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PURPOSE CMB305 is a heterologous prime-boost vaccination regimen created to prime NY-ESO-1–specific CD8 T-cell populations and then activate the immune response with a potent TLR-4 agonist. This open-label randomized phase II trial was designed to investigate the efficacy and safety of adding the CMB305 regimen to atezolizumab (anti–programmed death ligand-1 therapy) in comparison with atezolizumab alone in patients with synovial sarcoma or myxoid liposarcoma. PATIENTS AND METHODS Patients with locally advanced, relapsed, or metastatic synovial sarcoma or myxoid liposarcoma (any grade) were randomly assigned to receive CMB305 with atezolizumab (experimental arm) or atezolizumab alone (control arm). The primary end points were progression-free survival (PFS) and overall survival (OS) analyzed using the Kaplan-Meier method. Safety and immune responses were assessed. RESULTS A total of 89 patients were enrolled; 55.1% had received ≥ 2 prior lines of chemotherapy. Median PFS was 2.6 months and 1.6 months in the combination and control arms, respectively (hazard ratio, 0.9; 95% CI, 0.6 to 1.3). Median OS was 18 months in both treatment arms. Patients treated with combination therapy had a significantly higher rate of treatment-induced NY-ESO-1–specific T cells ( P = .01) and NY-ESO-1–specific antibody responses ( P < .0001). In a post hoc analysis of all dosed patients, OS was longer (36 months) in the subset who developed anti-NY-ESO-1 T-cell immune response (hazard ratio, 0.3; P = .02). CONCLUSION Although the combination of CMB305 and atezolizumab did not result in significant increases in PFS or OS compared with atezolizumab alone, some patients demonstrated evidence of an anti-NY-ESO-1 immune response and appeared to fare better by imaging than those without such an immune response. Combining prime-boost vaccines such as CMB305 with anti–programmed death ligand-1 therapies merits further evaluation in other clinical contexts.

PURPOSE SARC024 is a phase II clinical trial of the multikinase inhibitor regorafenib in specific sarcoma subtypes, including advanced osteosarcoma. We hypothesized that regorafenib would improve progression-free survival (PFS) in patients with sarcoma and report the results of the osteosarcoma cohort. PATIENTS AND METHODS This trial enrolled patients with progressive metastatic osteosarcoma with measurable disease by RECIST who had received at least one prior line of therapy. Patients were randomly assigned at a ratio of one to one to regorafenib or placebo. Crossover was allowed at time of disease progression. PFS was the primary end point of the study, which was powered to detect a difference of at least 3 months in median PFS. RESULTS Forty-two patients from 12 centers were enrolled between September 2014 and May 2018. Median age was 37 years (range, 18 to 76 years). Patients had received an average of 2.3 prior therapy regimens. Ten patients receiving placebo crossed over to active drug at time of progression. Study enrollment was stopped early, after a data safety monitoring committee review. Median PFS was significantly improved with regorafenib versus placebo: 3.6 months (95% CI, 2.0 to 7.6 months) versus 1.7 months (95% CI, 1.2 to 1.8 months), respectively (hazard ratio, 0.42; 95% CI, 0.21 to 0.85; P = .017). In the context of the crossover design, there was no statistically significant difference in overall survival. Fourteen (64%) of 22 patients initially randomly assigned to regorafenib experienced grade 3 to 4 events attributed to treatment, including one grade 4 colonic perforation. CONCLUSION The study met its primary end point, demonstrating activity of regorafenib in patients with progressive metastatic osteosarcoma. No new safety signals were observed. Regorafenib should be considered a treatment option for patients with relapsed metastatic osteosarcoma.

TPS11589 Background: Murine double minute 2 (MDM2) is a negative regulator of tumor suppressor protein p53. MDM2 induces degradation of p53 and promotes tumorigenesis. MDM2 amplification occurs in many cancers but is documented in up to 100% of well-differentiated or dedifferentiated liposarcomas (WD/DDLPS) [Cancer Genome Atlas Research Network. Cell 2017]. Inhibition of the MDM2-p53 interaction is a promising therapeutic approach to restore p53 tumor suppressor activity in WD/DDLPS. Milademetan (RAIN-32) is a small-molecule MDM2 inhibitor that inhibits the MDM2-p53 interaction and restores p53 function at nanomolar concentrations. In a phase 1 study, milademetan showed promising efficacy in 53 patients with WD/DDLPS when administered on an intermittent schedule (260 mg QD on Days 1–3 and 15–17 on a 28-day cycle), with a median progression-free survival (PFS) of 7.4 months [Gounder et al. AACR-NCI-EORTC 2020]. WD/DDLS are relatively resistant to chemotherapy, and systemic treatment options for patients with advanced disease are limited. MANTRA (RAIN-3201) is a randomized, multicenter, open-label, phase 3 registration study designed to evaluate the efficacy and safety of milademetan versus trabectedin in patients with unresectable or metastatic DDLPS with disease progression on ≥ 1 prior systemic therapies. Methods: Eligible patients are ≥ 18 years of age with histologically confirmed unresectable and/or metastatic DDLPS, with or without a WD component, who have received ≥ 1 prior systemic therapies, including ≥ 1 anthracycline-based regimen, with radiographic evidence of progression by RECIST v1.1 within 6 months before study entry. Prior treatment with trabectedin or an MDM2 inhibitor is not permitted. Patients will be randomly assigned (1:1) to receive milademetan (260 mg once daily orally Days 1–3 and 15–17 on a 28-day cycle) or trabectedin (1.5 mg/m2 as a 24-hour intravenous infusion every 3 weeks). Randomization is stratified by Eastern Cooperative Oncology Group performance status (0 or 1) and number of prior treatments for WD/DDLPS (≤ 2 or > 2). Tumor response will be evaluated by RECIST v1.1 at Weeks 8, 16, 24, and 32, and then every 12 weeks. Primary endpoint: PFS by blinded independent central review. Secondary endpoints: overall survival; disease control rate; objective response rate; duration of response; PFS by investigator assessment; safety; health-related quality of life. Exploratory endpoints: molecular markers in peripheral blood and/or tumor tissue; milademetan pharmacokinetics. To demonstrate a 3-month increase in PFS (from 3 to 6 months) corresponding to a hazard ratio of 0.5, approximately 160 patients will be required to observe 105 events with 93.9% power and 2-sided significance level of 5%. Clinical trial information: NCT04979442.

TPS3167 Background: Protein arginine methyltransferase 5 (PRMT5) is an emerging target for cancer treatment. MTAP homozygous deletion occurs in 15% of cancers and often coincides with deletion of the tumor suppressor gene CDKN2A, leading to buildup of its substrate MTA. MTA shares close structural similarity to S-adenosyl methionine (SAM), the substrate methyl donor for PRMT5. By competing with SAM, MTA partially inhibits PRMT5. Thus, MTAP-null cancers are susceptible to further PRMT5 inhibition (Kryukov Science 2016). Current direct/indirect PRMT5 inhibitors (PRMT5i) showed preliminary anticancer activity, albeit with considerable toxicities due to their indiscriminate activities. AMG 193 is an MTA-cooperative PRMT5i that preferentially targets the MTA-bound state of PRMT5 that is enriched in MTAP-null tumors and represents a novel strategy to increase the therapeutic margin of this class of inhibitors. AMG 193 potently inhibits MTAP-null cancer cell lines and patient-derived xenografts. Methods: NCT05094336 is a first-in-human (FIH), multicenter, open-label, phase 1/1b/2 trial evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and efficacy of AMG 193 in patients with advanced MTAP-null solid tumors. Eligible patients (≥ 18 years) with histologically confirmed locally advanced/metastatic solid tumors not amenable to curative treatment with surgery and/or radiation, homozygous MTAP and/or CDKN2A deletion (by local next generation sequencing), or MTAP protein loss in tumors (by central immunohistochemistry), measurable disease, ECOG PS 0‒1, adequate hematopoietic, renal, liver, pulmonary, cardiac, coagulation function and glucose control will be included. The study will be conducted in 3 parts, each with subparts. Here, we describe Part 1a/b (dose exploration). Five dose levels are planned. Treatment continues until progression or withdrawal. The primary objectives are to evaluate the safety and tolerability of AMG 193 monotherapy; endpoints include dose-limiting toxicities, treatment-emergent adverse events, serious adverse events, electrocardiograms, laboratory abnormalities, and vital signs. Secondary objectives include the characterization of the PK parameters of AMG 193 including Cmax, Tmax, and AUC after single or multiple doses. This study is expected to enroll approximately 30 patients in Part 1a/b. This is the first FIH trial open for enrollment for this new class of PRMT5i and enrollment is ongoing. Clinical trial information: NCT05094336.

A MESSAGE FROM ASCO’S PRESIDENT I remember when ASCO first conceived of publishing an annual report on the most transformative research occurring in cancer care. Thirteen reports later, the progress we have chronicled is remarkable, and this year is no different. The research featured in ASCO's Clinical Cancer Advances 2018 report underscores the impressive gains in our understanding of cancer and in our ability to tailor treatments to tumors’ genetic makeup. The ASCO 2018 Advance of the Year, adoptive cell immunotherapy, allows clinicians to genetically reprogram patients’ own immune cells to find and attack cancer cells throughout the body. Chimeric antigen receptor (CAR) T-cell therapy—a type of adoptive cell immunotherapy—has led to remarkable results in young patients with acute lymphoblastic leukemia (ALL) and in adults with lymphoma and multiple myeloma. Researchers are also exploring this approach in other types of cancer. This advance would not be possible without robust federal investment in cancer research. The first clinical trial of CAR T-cell therapy in children with ALL was funded, in part, by grants from the National Cancer Institute (NCI), and researchers at the NCI Center for Cancer Research were the first to report on possible CAR T-cell therapy for multiple myeloma. These discoveries follow decades of prior research on immunology and cancer biology, much of which was supported by federal dollars. In fact, many advances that are highlighted in the 2018 Clinical Cancer Advances report were made possible thanks to our nation’s support for biomedical research. Funding from the US National Institutes of Health and the NCI helps researchers pursue critical patient care questions and addresses vital, unmet needs that private industry has little incentive to take on. Federally supported cancer research generates the biomedical innovations that fuel the development and availability of new and improved treatments for patients. We need sustained federal research investment to accelerate the discovery of the next generation of cancer treatments. Another major trend in this year’s report is progress in precision medicine approaches to treat cancer. Although precision medicine offers promise to people with cancer and their families, that promise is only as good as our ability to make these treatments available to all patients. My presidential theme, “Delivering Discoveries: Expanding the Reach of Precision Medicine,” focuses on tackling this formidable challenge so that new targeted therapies are accessible to anyone who faces a cancer diagnosis. By improving access to high-quality care, harnessing big data on patient outcomes from across the globe, and pursuing innovative clinical trials, I am optimistic that we will speed the delivery of these most promising treatments to more patients. Sincerely, Bruce E. Johnson, FASCO ASCO President, 2017 to 2018

In this review, we outline the biology and management of patients with carcinosarcomas and related malignancies, which are often included under the broader concept of sarcomatoid carcinomas. Carcinosarcomas are unusual tumors that are commonly gynecologic in origin, where they are referred to as malignant mixed Müllerian tumors, but may appear in any anatomic site. Although a variety of hypotheses have been presented as to the biphasic nature of these tumors, carcinosarcomas seem to represent the best example in human cancers of the concept of epithelial-mesenchymal transition (EMT), in which the two parts of the tumor are genomically related to one another, as opposed to the mesenchymal component that represents a second neoplasm or (benign) reactive process. In general, patients with carcinosarcomas fare worse than patients with carcinomas of the same anatomic site. Treatment paradigms for carcinosarcomas generally follow those of carcinomas of the same organ site, except where clinical trials provide more specific options. Agents that block or reverse EMT are worth examination in patients with carcinosarcoma and arguably may be even more effective in carcinomas, given evidence of dependence on EMT to generate successful metastases. Information about EMT may also inform other phase transitions in cancer, such as those between prostate or lung carcinoma and more aggressive tumors with neuroendocrine differentiation.

Purpose A phase III study comparing eribulin with dacarbazine in patients with advanced liposarcoma (LPS) or leiomyosarcoma showed a significant improvement in overall survival (OS) for the eribulin arm, with a manageable toxicity profile. We now report the histology-specific subgroup analysis of the efficacy and safety of eribulin compared with dacarbazine in patients with LPS, an independently randomized stratified subgroup of this phase III trial. Methods Patients ≥ 18 years with advanced or metastatic dedifferentiated, myxoid/round cell, or pleomorphic LPS incurable by surgery or radiotherapy were included. Patients with Eastern Cooperative Oncology Group performance status ≤ 2 and two or more prior systemic treatment regimens, including one with anthracycline, were randomly assigned 1:1 to receive eribulin mesylate (1.4 mg/m2 intravenously on days 1 and 8) or dacarbazine (850, 1,000, or 1,200 mg/m2 intravenously on day 1) every 21 days. OS, progression-free survival (PFS), and safety were analyzed. Results In the LPS subgroup, OS was significantly improved: 15.6 versus 8.4 months (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P < .001) with eribulin versus dacarbazine, respectively. Longer OS with eribulin was observed in all LPS histologic subtypes and in all geographic regions evaluated. PFS was also improved with eribulin versus dacarbazine (2.9 v 1.7 months, respectively; hazard ratio, 0.52; 95% CI, 0.35 to 0.78; P = .0015). Adverse events were similar between arms. Conclusion In patients with previously treated LPS, eribulin was associated with significantly superior OS and PFS compared with dacarbazine. Eribulin represents an important treatment option for patients with LPS, a sarcoma subtype for which limited effective systemic treatments are available. Further studies are justified to explore the role of eribulin in earlier lines of therapy as well as in combination with other agents.

TPS11581 Background: Metastatic undifferentiated Pleomorphic Sarcoma (UPS) and the genetically related myxofibrosarcoma (MFS) are soft tissue sarcoma (STS) subtypes with poor prognoses. While responses to front line chemotherapy can approach 20%, efficacy remains limited in the 2nd line setting and beyond. Pazopanib, the only approved treatment in the refractory setting, has demonstrated an objective response rate (ORR) of 4%. Envafolimab is a single domain PD-L1 antibody administered rapidly by subcutaneous (SQ) injection that is being studied in two additional pivotal trials: microsatellite instability-high (MSI-H) cancer and biliary tract cancer. The activity of envafolimab appears to be similar to other PD-1 antibodies administered i.v. Envafolimab demonstrated a 32% objective response rate (ORR) in MSI-H colorectal cancer patients who failed three approved chemotherapeutics, similar to the ORR of 28% and 33% with nivolumab and pembrolizumab in these patient populations, respectively. The rationale for the ENVASARC trial is based on the previously reported activity of checkpoint inhibition in UPS/MFS. Single agent pembrolizumab demonstrated a 23% ORR, while the combination of nivolumab and ipilimumab demonstrated a 29% ORR in refractory UPS/MFS. Methods: ENVASARC (NCT 04480502) is a pivotal multicenter (at ̃25 U.S. centers) open-label, randomized, non-comparative, parallel cohort study of treatment with envafolimab 300 mg every 3 weeks by SQ injection (cohort A; n = 80) or envafolimab 300 mg every 3 weeks by SQ injection combined with ipilimumab 1 mg/kg every 3 weeks i.v. for four doses (cohort B; n = 80) in patients with locally advanced, unresectable or metastatic UPS/MFS who have progressed on one or two lines of prior therapy. The primary objective of each of parallel cohort is to demonstrate an ORR with a lower limit of the 95% confidence interval that excludes 5.0% in each cohort. If ≥ 9 responders are observed of the 80 patients enrolled in each cohort, then the lower bound of the 95% confidence interval will exclude 5.0%. Secondary endpoints include duration of response (DOR), PFS and OS. Key inclusion criteria: ≤ 2 prior lines of therapy (neoadjuvant and adjuvant therapy excluded), ECOG ≤ 1. Clinical trial information: NCT 04480502.

e23574 Background: FDCS and HS are rare tumors arising from sustentacular cells of the lymph node, rather than lymphocytes. Surgical resection is often employed in case of localized disease, but for unresectable disease, anthracycline-based therapy is commonly used. PD-L1 staining is reportedly positive in 50-80% of FDCS. As a result, we treated 3 patients (pts) with ICI ipilimumab and nivolumab (Ipi/Nivo), and demonstrated the activity of these agents in these rare cancers. Methods: Two FDCS pts and one HS pt, all with B symptoms at the start of treatment, received Ipi/Nivo in the approved dose/schedule (Table). The HS patient was HIV(+) with undetectable viral load on treatment. One FDCS patient received radiation therapy to an active site of disease during immunotherapy. We reimaged patients every 2 months for the first 6 months, then less frequently. PDL-1 IHC and mutation data were available in all cases. Results: Mutation burden varied from low to intermediate; mutations in kinase genes were also observed. Case 1 (FDCS) demonstrated RECIST 1.1 complete response, but also received radiation, and Case 2 (FDCS) had RECIST partial response. Both continue on treatment 9 months after initiation. Case 3 (HS) demonstrated a minor response to treatment, then disease worsened after 4 months, and he subsequently received radiation to the residual site of disease. All patients showed resolution of B symptoms on ICI. Conclusions: We treated these pts with ICI based on their role as antigen presenting cells, as well as their high PD-L1 expression. We speculate that FDCS and related tumors such as HS represent extreme examples of cancers that have evidence of tertiary lymphoid structures, increasingly recognized as important in ICI responsiveness. Prospective clinical trials of ICI in these diagnoses will help us understand the basis of immune responses to ICI in other cancers. [Table: see text]

Purpose The ACOSOG (American College of Surgeons Oncology Group) Z9001 (Alliance) study, a randomized, placebo-controlled trial, demonstrated that 1 year of adjuvant imatinib prolonged recurrence-free survival (RFS) after resection of primary GI stromal tumor (GIST). We sought to determine the pathologic and molecular factors associated with patient outcome. Patients and Methods There were 328 patients assigned to the placebo arm and 317 to the imatinib arm. Median patient follow-up was 74 months. There were 645 tumor specimens available for mitotic rate or mutation analysis. Results RFS remained superior in the imatinib arm (hazard ratio, 0.6; 95% CI, 0.43 to 0.75; Cox model–adjusted P < .001). On multivariable analysis of patients in the placebo arm, large tumor size, small bowel location, and high mitotic rate were associated with lower RFS, whereas tumor genotype was not significantly associated with RFS. Multivariable analysis of patients in the imatinib arm yielded similar findings. When comparing the two arms, imatinib therapy was associated with higher RFS in patients with a KIT exon 11 deletion of any type, but not a KIT exon 11 insertion or point mutation, KIT exon 9 mutation, PDGFRA mutation, or wild-type tumor, although some of these patient groups were small. Adjuvant imatinib did not seem to alter overall survival. Conclusion Our findings show that tumor size, location, and mitotic rate, but not tumor genotype, are associated with the natural history of GIST. Patients with KIT exon 11 deletions assigned to 1 year of adjuvant imatinib had a longer RFS.

11015 Background: Immune checkpoint inhibitors have demonstrated activity in multiple tumor types but their activity in soft tissue sarcomas remains limited. In the multicenter phase II study, SARC028, the anti-PD-1 antibody, P demonstrated objective responses that were largely restricted to UPS and LPS subtypes. We now report outcomes from 2 expansion cohorts of SARC 028 in advanced UPS and LPS. Methods: To further confirm the clinical activity of P in UPS and LPS, we enrolled an additional 30 pts in each of 2 expansion cohorts for a total of 40 UPS and 40 LPS pts. Primary endpoint was investigator-assessed response by RECIST v1.1. Secondary endpoints were safety, progression-free survival (PFS), 12-week PFS rate, and overall survival (OS). An ORR of 25% was considered clinically meaningful and < 10% was considered to show lack of efficacy. P was to be considered a success if 8 or more of 40 enrolled patients had a PR or better (1-sided α = 0.042, 82% power). Pts age ≥18 with advanced, refractory UPS or LPS received 200 mg of P IV every 3 weeks until progression or unacceptable toxicity. Results: Preliminary results from the first 10 pts in each of the UPS and LPS cohorts have been reported. We now present summary data after enrolling an additional 30 pts in each cohort. The ORR in the UPS cohort was 23% (9/40), with an additional 5/30 PRs observed in the expansion cohort (total 2 CRs, 7 PRs). In the LPS cohort, the ORR was 10% (4/39 evaluable pts), with an additional 2/30 PRs observed (total 4 PRs). Median PFS for the UPS group was 3 months [95% CI: 2, 5] and 2 months [95% CI: 2, 4] for the LPS group. 12-week PFS rate was 50% in UPS [95% CI: 35, 65] and 44% in LPS [95% CI: 28, 60]. The UPS group had a median OS of 12 months [95% CI: 7, 34] and 13 months [95% CI: 8, NR] for the LPS group. P was well tolerated with no unexpected toxicities. Conclusions: The UPS cohort achieved its primary endpoint, however the activity of P in UPS deserves further evaluation in a randomized study. The activity of P was not confirmed in the LPS cohort. Ongoing biomarker analyses may direct better patient selection and guide future combination strategies. Clinical trial information: NCT02301039.

2508 Background: We present initial safety, pharmacokinetics (PK), and efficacy from the dose escalation study of R3767, alone (mono) or in combination with cemiplimab (REGN2810), a PD-1 mAb (combo), in pts with advanced malignancies (NCT03005782). Methods: Pts who had progressed on prior therapy(ies) and/or for whom no therapy with clinical benefit was available were enrolled; most pts had received no prior anti-PD-1/PD-L1. Pts received R3767 1, 3, 10, or 20 mg/kg every 3 weeks (Q3W) ± cemiplimab 3 mg/kg or 350 mg Q3W IV for ≤51 weeks. Crossover from mono to combo was allowed at progression. R3767 PK were evaluated. Tumor measurements were performed Q6W for the first 24 weeks and subsequently Q9W. Data cut-off date was Aug 25, 2018. Results: Mono: 27 pts (median age: 66 yr; ECOG PS: 0 [n=4], 1 [n=23]) were treated. There were no dose-limiting toxicities (DLTs). The most common treatment-emergent adverse event (TEAE) was nausea (22.2%). Grade ≥3 immune-related adverse events (irAEs) of increased alanine and aspartate aminotransferases (each 3.7%) were reported. By investigator-assessment (per RECIST 1.1; INV), best response was stable disease in 11 pts. Combo: 42 pts (median age: 60 yr; ECOG PS: 0 [n=15], 1 [n=27]) were treated. One pt treated with R3767 3 mg/kg Q3W + cemiplimab 3 mg/kg Q3W experienced DLT of grade 4 elevated blood creatine phosphokinase, associated with grade 3 myasthenia syndrome and grade 1 elevated troponin. The most common TEAEs were fatigue (33.3%) and nausea (21.4%). Grade 3 irAE of hypothyroidism (2.4%) was also reported. By INV, 2 (both small cell lung cancer) combo pts and 2 (endometrial cancer and cutaneous squamous cell carcinoma) of 12 additional pts who crossed over from mono to combo had partial responses. PK: R3767 concentrations in serum increased in a dose-dependent manner and were unaffected by combo. Conclusions: The safety profile of R3767 ± cemiplimab was generally tolerable; PK was linear. Early efficacy signals were detected despite the difficult-to-treat pt population. Biomarker studies are ongoing. R3767 20 mg/kg or 1600 mg fixed dose equivalent Q3W as mono and combo were selected for further evaluation. Clinical trial information: NCT03005782.

11011 Background: CMB305 (C) is an immunotherapy designed to generate an anti-NY-ESO-1 immune response (IR). C consists of a dendritic cell-targeting lentiviral vector encoding NY-ESO-1 gene (LV305), and a TLR-4 agonist NY-ESO-1 recombinant protein plus GLA-SE (G305). A Phase 1 study demonstrated C is safe, generates IR and conveys a median overall survival (mOS) of 23.7 months (15.5, not reached [NR]) for soft tissue sarcomas & 29.2 months (12.2, NR) for synovial sarcoma (SS) (ESMO 2018). We evaluated efficacy and safety of C and atezolizumab (A) vs A alone in NY-ESO-1+ SS and myxoid round cell liposarcoma (MRCL). Methods: A prospective randomized open label phase 2 study of C (LV305 Intradermal Days 0, 14, 42, 70 + G305 Intramuscular Days 28, 56, 84 then q 6wk up to one year (yr)) + A (1200mg IV q3wk) vs A alone in advanced NY-ESO-1+ SS/MRCL. Primary endpoints of OS and progression-free survival (PFS); secondary endpoints of safety, IR, and response rate and post hoc analysis by line of therapy. Results: 88 patients (pts) were enrolled and dosed. Arm C+A: median age 48 yrs, 73% SS, 98% relapsed metastatic, 73% ≥2 prior lines chemotherapy; Arm A: 47 yrs, 67% SS, 84% relapsed metastatic, 53% ≥2 prior lines chemotherapy. Most treatment-related adverse events (TRAE) Grade 1/2, no treatment related deaths. Summary of clinical outcomes. Conclusions: Despite no major differences in PFS and OS between the treatment arms (Arm C+A had more advanced disease and more prior lines of chemotherapy), Arm A +C achieved PRs, a higher level of anti-NY-ESO-1 IR, and pts with IR had numerically superior outcomes. Moreover, the clinical benefit of C+A in earlier lines of therapy warrant further study. Clinical trial information: NCT02609984. [Table: see text]

11500Background: DT is a rare cancer of connective tissue affecting young patients (pts), arising in any location, with a wide natural histories. DT is locally infiltrative and may cause pain, loss of mobility, bowel obstruction and visceral organ compromise. Death is rare. There is no standard of care (SoC), but surgery, observation and systemic therapies are used. S is an oral drug inhibiting VEGFR2/PDGFRB/RAF, showing activity in DT in case series. Methods: We conducted an international prospective study to evaluate efficacy of S (400 mg qd) in unresectable progressive (PD) or symptomatic DT. Pts were randomized 2:1 (S:P) and crossover to S upon RECIST 1.1 PD. Stratification: pain-level and disease site. Primary endpoint was progression-free survival (PFS). 75 pts yielded 90% power (1-sided α = 0.025, 1 interim analysis) to detect a hazard ratio (HR) of 0.4 (favoring S), assuming 6 month (mo) median (md) PFS for P and 15 mo for S, requiring 52 PFS events. Other endpoints: response rates (RR); toxicity ...

e21158Background: While prior studies demonstrated that pre-treatment Neutrophil Lymphocyte Ratio (NLR) < 5 and tobacco exposure predict benefit from checkpoint inhibition, presently, the only regu...

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

11505Background: Pazopanib, a multi-targeted tyrosine kinase inhibitor, has shown activity in various soft tissue sarcomas. Activity in liposarcoma, however, is limited. Regorafenib is a multi-kina...

Purpose Perivascular epithelioid cell tumors (PEComas) represent a family of mesenchymal neoplasms, mechanistically linked through activation of the mTOR signaling pathway. There is no known effective therapy for PEComa, and the molecular pathophysiology of aberrant mTOR signaling provided us with a scientific rationale to target this pathway therapeutically. On this mechanistic basis, we treated three consecutive patients with metastatic PEComa with an oral mTOR inhibitor, sirolimus. Patients and Methods Patients with advanced PEComa were treated with sirolimus and consented to retrospective collection of data from their medical records and analysis of archival tumor specimens. Tumor response was determined by computed tomography scans obtained at the clinical discretion of the treating physicians. Tumors were assessed for immunohistochemical evidence of mTORC1 activation and genetic evidence of alterations in TSC1 and TSC2. Results Radiographic responses to sirolimus were observed in all patients. PEComas demonstrated loss of TSC2 protein expression and evidence of baseline mTORC1 activation. Homozygous loss of TSC1 was identified in one PEComa. Conclusion Inhibition of mTORC1, pathologically activated by loss of the TSC1/TSC2 tumor suppressor complex, is a rational mechanistic target for therapy in PEComas. The clinical activity of sirolimus in PEComa additionally strengthens the pathobiologic similarities linking PEComas to other neoplasms related to the tuberous sclerosis complex.

PurposeMost gastrointestinal stromal tumors (GISTs) harbor mutant KIT or platelet-derived growth factor receptor α (PDGFRA) kinases, which are imatinib targets. Sunitinib, which targets KIT, PDGFRs, and several other kinases, has demonstrated efficacy in patients with GIST after they experience imatinib failure. We evaluated the impact of primary and secondary kinase genotype on sunitinib activity.Patients and MethodsTumor responses were assessed radiologically in a phase I/II trial of sunitinib in 97 patients with metastatic, imatinib-resistant/intolerant GIST. KIT/PDGFRA mutational status was determined for 78 patients by using tumor specimens obtained before and after prior imatinib therapy. Kinase mutants were biochemically profiled for sunitinib and imatinib sensitivity.ResultsClinical benefit (partial response or stable disease for ≥ 6 months) with sunitinib was observed for the three most common primary GIST genotypes: KIT exon 9 (58%), KIT exon 11 (34%), and wild-type KIT/PDGFRA (56%). Progression-free survival (PFS) was significantly longer for patients with primary KIT exon 9 mutations (P = .0005) or with a wild-type genotype (P = .0356) than for those with KIT exon 11 mutations. The same pattern was observed for overall survival (OS). PFS and OS were longer for patients with secondary KIT exon 13 or 14 mutations (which involve the KIT-adenosine triphosphate binding pocket) than for those with exon 17 or 18 mutations (which involve the KIT activation loop). Biochemical profiling studies confirmed the clinical results.ConclusionThe clinical activity of sunitinib after imatinib failure is significantly influenced by both primary and secondary mutations in the predominant pathogenic kinases, which has implications for optimization of the treatment of patients with GIST.

Purpose To assess potential differences in progression-free or overall survival when imatinib mesylate is administered to patients with incurable gastrointestinal stromal tumors (GIST) at a standard dose (400 mg daily) versus a high dose (400 mg twice daily). Patients and Methods Patients with metastatic or surgically unresectable GIST were eligible for this phase III open-label clinical trial. At registration, patients were randomly assigned to either standard or high-dose imatinib, with close interval follow-up. If objective progression occurred by Response Evaluation Criteria in Solid Tumors, patients on the standard-dose arm could reregister to the trial and receive the high-dose imatinib regimen. Results Seven hundred forty-six patients with advanced GIST from 148 centers across the United States and Canada were enrolled onto this trial in 9 months. With a median follow-up of 4.5 years, median progression-free survival was 18 months for patients on the standard-dose arm, and 20 months for those receiving high-dose imatinib. Median overall survival was 55 and 51 months, respectively. There were no statistically significant differences in objective response rates, progression-free survival, or overall survival. After progression on standard-dose imatinib, 33% of patients who crossed over to the high-dose imatinib regimen achieved either an objective response or stable disease. There were more grade 3, 4, and 5 toxicities noted on the high-dose imatinib arm. Conclusion This trial confirms the effectiveness of imatinib as primary systemic therapy for patients with incurable GIST but did not show any advantage to higher dose treatment. It appears reasonable to initiate therapy with 400 mg daily and to consider dose escalation on progression of disease.

Purpose Gemcitabine as a single agent and the combination of gemcitabine and docetaxel have activity in patients with metastatic soft tissue sarcoma. To determine if the addition of docetaxel to gemcitabine improved clinical outcome of patients with metastatic soft tissue sarcomas, we compared a fixed dose rate infusion of gemcitabine versus a lower dose of gemcitabine with docetaxel. Patients and Methods In this open-label phase II clinical trial, the primary end point was tumor response, defined as complete or partial response or stable disease lasting at least 24 weeks. A Bayesian adaptive randomization procedure was used to produce an imbalance in the randomization in favor of the superior treatment, accounting for treatment-subgroup interactions. Results One hundred nineteen of 122 randomly assigned patients had assessable outcomes. The adaptive randomization assigned 73 patients (60%) to gemcitabine-docetaxel and 49 patients (40%) to gemcitabine alone, indicating gemcitabine-docetaxel was superior. The objective Response Evaluation Criteria in Solid Tumors response rates were 16% (gemcitabine-docetaxel) and 8% (gemcitabine). Given the data, the posterior probabilities that gemcitabine-docetaxel was superior for progression-free and overall survival were 0.98 and 0.97, respectively. Median progression-free survival was 6.2 months for gemcitabine-docetaxel and 3.0 months for gemcitabine alone; median overall survival was 17.9 months for gemcitabine-docetaxel and 11.5 months for gemcitabine. The posterior probability that patients receiving gemcitabine-docetaxel had a shorter time to discontinuation for toxicity compared with gemcitabine alone was .999. Conclusion Gemcitabine-docetaxel yielded superior progression-free and overall survival to gemcitabine alone, but with increased toxicity. Adaptive randomization is an effective method to reduce the number of patients receiving inferior therapy.

There has been a gradual migration in the local treatment of soft tissue sarcomas from amputation and similar radical resectional approaches to more conservative, function-preserving surgery combined with radiotherapy. This progress has been made possible by small, single-institution, randomized trials that demonstrated the superiority of this more conservative, combined-modality approach. In the new millennium, attention has shifted to defining subsets of patients who might be adequately treated by surgery alone and defining the optimal sequence of surgery and radiation for patients who require both types of local therapy. There remains considerable discussion and debate surrounding the issue of pre- and postoperative chemotherapy for patients with localized soft tissue sarcomas. Adjuvant chemotherapy is a standard of care for adults who have the subtypes of soft tissue sarcomas that typically occur in pediatric patients (Ewing sarcoma, rhabdomyosarcoma), and just as clearly, adjuvant chemotherapy is not warranted in patients with low- and intermediate-risk disease (stages I and II). For patients with higher risk disease (stage III), the available randomized trials do not convincingly demonstrate a clinical benefit to adjuvant chemotherapy. As such, a complete accounting of potential risks and benefits is appropriate when discussing adjuvant chemotherapy with patients who have stage III disease.

Purpose To evaluate the antitumor activity and tolerability of bevacizumab and doxorubicin in patients with metastatic soft-tissue sarcoma (STS). Patients and Methods Patients may have had up to one nonanthracycline line of therapy. Seventeen patients with metastatic STS were treated with doxorubicin at 75 mg/m2 intravenous (IV) push followed by bevacizumab 15 mg/kg IV every 3 weeks. Dexrazoxane was started for total doxorubicin dose exceeding 300 mg/m2. Results A total of 85 cycles of doxorubicin/bevacizumab were administered, median four cycles (range, one to 11), with three patients receiving one to four cycles of bevacizumab maintenance after reaching 600 mg/m2 doxorubicin. All 17 patients were assessable for response. Two partial responses (12%, 95% CI = 1% to 36%) were observed, lasting seven and 12 cycles of therapy. Eleven patients (65%) had stable disease for four cycles or more. Six patients developed cardiac toxicity grade 2 or greater, with four patients grade 2 (cumulative doxorubicin 75, 150, 300, 300 mg/m2, respectively), one grade 3 (total doxorubicin 591 mg/m2), and one grade 4 (total doxorubicin 420 mg/m2). One patient with extensive lung disease died of recurrent bilateral pneumothoraces, possibly treatment-related. Conclusion The 12% response rate for these patients was no greater than that observed for single-agent doxorubicin. However, the 65% of patients with stable disease lasting four cycles or longer suggests further study is warranted in STSs. The observed cardiac toxicity, despite close monitoring and standard use of dexrazoxane, obliges a change in the dose and/or schedule in future studies of this combination.

Purpose Preclinical studies indicate that the cyclin-dependent kinase and protein kinase C inhibitor 7-hydroxystaurosporine (UCN-01) potentiates the cytotoxic effects of fluorouracil (FU). We designed a phase I clinical trial of FU in combination with UCN-01. Patients and Methods FU was administered as a weekly 24-hour infusion. Doses were escalated in successive cohorts according to a modified Fibonacci design. UCN-01 was administered once every 4 weeks, immediately after disconnection from FU, at a dose of 135 mg/m2 over 72 hours in cycle 1 and 67.5 mg/m2 over 36 hours in subsequent cycles. FU and UCN-01 pharmacokinetics were obtained on all patients, and thymidylate synthetase (TS) activity was measured in peripheral-blood mononuclear cells by reverse-transcriptase polymerase chain reaction. Results We escalated the weekly FU dose to 2,600 mg/m2 in combination with once a month infusions of UCN-01. Dose-limiting toxicity included arrhythmia and syncope. Other toxicities included hyperglycemia, headache, and nausea and vomiting. The mean maximal plasma concentration of UCN-01 was 33.5 μmol/L. There was significant interpatient variability, which correlated with plasma concentrations of alpha-1 acid glycoprotein. FU was rapidly cleared and the dose had no effect on the area under the curve of UCN-01. Changes in TS expression were detectable in peripheral-blood mononuclear cells after administration of UCN-01 but did not correlate with toxicity or activity. We observed no objective response, although seven patients had stable disease, six of whom had received prior fluoropyrimidines. Conclusion The combination of weekly infusions of FU and monthly UCN-01 can be administered safely and warrants further study in phase II trials. The recommended phase II dose of FU in combination with monthly UCN-01 is 2,600 mg/m2.

Osteogenic sarcoma is the most common primary tumor of bone, with an approximate incidence of three per million. There are two peaks of incidence: one during adolescence, and a later peak in the eighth decade. Despite what can be considered adequate therapy, adults fare worse than children. Nonetheless, the treatment of osteosarcoma represents one of the genuine success stories in oncology. Limb-sparing surgery minimizes the need for physically and psychologically scarring amputations, and newer generations of implants account for bone growth, because these tumors are most common in adolescence. Chemotherapy, administered in both the neoadjuvant and adjuvant settings, has improved the cure rate for osteosarcoma from 5% to 20% in the prechemotherapy era to the 60% to 70% range. On the basis of single-arm phase II studies, single agents and combinations of systemic therapeutics have demonstrated the activity of methotrexate, doxorubicin, and cisplatin (MAP) in metastatic osteosarcoma, leading to two seminal randomized studies confirming the activity of adjuvant chemotherapy. This three-drug combination represents a standard of care for osteogenic sarcoma therapy in the United States. No randomized studies have examined the role of doxorubicin in adjuvant therapy, and randomized studies of cisplatin have been performed based only on patient response to other therapy. However, a methotrexate-free alkylating agent– intensive regimen yielded survival results similar to those of MAP in a single-arm phase II study, and two randomized multicenter clinical trials demonstrated that regimens without methotrexate resulted in overall survival (OS) rates no different than those of more complex combinations containing methotrexate. A separate study examining highversus intermediate-dose methotrexate in the adjuvant setting favored high-dose methotrexate. Criticisms of the negative randomized studies include low dose-intensity and lack of adjustment of methotrexate levels in the experimental arms. Early studies of primary and metastatic osteosarcoma gave rise to other key clinical observations: one, the degree of necrosis observed with neoadjuvantchemotherapypredicts foroverall survival,withaminimum of 90% to 95% tumor necrosis defining a good response; and two, resection of isolated lung metastatic disease may be curative, whereas multifocal disease to bone is generally not curable. Caveats to each observation exist. For example, chondroblastic osteogenic sarcoma may not respond as well to chemotherapy as osteoblastic osteosarcoma, but the poorer response does not portend poorer prognosis; isolated bone metastatic lesions may be resected with curative intent. Dose-intensification and the addition of newer agents have been examined in a variety of single-arm phase II studies, which are inherently difficult to compare. Nonetheless, well-conducted phase III studies performed in pediatric and expert adult sarcoma centers have provided oncologists with strong foundations on which to make clinical decisions. It is in this light that Ferrari et al applied the experience with ifosfamide in the recurrent setting to primary disease. Ifosfamide, in phase I to II combination studies with other agents, has significant activity in recurrent or metastatic osteosarcoma. Thus, it was anticipated that ifosfamide would be useful in primary disease. Supportive data for the adjuvant use of ifosfamide have come from the Istituto Ortopedici Rizzoli, where the authors conducted the present study, and elsewhere. In a study accruing patients with suboptimal necrosis of tumor after neoadjuvant therapy, ifosfamide and etoposide were added to MAP therapy, which had been administered preoperatively. This cohort of high-risk patients had a 56% event-free survival (EFS) rate, which was heartening enough to move ifosfamide into the neoadjuvant setting. In the article that accompanies this editorial, Ferrari et al describe the results of their randomized study of 246 patients with osteosarcoma, younger than age 40 years, who were treated between 2001 and 2006 with neoadjuvant MAP chemotherapy with or without ifosfamide. After surgery, treatment was stratified but not randomized. Patients receiving ifosfamide before surgery continued with it to complete adjuvant treatment, whereas those patients receiving MAP alone received ifosfamide only if they had suboptimal tumor necrosis ( 90%) at time of surgery. The experimental arm demonstrated more hematologic toxicity, as anticipated. However, with a 66-month medianfollow-up, therewasnostatisticallysignificantdifferencebetween the standard and experimental arms in the proportions of patients with at least 90% tumor necrosis (48% v 42%), in EFS (64% v 55%), or in 5-year OS (73% v 74%), the primary end point of the study. The principal conclusion was that ifosfamide did not improve the degree of tumor necrosis significantly and thus was not recommended as part of neoadjuvant chemotherapy. The present study highlights results of the adjuvant osteogenic sarcoma study from the Children’s Cancer Group (CCG) and Pediatric Oncology Group (POG), which was conducted between 1993 and 1997 with 777 eligible patients, 662 without metastases. The CCG/ POG study was hampered in data collection, because the primary end JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 17 JUNE 1

e22516 Background: Trabectedin (T) has been shown to improve progression free survival (PFS) (4.2 vs 1.5 months, HR 0.55, p < 0.0001) in comparison to dacarbazine (D) in patients (pts) with advanced leiomyosarcoma or liposarcoma following failure of prior chemotherapy. Pts randomized to T in this phase III trial (ET743-SAR 3007) received T as a 24 hr IV infusion in either an inpatient (InP) or outpatient (OP) setting, based upon site preference. Here we report the safety, efficacy, and patient reported outcomes (PROs) of pts based on first infusion site of care. Methods: Pts were randomized 2:1 to receive T (1.5 mg/m2) or D (1 g/m2 over 20-120 min). Site of T infusion was based on institutional preference/standard of care. The site of T administration (InP vs OP) was collected for the first infusion with the assumption that site of care was unchanged for subsequent doses. Results: Of 378 pts treated with T, 100 (27%) and 277 (73%) pts received T as InP or OP, respectively. No differences were observed in PFS or overall survival (OS) by site of care (InP vs OP): Median PFS of 4.1 vs 4.2 months; HR 0.90, p = 0.49 and median OS of 14.3 vs 13.7 months; HR 0.89, p = 0.40. No difference in other efficacy endpoints between InP vs OP were observed: disease control rate (CR+PR+(SD≥18wks)) (38% vs 33%; Odds Ratio [OR] 1.22; p = 0.44) and Overall Response Rate (14% vs 8%; OR 1.76; p = 0.15)). Grade 3-4 adverse events (AEs) occurred in 87% InP vs 79% OP pts and grade 3-4 SAEs occurred in 43% InP vs 33% OP. The most common grade 3-4 AEs in both groups were increased ALT/AST, hematologic toxicity, nausea and fatigue. The incidence of grade 3-4 febrile neutropenia was similar in both groups at 5.0% InP vs 4.7% OP, as was increased blood creatine phosphokinase at 5.0% InP vs 6.1% OP, and catheter related complications of any grade at 16% InP vs 15% OP. No clinically meaningful differences were observed in PROs measured by MD Anderson Symptom Inventory scores. Conclusions: The majority of patients randomized to the trabectedin arm of the ET743-SAR-3007 Phase III study received trabectedin in the OP setting. Treatment outcomes with trabectedin suggest equivalent efficacy and safety when administered in the InP or OP setting. Clinical trial information: NCT01343277.

11005 Background: Pazopanib is approved for soft tissue sarcoma pts after failure of other therapy, but there are few subtype-specific data regarding kinase inhibitor activity. We report on a single arm, phase II trial of REGO in advanced EWS. Methods: EWS pts (age > 18, ECOG 0-2, good organ function) who had at least 1 line of therapy and had PD within 6 mo were eligible. Prior oral kinase inhibitors were not allowed. Initial REGO dose was 160 mg PO QD x21 q28d. Dose reductions were employed for toxicity and AEs. The primary endpoint was PFS at 8 weeks (PFS8w) employing RECIST 1.1. Sample size of 30 allowed determination of the difference between PFS8w of 50% vs 25% with alpha = 0.05 and power of 91%. Results: 30 pts (median age 32, range 19-65; M/F = 20/10; ECOG 0/1/2 = 16/13/1; bone, 12; soft tissue, 18; median prior treatments 5, range 1-10) enrolled at 14 US sites (09/2014-03/2016). Most common grade (G3) toxicities were hypophosphatemia (6), hypertension (2), high ALT (2) and 1 each: fatigue, abd pain, diarrhea, hypokalemia, oral mucositis, neutropenia and rash; no G4 toxicities were noted. 13 pts required ≥1 dose reduction, most commonly hypophosphatemia (n = 7); 2 stopped REGO for toxicity. There was 1 death in the 30 day post study period, not REGO related. Median dose at study end: 140 mg (3.5 tabs, range 80-160 mg) 3 wks on/1wk off. 18/30 pts were without PD at 8 wks. Median PFS: 3.6 mo (95%CI 2.8-3.8 mo). PFS8w by KM was 73% (95%CI 57-89%). Best responses: PR/SD/PD/not evaluable of 3/18/7/2, for RECIST RR 10%. Two pts with PR had EWSR1 translocation by FISH; a third had CIC-DUX4. Median duration of response: 5.5 mo (95%CI 2.9-8.0). Median OS is not reached. Conclusions: The substudy met its primary endpoint. REGO toxicity was similar to that seen previously. Enrollment continues in LPS and OGS cohorts, and is being expanded to further study variant EWS without EWSR1-FLI1 fusion. Study of the existing tissue may elucidate which EWS patients may benefit from REGO. Clinical trial information: NCT02048371.

TPS11081 Background: AAS is an aggressive soft tissue sarcoma (STS) of endothelial cell origin with an expected median overall survival of 8-12 months. Pazopanib (P) is approved for treatment of advanced STS following progression on chemotherapy. In a retrospective study of 40 AAS patients treated with single agent P the median PFS was 3.1 months and median OS 9.9 months with no complete responses. Endoglin is an essential angiogenic receptor expressed on AAS that is upregulated following VEGF inhibition, and TRC105, an endoglin antibody, given with P produced durable complete responses in AAS patients with median PFS of 5.6 months in refractory patients including those receiving prior P. The TAPPAS trial is the first randomized Phase 3 trial performed in AAS, and was initiated following protocol assistance from the EMA and Special Protocol Assessment from the FDA. Methods: TAPPAS is a randomized multicenter study of TRC105/P vs P alone in the United States and Europe that is actively enrolling cutaneous and non-cutaneous AAS patients and incorporates an adaptive enrichment design. Key inclusion criteria: 0, 1 or 2 prior lines of therapy, ECOG ≤ 1. Primary endpoint is PFS and secondary endpoints include ORR and OS. The initial sample size of 124 patients, followed until 95 PFS events, provides more than 80% power to detect a hazard ratio of 0.55. At the time of interim analysis, projected to occur upon the occurrence of 40 events in approximately 70 patients, the result will be classified as belonging to either the favorable, promising, enrichment or unfavorable zones, based on conditional power. The sample size and PFS events will be unchanged in the favorable and unfavorable zones, and will be increased to a total of 200 patients followed for 170 PFS events in the promising zone. The trial will enroll 100 additional patients, with cutaneous disease only, in the enrichment zone and will follow them until 110 events are observed in the total cutaneous population. An independent DMC will follow the trial for safety and futility. The adaptive design requires the enrollment of fewer patients, preserves type-1 error, and protects power to detect a clinically meaningful survival benefit. (NCT 02979899). Clinical trial information: NCT02979899.

11009 Background: Adjuvant IM reduces risk of recurrence and improves survival in pts with high-risk primary GIST. Joensuu et al 2016 demonstrated higher 5-yr overall survival (OS) rates of 91.9% vs 85.3% in pts treated with adjuvant IM for 3 vs 1 yr, respectively. It is unknown if further extension of treatment duration can improve outcome. Methods: PERSIST-5 is a single-arm, phase II trial that enrolled pts ≥18 yrs of age, who underwent macroscopically complete resection of primary KIT (+) GIST with high risk of recurrence within 12 wks prior to IM treatment. High risk was defined as primary GIST (any site) ≥2 cm with a mitotic count ≥ 5/50 HPF or non-gastric primary GIST ≥5 cm. Pts were treated with IM 400 mg/d for 5 yrs or until progression, relapse, or intolerance. Primary endpoint was recurrence-free survival (RFS, defined as time of treatment start to first recurrence or death). Results: IM was administered to 91 pts with a median age of 60 yrs (range 30-90). Median tumor size was 6.5 cm (range 2.3-30 cm; 55% gastric origin). Median treatment duration was 55.7 mos (range, 0.5-75). Forty-six (50.5%) pts completed study treatment. The 5- and 8-yr estimated RFS rates were 90% (95% CI, 80-95) and 81% (95% CI, 62-91), respectively. The 5- and 8 year OS rate was 95% (95% CI, 86-99). There were 7 recurrences; 1 pt recurred and died while on IM ( PDGFRA D842V mutation) and 6 pts recurred after IM discontinuation. Two pts died after IM discontinuation, unrelated to study treatment and without recurrence. Forty-five pts discontinued study treatment; common reasons included patient choice (20%), adverse events (AEs, 17%), protocol deviation (4%), and loss of follow-up (4%). The most common AEs of all grades (regardless of relationship to IM) were nausea (71%), diarrhea (63%), fatigue (50%), muscle spasm (41%), vomiting (39%), and periorbital edema (34%). Conclusions: Five yrs of IM treatment was effective in preventing recurrence in pts with sensitive mutations who underwent resection of primary GIST. Nearly half of the patients discontinued treatment early, and most recurrences occurred after IM discontinuation. Clinical trial information: NCT00867113.

11001 Background: The utility of NGS in management of sarcoma pts remains undefined. Methods: We retrospectively analyzed the NGS profile of patients who were sequenced using a panel of 405 cancer-related genes in DNA and 265 genes rearranged in RNA. Diagnostic and therapeutic implications of mutations (mut) were evaluated through published literature (OncoKb.org, Pubmed). An algorithm was applied to determine germline mut. Following IRB approval, we evaluated the clinical outcomes of pts who underwent NGS at MSKCC. Results: From 2012–2016, 5635 pts worldwide with 56 histologies were tested. Median age of 52 yrs ( < 1-88), 52% females and sarcoma NOS (n = 858) was most frequent. Tumors were sequenced to a mean coverage of 634X; 1165 fusions and > 60,000 mut were found. Mut suspicious for germline defects were seen in 542 pts (9.6%) in known and novel genes ( BRCA, ARID1, FANC). Tumor mutational burden was 2.5/Mb (0–329) and glomus tumors and EHE had the highest and lowest mut, respectively. 16% and 7% of pts had treatment-linked alterations (TLA) known to respond to an FDA approved or study drug, respectively. 42% of pts had TLA eligible for NCI-MATCH, ASCO-TAPUR or other studies. Novel TLA include AKT, ESR1, BRCA, NTRK, PTCH1, SMARCB1 and others. Of the 107 MSKCC pts with clinical data, 60/107 (57%) had at least one TLA, of which 31 (30%) enrolled on a matched trial and 26 pts were ineligible or lacked access to trials. Partial/complete responses were seen with inhibitors to NTRK, IDH1, BRAF, PI3K/mTOR, MDM2, SMARCB1 and others. NGS changed the initial pathology diagnosis and treatments in 5% pts (e.g. LMS to liposarcoma, clear cell to melanoma). Resistance mutations averted futile therapies in 5% pts (e.g. Rb loss and palbociclib in liposarcoma). Conclusions: Our data suggests that NGS has a significant impact in aiding diagnosis and selecting matched therapies in sarcoma. Suspected germline aberrations, while intriguing, needs further validation.

11008 Background: SARC028 is the first multicenter Phase II study of P monotherapy in patients (pts) with STS and BS. Designed to detect clinical efficacy signals in multiple histologies, the study collected blood & tissue samples on all pts. We report extended clinical follow-up and in-depth biomarker correlates of response. Methods: The primary endpoint was objective response rate (ORR) by RECIST 1.1. Secondary endpoints were safety, 12 wk progression-free survival (PFS), and overall survival (OS). The STS arm had 10 pts in each of 4 cohorts: undifferentiated pleomorphic sarcoma (UPS), dedifferentiated liposarcoma (DDLPS), synovial sarcoma (SS) and leiomyosarcoma (LMS). The BS arm included 40 pts with osteosarcoma (OS), Ewing sarcoma (ES) or dedifferentiated chondrosarcoma (CS). Pre- and on-P biopsies were required as well as blood at multiple time points. Tumor was assessed for PD-L1 expression (clone 22C3) and immune infiltrates by multi-color IHC (Vectra). Ongoing analyses include circulating cytokine and checkpoint levels and exome (DNA), transcriptome (RNA), and T-cell receptor (TCR) sequencing. Results: 86 pts were enrolled, 80 were evaluable for response. For STS, median follow-up was 14.5 months. The ORR in the overall STS cohort was 18% and the 12-wk PFS 55% [95% CI, 42-71]). Clinical activity was variable by histologic subtype with 40% ORR in UPS (1 CR and 3PR out of 10 evaluable pts), 2 PR/10 were seen in DDLPS, 1PR/10 in SS and 0/10 in LMS. For BS, median follow-up was 12.3 months (ORR 5%; 12-wk PFS 28% [95% CI, 14-41]), with 1PR/22 OS, 1PR/5 CS and 0/13 ES. 70 pre-P tissues were analyzed (11 excluded for insufficiency), with PD-L1+ in 3/70 (4%); all 3 were UPS. Of the 2 evaluable pts, 1 had CR and 1 PR. 2 OS were PD-L1+ on multi-color IHC, 1 had PR. All PD-L1+ samples had CD8+ T-cell infiltration. There were no post-P PD-L1+ samples. Conclusions: P has clinical activity in UPS and LPS, and expansion cohorts in those subtypes are planned. Pre-treatment PD-L1 expression was infrequent, but correlated with T-cell infiltration and response in UPS & OS. Ongoing biomarker analyses that may guide combination strategies are ongoing and will be presented at the meeting. Clinical trial information: NCT02301039.

e22522 Background: In the AJCC version 7 TNMG staging of soft tissue sarcomas (STS), the longest dimension (1D) of the primary tumor at pathology analysis is the gold standard for tumor size (T) staging. However, measurements may differ between scans and actual tissue measurement, due to tissue elasticity, deformation, and/or formalin fixation. Thus, tumor size may change compared to preoperative imaging. Should STS T stage be defined by imaging or by direct tumor measurement? We examined the variability of the measurements between radiology and pathology data, examining 1D, cross sectional area (2D), and tumor volume (3D) to assign a T stage. Methods: We reviewed all patients (pts) with extremity STS who had surgery at Mt Sinai Hospital New York (2010-2015). MRI or CT and resected gross tumor measurements were available for 79 pts. After eliminating 10 samples with grossly irregular shapes and 11 samples with incomplete data, 58 tumors had complete 3D measurements. We calculated Pearson correlation coefficients for paired variables (radiology vs pathology size in 1D, 2D and 3D). Results: Imaging measures correlated well with direct tumor measurements. Pearson correlation coefficients for 1D, 2D and 3D measurements were 0.93, 0.72 and 0.78, respectively (all p < 0.01). The SEM (radiology/pathology size) = 0.13, i.e. 13% for 1D measurements. Thus, T stage could be incorrectly assigned in up to 13% of samples near 5 cm in size; this proportion decreases the further the tumor is from the 5 cm cutoff. Conclusions: As shown previously in the rationale for RECIST, 1D measures provide the smallest variance between radiology and pathology. The situation is made more complex in AJCC version 8, with four T categories. It remains unclear how to stage the 10-15% of primary STS with irregular shapes. These data support the use of nomograms for risk assessment rather than using bins created by the AJCC tumor staging system. 3D tumor volumes, if used at all, may play a greater role when assessing therapy responses or contending with tumors of irregular shape, rather than for routine STS staging.

60 Background: The activity of the anti-PD-1 antibody P in pts with advanced STS was evaluated in a prospective multicenter Phase II study conducted by the Sarcoma Alliance for Research through Collaboration (SARC). SARC028 enrolled 40 patients with advanced soft tissue sarcoma. Pembro had an ORR of 19% and PFS rate at 12 weeks of 55%, suggesting clinical activity. We investigated biomarkers of response to P. Methods: The primary endpoint was Objective Response Rate (ORR) by RECIST 1.1. Secondary endpoints included progression-free survival (PFS), overall survival, and biomarkers of response in blood and tumor. Pre- and on-treatment biopsies were required and obtained from over 90% and 72% of pts respectively. Serum was obtained from all pts at baseline and at multiple time points on therapy (pre-, week 8, and every 12 weeks). Sera were examined for candidate circulating biomarkers by Affymetrix Luminex platform array, including PD-L2. To determine whether there is a statistically significant difference between different conditions, we used Mann-Whitney and two-tailed t tests. Log-rank p-values in Kaplan-Meier survival analyses were calculated using the "survival" R package. Results: Forty pts with STS were enrolled into 4 cohorts (10 each) based on histological subtype including undifferentiated pleomorphic sarcoma (UPS), dedifferentiated liposarcoma (LPS), synovial sarcoma (SS), and leiomyosarcoma (LMS). 4 pts with UPS, 2 pts with LPS, and one pt with SS achieved a response. Six of seven responses were durable at the time of this analysis. Circulating levels at baseline or after therapy of PD-1, PD-L1, 4-1BB, IDO, BTLA, CTLA-4, LAG-3, and TIM-3 did not correlate with outcome. However, pre-treatment and week 8 PD-L2 levels correlated best with clinical outcome: high PD-L2 levels were associated with better PFS (p=0.019) in STS. Conclusions: P has clinical activity in specific histologic subtypes of STS, namely UPS and LPS. Pre-treatment circulating PD-L2 levels correlated with progression-free survival and is a novel and promising predictor of improved clinical outcome of PD-1 therapy in STS.

11006Background: Inhibition of the programmed death-1 (PD-1)-PD-ligand 1 (PD-L1) axis has shown durable clinical benefit in melanoma, lung, renal, and bladder carcinomas. Herein, we report results ...

11065Background: Desmoid tumors (DT) are rare fibroblastic neoplasms with a variable course. Observation, surgery, radiation and systemic agents are known therapies with variable outcomes. We previously reported on the efficacy of sorafenib (SO). Here we review a larger cohort with long-term follow up (FU). Methods: Patients (pts) with DT treated with SO were retrospectively identified. Baseline/treatment characteristics were analyzed using descriptive statistics. Response rates (RR) were calculated according to RECIST 1.1 and WHO criteria. Kaplan-Meier curves were estimated for survival and variables correlated with treatment outcomes were investigated. Results: We treated 79 pts with progressive or symptomatic DT with SO; median age was 37 years (range 17-81), 67% were female. Primary sites included extremities (n = 22; 28%), abdomen (n = 19; 24%), chest wall (n = 15; 19%), abdominal wall (n = 13; 16%) and other (n = 10; 13%). SO was the first systemic treatment in 49 pts (62%), most frequently at 400mg...

11061Background: T is recently approved in the US for treatment of advanced LMS or LPS after prior chemotherapy failure based on results from a randomized, phase-3 study (Demetri et al, 2015, J Cli...

6605Background: Both efficacy and toxicity impact a person’s experience with chemotherapy, as recognized in a recently published ASCO framework. A number of approved chemotherapy agents require ear...

11032Background: Aggressive fibromatoses (desmoid tumors, DT) are locally aggressive connective tissue tumors prone to local recurrences. There is a thin line between the morbidity of aggressive su...

11016Background: P, a VEGFR TKI, is approved for advanced STS based on median PFS (mPFS) in the absence of CR. Endoglin is a receptor expressed on tumor vessels that is overexpressed in certain STS...

3086Background: Poly-ICLC, a double-stranded RNA complex, can directly activate dendritic cells and trigger NK cells to kill tumor cells. It can be given intramuscularly (IM) to induce systemic inf...

10514 Background: The VEGFR inhibitor pazopanib is approved for the treatment of advanced STS. Resistance to pazopanib is a challenge in the treatment of STS, and endoglin (CD105) activation may be an important resistance mechanism. Endoglin is an angiogenic receptor expressed on proliferating tumor vessels, which is upregulated following VEGF inhibition and expressed on certain STS subtypes, including angiosarcoma. A phase Ib study of TRC105, an anti-endoglin antibody, in combination with pazopanib was performed in patients (pts) with advanced STS. Methods: Heavily-pretreated STS pts with leiomyosarcoma (11); angiosarcoma (2); synovial sarcoma (2); epithelioid sarcoma (1); myxofibrosarcoma (1); epithelioid hemangioendothelioma (1); and unclassifiable high grade sarcoma (2), ECOG PS 0-1, were treated with infusional TRC105 weekly in two cohorts (8mg/kg and 10mg/kg). TRC105 was initiated following a 2 to 4 week lead-in period of pazopanib starting at 800 mg PO daily. Results: Twenty pts (median age = 57; M...

LBA10502 Background: In a phase II study of pts with advanced soft tissue sarcoma, 32% and 47% of pts with LMS and ADI respectively, treated with the microtubule dynamics inhibitor eribulin achieved progression-free survival (PFS) at the 12 wk timepoint (Schöffski et al. Lancet Oncol. 2011; NCT00413192). Based on these findings, this phase III study (NCT01327885) compared overall survival (OS) in pts with advanced LMS and ADI treated with eribulin or dacarbazine. Methods: Pts aged ≥ 18 yrs with advanced high/intermediate grade LMS or dedifferentiated, myxoid, round cell or pleomorphic variants of ADI incurable by surgery and/or radiotherapy were enrolled. Pts had ECOG status ≤ 2 and had received ≥ 2 standard systemic treatment regimens including an anthracycline. Pts were randomized 1:1 to eribulin (1.4 mg/m2, IV on D1 and D8) or dacarbazine (850–1200 mg/m2, IV on D1) every 21 days until disease progression. Primary endpoint was OS. Secondary endpoints included PFS, PFS rate at Wk 12 and safety. Results: Overall, 452 pts (67% female; 79% < 65 yrs) were randomized (228 eribulin; 224 dacarbazine). Median OS for eribulin and dacarbazine was 13.5 and 11.5 months, respectively (HR = 0.768, 95% CI 0.618–0.954; P= 0.017). PFS was 2.6 months in both arms (HR = 0.877, 95% CI 0.710–1.085; P= 0.229). PFS rate at Wk 12 was 33% and 29% for eribulin and dacarbazine, respectively. In eribulin and dacarbazine arms, respectively, 26% and 14% of pts required dose reductions and 8% and 5% discontinued due to treatment-emergent adverse events (TEAEs). TEAEs were more frequent in eribulin than dacarbazine arm, including neutropenia (44% vs 24%), pyrexia (28% vs 14%), peripheral sensory neuropathy (20% vs 4%) and alopecia (35% vs. 3%); as were TEAEs of grade 3 (63% vs 53%), grade 4 (26% vs 20%), and fatal TEAEs (4% vs 1%). Thrombocytopenia was more frequent in dacarbazine than eribulin arm (28% vs 6%). Conclusions: This phase III trial of eribulin trial met its primary objective of OS benefit in pretreated pts with advanced LMS or ADI. Eribulin had a toxicity profile consistent with prior experience, with no unexpected or new safety findings. Funding Source: Eisai Inc. Clinical trial information: NCT01327885.

10561 Background: TGCT is a rare disease affecting the synovium and tendon sheaths of young adults. This usually benign neoplasm is driven by overexpression of CSF1, in some cases as a result of fu...

TPS10578 Background: Immune checkpoint inhibition with antibodies (abs) to cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death 1 (PD-1), and programmed death ligand 1 (PD-L1) have made a si...

10503 Background: This phase III multicenter trial compared T with D in pts with advanced LPS or LMS previously treated with an anthracycline and at least one additional systemic therapy. Methods: ...

10508 Background: The widespread use of next-generation sequencing has uncovered the genomic landscape in many tumor types. Given the disease rarity and histologic diversity, much less is known abo...

231 Background: Effectively managing patient distress in oncology is challenging. Just as patients and their families experience distress over cancer, trainees in oncology also experience distress. This study evaluates whether increased physician-in-training distress acutely reduces empathy. Terror Management Theory provides the theoretical framework for the hypothesis. Methods: 35 internal medicine interns and residents completed a pre and post rotation Impact of Events (IES) and Interpersonal Reactivity Index (IRI) for comparison after 2-4 weeks. IES and IRI measure distress and empathy respectively. Results: Overall IRI empathy decreased (paired t-test, p=0.02) but only significantly in the Fantasy subscale (p=0.008). Empathy scores were below historical controls and did not differ between males and females (p=0.06). Pre and post rotation IES scores averaged 19.7 and 20.7. Distress was significant (>8) in 82% and 88% and severe (>33-PTSD range) in 20% and 22% of Pre/Post IES, respectively. Time on the ward averaged 2.6 weeks and residents attended to 4.6 actively dying patients, of which 38% stated it was "the most stressful experience"; however, 56% found "meaning" in the work. 48% mentioned patient death as the traumatic event (responding to IES). Conclusions: Residents demonstrated pathological levels of distress which affected aspects of empathy in a short period of time and related predominately to death experiences. Ultimately, physician self-management of vicarious distress during oncology training and enhanced maintenance of empathy could improve patient distress management, but this idea will require further study. [Table: see text]