scores reach P < 0.05. All PRO p-values are nominal, and no statistical significance is being claimed. Conclusions: Ripretinib had a favorable overall safety and tolerability profile. When stratified by alopecia and PPES, patient-reported assessments of function, overall health, and overall QoL were maintained over time. For both alopecia and PPES, onset and maximum severity occurred almost simultaneously, indicating that these events generally did not progressively worsen. These results suggest that alopecia and PPES are manageable and do not have a negative effect on function, overall health, and QoL. Clinical trial information: NCT03353753 .

Background Resistance to approved inhibitors of KIT proto-oncogene, receptor tyrosine kinase (KIT), and platelet-derived growth factor receptor alpha (PDGFRA) is a clinical challenge for patients with advanced gastrointestinal stromal tumours. We compared the efficacy and safety of ripretinib, a switch-control tyrosine kinase inhibitor active against a broad spectrum of KIT and PDGFRA mutations, with placebo in patients with previously treated, advanced gastrointestinal stromal tumours.Methods In this double-blind, randomised, placebo-controlled, phase 3 study, we enrolled adult patients in 29 specialised hospitals in 12 countries. We included patients aged 18 years or older who had advanced gastrointestinal stromal tumours with progression on at least imatinib, sunitinib, and regorafenib or documented intolerance to any of these treatments despite dose modifications, and who had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Eligible patients were randomly assigned (2:1) to receive either oral ripretinib 150 mg once daily (ripretenib group) or placebo once daily (placebo group). Randomisation was done via an interactive response system using randomly permuted block sizes of six and stratified according to number of previous therapies and ECOG performance status. Patients, investigators, research staff, and the sponsor study team were masked to a patient's treatment allocation until the blinded independent central review (BICR) showed progressive disease for the patient. The primary endpoint was progression-free survival, assessed by BICR. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who received at least one dose of study drug. Patients randomly assigned to placebo were permitted to cross over to ripretinib 150 mg at the time of disease progression. The INVICTUS study is registered with ClinicalTrials.gov , number NCT03353753, and with WHO International Clinical Trials Registry Platform, number EUCTR2017-002446-76-ES; follow-up is ongoing.Findings Between Feb 27, 2018, and Nov 16, 2018, 129 of 154 assessed patients were randomly assigned to receive either ripretinib (n=85) or placebo (n=44). At data cutoff (May 31, 2019), at a median follow-up of 6.3 months (IQR 3. 2-8. 2) in the ripretinib group and 1.6 months (1.1-2.7) in the placebo group, 51 patients in the ripretinib group and 37 in the placebo group had had progression-free survival events. In the double-blind period, median progression-free survival was 6.3 months (95% CI 4.6-6.9) with ripretinib compared with 1.0 months (0.9-1.7) with placebo (hazard ratio 0.15, 95% CI 0.09-0.25; p2%) grade 3 or 4 treatment-related treatment-emergent adverse events in the ripretinib group (n=85) included lipase increase (four [5%]), hypertension (three [4%]), fatigue (two [2%]), and hypophosphataemia (two [2%]); in the placebo group (n=43), the most common (>2%) grade 3 or 4 treatment-related treatment-emergent adverse events were anaemia (three [7%]), fatigue (one [2%]), diarrhoea (one [2%]), decreased appetite (one [2%]), dehydration (one [2%]), hyperkalaemia (one [2%]), acute kidney injury (one [2%]), and pulmonary oedema (one [2%]). Treatment-related serious adverse events were reported in eight (9%) of 85 patients who received ripretinib and three (7%) of 43 patients who received placebo. Treatment-related deaths occurred in one patient in the placebo group (septic shock and pulmonary oedema) and one patient in the ripretinib group (cause of death unknown; the patient died during sleep).Interpretation Ripretinib significantly improved median progression-free survival compared with placebo and had an acceptable safety profile in patients with advanced gastrointestinal stromal tumours who were resistant to approved treatments. Copyright (C) 2020 Elsevier Ltd. All rights reserved.

Simple Summary Primary angiosarcoma of the breast (PAS) and radiation-associated angiosarcoma of the breast (RAAS) are rare sarcomas that affect the inner lining of blood vessels in the breast with incidences of 0.05% and 0.02%, respectively. This study demonstrates that multimodal treatment with neoadjuvant chemotherapy, radiation therapy (in some patients), surgery, and adjuvant chemotherapy may result in optimal clinical outcomes, including prolonged survival. While this study reflects a small sample size, it demonstrates that neoadjuvant chemotherapy, especially when associated with a pathologic complete response, may contribute to these substantial results. Breast angiosarcoma, however, remains a rare disease and prospective, multi-institutional studies need to be performed to overcome the inherent limitations associated with low incidence. Abstract Background: The optimal management of primary angiosarcoma (PAS) and radiation-associated angiosarcoma (RAAS) of the breast remains undefined. Available data show persistently poor survival outcomes following treatment with surgery or chemotherapy alone. The objective of this study was to evaluate long-term outcomes in patients treated with multimodality therapy. Methods: Patients diagnosed with stage I–III PAS or RAAS of the breast were identified from our local tumor registry (2010–2020). Patient demographics, tumor characteristics, and treatment were collected. Primary outcomes were local recurrence (LR), distant recurrence (DR), and median overall survival (OS). A secondary outcome was pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC). Mann–Whitney U, chi-squared, or Fisher exact tests were used to analyze data. Kaplan–Meier curves compared OS for PAS and RAAS. Results: Twenty-two patients met inclusion criteria, including 11 (50%) with RAAS and 11 (50%) with PAS. Compared to PAS patients, RAAS patients were older and had more comorbidities. For RAAS patients, median time from radiation to diagnosis was 6 years (IQR: 5–11). RAAS patients were more likely to have a pCR to NAC (40% vs. 20%, p = 0.72). RAAS patients had a higher LR rate (43% vs. 38%, p = 0.83), and PAS patients were more likely to develop a DR (38% vs. 0%, p = 0.07). Median OS was 81 months in PAS patients and 90 months in RAAS patients (p = 1.00). Discussion: Long-term survival can be achieved in patients with PAS and RAAS who undergo multimodality treatment. NAC can result in pCR. The long-term clinical implications of pCR warrant further investigation.

11555 Background: Leiomyosarcoma (LMS) is a rare group of mesenchymal malignancies found in the uterus, retroperitoneum, skin, or other soft-tissue sites. Treatment for LMS is extrapolated from trials including both uterine (uLMS) and non-uLMS subtypes, although whether they respond similarly and have similar outcomes from treatment is not clear. We examined the molecular composition of LMS by site of origin to better inform future drug development and trial design. Methods: We reviewed 1115 specimens with LMS histology tested by Caris Life Sciences for targeted exome (NextSeq, 592 gene panel), whole exome, and whole transcriptome sequencing (NovaSeq). Specimens were stratified into uLMS, rpLMS (retroperitoneal), and otherLMS (non-uterine/retroperitoneal) subgroups based on tumor origin sites. Genomic data was analyzed for mutations, copy number aberrations, and fusions. RNA expression profiling included evaluation of individual genes and gene set enrichment analysis (GSEA). P-value adjustment performed by the Benjamini-Hochberg procedure. Results: The study cohort was comprised of 62.9% uLMS (n = 701), 14.9% rpLMS (n = 166) and 22.2% otherLMS (n = 248) specimens. Overall, LMS specimens most frequently harbored TP53 (64%, n = 612), ATRX (30%, n = 219), RB1 (22%, n = 156), and MED12 (16%, n = 94) mutations, with these genes accounting for 74.4% (n = 1044) of all observed pathogenic/likely pathogenic mutations. RB1 mutations were significantly less common in uLMS (15%) compared to rpLMS (30%, p < 0.05) and otherLMS (33%, p < 0.01), whereas MED12 mutations were almost exclusive to uLMS (22% vs 1% rpLMS, 3% otherLMS, p < 0.05). MAP2K4 copy number amplification were more common in rpLMS (22%, p < 0.001) and otherLMS (14%, p < 0.182) compared to uLMS (7%), with frequent co-amplification of nearby genes ( FLCN, GID4, SPECC1, GAS7, PER1, and AURKB) located at chr17p11-13. Actionable gene fusions involving ALK (2.1%, n = 11), FGFR1 (0.2%, n = 1), and NTRK1/2 (0.2%, n = 1 each) were rare overall, with similar prevalence across subtypes. Genomic alteration rates were not significantly different between rpLMS and otherLMS subtypes . RNA expression profiling identified significant upregulation of PI3K/AKT/mTOR, DDR, WNT/Beta-Catenin pathway genes in non-uLMS. GSEA indicated several immune-related gene sets were enriched in rpLMS and otherLMS compared to uLMS. Conclusions: Comprehensive molecular profiling suggests that LMS originating from the uterus represents a molecularly distinct disease compared to other primary sites of origin. We identified key genomic patterns which have potential for targeted therapy. These data provide insight for the framework of future clinical trials designed to separate uLMS from non-uLMS histologies, although further subdivision does not appear to be warranted.

e23552 Background: Synovial sarcoma (SS) accounts for 5-10% of all soft tissue sarcoma. SS are aggressive tumors with a median 5-year survival of 60-70% when localized disease but also a propensity for metastatic spread with 40-45% of patients developing metastasis within 5 years. It is considered a chemotherapy-sensitive sarcoma and treatment options are increasing. Herein, we present the outcomes of SS patients by systemic regimen and multimodality approach. Methods: This is a single institution, retrospective cohort of 79 patients with histopathologically confirmed SS treated at from 2004 to 2019. Clinical characteristics, treatment, response and survival were analyzed. We estimated medians of progression-free survival (PFS) and overall survival (OS) using the method of Kaplan-Meier along with the Log-Rank test. All tests were two-sided and statistical significance was considered when p

e23551 Background: Uterine sarcomas are malignant tumors of the smooth muscle or connective tissue of the uterus. Its main histological types are leiomyosarcomas and endometrial stromal sarcomas, with recent classifications considering malignant mixed müllerian tumors (MMMT) as a dedifferentiated endometrial carcinoma rather than a primary uterine sarcoma. We hypothesize there are different risk factors which predispose to MMMT as compared to uterine sarcomas. This study investigates these risk factors to determine if they contribute to the development of either disease. Methods: Under an IRB-approved protocol, we identified patients with uterine sarcomas and MMMT treated at Sylvester Comprehensive Cancer Center and University of Miami Hospital between 2010 and 2020 by Patient Atlas (clinical database tool; Miami, FL). We compared the risk factors known to be associated with endometrial carcinomas between uterine sarcomas and MMMT using independent sample t-test, Chi Square, Spearman Rho and Pearson correlation. Results: A total of 59 patients with MMMT and 115 cases of uterine sarcoma were identified in our database. In the sarcoma group, the most common histology was leiomyosarcoma (n = 76, 66%). Upon analysis of the characteristics of the sarcoma and MMMT cohorts respectively, 38 (33%) vs 16 (27%) were Hispanics, 18 (15%) vs 13 (22%) had diabetes, 26 (22%) vs 20 (34%) used contraception or hormonal replacement therapy (HRT), 35 (30%) vs 17 (28%) were alcohol users, 26 (22%) vs 15 (25%) were smokers, and 54 (47%) vs 31 (52%) had a positive family history of cancer, with no statistically significant differences found (p > 0.05). The sarcoma group had a significantly lower age at diagnosis (AAD) (53 vs. 65, P < 0.001) and a larger tumor size (11.3 vs. 7.3 cm, p < 0.0005). Use of contraception or HRT was not significantly different among the 2 groups (χ(1) = 0.699, p = 0.4). Similarly, no significant difference was found in the mean age of menarche/menopause, patient’s weight, median gravidity and parity (p > 0.05). The patient’s weight and BMI negatively correlated with the AAD in the MMMT group (ρ = - 0.279, p = 0.043 and r = -0.274, p = 0.041 respectively). Older age at menopause was associated with older AAD in the sarcoma group (ρ = 0.571, p = 0.0001). Patients with higher gravidity and parity had an older AAD among the 2 groups (p ≤ 0.05). Conclusions: The uterine sarcoma patients had significantly younger AAD than the MMMT group, with the age at menopause being positively correlated with the AAD. The use of contraception or HRT were not significantly different among the 2 cohorts, suggesting that there could be an overlap of the risk factors of MMMT and uterine sarcomas. Interestingly, higher gravidity and parity were associated with an older AAD. In the MMMT group, patient’s weight and BMI were inversely associated with the AAD. Larger studies are needed to investigate whether similarities or discrepancies in the studied risk factors truly exist.

11512 Background: Leiomyosarcomas (LMS) have been reported to have immunohistochemical (IHC) and gene expression signatures suggestive of an immune-responsive tumor microenvironment. Despite this, immune checkpoint inhibitors have demonstrated minimal activity in LMS. We examined molecular profiles of LMS specimens from multiple institutions to explore mechanisms of immunotherapy (IO) resistance. Methods: LMS specimens (n = 1115), including 701 uterine (uLMS) and 414 soft tissue site (stLMS) samples, underwent next-generation sequencing (NGS) of DNA (592-gene panel or whole exome) and RNA (whole transcriptome, n = 537) at Caris Life Sciences (Phoenix, AZ). A threshold of 10 mut/Mb was used to identify high tumor mutational burden (TMB-H). IHC was performed for PD-L1 (SP142; 2+|5% positive). Deficient mismatch repair (dMMR)/high microsatellite instability (MSI-H) was tested by IHC and NGS, respectively. RNA expression was analyzed using Gene Set Enrichment Analysis and Microenvironment Cell Populations-counter, with results compared to melanoma (n = 1255) as a representative immunogenic tumor type. P-values were adjusted for multiple hypothesis testing. Results: TMB-H was observed in 3.8% (n = 41) of LMS specimens, with a median of 5 mut/Mb (IQR 3.3-6.7). dMMR/MSI-H was rarely detected (1.5%, n = 17), whereas 8.2% (n = 88) were positive for PD-L1 expression. uLMS and stLMS did not differ in TMB-H (3.4 vs 4.5%, p = 0.277), PD-L1 expression (8.6 vs 7.4%, p = 0.322), or dMMR/MSI-H (2.0 vs 0.7% p = 0.207). stLMS demonstrated upregulation of immune-related gene sets, including interferon γ (p = 0.035) and α (p = 0.033) response, inflammatory response (p = 0.038), interleukin-6/STAT3 signaling (p = 0.030), and TNFα signaling (p = 0.026) compared to uLMS. Immune cell infiltration was increased in stLMS over uLMS, most notably for CD8 T-cell and B-cell abundance ( > 2-fold increase, p < 0.0001). Compared to melanoma, all LMS had lower abundance of CD8 T cells, cytotoxic lymphocytes, and B-cells ( > 2-fold decrease, p < 0.0001). Fibroblasts were more prevalent in LMS relative to melanoma (3.2-fold increase, p < 0.0001). Interestingly, while higher CD8 T-cell infiltration was positively associated with dMMR/MSI-H among LMS specimens (p = 0.032), TMB-H and PD-L1 expression were associated with lower CD8 T-cell infiltration (p < 0.01). Conclusions: Only a small proportion of LMS are TMB-H or MSI-H, suggesting that the neoantigen burden in LMS may be insufficient to promote a robust anti-tumor response, even in the presence of PD-L1 positive tumor cells. Traditional predictive biomarkers of response to IO are unlikely to be useful in LMS. Furthermore, both uLMS and stLMS have an immune microenvironment characterized by a high fibroblast and low T cell abundance relative to melanoma. Future IO trials in LMS should focus on combination therapies that may reverse the observed T-cell exclusion/desmoplastic phenotype.

11536 Background: Ripretinib is a switch-control tyrosine kinase inhibitor that broadly inhibits KIT and PDGFRA kinase signaling. In the INVICTUS study (NCT03353753), patients with advanced GIST (≥4th-line) receiving ripretinib had a median progression-free survival (mPFS) of 6.3 months vs 1.0 month for patients receiving placebo (HR = 0.15, p

BACKGROUND Alveolar soft part sarcoma (ASPS), chondrosarcoma (CS), chordoma, epithelioid sarcoma, and solitary fibrous tumor (SFT) are malignant tumors that are relatively resistant to chemotherapy and for which more effective drug therapy is needed. METHODS The 5 listed subtypes were enrolled into a single indolent sarcoma cohort in a phase 2 study of dasatinib using a Bayesian continuous monitoring rule for enrollment. The primary objective was to estimate the 6-month progression-free survival (PFS) rate according to the Choi criteria with a target of ≥50%. Cross-sectional imaging was performed before the start of treatment, every 2 months for 6 months, and then every 3 months during treatment. The 2- and 5-year survival rates were determined. RESULTS One hundred sixteen patients were enrolled within 45 months, and 109 began treatment with dasatinib. The 6-month PFS rate and the median PFS were 48% and 5.8 months, respectively. The PFS rate at 6 months was highest with ASPS (62%) and lowest with SFT (30%). More than 10% of the patients with ASPS, CS, or chordoma had stable disease for more than 1 year. Collectively, for all 5 subtypes, the 2- and 5-year overall survival rates were 44% and 13%, respectively. An objective response was observed in 18% of the patients with CS or chordoma. CONCLUSIONS Dasatinib failed to achieve control of sarcoma growth for at least 6 months in more than 50% of the patients in this trial according to the Choi tumor response criteria. An objective tumor response and prolonged stable disease was observed in >10% of patients with CS or chordoma. Cancer 2016. © 2016 American Cancer Society.

e23540 Background: Uterine sarcomas are rare and aggressive malignant tumors that arise from the smooth muscle or connective tissue cells of the uterus. They account for approximately 1% of the female tract malignancies and 3% of all malignant tumors of the uterus. The risk factors that would predispose to uterine sarcomas have always been unknown, with no clear correlation with specific etiologies. This review is to investigate the risk factors that have been looked at by prior studies to have a better understanding of the population at higher risk for uterine sarcomas. Methods: A total of 88 studies were obtained via Pubmed search. The search terms included: Uterus, sarcoma, and risk factors. We also included reviews with the following mesh terms: Uterus, Sarcoma, Etiology and factors. We reviewed studies in English (n = 75) and French (n = 4) languages, human studies and comprising adults. We included only studies with electronic copies. Retrospective, case-control studies and systematic reviews were included. Results: Of the 88 studies, 18 mentioned risk factors and demographic characteristics of the population with uterine sarcomas. Some studies have shown an association with the tumor size – especially more than or equal to 8cm-, uterine weight, patient’s age being > 45-50 years old, age at menarche, obesity, tamoxifen use, previous pelvic irradiation, as well as genetic associations. Mixed evidence has been found regarding the role of the ethnicity, age at menopause, age at first live birth and exogenous estrogen use. Breast cancer has been linked to more aggressive histologic cell types. Conclusions: Given its relatively rare incidence, uterine sarcoma has been mysterious in regards to its risk factors. The results of this review highlight the need for further studies to investigate the risk factors and exposures that may lead to development of uterine sarcomas, as well as linking them to the different histologic types.

11535 Background: Ripretinib is a novel switch-control tyrosine kinase inhibitor (TKI) that broadly inhibits KIT and PDGFRA kinase signaling through a dual mechanism of action. In INVICTUS (NCT03353753), a randomized, double-blind, placebo-controlled trial of ripretinib in ≥4th-line advanced GIST, ripretinib reduced the risk of disease progression or death by 85% vs placebo and had a favorable overall safety profile in patients previously treated with ≥3 prior TKIs. Methods: As part of the INVICTUS trial, patient reported outcome (PRO) measures were collected using EQ-5D-5L (EQ5D) and EORTC QLQ-C30 (C30). In prespecified and additional analyses, ANCOVA models were built to compare changes from baseline to cycle 2 day 1 (C2D1) for PRO measures within the ripretinib and placebo arms and determine the difference between treatment arms. PRO measures included the EQ5D visual analogue scale (VAS) and the C30 physical functioning (PF) and role functioning (RF) scales (all scores range from 0–100; higher scores are better). The C30 overall health and overall QoL questions were also assessed (scores range from 1–7; higher scores are better). Fixed effects included treatment arm, number of previous anticancer treatments (3 vs ≥4), and ECOG score at baseline (0 vs 1/2). Results: Overall, 129 patients were randomized and 128 received treatment (85 to ripretinib 150 mg QD; 43 to placebo). All PRO p-values are nominal, and no statistical significance is being claimed. VAS scores improved an average 3.7 points from baseline to C2D1 with ripretinib vs an average decline of 8.9 with placebo (P = 0.004; improvement or no change, 67% vs 41% of patients, respectively). Similarly, the average PF score improved 1.6 points with ripretinib and decreased 8.9 with placebo (P = 0.004; improvement or no change, 68% vs 44%). RF scores also improved an average of 3.5 points with ripretinib vs a decrease of 17.1 with placebo (P = 0.001; improvement or no change, 77% vs 50%). For the overall health and overall QoL questions, scores increased with ripretinib an average of 0.20 and 0.28, respectively, and decreased 0.78 and 0.76 with placebo (both P = 0.001; improvement or no change, 74% vs 47% and 79% vs 59%, respectively). Conclusions: Based on the 5 PRO measures assessed, when compared with placebo and best supportive care, ripretinib provided patient-benefit in advanced GIST with PRO measures of role and physical function, VAS, overall health, and overall QoL remaining stable. Clinical trial information: NCT03353753 .

Importance Gastrointestinal stromal tumors (GISTs) are life-threatening when metastatic or not amenable to surgical removal. In a few patients with advanced GISTs refractory to imatinib mesylate, treatment with sunitinib malate followed by regorafenib provides tumor control; however, additional active treatments are needed for most patients. Objective To evaluate the 6-month progression-free survival (PFS), tumor objective response, and overall survival rates in patients with GISTs treated with dasatinib. Design, Setting, and Participants This single-arm clinical trial used a Bayesian design to enroll patients 13 years or older with measurable imatinib-refractory metastatic GISTs treated at 14 sarcoma referral centers from June 1, 2008, through December 31, 2009. A control group was not included. Patients were followed up for survival for a minimum of 5 years from date of enrollment. Tumor imaging using computed tomography or magnetic resonance imaging was performed every 8 weeks for the first 24 weeks and every 12 weeks thereafter. Tumor response was assessed by local site using the Choi criteria. Treatment was continued until tumor progression, unacceptable toxic effects after reduction in drug dose, or patient or physician decision. Archival tumor tissue was evaluated for expression of the proto-oncogene tyrosine-protein kinase Src (SRC), phosphorylated SRC (pSRC), and succinate dehydrogenase complex iron sulfur subunit B (SDHB) proteins and for mutation in the V-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog ( KIT ) and platelet-derived growth factor receptor α ( PDGFRA ) genes. Data analysis was performed from May 19, 2017, through December 20, 2017. Interventions Dasatinib, 70 mg orally twice daily. Main Outcomes and Measures The primary end point was the 6-month PFS estimate using greater than 30% as evidence of an active drug and less than 10% as evidence of inactive treatment. Results In this study, 50 patients were enrolled (median age, 60 years; age range, 19-78 years; 31 [62%] male and 19 [38%] female; 41 [82%] white), and 48 were evaluable for response. The estimated 6-month PFS rate was 29% in the overall population and 50% in a subset of 14 patients with pSRC in GISTs. Objective tumor response was observed in 25%, including 1 patient with an imatinib-resistant mutation in PDGFRA exon 18. Conclusions and Relevance Dasatinib may have activity in a subset of patients with imatinib-resistant GISTs. Further study is needed to determine whether pSRC is a prognostic biomarker.

Neutropenic enterocolitis (NE) is an unusual acute complication of neutropenia, most often associated with leukemia and lymphoma which is characterized by segmental cecal and ascending colon ulceration that may progress to necrosis, perforation, and septicemia. We present a case of neutropenic enterocolitis in a patient with non-small-cell lung cancer who received docetaxel and flavopiridol as part of a phase I clinical trial and review cases in the literature where docetaxel was involved. Given the increased use of docetaxel and other taxanes in the treatment of advanced lung cancer, physicians should be aware of this potential toxicity of therapy.

Purpose Ridaforolimus is an inhibitor of mammalian target of rapamycin, an integral component of the phosphatidyl 3-kinase/AKT signaling pathway, with early evidence of activity in sarcomas. This multicenter, open-label, single-arm, phase II trial was conducted to assess the antitumor activity of ridaforolimus in patients with distinct subtypes of advanced sarcomas. Patients and Methods Patients with metastatic or unresectable soft tissue or bone sarcomas received ridaforolimus 12.5 mg administered as a 30-minute intravenous infusion once daily for 5 days every 2 weeks. The primary end point was clinical benefit response (CBR) rate (complete response or partial response [PR] or stable disease ≥ 16 weeks). Safety, progression-free survival (PFS), overall survival (OS), time to progression, and duration of response were also evaluated. Results A total of 212 patients were treated in four separate histologic cohorts. In this heavily pretreated population, 61 patients (28.8%) achieved CBR. Median PFS was 15.3 weeks; median OS was 40 weeks. Response Evaluation Criteria in Solid Tumors (RECIST) confirmed response rate was 1.9%, with four patients achieving confirmed PR (two with osteosarcoma, one with spindle cell sarcoma, and one with malignant fibrous histiocytoma). Archival tumor protein markers analyzed were not correlated with CBR. Related adverse events were generally mild or moderate and consisted primarily of stomatitis, mucosal inflammation, mouth ulceration, rash, and fatigue. Conclusion Single-agent ridaforolimus in patients with advanced and pretreated sarcomas led to PFS results that compare favorably with historical metrics. A phase III trial based on these data will further define ridaforolimus activity in sarcomas.

Soft tissue sarcomas (STS) represent a diverse group of histologic subtypes with targetable molecular alterations, often treated as a single disease. Sunitinib malate is a multitargeted receptor tyrosine kinase inhibitor active in other solid tumors carrying similar alterations (i.e., imatinib mesylate-refractory gastrointestinal stromal tumors). This single-institution phase II study investigated the safety and efficacy of sunitinib malate in three common STS subtypes. Patients with documented unresectable or metastatic STS (liposarcoma, leiomyosarcoma, and malignant fibrous histiocytoma [MFH]), measurable disease, and 3 or less prior lines of therapy were eligible. Treatment consisted of sunitinib malate, 50 mg daily, for 4 weeks every 6 weeks. Forty-eight patients were enrolled, and 35% were heavily pretreated (≥2 prior lines of chemotherapy). The safety profile resembled previously known sunitinib malate toxicities. Median progression-free and overall survivals for liposarcoma, leiomyosarcoma, and MFH were 3.9 and 18.6, 4.2 and 10.1, and 2.5 and 13.6 months, respectively. The 3-month progression-free rates in the untreated and pretreated (chemotherapy) patients with liposarcoma, leiomyosarcoma, and MFH were 75% and 69.2%, 60%, and 62.5%, and and 25% and 44.4%, respectively. With the caveats that a minority of patients with potentially indolent or low-grade disease could have been included and the small numbers, a 3-month progression-free rate of >40% suggests activity for sunitinib malate at least in liposarcomas and leiomyosarcomas. Thus, we believe that further investigation in these susceptible STS subtypes is warranted.

Background Sunitinib inhibits KIT and other members of the split-kinase-domain family of receptor tyrosine kinases. Sunitinib prolongs survival in adult patients with imatinib-resistant gastrointestinal stromal tumor (GIST). We report the experience with sunitinib in pediatric patients with advanced GIST following failure of imatinib. Procedure Sunitinib therapy was provided through a treatment-use protocol. Patients were 10–17 years old at enrollment. All patients had GIST resistant to imatinib therapy. Sunitinib was administered daily for 4 weeks in 6-week treatment cycles. KIT and platelet-derived growth factor receptor alpha (PDGFRA) genotyping of tumor tissue were performed. Results One patient achieved a partial response, five patients had stable disease and one patient had progressive disease on sunitinib. The duration of disease stabilization was between 7 and 21+ months, with a mean of 15 months. Time to tumor progression was longer on sunitinib than on prior imatinib treatment for five of six patients. Two patients experienced grade 3 adverse events. All other adverse events were grade 1–2. None of the five patients tested had mutations in KIT or PDGFRA. Conclusion Sunitinib treatment was associated with substantial initial antitumor activity and acceptable tolerability in this group of pediatric patients with imatinib-resistant GIST. Pediatr Blood Cancer 2009;52:767–771. © 2009 Wiley-Liss, Inc.

BackgroundSarcomas are rare mesenchymally derived tumors for which there are limited treatment options. This paper discusses the current therapeutic potential of directed tyrosine kinase inhibitors (TKIs) in sarcoma.MethodsThe authors review antibody-based strategies and small molecular inhibitors of TKIs, with specific emphasis placed on the potential use of these targeted agents as therapeutic options for the treatment of sarcomas that are not gastrointestinal stromal tumors.ResultsMany TKs have been shown to be mutated or overexpressed in human sarcoma tumors and cell lines and may serve as potential targets for promising new sarcoma therapies. Furthermore, the novel mechanism of targeting TKs may complement the antitumor activity of existing sarcoma treatment options.ConclusionsTKIs such as imatinib, sunitinib, and sorefanib are promising new therapeutic options for the management of patients with soft tissue sarcoma.

The soft-tissue sarcomas (STS) of childhood are a relatively rare and heterogeneous group of tumors that may occur anywhere in the body and respond quite differently to therapy. STSs account for 7.4% of all cancers in children younger than 20 years [1]. These soft tissue sarcomas are divided almost equally between rhabdomyosarcomas originating from striated muscle and nonrhabdomyosarcoma soft tissue sarcomas (NRSTS). Sarcomas are malignant tumors of mesenchymal cell origin. They are named according to the normal tissue they resemble — for example, rhabdomyosarcoma (skeletal muscle), leiomyosarcoma (smooth muscle), and fibrosarcoma and malignant fibrous histiocytoma (connective tissue), neurofibrosarcoma or malignant peripheral nerve sheath tumor (neurofibrosarcomas, as seen in patients with neurofibromatosis), liposarcoma (adipose), synovial sarcoma (synovium), peripheral nerve sheath tumors (peripheral nerve), and angiosarcoma (blood and/or lymphatic vessels). Other sarcomas include rare entities such as alveolar softpart sarcoma, extraosseous Ewing’s sarcoma, peripheral neuroectodermal tumors, epitheloid sarcoma, and hemangiopericytoma.

Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, are an example of a disease with an effective, molecularly targeted therapy.Published articles and author experience were used to comprehensively define the clinical features, biology, and state-of-the-art therapy of GISTs.GISTs are thought to originate from the neoplastic transformation of the interstitial cells of Cajal, the intestinal pacemaker cells. GISTs commonly have mutations in the kit gene, resulting in a gain-of-function mutation and ligand-independent constitutive activation of the KIT receptor tyrosine kinase. Successful tyrosine kinase inhibitors target the aberrant pathways that are critical for tumor cell viability. The development of imatinib mesylate (formerly STI 571) in the treatment of metastatic GISTs represents a therapeutic breakthrough.Progress in the clinical diagnosis has led to an increased recognition of this disease as a distinct clinical entity. Treatment of metastatic GIST with imatinib has led to unprecedented improvements in progression-free and overall survival. The use of imatinib in the preoperative and postoperative treatment of GISTs is an area of intense investigation.

10535 Background: Metastatic soft tissue sarcoma represents a diverse collection of disease types. Sunitinib malate is a multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and stem cell factor receptor, with proven efficacy in imatinib mesylate-refractory or intolerant gastrointestinal stromal tumors (GIST). This study was designed to evaluate the efficacy and tolerability of sunitinib malate in four non-GIST sarcoma subytpes (liposarcoma, malignant fibrous histiocytoma, fibrosarcoma and leiomyosarcoma). Methods: Eligibility criteria included tissue documented metastatic soft tissue sarcomas, measurable disease (by RECIST criteria), and a maximum of three prior lines of therapy for metastatic disease. Treatment was with sunitinib malate 50 mg orally daily in 6 week cycles (4 weeks on/ 2 weeks off). Results: Thirty-six subjects have been accrued to date, 12 patients with leiomyosarcoma, 12 with liposarcoma, 11 with...

10076 Background: AP23573 is an mTOR inhibitor that has demonstrated single-agent activity in a broad range of sarcoma tumor types in phase I phase II trials. Overall survival (OS) was monitored to characterize OS in the treated population and in the subset of patients who achieved a clinical benefit response (CBR). Methods: Pts with advanced sarcomas, with no restrictions on prior therapies, were enrolled into 4 cohorts based on histologic subtype, in a phase 2, Simon's 2-stage trial. AP23573 (12.5 mg, i.v.) was administered daily × 5 every 2 wks. Efficacy was assessed using RECIST, with CBR defined as a complete or partial response or stable disease for at least 16 wks duration. OS was defined as the time from the first dose of AP23573 to the date of death from any cause. Kaplan-Meier estimates of the survival times of the population were calculated with OS time censored at the last date the pt was known to be alive when the confirmation of death is absent or unknown. Patients are continuing to be followed for OS in this ongoing trial. Results: 212 pts (105 M/107 F; median age, 50.6 yrs ([17–79 yrs]) were treated. Most pts (79%) had received =2 prior treatments, and over 90% of pts had disease progression at time of enrollment. The overall CBR rate was 29%, including 5 PRs (4 bone sarcoma, 1 MFH). The median OS was 40.1 wks for the entire study population. In the subset of patients achieving CBRs the median time to OS was 67.6 wks, suggesting that achievement of CBR, which is a measure of tumor control, correlates with extending OS. Conclusions: AP23573 exhibits single-agent activity in pts with advanced sarcomas as demonstrated by the CBR rate as a primary efficacy endpoint. The results of the OS analysis suggest that achieving a CBR in this pt population can result in prolonged survival. The consistency of this finding should be further examined with other pt factors that are also hypothesized to correlate for survival in this pt population. [Table: see text] [Table: see text]

Soft tissue sarcomas are the most frequent sarcomas; the annual incidence for 2007 in the United States is estimated at about 9220 cases, with an overall mortality rate of approximately 3560 cases per year. Important updates for the 2007 version of the guidelines include the addition of epirubicin (single agent) and the combination of epirubicin, ifosfamide, and mesna as generally accepted systemic therapy. Imatinib was added as an option for desmoid tumors. For the most recent version of the guidelines, please visit NCCN.org

9519 Background: The genotype of most GIST in pediatric patients (pts) is “wild type” (WT-GIST), with no detectable KIT or PDGFR-α mutations. Adults with metastatic WT-GIST often have suboptimal results and primary resistance to imatinib (IM) therapy. Treatment with sunitinib malate (SU11248), an oral, multitargeted tyrosine kinase inhibitor with antiangiogenic and antitumor activities, results in significant clinical benefit, such as improved survival, for adult pts with IM-resistant GIST, including WT-GIST. We report here the treatment of 3 pediatric pts with IM-resistant, metastatic GIST using sunitinib. Methods and Patients: Pt 1 presented at age 17 with numerous abdominal and hepatic GIST metastases. Following surgical debulking and 6 wks of IM treatment, objective progression was noted due to growth of omental masses and a new hepatic lesion. Pt 2 presented at age 8 with an isolated gastric GIST, fully resected, followed by adjuvant IM that continued until resection of a local recurrence 14 mos later. She had 2 more local recurrences and developed lung metastases. Pt 3 presented at age 13 with a large gastric GIST and a retroperitoneal metastasis, both fully resected and followed by adjuvant IM for 18 mos. Six mos after discontinuing IM, recurrent metastatic GIST was noted in the liver and retroperitoneum; IM therapy was resumed with stable disease for 1 yr when new hepatic lesions appeared with progression of the retroperitoneal mass. Pts 1 and 2 had WT-GIST, while genotyping of Pt 3 is pending. Sunitinib, obtained via an expanded-access protocol, was administered in 6-wk cycles, orally QD for 4 wks followed by 2 wks off dosing. Results: All pts have received 5 cycles of sunitinib. All GIST lesions have stabilized or decreased in size by CT imaging, with complete regression of 2 lung nodules in Pt 2. 18FDG-PET imaging obtained in 2 pts showed significant decreases in tumor-associated activity at all disease sites. Side effects with sunitinib have been manageable, including grade 2 GI and hematologic toxicities in pt 1, grade 3 fatigue in pt 2 and grade 3 hematologic toxicity in pt 3. Conclusions: Sunitinib shows important antitumor activity in pediatric pts with IM-resistant GIST. An expanded phase I/II trial of sunitinib in pediatric GIST is warranted. [Table: see text]

9505 Background: AP23573 is an mTOR inhibitor that has shown anti-tumor activity in phase 1 clinical trials, particularly in patients with advanced sarcomas. Given this observation, this phase 2 trial was undertaken to assess further the efficacy and safety of AP23573 across various sarcoma subtypes. Methods: Advanced sarcoma pts, with no restrictions on prior therapies, were enrolled into 4 cohorts based on histologic subtype, in a phase 2 trial with Simon’s 2-stage design. AP23573 (12.5 mg, i.v.) is administered for 5 days every 2 wks. Efficacy is assessed using RECIST guidelines, with clinical benefit response (CBR) defined as complete or partial response (PR) or stable disease (SD) for at least 16 wks duration. For each cohort, treatment was defined as successful if the proportion of patients with CBR was ≥ 25%. Studies of potential predictive markers of response include 18FDG-PET imaging, analysis of mTOR pathway proteins in tumoral tissue, and measurement of plasma cytokines and angiogenic factors. Results: In total, 216 pts were enrolled as all cohorts met criteria to enter Stage 2 of the trial. Of these pts, 213 were treated (106 M/107 F) (age 17–79 yrs, median 50 yrs). Most frequent related adverse events included mucositis, rash, hyperlipidemia, fatigue, and thrombocytopenia. Preliminary response data for 193 evaluable pts are available: overall 54 (28%) had CBRs, including 5 PRs (3 pts with osteo, 1 with spindle cell of bone, and 1 with MFH). Twenty of 76 pts (26%) imaged with PET had rapid induction of partial metabolic responses following 3 to 5 days of study treatment. Conclusions: Initial assessments from this trial show that single-agent AP23573 is well tolerated and has efficacy in pts with advanced sarcomas that warrants evaluation in phase 3. Analysis of the potential utility of FDG-PET and a broad set of candidate biomarkers continues. Enrollment is complete, and pt treatment and follow-up are ongoing. [Table: see text] [Table: see text]

9040 Background: Leiomyosarcomas (LMS) are one of the most common histologic types of soft tissue sarcoma and are usually resistant to standard chemotherapy. Bortezomib (PS 341) a reversible inhibi...

9002 Background: Leiomyosarcomas (LMS) are one of the most common histological types of soft tissue sarcomas and are usually resistant to standard chemotherapy. Novel agents that can cause apoptosi...