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Purpose: Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor with few treatment options. We designed a phase II randomized trial to determine the activity and tolerability of single-agent cediranib or sunitinib in patients with advanced metastatic ASPS. Patients and Methods: Patients 16 years of age and older were randomized to receive cediranib (30 mg) or sunitinib (37.5 mg) in 28-day cycles. Patients could cross over to the other treatment arm at disease progression. The primary endpoint was to measure the objective response rate (ORR) for each agent. Median progression-free survival (mPFS) for the two arms was also determined. Results: Twenty-nine of 34 enrolled patients were evaluable for response. One patient on each of the initial two treatment arms had a partial response (ORR: 6.7% and 7.1% for cediranib and sunitinib, respectively). Twenty-four patients had a best response of stable disease (86.7% and 78.6% for cediranib and sunitinib, respectively). There were no significant differences in mPFS for the two treatment arms. Clinical benefit (i.e., objective response or stable disease for a minimum of four or six cycles of therapy) on the first-line tyrosine kinase inhibitor (TKI) therapy did not predict benefit on the second-line TKI. Both drugs were well tolerated. As of August 2021, 1 patient (unevaluable for ORR) remains on study. Conclusions: The study did not meet its endpoints for ORR. Although both TKIs provided clinical benefit, the outcomes may have been attenuated in patients who had progressed ≤6 months before enrollment, potentially accounting for the low response rates. See related commentary by Wilky and Maleddu, p. 1163

Normalized Tryptophan Concentrate Over Time

Purpose:Epacadostat, an indole 2,3 dioxygenase 1 (IDO1) inhibitor, proposed to shift the tumor microenvironment toward an immune-stimulated state, showed early promise in melanoma but has not been studied in sarcoma. This study combined epacadostat with pembrolizumab, which has modest activity in select sarcoma subtypes.Patients and Methods:This phase II study enrolled patients with advanced sarcoma into five cohorts including (i) undifferentiated pleomorphic sarcoma (UPS)/myxofibrosarcoma, (ii) liposarcoma (LPS), (iii) leiomyosarcoma (LMS), (iv) vascular sarcoma, including angiosarcoma and epithelioid hemangioendothelioma (EHE), and (v) other subtypes. Patients received epacadostat 100 mg twice daily plus pembrolizumab at 200 mg/dose every 3 weeks. The primary endpoint was best objective response rate (ORR), defined as complete response (CR) and partial response (PR), at 24 weeks by RECIST v.1.1.Results:Thirty patients were enrolled [60% male; median age 54 years (range, 24–78)]. The best ORR at 24 weeks was 3.3% [PR, n = 1 (leiomyosarcoma); two-sided 95% CI, 0.1%–17.2%]. The median PFS was 7.6 weeks (two-sided 95% CI, 6.9–26.7). Treatment was well tolerated. Grade 3 treatment-related adverse events occurred in 23% (n = 7) of patients. In paired pre- and post-treatment tumor samples, no association was found between treatment and PD-L1 or IDO1 tumor expression or IDO-pathway–related gene expression by RNA sequencing. No significant changes in serum tryptophan or kynurenine levels were observed after baseline.Conclusions:Combination epacadostat and pembrolizumab was well tolerated and showed limited antitumor activity in sarcoma. Correlative analyses suggested that inadequate IDO1 inhibition was achieved.

Representativeness of study participants.

Purpose: Dysregulated cyclin-dependent kinases are important to the growth of some sarcomas. Flavopiridol is a pan-CDK inhibitor that has been shown to potentiate chemotherapy. As such, we explored the potentiation of doxorubicin by flavopiridol in sarcoma, in vitro and in vivo, and conducted a phase I trial of flavopiridol with doxorubicin in patients with advanced sarcomas.Experimental Design: Sarcoma cell lines and xenografts were treated with flavopiridol alone and in combination with doxorubicin. In the phase I study, doxorubicin and flavopiridol were administered on two flavopiridol schedules; a 1-hour bolus and split dosing as a 30-minute bolus followed by a 4-hour infusion.Results: Preclinically, flavopiridol potentiated doxorubicin. In vivo, doxorubicin administered 1 hour before flavopiridol was more active than doxorubicin alone. Clinically, 31 patients were enrolled on protocol and flavopiridol was escalated to target dose in two schedules (90 mg/m2 bolus; 50 mg/m2 bolus + 40 mg/m2 infusion) both in combination with doxorubicin (60 mg/m2). Dose-limiting toxicities were neutropenia, leukopenia, and febrile neutropenia but no maximum tolerated dose was defined. Flavopiridol pharmacokinetics showed increasing Cmax with increasing dose. Response Evaluation Criteria in Solid Tumors (RECIST) responses included two partial responses, however, stable disease was seen in 16 patients. Of 12 evaluable patients with progressive well- and dedifferentiated liposarcoma, eight had stable disease greater than 12 weeks.Conclusions: The sequential combination of doxorubicin followed by flavopiridol is well tolerated on both schedules. Disease control was observed in well- and dedifferentiated liposarcoma specifically, a disease in which CDK4 is known to be amplified. Clin Cancer Res; 18(9); 2638–47. ©2012 AACR.

Synergy of dasatinib and anti-CTLA-4. Using murine GIST mouse, it was observed that treatment with the KIT-targeted dasatinib for 7 days alone or with chronic anti-CTLA-4 alone decreased tumor volume initially; however tumors rapidly re-grew. Mice treated with KIT-targeted TKI for 7 days and chronic anti-CTLA-4 blockade showed augmentation and durability of the initial response. KITV5880+ mice received dasatinib 15mg/kg i.p. bid (Bristol Myers Squibb) on days 1 through 7, with or without anti-CTLA-5 (BioXcell.) Mice were imaged at baseline and serially during therapy using MRI and volumetric analysis was done using Image K software. Anti-CTLA-4 dosing regimen 200 microgram of clone 9H10 i.p. on day 3, then 100 microgram on day 6, 9 and 12, followed by clone 9D (100 micrograms i.p. every 3 days thereafter.)

Purpose: A phase Ib study of dasatinib plus ipilimumab in patients with gastrointestinal stromal tumor (GIST) and other sarcomas was performed on the basis of preclinical data demonstrating that combined KIT and CTLA-4 blockade is synergistic.Experimental Design: A standard 3 + 3 design was used to evaluate the safety, efficacy, and immune correlates of treatment. Dose escalation cohorts received ipilimumab 10 or 3 mg/kg every 3 weeks, followed by maintenance every 12 weeks with escalating doses of dasatinib (70 mg daily, 100 mg daily, or 70 mg twice daily). Response was assessed by RECIST 1.1, Choi, and immune-related RECIST criteria (irRC).Results: A total of 28 patients (17 male) were enrolled. Histologic subtypes included GISTs (n = 20) and other sarcomas (n = 8.) Dasatinib 70 mg/day with ipilimumab 10 mg/kg or dasatinib 140 mg/day with ipilimumab 3 mg/kg can be safely administered. Dose-limiting toxicities included grade 3 gastric hemorrhage and anemia. No partial or complete responses were noted by RECIST or irRC. There were 7 of 13 partial responses in the GIST patients by Choi criteria, and 3 of 13 patients each had stable and progressive disease, respectively.Conclusions: Dasatinib and ipilimumab can be safely administered to GIST and sarcoma patients. However, dasatinib was not synergistic with ipilimumab, as there was limited clinical efficacy with the combination. This limited cohort provides prospective data that indoleamine-2,3-dioxygenase (IDO) suppression may potentially correlate with antitumor efficacy in GIST. Given the small cohort, it is only hypothesis generating and additional data would be required. In the era of more modern and effective checkpoint inhibitors, next steps could be consideration of tyrosine kinase inhibitors or IDO inhibitors in combination with anti-PD-1 therapy. Clin Cancer Res; 23(12); 2972–80. ©2016 AACR.

PDF file - 66K, Cumulative grade 2 or greater hematologic toxicity throughout all cycles.

Table of adverse events grade 1-4, at least possibly related to treatment. All G1-G4 at least possible related toxicity.

Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor with few treatment options. We designed a phase 2 randomized trial to determine the activity and tolerability of single-agent cediranib or sunitinib in patients with advanced metastatic ASPS.Patients 16 years of age and older were randomized to receive cediranib (30 mg) or sunitinib (37.5 mg) in 28-day cycles. Patients could crossover to the other treatment arm at disease progression. The primary endpoint was to measure the objective response rate (ORR) for each agent. Median progression-free survival (mPFS) for the 2 arms was also determined.Results: Twenty-nine of 34 enrolled patients were evaluable for response. One patient on each of the initial 2 treatment arms had a partial response (ORR: 6.7% and 7.1% for cediranib and sunitinib, respectively). Twenty-four patients had a best response of stable disease (86.7% and 78.6% for cediranib and sunitinib, respectively). There were no significant differences in mPFS for the 2 treatment arms. Clinical benefit (i.e., objective response or stable disease for a minimum of 4 or 6 cycles of therapy) on the first-line tyrosine kinase inhibitor (TKI) therapy did not predict benefit on the second-line TKI. Both drugs were well tolerated. As of August 2021, 1 patient (unevaluable for ORR) remains on study.The study did not meet its endpoints for ORR. Although both TKIs provided clinical benefit, the outcomes may have been attenuated in patients who had progressed ≤6 months before enrollment, potentially accounting for the low response rates.

Purpose: To determine if a targeted exome panel utilizing matched normal DNA can accurately detect germline and somatic HLA genes in patients with synovial sarcoma (SS) and whether select HLA-A*02 genotypes are prognostic or predictive of outcome in metastatic SS. Experimental Design: Patients with metastatic SS consented to HLA typing by a Clinical Laboratory Improvement Amendments (CLIA)-certified test to determine eligibility for a clinical trial of NY-ESO-1–specific engineered T cells restricted to carriers of HLA-A*02:01, -A*02:05, or -A*02:06 (HLA-A*02 eligible). HLA genotype was determined from Memorial Sloan Kettering Integrated Molecular Profiling of Actionable Cancer Targets (MSK-IMPACT), where feasible, and somatic loss of heterozygosity (LOH) in HLA alleles was identified. Overall survival (OS) was estimated and stratified by HLA-A*02 eligibility. Results: A total of 23 patients had HLA genotyping by a CLIA-certified lab and MSK-IMPACT. Ninety percent (108/110) of the sequenced alleles were concordant between IMPACT and the outside lab. LOH of HLA genes was detected in three tumors, one had loss of HLA-A*02:01. In total, 66 patients were screened for T-cell therapy and 20 (30%) were HLA-A*02 eligible on outside testing. Univariate analysis of OS from the time of metastasis found HLA-A*02 eligibility was marginally associated with shorter OS [HR = 1.95; 95% confidence interval (CI), 0.995–3.813; P = 0.052]. On multivariate analysis, older age and larger tumor size, but not HLA-A*02 eligibility, were significantly associated with decreased OS. HLA-A*02 eligibility did not impact OS after chemotherapy or pazopanib in the metastatic setting. Conclusions: Targeted gene panels like MSK-IMPACT may accurately report HLA type and identify loss of somatic HLA alleles. In a multivariable model, HLA-A*02 eligibility was not significantly associated with OS in patients with metastatic SS.

To evaluate the feasibility, efficacy, and safety of doxorubicin-eluting bead transarterial chemoembolization (DEB-TACE) as an alternative local treatment for extra-abdominal desmoid tumors (DTs).Eleven adult female patients (mean age = 40.1 years) with symptomatic, progressively enlarging extra-abdominal DTs were determined ineligible for cryoablation after failing observation or systemic therapy and treated with a single session doxorubicin DEB-TACE. Six rectus sheath, one chest wall, three axilla, and one upper extremity DTs were included. The median follow-up was 155.0 ± 52.3 days. Treatment response was assessed by MRIs and maximum visual analog scale (VAS).All procedures were technically successful without immediate complications. The average size of treated DT was 161.8 ml (range: 28.3-420.0 ml). The mean doxorubicin dose was 13.3 mg/mDEB-TACE may be a safe and effective local treatment alternative in DT patients.

The genetic, biologic, and clinical heterogeneity of sarcomas poses a challenge for the identification of therapeutic targets, clinical research, and advancing patient care. Because there are > 100 sarcoma subtypes, in-depth genetic studies have focused on one or a few subtypes. Herein, we report a comparative genetic analyses analysis of 2,138 sarcomas representing 45 pathological entities. This cohort was prospectively analyzed using targeted sequencing to characterize subtype-specific somatic alterations in targetable pathways, rates of whole genome doubling, mutational signatures, and subtype-agnostic genomic clusters. The most common alterations were in cell cycle control andTP53, receptor tyrosine kinases/PI3K/RAS, and epigenetic regulators. Subtype-specific associations includedTERTamplification in intimal sarcoma and SWI/SNF alterations in uterine adenosarcoma. Tumor mutational burden, while low compared to other cancers, varied between and within subtypes. This resource will improve sarcoma models, motivate studies of subtype-specific alterations, and inform investigations of genetic factors and their correlations with treatment response.

PD-1 blockade (nivolumab) efficacy remains modest for metastatic sarcoma. In this paper, we present an open-label, non-randomized, non-comparative pilot study of bempegaldesleukin, a CD122-preferential interleukin-2 pathway agonist, with nivolumab in refractory sarcoma at Memorial Sloan Kettering/MD Anderson Cancer Centers (NCT03282344). We report on the primary outcome of objective response rate (ORR) and secondary endpoints of toxicity, clinical benefit, progression-free survival, overall survival, and durations of response/treatment. In 84 patients in 9 histotype cohorts, all patients experienced ≥1 adverse event and treatment-related adverse event; 1 death was possibly treatment-related. ORR was highest in angiosarcoma (3/8) and undifferentiated pleomorphic sarcoma (2/10), meeting predefined endpoints. Results of our exploratory investigation of predictive biomarkers show: CD8 + T cell infiltrates and PD-1 expression correlate with improved ORR; upregulation of immune-related pathways correlate with improved efficacy; Hedgehog pathway expression correlate with resistance. Exploration of this combination in selected sarcomas, and of Hedgehog signaling as a predictive biomarker, warrants further study in larger cohorts.

A hallmark of sarcomas is genetic, biologic, and clinical heterogeneity, which is a challenge for preclinical development of therapeutic targets, clinical trial design, and patient care. Because sarcomas comprise over 100 subtypes, a broad comparative genetic analysis of subtypes has been lacking and sarcoma genetic studies have by necessity focused on one or a few subtypes. We will report the results of a comprehensive analysis of somatic genetic alterations detected by a targeted sequencing platform in a single institution cohort of 2,138 patient-specific samples of soft tissue and bone sarcoma representing 45 distinct pathological entities. We determined subtype-specific mutation and copy number (arm and gene level) events with a focus on pathways in which there are therapeutic targets under clinical or preclinical investigation. The most commonly altered pathways are cell cycle control, TP53, PI3K, receptor tyrosine kinase/RAS, and epigenetic regulators (e.g. >40% of uterine leiomyosarcoma [n=165], undifferentiated pleomorphic sarcoma [UPS, n=145] and pleomorphic liposarcoma [n=22]). Subtype-specific associations in rare subtypes include TERT amplification in 41% of intimal sarcoma (n=18) and alterations in chromatin remodeling and histone modifying complexes in uterine adenosarcoma (43% and 36%, respectively; n=14). Epigenetic pathway alterations in common sarcomas were also noted, including an increased frequency of oncogenic alterations in epigenetic regulators in dedifferentiated liposarcoma (DDLS; n=167) (25%) vs. well differentiated liposarcoma (8%; n=48). We evaluated rates of whole genome doubling (WGD), which in subtypes such as UPS and osteosarcoma (n=129) were >45%, which is more frequent than many carcinomas. WGD associated with worse overall survival in metastatic (p=0.042) but not primary samples (p=0.391). Among specific subtypes, WGD was associated with worse overall survival in metastatic UPS (p=0.022). Unsupervised clustering of samples based on genetic features revealed that in some cases sarcomas are more similar to individual tumors of distinct histology than to other sarcomas of the same subtype. For example, UPS and soft tissue leiomyosarcoma (n=125) segregated into multiple genetic clusters (high entropy) compared to others with low entropy (DDLS), which could have implications for future clinical trial interpretation and/or design. We also determined the subtype-specific rate of tumor mutation burden, which was overall low compared to many carcinomas, but notably varied between and within subtypes, with some having a long tail in the upper range of the distribution. Lastly, we assessed targetable alterations on a subtype-specific basis. Together with other ‘multiomic’ approaches, we anticipate this work will motivate preclinical studies of subtype-specific sarcoma biology and potential therapeutic targets and will inform efforts to interpret outcomes in sarcoma clinical trials with respect to underlying genetic subtypes. Citation Format: Benjamin A. Nacev, Francisco Sanchez-Vega, Shaleigh Smith, Cristina Antonescu, Evan Rosenbaum, Hongyu Shi, Cerise Tang, Nicholas Socci, Satshil Rana, Rodrigo Gularte-Merida, Ahmet Zehir, Mrinal Gounder, Timothy Bowler, Anisha Luthra, Bhumika Jadeja, Azusa Okada, Jonathan Strong, Jake Stoller, Jason Chan, Ping Chi, Sandra D'Angelo, Mark Dickson, Ciara Kelly, Mary Louise Keohan, Sujana Movva, Katherine Thornton, Paul Meyers, Leonard Wexler, Emily Slotkin, Julia Glade Bender, Neerav Shukla, Martee Hensley, John Healey, Michael La Quaglia, Kaled Alektiar, Aimee Crago, Sam Yoon, Brian Untch, Sarah Chiang, Narasimhan Agaram, Meera Hameed, Michael Berger, David Solit, Nikolaus Schultz, Marc Ladanyi, Samuel Singer, William Tap. Targeted sequencing of 2,138 bone and soft tissue sarcomas reveals commonly altered pathways, subtype-independent genetic clusters, and potential therapeutic targets [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr PR012.

Background: Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor with few effective treatment options. Cediranib (C) and sunitinib (S) are potent oral inhibitors of all 3 VEGF receptors. Cediranib showed substantial single-agent activity (objective response rate [ORR] = 35%) in our previous trial in patients (pts) with metastatic ASPS (NCT00942877). Here we report a phase 2 randomized multicenter trial of single agent C or S in pts with ASPS (NCT01391962). Methods: We conducted a multicenter phase 2 trial with an optimal 2-stage design targeting an ORR of 40%. Enrolled pts were >16 years with metastatic ASPS, previously not treated (N) and unresectable, or previously treated (T), who have progressed per RECIST 1 within the 6-month period preceding enrollment. Pts were randomized to receive C (30 mg) or S (37.5 mg) orally, once a day, in 28-day cycles and could crossover to the other treatment arm at disease progression. ORR (primary endpoint), median progression-free survival (mPFS), and PFS rate at 24 weeks for the 2 arms (C and S) were evaluated; T and N cohorts were assessed separately in each arm. Arm accrual closed if ≤ 1 of the first 10 enrolled pts responded to the first treatment. Results: Thirty-four pts (47% white, 29.4% black, 17.6% Asian, 5.8% Pacific Islander) were enrolled; 29 pts were evaluable for response. One pt on each of the initial treatment arms had a confirmed partial response (PR), rates of 6.7% (1/154) and 7.1% (1/14) for C and S tx or tx-naive, respectively. Among pts who crossed over, there was 1 PR in a pt receiving C after initially responding (PR) on S (1/9; ORR 11.1%). Twenty-four pts had a best response of stable disease (86.7% and 78.6%) for C and S, respectively. The mPFS was 7.6 months (mo) (95% CI: 3.7-9.9 mo) and 5.5 mo (95% CI: 1.8-14.5 mo) for C and S, respectively administered as first therapy (p=0.92). PFS rate at 24 weeks was 62.5% (95% CI: 29.5-76.2%) and 50% (95% CI: 25.9-70.1%) for pts receiving C and S respectively, as initial therapy. There was no difference in mPFS between T or N pts in the C (6.7 mo [95% CI: 1.4-9.9 mo] vs 8.3 mo [95% CI: 2.7 - 16.6 mo]; P=0.35) arm, but some evidence of a potential difference in the S (4.8 mo [95% CI: 0.9-7.9 mo] vs 14.7 mo 95% CI: 1.8 - 21.6 mo]; P=0.058) arm. Overall, 43.7% (C) and 77.8% (S) of pts experienced grade ≥3 adverse events (AEs) at least possibly related to the study drug. Common grade ≥3 AEs included: diarrhea (C), neutropenia (S), hypertension (C and S). AEs were in line with the known safety profiles of each agent. As of August 2021, 1 pt (unevaluable for ORR) remains on study. Conclusions: The study did not meet its endpoints for ORR. There were no differences in mPFS for the 2 treatment arms. The selection of pts with more aggressive disease, who had progressed in the 6 months prior to enrollment, may account for the low patient response rates compared to our previous study of cediranib in ASPS. Funded by NCI Contract No. HHSN261200800001E. The study was a collaboration between NCI and Pfizer. Citation Format: Naoko Takebe, James Nguyen, Shivaani Kummar, Albiruni Abdul Razak, Sant P. Chawla, Suzanne George, Shreyaskumar R. Patel, Mary Louise Keohan, Sujana Movva, Geraldine O’Sullivan, Khanh Do, Larry Anderson, Lamin Juwara, Brooke Augustine, Seth Steinberg, Laura Kuhlmann, S. Percy Ivy, James H. Doroshow, Alice P. Chen. Randomized phase 2 trial of sunitinib or cediranib in alveolar soft part sarcoma [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 CT168.

11516 Background: In a phase III trial, GD had similar response and survival rates to doxorubicin when administered as first-line therapy to advanced STS pts. G and D have each demonstrated synergy with PD-1 blockade in pre-clinical or clinical studies. We hypothesized that GD plus R would be safe, tolerable, and have synergistic activity in STS. Methods: This is an ongoing open-label, single-center, phase I/II trial of R (INCMGA00012) combined with GD in pts with treatment-naïve unresectable or metastatic high-grade STS. Herein, we report the phase I results, which included a safety run-in followed by a 3+3 dose de-escalation design. G (900 mg/m2) was administered on days 1 and 8 and D (75 mg/m2) on day 8, in 21-day cycles. R (210 mg IV flat dose on the run-in portion and 375 mg on the dose de-escalation portion) was administered on day 1 of each cycle starting in cycle 2 and continued as monotherapy after completion of 6 cycles of GD. The primary endpoint of the phase I was to determine the recommended phase 2 dose (RP2D) of R plus GD. Secondary endpoints included describing the safety, assessing best overall response rate (ORR) by RECIST 1.1, disease control rate (DCR), and progression-free survival (PFS). Results: Thirteen pts were treated, 7on the run-in and 6 on the de-escalation portion. One pt progressed prior to starting R and was replaced. Median pt age was 53 (range 28 – 74) and 7 were female. Histologies included leiomyosarcoma (n = 6), undifferentiated pleomorphic sarcoma (2), dedifferentiated liposarcoma (2), pleomorphic liposarcoma (1), angiosarcoma (1), and myxofibrosarcoma (1). The Table lists treatment-related adverse events (TRAEs) that occurred in ≥ 20% pts in descending order of frequency. Additional Grade (Gr) 3 TRAEs occurring in 1 pt each, included: infusion reaction, leukopenia, anorectal infection, neutropenia, and pyelonephritis. Gr 3 pyelonephritis was the only dose-limiting toxicity. There were no Gr ≥ 4 TRAEs. One pt (Gr 3 elevated AST/ALT) required corticosteroids and cessation of study therapy. The RP2D was determined to be 375 mg of R plus GD. Twelve pts were evaluable for response. ORR was 17% (1 of 6; 95% CI 1 - 64%) and 50% (3 of 6; 95% CI 19% - 81%) in the run-in and de-escalation cohorts, respectively. DCR was 100% (6 of 6; 95% CI 52 - 100%) and 83% (5 of 6; 95% CI: 36 - 99%). PFS rates at 24 weeks were 60% (95% CI: 29 - 100%) and 44% (95% CI: 17 - 100%). Conclusions: R plus GD was generally safe and well tolerated with no unexpected safety signals to date. The phase II portion evaluating efficacy of R plus GD at the RP2D is ongoing. Clinical trial information: NCT04577014. [Table: see text]

TPS11588 Background: New treatment options are needed for sarcomas. Pazopanib is the only targeted agent approved for multiple soft tissue sarcoma (STS) subtypes with a response rate of 6% and a PFS of 4.6 months. Immunotherapy has a limited role in STS, as the SARC028 study of pembrolizumab demonstrated an overall response rate of 18%, with the highest response rate seen in the undifferentiated pleomorphic sarcoma (UPS) cohort at 23%. Lenvatinib is an oral, multi-tyrosine kinase inhibitor approved for the treatment of multiple cancer types including progressive, radioiodine-refractory thyroid cancer and unresectable hepatocellular carcinoma with inhibitory activity against the receptor tyrosine kinases VEGFR 1-3, FGFR 1-3, KIT, PDGFR alpha/beta, and RET. Early outcomes with the combination of lenvatinib and pembrolizumab suggest that this regimen could be broadly superior to PD-1 targeting alone for several tumor types as high rates of objective response have been noted. The rationale for this study is based on preclinical work demonstrating the immunosuppressive effects of VEGF in the tumor immune microenvironment including inhibition of dendritic cell maturation, recruitment of immunosuppressive Tregs, MDSCs and TAMs and up-regulation of PD-1 on CD8+ cells. Methods: This is a pilot study evaluating the efficacy of lenvatinib and pembrolizumab in the treatment of select metastatic and/or unresectable sarcomas. Patients will be enrolled in one of five cohorts: Cohort A: leiomyosarcoma; Cohort B: UPS; Cohort C: vascular sarcomas (including angiosarcoma and epithelioid hemangioendothelioma); Cohort D: synovial sarcoma and malignant peripheral nerve sheath tumor; and Cohort E: bone sarcomas (limited to osteosarcoma and chondrosarcoma). Eligible patients should have had at least one prior therapy for unresectable and/or metastatic disease, but no more than three prior lines of therapy. Prior treatment with angiogenesis inhibitors or immunotherapy is excluded. Archival tissue is required for eligibility. Patients enrolled in the study will be treated initially with a 2 week run-in of lenvatinib 20 mg orally daily which will be continued daily thereafter. Subsequently, they will start pembrolizumab 200 mg intravenously every 21 days. The primary endpoint for each cohort is best overall response rate documented by RECIST v1.1 Criteria at 27 weeks. A sample size of 10 patients is planned for each of the five histological cohorts. If 2 or more confirmed responses are observed among the 10 patients in an arm, the drug combination will be considered positive and worthy of further investigation for that arm. Secondary endpoints are PFS, OS, duration of response and safety/tolerability of the combination. On-treatment biopsy and blood samples will be required for correlative assessments. Accrual in all cohorts is ongoing. Clinical trial information: NCT04784247.

11510 Background: Response to checkpoint inhibition (CPI) in sarcoma is overall low and varies between and within subtypes. Understanding tumor intrinsic determinants of this response may improve efficacy and patient selection. The de-repression of transposable elements (TEs), which are epigenetically silenced repetitive DNA elements of viral origin, is linked to anti-tumor immunity through an antiviral inflammatory response. We hypothesize that baseline expression of TEs and epigenetic regulators correlates with overall response rate (ORR) in sarcoma CPI clinical trials. Methods: This is a retrospective analysis of bulk RNA-sequencing data from pre-treatment biopsies of patients on CPI trials in sarcoma (pembrolizumab plus talimogene laherparepvec, nivolumab plus bempegaldesleukin, and pembrolizumab plus epacadostat). Sixty-seven samples from unique patients representing 12 subtypes were analyzed. The MCP counter deconvolution method and unsupervised clustering were used to group samples by immune phenotypes resulting in immune ‘hot’ and ‘cold’ clusters. ORR was defined by RECIST. To determine if baseline expression of TEs and epigenetic regulators significantly predicted immune types, we implemented a lasso penalized logistic regression. Results: Immune ‘hot’ tumors were characterized by increased immune infiltrates including CD8+ T-cells, B-cells, and NK cells vs ‘cold’ tumors. Patients with ‘hot’ vs ‘cold’ tumors had an ORR of 30.5% (11/36) vs. 3.2% (1/31) (p = 0.003; chi-squared). The best predictors of ‘hot vs ‘cold’ was the increased expression of multiple TE families including MER45A, MER57F, and LTR21B (respective lasso coefficients, 0.27, 0.07, and 0.07). Expression of IKZF1, a chromatin-interacting transcription factor, was also predictive (lasso coefficient, 0.35) and increased expression correlated with improved ORR (p = 0.003; unpaired t-test). TE and IKFZ1 expression was significantly correlated with CD8+ T-cell signaling and antiviral response pathways such as cGAS-STING (MER57F, r2= 0.43, padj = 1.75E-4; IKZF1, r2= 0.63, padj = 6.28E-9) and type II interferon (MER57F, r2= 0.67, padj = 2.51E-10; IKZF1, r2= 0.60, padj = 7.19E-8). Increased expression of cGAS-STING (p = 3.9E-4; unpaired t-test) and type II interferon pathways (p = 1.89E-10; unpaired t-test) was significant in ‘hot’ tumors. Conclusions: Immune ‘hot’ baseline immune profiles of sarcoma are associated with improved ORR to CPI and with increased expression of TEs and IKZF1. These differences in gene expression correlate with increased inflammatory signaling, which suggests a response to TE-encoded viral-like sequences that are typically epigenetically silenced. Induction of TE de-repression and IKZF1 expression through epigenetic targeting warrants pre-clinical investigation as a strategy to promote CPI response in sarcomas.

11503 Background: Prexasertib (PRX) is an inhibitor of CHK1, prevents DNA repair leading to mitotic catastrophe, and can enhance the activity of DNA-damaging chemotherapy. Translocation driven sarcomas exhibit high levels of replication stress and have demonstrated susceptibility to CHK1 inhibition in preclinical models. Desmoplastic small round cell tumor (DSRCT) and rhabdomyosarcoma (RMS) are aggressive sarcomas of children, adolescents and young adults for which novel therapies are urgently required. Methods: We conducted a phase I/II trial of PRX with irinotecan (irino) in patients ≥ 12 months of age with relapsed or refractory DSRCT or RMS. Eligible patients could have any number of prior therapies, including irino. Dose level 1 was PRX 80 mg/m2 on day 1 + irino 20 mg/m2 for 10 days. Dose levels 2 and 2A were PRX 105 or 150 mg/m2 (>21 years or ≤ 21 years) on day 1 and irino 20 mg/m2 for 10 (level 2) or 5 (level 2A) days. All cycles were 21 days. The primary objectives were to determine the RP2D of PRX with irino, and to determine the best overall response rate (ORR) in 6 months at the RP2D (RECIST v1.1) in DSRCT, with 3 or more responses out of 16 considered promising. Results: 21 patients were enrolled (DSRCT: 19; 2 RMS:2). The RP2D was dose level 2A. Treatment was well tolerated with the most common adverse events being neutropenia (48%), nausea (48%), and fatigue (52%). Cytopenias were managed with the aid of growth factor support in all patients once the RP2D was established. The DSRCT expansion enrolled 13 of 16 planned patients due to discontinuation of PRX supply prior to study completion. Four patients remain on therapy at the time of this submission. Responses in DSRCT patients at all dose levels are shown in Table. Sixteen of 21 enrolled patients, and 5 of 6 patients achieving PR had previously received irino. The median (range) number of cycles was 7 (2-26). Both RMS patients treated at the RP2D experienced SD as best response. The estimated ORR at the RP2D was 23%, and lower boundary of the one-sided 90% confidence interval was 9%, exceeding the unpromising rate of 5%. The two-sided 90% confidence interval was 7 to 49%. In addition, 3 patients had a PR at doses lower than the RP2D, bringing the ORR for all dose levels (n = 19) to 32% (90%CI: 15 to 53%). Conclusions: The RP2D of PRX in combination with irino is PRX 105 or 150 mg/m2 (>21 years or ≤ 21 years) on day 1 and irino 20 mg/m2 for 5 days in 21 day cycles with myelosuppression successfully managed with growth factor support. The study met its primary objective to consider PRX + irino promising in DSRCT and should be further investigated. Clinical trial information: NCT04095221. [Table: see text]

PURPOSE To detect alterations in DNA damage repair (DDR) genes, measure homologous recombination deficiency (HRD), and correlate these findings with clinical outcome in patients with leiomyosarcoma (LMS). PATIENTS AND METHODS Patients with LMS treated at Memorial Sloan Kettering (MSK) Cancer Center who consented to prospective targeted next-generation sequencing with MSK-IMPACT were screened for oncogenic somatic variants in one of 33 DDR genes; where feasible, an experimental HRD score was calculated from IMPACT data. Progression-free survival (PFS) and overall survival (OS) were estimated after stratifying patients by DDR gene alteration status and HRD score. RESULTS Of 211 patients with LMS, 20% had an oncogenic DDR gene alteration. Univariable analysis of PFS in 117 patients who received standard frontline chemotherapy in the metastatic setting found that an altered homologous recombination pathway gene was significantly associated with shorter PFS (hazard ratio [HR], 1.79; 95% CI, 1.04 to 3.07; P = .035). Non- BRCA homologous recombination gene alteration was associated with shorter PFS (HR, 2.61; 95% CI, 1.35 to 5.04; P = .004) compared with BRCA-altered and wild-type homologous recombination genes. Univariable analysis of OS from diagnosis in the entire cohort of 211 patients found that age, tumor size, number of metastatic sites, localized disease, and non- BRCA homologous recombination gene alteration were significantly associated with OS. On multivariable analysis, non- BRCA homologous recombination pathway gene alteration remained significant (HR, 4.91; 95% CI, 2.47 to 9.76; P < .001). High HRD score was not associated with a different PFS or OS. CONCLUSION Patients with LMS with homologous recombination pathway gene alterations have poor clinical outcomes, particularly those with non- BRCA gene alterations. HRD score calculated from a targeted exome panel did not discern disparate clinical outcomes.

PURPOSE. The aim of this study was to determine outcomes and prognostic factors for patients with primary and locally recurrent extraabdominal desmoid tumors who underwent percutaneous cryoablation, and to compare with patients treated with surgery. METHODS. Group characteristics were compared using Fisher’s exact test, and propensity score matching was performed using the nearest-neighbor approach. Kaplan–Meier and log-rank analyses were used to evaluate the variation in first local recurrence and disease control, while multivariate Cox regression was used to identify factors associated with first local recurrence. All statistical tests were two-sided and a p-value of 0.05 was considered statistically significant. RESULTS. Twenty-two cryoablation patients were matched with 33 surgical patients (n = 55). Median follow-up after cryoablation was 16.3 months versus 14.9 months after surgery. Two-year local recurrence-free survival (LRFS) was 59% after cryoablation and 71% after surgery, and median LRFS was 26.6 months after cryoablation but was not reached after surgery. Two-year disease control for all patients was 85%, however median disease control was not reached in either the cryoablation or surgery groups. There was no significant difference in LRFS or disease control between matched cryoablation and surgical patients. No local recurrences occurred after the first cryoablation in patients with zero or one of the following risk factors: tumor size > 5 cm, age ≤ 25 years, or locally recurrent disease. All patients with two or more of these risk factors recurred locally after the first cryoablation. CONCLUSION. Percutaneous cryoablation of primary and locally recurrent extra-abdominal desmoid tumors provides freedom from first local recurrence and long-term disease control comparable with surgery.

Importance Patients with advanced sarcoma have limited treatment options. Talimogene laherparepvec (T-VEC) has been shown to increase tumor-specific immune activation via augmenting antigen presentation and T-cell priming. Objective To examine whether T-VEC in combination with pembrolizumab is associated with increased tumor-infiltrating lymphocyte infiltration and programmed death-ligand 1 expression and thus with increased antitumor activity in patients with locally advanced or metastatic sarcoma. Design, Setting, and Participants This open-label, single-institution phase 2 interventional trial of T-VEC plus pembrolizumab enrolled 20 patients with locally advanced or metastatic sarcoma between March 16 and December 4, 2017, for whom at least 1 standard systemic therapy had failed. The median duration of therapy was 16 weeks (range, 7-67 weeks). Reported analyses include data through December 14, 2018. Intervention Patients received pembrolizumab (200-mg flat dose) intravenously and T-VEC (first dose, ≤4 mL × 106plaque-forming units [PFU]/mL; second and subsequent doses, ≤4 mL × 108PFU/mL) injected into palpable tumor site(s) on day 1 of each 21-day cycle. Main Outcomes and Measures The primary end point was objective response rate (ORR; complete response and partial response) at 24 weeks determined by Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1, criteria. Secondary end points included best ORR by immune-related RECIST criteria, progression-free survival rate at 24 weeks, overall survival, and safety. Results All 20 patients (12 women [60%]; median age, 63.5 years [range, 24-90 years]) were evaluable for response. The study met its primary end point of evaluating the best ORR at 24 weeks determined by RECIST, version 1.1, criteria; the best ORR was 30% (95% CI, 12%-54%; n = 6). The ORR overall was 35% (95% CI, 15%-59%; n = 7). The incidence of grade 3 treatment-related adverse events was low (4 patients [20%]). There were no grade 4 treatment-related adverse events or treatment-related deaths. Conclusions and Relevance In this phase 2 clinical trial, treatment with T-VEC plus pembrolizumab was associated with antitumor activity in advanced sarcoma across a range of sarcoma histologic subtypes, with a manageable safety profile. This combination therapy met its predefined primary study end point; further evaluation of T-VEC in combination with pembrolizumab for patients with select sarcoma subtypes is planned. Trial Registration ClinicalTrials.gov identifier:NCT03069378

Lessons Learned The combination of pexidartinib and binimetinib was safe and tolerable and demonstrated encouraging signs of efficacy in two patients with advanced gastrointestinal stromal tumor (GIST) refractory to tyrosine kinase inhibitors (TKIs). Molecular profiling of GISTs at diagnosis and upon progression may provide insight into the mechanisms of response or resistance to targeted therapies. Additional trials are needed to further explore combined KIT and MEK inhibition in treatment-naïve and TKI-refractory patients with advanced GIST. Background Nearly all patients with advanced gastrointestinal stromal tumor (GIST) develop resistance to imatinib, and subsequent treatments have limited efficacy. Dual inhibition of KIT and MAPK pathways has synergistic antitumor activity in preclinical GIST models. Methods This was an investigator-initiated, phase I, dose escalation study of the MEK inhibitor binimetinib combined with pexidartinib, a potent inhibitor of CSF1R, KIT, and FLT3, in patients with advanced or metastatic GIST who progressed on imatinib. The primary endpoint was phase II dose determination; secondary endpoints included safety, tolerability, and efficacy. An expansion cohort to further evaluate safety and efficacy was planned. Results Two patients were treated at dose level one (binimetinib 30 mg b.i.d. and pexidartinib 400 mg every morning and 200 mg every evening), after which the study was terminated by the manufacturer. No dose-limiting toxicities (DLTs) were reported, and treatment was well tolerated. The only grade ≥3 treatment-emergent adverse event (TEAE) was asymptomatic elevated creatine phosphokinase (CPK). Both patients had a best response of stable disease (SD) by RECIST. Progression-free survival (PFS) and overall survival (OS) were 6.1 and 14.6 months, respectively, in one patient with five prior lines of therapy. The second patient with NF1-mutant GIST had a 27% decrease in tumor burden by RECIST and remains on study after 19 months of treatment. Conclusion Pexidartinib combined with binimetinib was tolerable, and meaningful clinical activity was observed in two imatinib-refractory patients.

11549 Background: Select sarcomas are infiltrated with immunosuppressive myeloid cells. DCC-3014 is an inhibitor of the CSF1R kinase that decreases tumor infiltrating myeloid cells in preclinical models. We hypothesized that DCC-3014 combined with the anti-PDL1 inhibitor avelumab would be safe and tolerable, decrease immunosuppressive myeloid cells, and increase cytotoxic T cells. Methods: This investigator initiated, open label, single center, phase I study of DCC-3014 plus avelumab in patients (pts) with unresectable or metastatic sarcoma utilized a standard 3+3 dose escalation design. DCC-3014 was administered on days 1-3 (loading dose of 20, 30, or 50 mg) followed by oral daily maintenance (10, 14, or 20 mg) in 28-day cycles; 800 mg of IV avelumab was administered q2weeks. The primary endpoint was to determine the recommended phase 2 dose (RP2D). Secondary endpoints defined the adverse event (AE) profile and assessed clinical efficacy. Peripheral blood CD14+Lin-HLA-DRlo myeloid-derived suppressor cells (MDSCs) were measured by flow cytometry. Results: 13 pts were treated; median age was 61 (range 32 – 71), 8 were female, and median prior lines of therapy was 5 (range 2 – 10). Histologic subtypes included leiomyosarcoma (LMS, n = 7), undifferentiated pleomorphic sarcoma (2), dedifferentiated liposarcoma (LPS, 2), synovial sarcoma (1), and pleomorphic LPS (1). The Table lists treatment-related AEs (TRAEs) of any grade (G) occurring in ≥ 10% of pts and all G ≥ 3 TRAEs, sorted by frequency. All pts had at least 1 TRAE. Seven pts (54%) had a G ≥ 3 TRAE. Most TRAEs were either G ≤ 2 or expected on-target effects of CSF1R inhibition. 1 of 6 pts on the highest dose level had a dose limiting toxicity (G4 elevated AST with abdominal pain) that resolved with treatment cessation. The highest dose level was declared the RP2D. Best objective response by RECIST 1.1 was stable disease in 3 pts; 2 had LMS and were treated at the highest dose level. At baseline, the mean proportion of monocytes in peripheral blood samples with an MDSC phenotype was 12.2% (range 7.1 – 19.9). 5 of 7 pts with serial blood samples had decreased circulating MDSCs (mean decrease of 26.9% from baseline to last time point). Conclusions: DCC-3014 combined with avelumab was safe and tolerable. Study therapy decreased circulating MDSCs in select patients; T cell analyses will be reported. Study expansion at the RP2D is ongoing. Clinical trial information: NCT04242238. [Table: see text]

Purpose We evaluated the pharmacokinetics (PKs), pharmacodynamics, safety, and efficacy of selinexor, an oral selective inhibitor of nuclear export compound, in patients with advanced soft tissue or bone sarcoma with progressive disease. Patients and Methods Fifty-four patients were treated with oral selinexor twice per week (on days 1 and 3) at one of three doses (30 mg/m2, 50 mg/m2, or flat dose of 60 mg) either continuously or on a schedule of 3 weeks on, 1 week off. PK analysis was performed under fasting and fed states (low v high fat content) and using various formulations of selinexor (tablet, capsule, or suspension). Tumor biopsies before and during treatment were evaluated for pharmacodynamic changes. Results The most commonly reported drug-related adverse events (grade 1 or 2) were nausea, vomiting, anorexia, and fatigue, which were well managed with supportive care. Commonly reported grade 3 or 4 toxicities were fatigue, thrombocytopenia, anemia, lymphopenia, and leukopenia. Selinexor was significantly better tolerated when administered as a flat dose on an intermittent schedule. PK analysis of selinexor revealed a clinically insignificant increase (approximately 15% to 20%) in drug exposure when taken with food. Immunohistochemical analysis of paired tumor biopsies revealed increased nuclear accumulation of tumor suppressor proteins, decreased cell proliferation, increased apoptosis, and stromal deposition. Of the 52 patients evaluable for response, none experienced an objective response by RECIST (version 1.1); however, 17 (33%) showed durable (≥ 4 months) stable disease, including seven (47%) of 15 evaluable patients with dedifferentiated liposarcoma. Conclusion Selinexor was well tolerated at a 60-mg flat dose on a 3-weeks-on, 1-week-off schedule. There was no clinically meaningful impact of food on PKs. Preliminary evidence of anticancer activity in sarcoma was demonstrated.

e23560 Background: Patients (pts) with synovial sarcoma (SS) and an HLA-A*02 genotype whose tumors express NY-ESO-1 may be eligible for clinical trials of adoptive T cell therapy. We reasoned that a next generation tumor sequencing platform utilizing matched normal DNA (MSK-IMPACT) could accurately identify HLA genotype. Although HLA-A*02 is necessary for some adoptive T cell therapies, the prognosis of this genotype on clinical outcome has not been described in SS. Methods: Pts with metastatic SS who consented to screen for a clinical trial of engineered T cells had high-resolution HLA genotyping performed with a Clinical Laboratory Improvement Amendments (CLIA)-certified test. Where feasible, HLA genotype and loss-of-heterozygosity (LOH) of HLA alleles were determined from IMPACT samples. Overall survival (OS) was estimated in three overlapping cohorts and stratified by HLA-A*02 status: pts treated with anthracyclines or alkylators in the first line, pazopanib in the second line or beyond, and all pts from time of metastasis. Results: 66 pts with SS were screened, but not treated with T cells; 30% (n = 20) were HLA-A*02-positive on a CLIA-certified outside test. 23 pts had HLA genotyping both by IMPACT and an outside laboratory, 22 (96%) of whom had concordant results. 3 pts had LOH of at least 1 HLA allele, including one with LOH of HLA*02:01 in the primary tumor. Among pts treated chemotherapy (n = 36) or pazopanib (n = 37), OS did not significantly differ between HLA-A*02-positive or negative pts. Univariable analyses of OS from the time of metastasis in the whole cohort identified primary tumor size and time to metastasis as variables significantly associated with outcome (hazard ratio (HR) 1.2, 95% confidence interval (CI) 1.123 – 1.345 [P < 0.001] and HR 0.99, 95% CI 0.976 – 0.999 [P = 0.032], respectively). HLA-A*02-positive status and age did not reach the significance threshold (HR 1.95, 95% CI 0.995 – 3.813 [P = 0.052] and HR 1.021, 95% CI 0.999 – 1.044 [P = 0.061], respectively). Multivariable analysis found older age and larger tumor size were independently associated with significantly shorter OS (HR 1.03, 95% CI 1.002 – 1.049 [P = 0.037] and HR 1.2, 95% CI 1.127 – 1.37 [P < 0.001], respectively). Conclusions: Targeted exome panels like IMPACT that utilize matched tumor-normal DNA may accurately identify HLA genotype. Detection of LOH at HLA loci may identify a subgroup of pts who would be refractory to treatment with HLA-A*02-restricted engineered T cells. HLA-A*02 status was not associated with a statistically significant survival difference in pts with metastatic SS.

11508 Background: ETV1 and KIT are lineage-specific master transcriptional and signaling survival factors in GIST. In preclinical models, dual lineage targeting of ETV1 by MEK inhibition with BINI and KIT by imatinib are synergistic in suppressing GIST tumorigenesis and progression. This single-arm phase II study is designed to test the efficacy of the BINI+imatinib as a first-line treatment in patients (pts) with advanced GIST. Methods: Adult pts with untreated advanced GIST received imatinib (400mg daily) plus BINI (30mg twice daily), 28-day cycles. The primary endpoint (EP) was RECIST1.1 objective response rate (ORR) (complete response [CR]+partial response [PR]). The study was designed to detect a 20% improvement in the ORR of imatinib alone (unacceptable rate of 45%; acceptable rate of 65%). A sample size of 44 patients was required, using an exact binomial test, one-sided type I error of 0.08 and type II error of 0.1. Confirmed PR in > 24 pts would be considered positive. Secondary EPs included RR by Choi and EORTC criteria, resectability conversion rate (RCR), progression free survival (PFS), overall survival (OS) and long-term AEs. Correlatives included characterization of tumor genomics by MSK-IMPACT, cfDNA by MSK-ACCESS, ETV1 protein levels and transcriptomes and signaling inhibition. Results: At data cutoff of Jan 31, 2020, 38/39 pts with advanced GIST of all genotypes, including 3 KIT/PDGFRA-wild type GIST pts, were evaluable for primary EP. Median age 60 (range 29-78), 29% female. 26/38 pts with confirmed PR; Best ORR was 68.4% (two-sided 95% CI, 51-83%; one-sided 90% CI, 57-100%). 8/9 pts became resectable after treatment; RCR was 88.9% (95% CI, 52-100%). 13 pts remain on trial (2-159 weeks [wks]). 9 pts discontinued trial due to disease progression (11-159 wks); one pt progressed within 3 months, indicating primary resistance. Grade 3/4 toxicity included CPK elevation (asymptomatic, 61%), neutrophil decrease (11%), maculopapular rash (8%), anemia (8%). No unexpected toxicities observed. Correlation of outcome with MSK-IMPACT, MSK-Access and paired tumor biopsies will be presented. Conclusions: This study met its primary endpoint. BINI plus imatinib is highly effective in treatment-naive advanced GIST, with expected and manageable long-term treatment-associated toxicities. The combination strategy warrants further evaluation in direct comparison with imatinib in the frontline treatment of GIST. Clinical trial information: NCT01991379 .

Rationale: Hepatic epithelioid hemangioendothelioma (EHE) is a rare malignant vascular tumor of endothelial origin with a highly variable clinical presentation and natural history. Given its vascular origin, new therapies with inhibitors of vascular endothelial growth factor (VEGF) have been introduced in the treatment of these patients and have shown promising results. Few reports have described the role of 18F-Fluorodeoxyglucose positron emission tomography/contrast-enhanced computed tomography (18F-FDG PET/CT) in the evaluation of this tumor after treatment with anti-angiogenic agents. Our case reports how 18F-FDG PET-CT scan was critical in the assessment of this tumor after treatment with an anti-angiogenic agent, Pazopanib, demonstrating complete metabolic response. Patient concerns: A 30-year-old man with no previous significant medical history presented with pain in the right upper quadrant for over a year. Diagnoses: Multiple hepatic masses were found on abdominal ultrasound. Liver biopsy confirmed the diagnosis of epithelioid hemangioendothelioma. 18F-FDG PET/CT was performed for staging. Multiple FDG-avid hepatic, splenic, and lymph nodes lesions were detected on 18F-FDG PET/CT. A subsequent spleen biopsy confirmed splenic involvement. Immunohistochemistry was positive for CD31, CD34, and ERG, supporting the diagnosis of epithelioid hemangioendothelioma. Interventions: A 1-year cyclophosphamide treatment was provided followed by Pazopanib for 17 months. Outcomes: Six years after the first 18F-FDG PET/CT, 18F-FDG PET/CT performed for restaging demonstrated complete metabolic response to therapy. Follow-up CT demonstrated no interval changes in size of some of the treated lesions. Lesson: 18F-FDG PET/CT is useful for baseline assessment and posttreatment follow-up of this rare cancer.

BACKGROUND. Sorafenib and dacarbazine have low single‐agent response rates in metastatic sarcomas. As angiogenesis inhibitors can enhance the efficacy of chemotherapy, we investigated the combination of sorafenib and dacarbazine in select sarcoma subtypes. MATERIALS AND METHODS. Patients with leiomyosarcoma (LMS), synovial sarcoma (SS), or malignant peripheral nerve sheath tumors (MPNST) with up to two previous lines of therapy and adequate hepatic, renal, and marrow function received 3‐week cycles of sorafenib at 400 mg oral twice daily and dacarbazine 1,000 mg/m(2) intravenously (later reduced to 850 mg/m(2)). Patients were evaluated for response every 6 weeks. The primary objective was to determine the disease control rate (DCR) of sorafenib plus dacarbazine in the selected sarcoma subtypes. RESULTS. The study included 37 patients (19 female); median age was 55 years (range 26–87); and histologies included LMS (22), SS (11), and MPNST (4). The DCR was 46% (17/37). Median progression‐free survival was 13.4 weeks. The RECIST response rate was 14% (5/37). The Choi response rate was 51% (19/37). Median overall survival was 13.2 months. Of the first 25 patients, 15 (60%) required dacarbazine dose reductions for hematologic toxicity, with one episode of grade 5 neutropenic fever. After reducing the starting dose of dacarbazine to 850 mg/m(2), only 3 of the final 12 (25%) patients required dose reduction. CONCLUSION. This phase II study met its primary endpoint with an 18‐week DCR of 46%. The clinical activity of dacarbazine plus sorafenib in patients with these diagnoses is modest. IMPLICATIONS FOR PRACTICE. Metastatic soft tissue sarcomas are a heterogeneous group of relatively rare malignancies. Most patients are treated with cytotoxic chemotherapy or targeted therapy in the form of tyrosine kinase inhibitors. Response rates are relatively low, and there is a need for better therapies. This clinical trial demonstrates that combining a cytotoxic therapy (dacarbazine) with an antiangiogenic small molecule (sorafenib) is feasible and associated with favorable disease‐control rates; however, it also increases the potential for significant toxicity.

The prognostic and predictive implications of programmed death-ligand 1 (PD-L1) is unknown in sarcoma. We sought to examine the immune milieu in sarcoma specimens. We evaluated PD-L1 expression by immunohistochemistry in sarcoma specimens and quantified tumor-infiltrating lymphocytes (TIL). We correlated expression with clinical parameters and outcomes. Fifty sarcoma patients treated at Memorial Sloan Kettering Cancer Center were selected. Using the DAKO PD-L1 immunohistochemistry assay and archival formalin-fixed paraffin-embedded tissue specimens; PD-L1 expression was examined. Macrophage and lymphocyte PD-L1 status was determined qualitatively. TIL was quantified. Associations between PD-L1 expression in tumor, macrophages and lymphocytes, TIL and clinical-pathological characteristics were performed. The median age was 46 years (range, 22-76), and 66% of patients were men. Tumor, lymphocyte and macrophage PD-L1 expression was noted in 12%, 30% and 58%, respectively, with the highest prevalence in gastrointestinal stromal tumors (29%). Lymphocyte and macrophage infiltration was present in 98% and 90%, respectively. There was no association between clinical features, overall survival and PD-L1 expression in tumor or immune infiltrates. Lymphocyte and macrophage infiltration is common in sarcoma, but PD-L1 tumor expression is uncommon in sarcoma with the highest frequency observed in gastrointestinal stromal tumors. There was no association between PD-L1 expression, TIL and clinicopathological features and overall survival; however, this is limited by the heterogenous patient sample and minimal death events in the studied cohort.

11010 Background: Monotherapy checkpoint inhibitors have minimal efficacy in most patients with metastatic sarcoma. NKTR-214 is a CD122-preferential IL-2 pathway agonist that activates and expands natural killer and CD8+ T cells. Phase I/II data demonstrated the safety and efficacy of nivolumab plus NKTR-214 in multiple tumor types. A trial of NKTR-214 plus nivolumab was initiated in patients with selected sarcomas. Methods: This is a multi-center pilot study enrolling patients (pts) failing prior regimens within 9 cohorts: leiomyosarcoma (LMS), undifferentiated pleomorphic sarcoma (UPS), dedifferentiated liposarcoma (DDLPS), chondrosarcoma (CS), osteosarcoma (OS), angiosarcoma (AS), alveolar soft part sarcoma (ASPS), synovial sarcoma/small blue round cell and other. Pts received NKTR 0.006mg/kg with nivolumab 360 mg every 3 weeks. Primary endpoint was objective response rate (ORR), secondary endpoints were adverse events (AEs), progression-free, overall survival (PFS,OS) and clinical benefit rate (CBR.) Pre/on treatment biopsies performed on patients for correlative studies including PD-L1 expression and TIL characterization by immunohistochemistry, whole exome sequencing and RNAseq. Results: Enrollment completed with 10 patients in cohorts below. 50 pts enrolled (median age 58, range 14-80), 54% female. Median follow-up time is 13m. 50% of patients were refractory ≥3 lines of therapy. Grade 3/4 treatment related adverse events occurred in 26% of patients. 2% of patients stopped due to AEs. Median time to response was 3.6m. Responses seen in LMS, UPS, dedifferentiated CS; on-going in UPS/CS. Prolonged disease stability in DDLPS. 6 patients remain on treatment. Conclusions: Nivolumab plus NKTR-214 was safe and tolerable in heavily pre-treated and refractory sarcoma patients. Responses were protracted overtime; on-going in UPS and dedifferentiated CS. Prolonged disease stability seen in DDLPS in patients. All correlative analyses are in progress and will be presented. Enrollment continues with plans to add a treatment naïve cohort. Clinical trial information: NCT03282344. [Table: see text]

11048 Background: Leiomyosarcoma (LMS) is a complex karyotype sarcoma with frequent alterations in the homologous recombination (HR) pathway. Genomically unstable tumors with DNA damage repair (DDR) deficiencies may have improved responses to DNA damaging therapies, such as cytotoxic chemotherapy or PARP inhibitors. Methods: We retrospectively reviewed LMS patients treated at MSKCC who had targeted somatic DNA sequencing (MSK-IMPACT) performed on tumor tissue. 33 DDR genes, including 16 HR genes, were analyzed for oncogenic alterations. A composite HR deficiency (HRD) score measured tumor genomic scarring for each patient. To determine if DDR alteration status is prognostic of outcome, we analyzed the recurrence-free survival (RFS) of patients who underwent complete resection, and the overall survival (OS) of the whole cohort. Results: 211 patients had IMPACT testing between March 2014 and October 2018; 48% of samples were primary tumors and 52% recurrent/metastatic sites. Among soft tissue LMS (stLMS), there were 35 men and 55 women. 20% of patients had an oncogenic DDR gene alteration, 72% of which were in the HR pathway (table below). Uterine LMS (uLMS) had more DDR alterations than stLMS, though not statistically significant (p = 0.084). BRCA2 (n = 14 cases), RAD51B (8), and ERCC5 (4) were most frequently altered. HRD score significantly correlated with HRD alteration status (p = 0.004). DDR or HRD altered status and HRD score were associated with shorter RFS in patients with resectable disease, independent of age (p < 0.05). Median OS for the cohort was 75 months (95% CI: 64 – 84). Men with stLMS had shorter OS compared to women (p = 0.025). OS did not significantly differ based on DDR or HRD status (p > 0.05). Conclusions: One-fifth of LMS patients have one or more oncogenic somatic alterations in the DDR pathway, predominantly in effectors of HR. DDR status may be prognostic of recurrence risk. Further analyses to determine the association between DDR status and response to cytotoxic chemotherapy are ongoing. [Table: see text]

11049 Background: Tumors express IDO1, an intracellular enzyme involved in the degradation of tryptophan to kynurenine, in order to evade immunosurveillance. Epacadostat inhibits IDO1 and shifts the tumor microenvironment from an immunosuppressive state to an immune-stimulated state. Pembrolizumab previously demonstrated activity in select sarcoma subtypes. We performed an open-label, single-center, phase II study of epacadostat and pembrolizumab in patients with advanced sarcoma. Methods: Patients received the recommended phase II dose of oral epacadostat (100mg) twice per day and intravenous pembrolizumab (200mg/dose) every 3 weeks. The primary endpoint was best objective response rate (ORR) (complete response and partial response [PR]) at 24 weeks by RECIST 1.1. Secondary endpoints included adverse events (AEs), ORR by irRECIST, progression free survival (PFS) and overall survival (OS). Correlative studies performed on pre/on-treatment biopsy specimens included PD-L1, IDO1, and kynurenine expression and characterization of tumor infiltrating lymphocytes by IHC, whole exome and RNA sequencing. Results: Twenty-nine patients were enrolled [median age 53 years (range, 24-78), 57% male, ECOG PS 0 83%]. Histological subtypes included leiomyosarcoma (17%), UPS (17%), myxofibrosarcoma (7%), liposarcoma (10.5%), EHE (10.5%), angiosarcoma (3%), “other” sarcoma subtype (35%). Patients were refractory to 0 (21%), 1 (38%), 2 (24%) and ≥ 3 (17%) prior lines of therapy. The most common ( > 20% of pts) grade (G)1 or 2 treatment related AEs (TRAEs) observed included fatigue (31%), rash (31%) and ALT elevation (24%). G3 TRAEs included AST elevation (10%), ALT elevation, anemia, hypophosphatemia and increased lipase each occurred in 3% of pts. Three patients discontinued therapy due to G3 immune mediated hepatitis. Among the 29 evaluable patients 1 (3%) confirmed PR (leiomyosarcoma), 13 stable diseases (45%) and 15 progressions (52%) were observed by RECIST 1.1. The median PFS was 8.0 weeks (two-sided 95% CI: 6.9 ~ 26.7) and the PFS rate at 24 weeks was 27.9% (two-sided 95% CI: 15.0% ~ 52.2%). The median OS was not estimable (two-sided 95% CI: 40.9 weeks ~ NE). The OS at 24 weeks was 85.2% (95% CI: 72.8%, 99.7%). Conclusions: Epacadostat in combination with pembrolizumab was generally well tolerated. Limited anti-tumor activity was observed among advanced sarcoma patients. Correlative analyses including determination of adequacy of IDO1 inhibition will be reported. Clinical trial information: NCT03414229.

11004 Background: The oncogene cyclin-dependent kinase 4 (CDK4) is amplified in > 90% of de-differentiated liposarcomas (DDLS). We previously demonstrated that treatment with the CDK4 inhibitor palbociclib results in favorable progression-free survival (PFS) in DDLS. Abemaciclib is a newer and more potent CDK4 inhibitor. This single-arm phase 2 study was designed to test the activity of abemaciclib in DDLS. Methods: Participants were adults with advanced DDLS, measurable disease by RECIST 1.1, any (or no) priory therapy, and progression by RECIST in the 6 months prior to study entry. The primary endpoint was PFS at 12 weeks. Based on historical data, promising drugs have 12-week PFS of ≥ 40% and not promising ≤ 20%. This study would be positive if 12-week PFS was ≥ 60%. The study was approved by the Institutional Review Board of Memorial Sloan-Kettering Cancer Center and all patients provided written informed consent. The study was registered at Clinicaltrials.gov (NCT02846987) and study drug was provided by Eli-Lilly. Results: Treatment was abemaciclib 200 mg by mouth twice daily continuously. 30 patients were treated and 29 were evaluable for the primary endpoint. Patient characteristics: Median age 62 (range 39-88), 60% male. Lines of prior therapy: 0 (50%); 1 (33%); ≥ 2 (17%). The observed PFS at 12 weeks was 76% (95% CI 57-90%). Median PFS was 30.4 weeks (95% CI 28.9-NE). There was one partial response. A further 3 patients had > 10% decrease in tumor size by RECIST but did not meet the criterion for partial response. Grade 3-4 toxicity included anemia (37%), neutropenia (20%), thrombocytopenia (17%) and diarrhea (7%). Conclusions: This study met its primary endpoint. In patients with advanced progressive DDLS, abemaciclib treatment results in favorable PFS and objective tumor response with manageable toxicity. Updated response data and results of paired tumor biopsies will be presented. Clinical trial information: NCT02846987.

Background: Radiation-associated breast angiosarcoma (RT-AS) is an uncommon malignancy with an incidence of less than 1 % of all soft tissue sarcomas. The overall prognosis is quite dismal with high rates of recurrences and poor overall survival. There is an obvious paucity of data regarding clinical outcomes of patients with breast RT-AS. Methods: We identified all patients with RT-AS treated at the Memorial Sloan-Kettering Cancer Center between 1982–2011 and collected their correlative clinical information. Results: We identified 79 women with RT-AS with a median age of 68 (range 36–87). The median interval between radiation and development of RT-AS was 7 years (range 3–19). The median time to local and distant recurrence was 1.29 years (95 % CI 0.72–NA) and 2.48 years (95 % CI 1.29–NA), respectively. The median disease-specific survival was 2.97 years (95 % CI 2.21–NA). Independent predictors of worse disease-specific survival included age ⩾68 years (HR 3.11, 95 % CI 1.20–8.08, P=0.020) and deep tumors (HR 3.23, 95 % CI 1.02–10.21, P=0.046.) Conclusion: RT-AS has high local/distant recurrence rates, limited duration on standard chemotherapy and poor disease-specific survival.

Purpose Rhabdomyosarcoma (RMS) is a pediatric sarcoma rarely occurring in adults. For unknown reasons, adults with RMS have worse outcomes than do children. Methods and Materials We analyzed data from all patients who presented to Memorial Sloan-Kettering Cancer Center between 1990 and 2011 with RMS diagnosed at age 16 or older. One hundred forty-eight patients met the study criteria. Ten were excluded for lack of adequate data. Results The median age was 28 years. The histologic diagnoses were as follows: embryonal 54%, alveolar 33%, pleomorphic 12%, and not otherwise specified 2%. The tumor site was unfavorable in 67% of patients. Thirty-three patients (24%) were at low risk, 61 (44%) at intermediate risk, and 44 (32%) at high risk. Forty-six percent were treated on or according to a prospective RMS protocol. The 5-year rate of overall survival (OS) was 45% for patients with nonmetastatic disease. The failure rates at 5 years for patients with nonmetastatic disease were 34% for local failure and 42% for distant failure. Among patients with nonmetastatic disease (n=94), significant factors associated with OS were histologic diagnosis, site, risk group, age, and protocol treatment. On multivariate analysis, risk group and protocol treatment were significant after adjustment for age. The 5-year OS was 54% for protocol patients versus 36% for nonprotocol patients. Conclusions Survival in adult patients with nonmetastatic disease was significantly improved for those treated on RMS protocols, most of which are now open to adults.

Background. Patients with recurrent synovial sarcomas have few options for systemic therapy. Since they express large amounts of endogenous CT (cancer testis) antigens such as NY-ESO-1, we investigated the clinical activity of single agent anti-CTLA4 antibody ipilimumab in patients with advanced or metastatic synovial sarcoma.Methods. A Simon two-stage phase II design was used to determine if there was sufficient activity to pursue further. The primary endpoint was tumor response rate by RECIST 1.0. Patients were treated with ipilimumab 3 mg/kg intravenously every 3 weeks for three cycles and then restaged. Retreatment was possible for patients receiving an extra three-week break from therapy. Sera and peripheral blood mononuclear cells were collected before and during therapy to assess NY-ESO-1-specific immunity.Results. Six patients were enrolled and received 1–3 cycles of ipilimumab. All patients showed clinical or radiological evidence of disease progression after no more than three cycles of therapy, for a RECIST response rate of 0%. The study was stopped for slow accrual, lack of activity, and lack of immune response. There was no evidence of clinically significant either serologic or delayed type hypersensitivity responses to NY-ESO-1 before or after therapy.Conclusion. Despite high expression of CT antigens by synovial sarcomas of patients treated in this study, there was neither clinical benefit nor evidence of anti-CT antigen serological responses. Assessment of the ability of synovial sarcoma cell lines to present cancer-germ cell antigens may be useful in determining the reason for the observed lack of immunological or clinical activity.

Background Aurora kinase A (AURKA) is commonly overexpressed in sarcoma. The inhibition of AURKA by shRNA or by a specific AURKA inhibitor blocks in vitro proliferation of multiple sarcoma subtypes. MLN8237 (alisertib) is a novel oral adenosine triphosphate-competitive AURKA inhibitor. Patients and methods This Cancer Therapy Evaluation Program-sponsored phase II study of alisertib was conducted through the Alliance for Clinical Trials in Oncology (A091102). Patients were enrolled into histology-defined cohorts: (i) liposarcoma, (ii) leiomyosarcoma, (iii) undifferentiated sarcoma, (iv) malignant peripheral nerve sheath tumor, or (v) other. Treatment was alisertib 50 mg PO b.i.d. d1–d7 every 21 days. The primary end point was response rate; progression-free survival (PFS) was secondary. One response in the first 9 patients expanded enrollment in a cohort to 24 using a Simon two-stage design. Results Seventy-two patients were enrolled at 24 sites [12 LPS, 10 LMS, 11 US, 10 malignant peripheral nerve sheath tumor (MPNST), 29 Other]. The median age was 55 years; 54% were male; 58%/38%/4% were ECOG PS 0/1/2. One PR expanded enrollment to the second stage in the other sarcoma cohort. The histology-specific cohorts ceased at the first stage. There were two confirmed PRs in the other cohort (both angiosarcoma) and one unconfirmed PR in dedifferentiated chondrosarcoma. Twelve-week PFS was 73% (LPS), 44% (LMS), 36% (US), 60% (MPNST), and 38% (Other). Grade 3–4 adverse events: oral mucositis (12%), anemia (14%), platelet count decreased (14%), leukopenia (22%), and neutropenia (42%). Conclusions Alisertib was well tolerated. Occasional responses, yet prolonged stable disease, were observed. Although failing to meet the primary RR end point, PFS was promising. Trial registration ID NCT01653028.

Background. Leiomyosarcomas (LMS) represent a heterogeneous subset of soft tissue sarcomas. Factors influencing prognosis for patients with metastatic extrauterine LMS (euLMS) are not well described. Limited data are available regarding responses to systemic therapy.Methods. We collected clinical and pathologic information for all patients with metastatic euLMS seen at Memorial Sloan Kettering Cancer Center between 1989 and 2012. Objective responses to first-line therapy were analyzed for a subset of patients with available baseline and on-treatment imaging using RECIST 1.1.Results. 215 patients with metastatic euLMS had a median overall survival (OS) of 2.6 years from the time of metastasis. Older age, male sex, and ≥3 initial sites of metastasis were associated with worse OS on multivariate analysis. Objective response rate (ORR) inN=113was 19% overall and 25%, 26%, and 25% for gemcitabine, gemcitabine plus docetaxel, and anthracycline-alkylator combinations. Patients whose tumors objectively responded to first-line therapy had a lower risk of death versus those who did not (Hazard Ratio 0.46; 95% CI: 0.26–0.79,p=0.005).Conclusions. Anthracycline- and gemcitabine-based regimens have similar activity in this cohort of euLMS. Prognostic factors for OS include older age, male sex, and ≥3 initial sites.

Background Tasisulam sodium (hereafter tasisulam), a novel anticancer agent, is being studied in a broad range of tumors. The primary objective of this phase II study was to determine progression-free survival (PFS) in patients with 1 or 2 prior chemotherapy regimens for unresectable/metastatic soft tissue sarcoma (STS). Secondary objectives included objective response rate (ORR), clinical benefit rate (CBR), overall survival (OS), pharmacokinetics, and safety. Methods Tasisulam was administered intravenously on day 1 of 21-day cycles according to a lean body weight–based dosing algorithm targeting a peak plasma concentration (Cmax) of 420 μg/mL; a 360-μg/mL dose level was also explored. Results The median age of patients treated at 420 μg/mL was 58.3 years (range, 18.6–80.4; n = 63). Median PFS was 2.64 months (90 % CI, 1.41–3.38), with a 6-month PFS rate of 11 % (90 % CI, 4–17). Median OS was 8.71 months (90 % CI, 7.39–16.23); ORR, 3.2 %; and CBR, 46.0 % (stable disease, n = 27; partial response/confirmed, n = 2 [angiosarcoma and leiomyosarcoma]; partial response/unconfirmed, n = 1 [desmoplastic small round cell tumor]). The most frequent drug-related grade 3/4 toxicities in patients treated at 420 μg/mL were thrombocytopenia (27.0 %) and neutropenia (22.2 %). Incidences of grade 4 thrombocytopenia and/or neutropenia were 20.6 % in patients treated at 420 μg/mL and 15.8 % in those treated at 360 μg/mL (n = 38). Conclusions Tasisulam at a target Cmax of 420 μg/mL on day 1 of 21-day cycles demonstrated modest activity as second-/third-line treatment in patients with STS. Grade 4 hematologic toxicity posed some challenges in these heavily pre-treated patients. Tasisulam dosing continues to be refined.

Background We tested whether an educational video on the goals of care in advanced cancer (life-prolonging, basic or comfort care) can help patients understand these goals and impact preferences for resuscitation.

BACKGROUND: Data regarding the role of anthracyclines and taxanes as first-line treatments of metastatic angiosarcoma are limited. METHODS: Records of 117 metastatic angiosarcoma patients who were treated with either doxorubicin or weekly paclitaxel were reviewed. RESULTS: Seventy-five patients (64%) were treated with weekly paclitaxel and 42 (36%) with single-agent doxorubicin. Patients in the weekly paclitaxel group were older and more frequently had angiosarcomas arising from the skin. In the doxorubicin group, 34 patients were evaluable for response: 2 (6%) had complete response, 8 (23.5%) had partial response, 10 (29.5%) had stable disease, and 14 (41%) had progressive disease. In the weekly paclitaxel group, 68 patients were evaluable for response: 9 (13%) had complete response, 27 (40%) had partial response, 20 (29.5%) had stable disease, and 12 (17.5%) had progressive disease. Objective responses to weekly paclitaxel were more frequent in cutaneous angiosarcomas, whereas tumor location did not impact response to doxorubicin. Median progression-free survival (PFS) was 4.9 months (95% confidence interval [95% CI], 3.9-6.0 months). Median overall survival (OS) was 8.5 months (95% CI, 6.4-10.7 months). On multivariate analysis, ECOG performance status (PS) was the sole independent factor associated with PFS and OS. CONCLUSIONS: First-line single-agent doxorubicin and weekly paclitaxel seem to have similar efficacy in metastatic angiosarcomas. Cutaneous angiosarcomas respond favorably to weekly paclitaxel. Best supportive care should be considered in patients with poor PS.

Background: Desmoid tumors (deep fibromatoses) are clonal connective tissue malignancies that do not metastasize, but have a significant risk of local recurrence, and are associated with morbidity and occasionally mortality. Responses of desmoid patients to sorafenib on an expanded access program led us to review our experience. Methods: After Institutional Review Board (IRB) approval, we reviewed data for 26 patients with desmoid tumors treated with sorafenib. Sorafenib was administered at 400 mg oral daily and adjusted for toxicity. Results: Sorafenib was the first-line therapy in 11/26 patients and the remaining 15/26 had received a median of 2 prior lines of therapy. Twenty-three of 26 patients had shown evidence of progressive disease by imaging, whereas 3 patients had achieved maximum benefit or toxicity with chemotherapy. Sixteen of 22 (∼70%) patients reported significant improvement of symptoms. At a median of 6 months (2–29) of treatment, the best response evaluation criteria in solid tumors (RECIST) 1.1 response included 6/24 (25%) patients with partial response (PR), 17/24 (70%) with stable disease, and 1 with progression and death. Twelve of 13 (92%) patients evaluated by MRI had > 30% decrease in T2 signal intensity, an indirect metric for increased fibrosis and loss of cellularity. Eighty percent of patients with radiological benefit had extra-abdominal desmoids. Discussion: Sorafenib is active against desmoid tumors. A prospective, randomized clinical trial of sorafenib against other active agents is warranted. Loss of MRI T2 signal may be a useful surrogate for defining responses, but requires validation by examination of tumor pathology. Clin Cancer Res; 17(12); 4082–90. ©2011 AACR.