Riedel, Richard F.

TPS11587 Background: Recurrent or metastatic dedifferentiated liposarcoma (DDLS) remains a difficult disease to treat. Available agents such as doxorubicin, eribulin, trabectedin, ifosfamide, dacarbazine, or gemcitabine-based regimens are associated with low response rates and only modest improvements in progression free or overall survival. The oncogene CDK4 is ubiquitously amplified in this disease and represents a rational therapeutic target. In single-arm phase 2 studies, treatment with selective CDK4 inhibitors resulted in clinical benefit (12-week progression-free survival (PFS) of 57% with palbociclib and 74% with abemaciclib). We hypothesize that treatment with abemaciclib will improve PFS compared to placebo in patients with recurrent or metastatic DDLS. Methods: This is a phase 3 randomized double-blind study of abemaciclib versus placebo. Eligible patients have recurrent or metastatic dedifferentiated liposarcoma (purely well-differentiated liposarcoma excluded), progression of disease by RECIST 1.1 in the 6 months prior to study entry, any number of prior systemic therapies, and adequate organ function and performance status. Patients are stratified by number of prior lines of therapy (0 vs 1 or more) and randomized 1:1 between abemaciclib 200 mg PO twice a day and matching placebo. Patients are followed with scans every 6 weeks (every 12w after 36w) and those with progression of disease on placebo may cross over to open label abemaciclib. The primary endpoint is PFS. Target enrollment is 108 evaluable patients which provides 80% power with two-sided 10% significance level to detect a hazard ratio of 0.6. Secondary endpoints include response rate, PFS and response rate after crossover, and overall survival. Archival tissue will be collected to explore potential biomarkers. As of Feb 1, 2023, 43 patients have been accrued at 9 participating centers. Clinical trial information: NCT04967521 .

11503 Background: Collectively, sarcomas have demonstrated less benefit from immunotherapy than many other cancers. Pts with AS have limited options, particularly after taxane chemotherapy. Although AS is a vascular malignancy, anti-VEGF therapies have minimal monotherapy clinical activity. Some cutaneous AS have a high UV damage signature, but other AS often do not. Cabozantinib (C) is a multikinase inhibitor that may alter PD-1 expression in regulatory T cells, promoting an immune permissive environment when combined with nivolumab (N), a fully human anti PD-1 MAB. We hypothesize that the combination of C+N will be an effective therapy in AS, across AS subtypes. Methods: This open-label multi-arm study enrolled pts with locally advanced/metastatic AS. Arm 3, reported here, enrolled pts who had received a taxane for AS (including adjuvant) prior to study enrollment. Pts were not restricted on number of prior lines, but prior anti-VEGF and immunotherapies were not allowed. Eligible pts received C (40 mg po daily) with N (480 mg IV every 4 wks). Treatment was permitted beyond progressive disease (PD) in the 1st 12 wks (4 wk confirmatory scan), but PD response was censored at 12 wks. The Simon 2-stage design (null and alternative overall response rate (ORR) were 10% and 35%, respectively) required ≥1 confirmed response in 9 pts in the 1st stage, and >4 of 18 pts (91.4% power, alpha 0.095) for the primary endpoint. Secondary endpoints were adverse events (AEs), progression free, overall survival (PFS, OS), and pt-reported outcomes (PRO). Results: 21 eligible pts [median age 66 yrs (32-92), 10 female] received ≥1 dose of C+N. Primary disease sites: 12 cutaneous (scalp/face), 1 liver, 2 breast, 6 other. All pts received prior taxanes (11/21 = 52% as adjuvant therapy) and 5/21 (24%) had also received prior anthracycline (all relapsed AS). Primary endpoint: 13 of the first 18 evaluable patients (72%) experienced objective response (OR, 95%CI: 47%-90%). After a median follow-up of 11.2 mo, 13 of 21 pts achieved OR (11 partial response, 2 complete), for ORR 62% (95%CI: 38-82%). Responses were seen in pts with primary cutaneous disease 7/12 (58%) and noncutaneous disease 6/9 (67%). Median PFS was 9.6 mo (5.3-NR), and OS 20.5 mo (14.4-NR). Off treatment reasons include: progressive disease (14), comorbid condition unrelated to AS or study (1); 6 pts remain on study. Grade (G) 3 hypertension was the only possibly treatment related AE (TRAE) occurring in ³10%. No G 4/5 TRAE were reported. Conclusions: C + N demonstrated significant antitumor activity in taxane-pretreated AS and was well tolerated without new safety concerns. Activity of the combination was seen across AS subtypes. PRO and exploratory analyses are ongoing. Support: U10CA180821, U10CA180882, U24 CA196171; U10CA180820; https://acknowledgments.alliancefound.org . U10CA180868; U10CA180888. NCT04339738. Clinical trial information: NCT04339738 .

Gastrointestinal stromal tumors (GIST) are the most common type of soft tissue sarcoma that occur throughout the gastrointestinal tract. Most of these tumors are caused by oncogenic activating mutations in the KIT or PDGFRA genes. The NCCN Guidelines for GIST provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with these tumors. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised systemic therapy options for unresectable, progressive, or metastatic GIST based on mutational status, and updated recommendations for the management of GIST that develop resistance to specific tyrosine kinase inhibitors.

Abstract Background Regorafenib is one of several FDA‐approved cancer therapies targeting multiple tyrosine kinases. However, there are few subtype‐specific data regarding kinase inhibitor activity in sarcomas. We report results of a single arm, phase II trial of regorafenib in advanced Ewing family sarcomas. Methods Patients with metastatic Ewing family sarcomas (age ≥ 18, ECOG 0–2, good organ function) who had received at least one line of therapy and experienced progression within 6 months of registration were eligible. Prior kinase inhibitors were not allowed. The initial dose of regorafenib was 160 mg oral days 1–21 of a 28‐day cycle. The primary endpoint was estimating progression‐free rate (PFR) at 8 weeks employing RECIST 1.1. Results Thirty patients (median age, 32 years; 33% women [10 patients]; bone primary, 40%; extraskeletal primary, 60%) enrolled at 14 sites. The most common grade 3 or higher toxicities were hypophosphatemia (5 grade 3, 1 grade 4), hypertension (2 grade 3), elevated ALT (2 grade 3). Sixteen patients required dose reductions, most often for hypophosphatemia ( n = 7 reductions in 6 patients); two stopped regorafenib for toxicity. There was one death unrelated to treatment in the 30‐day post‐study period. Median progression‐free survival (PFS) was 14.8 weeks (95% CI 7.3–15.9); PFR at 8 weeks by Kaplan–Meier analysis was 63% (95% CI 46–81%). The RECIST 1.1 response rate was 10%. Median OS was 53 weeks (95% CI 37–106 weeks). Conclusions Regorafenib has modest activity in the Ewing family sarcomas. Toxicity was similar to that seen in approval studies.

Soft tissue sarcomas (STS) are rare malignancies of mesenchymal cell origin that display a heterogenous mix of clinical and pathologic characteristics. STS can develop from fat, muscle, nerves, blood vessels, and other connective tissues. The evaluation and treatment of patients with STS requires a multidisciplinary team with demonstrated expertise in the management of these tumors. The complete NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Soft Tissue Sarcoma provide recommendations for the diagnosis, evaluation, and treatment of extremity/superficial trunk/head and neck STS, as well as retroperitoneal/intra-abdominal STS, desmoid tumors, and rhabdomyosarcoma. This portion of the NCCN Guidelines discusses general principles for the diagnosis and treatment of retroperitoneal/intra-abdominal STS, outlines treatment recommendations, and reviews the evidence to support the guidelines recommendations.

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

ARST1321, a trial of patients with advanced soft tissue sarcoma, was the first National Clinical Trials Network study codeveloped by pediatric and adult consortia with two treatment cohorts. We report on the findings of a survey to identify barriers to enrolling adolescent and young adult patients (15–39 years) onto the nonchemotherapy arm. The survey response rate was 31% with a 70% completion rate. Common identified reasons for low accrual in order of decreasing frequency included insufficient funding, lack of study awareness or interest, competing trials, toxicity concerns, philosophical differences in the therapy backbone, and regulatory and infrastructure barriers. Clinical Trials.gov ID: NCT02180867.

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.

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