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LBA2 Background: Dedifferentiated liposarcoma (DDLS) remains a difficult disease to treat with limited systemic therapy options. Approved drugs offer modest benefit such as trabectedin (median progression-free survival [mPFS] 2.2 months [m]) or eribulin (mPFS 2.0m). The Cyclin-dependent kinase 4 (CDK4) oncogene is ubiquitously amplified in DDLS and is a rational therapeutic target. In single-arm phase 2 studies, treatment with selective CDK4 inhibitors resulted in mPFS 4.2m with palbociclib and mPFS 7.7m with abemaciclib. We hypothesized that treatment with abemaciclib would improve PFS compared to placebo in patients with recurrent or metastatic DDLS. Methods: SARC041 was a phase 3 randomized double-blind study of abemaciclib versus placebo. The study was open at 9 academic medical centers in the USA. Eligible patients (pts) had recurrent or metastatic DDLS (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. Pts were stratified by prior lines of therapy (0 vs 1 or more) and randomized 1:1 between abemaciclib 200 mg PO twice a day or matching placebo. Scans were every 6 weeks (every 12 weeks after week 36) and pts with progression of disease on placebo could cross over to open label abemaciclib. The primary endpoint was PFS. The design provided 80% power with two-sided 10% significance level to detect a hazard ratio of 0.6 by log-rank test. Secondary endpoints were overall response rate (ORR), PFS and response rate after crossover, and overall survival (OS). Data cutoff was March 1, 2026. Results: In total, 108 pts were randomized to receive abemaciclib (n = 54) or placebo (n = 54). Demographic/baseline characteristics were generally similar across treatment arms. Abemaciclib demonstrated a statistically significant improvement in PFS at 9.67m vs placebo at 1.52m (hazard ratio [HR] 0.39; 95% confidence interval [CI], 0.25–0.59; p < 0.001). ORR was 9.3% for abemaciclib vs 0% for placebo (p = 0.057). mOS was not reached with abemaciclib vs 25.45m with placebo (HR 0.55; 95% CI, 0.28–1.07; p = 0.077). mPFS after crossover from placebo to abemaciclib was 3.44m (95% CI 2.66, 6.84). ORR after crossover was 4.3% (95% CI 0.53%, 15%). mOS after crossover was 24.03m (95% CI: 11.7, NA). Grade 3 or higher adverse event rates were similar in both arms (p > 0.99). No new safety signals were observed. Conclusions: Abemaciclib demonstrated a statistically significant improvement in PFS vs placebo in pts with dedifferentiated liposarcoma, with an encouraging OS trend. These results support abemaciclib as a new treatment option for dedifferentiated liposarcoma. Clinical trial information: NCT04967521 .

10030 Background: CABO is a multi-targeted kinase inhibitor of VEGFR2, c-MET, AXL and RET and has shown clinical evidence of activity in two prior studies of adult and pediatric patients with advanced OS. We report results of a feasibility cohort of CABO + MAP chemotherapy in patients with newly diagnosed high-risk OS. Methods: Patients <40 years, body surface area ≥ 0.8 m 2 and new diagnosis of high-grade OS with metastatic disease and resectable primary tumor were eligible. Patients were enrolled to two CABO dose levels (Dose Level 1 (DL1) 25 mg/m 2 /day, maximum 40 mg/day; Dose Level 2 (DL2) 35 mg/m 2 /day; maximum 60 mg/day) using a modified IQ 3+3 design. CABO was orally administered concomitantly with six 35-day cycles of MAP (cisplatin 60 mg/m 2 on days 1-2 (cycles 1-4), doxorubicin 37.5 mg/m 2 on days 1-2 (with dexrazoxane), methotrexate 12 g/m 2 on days 22, 29) and for 24 weeks as maintenance monotherapy. CABO was held after 7 weeks and resumed during 4 th MAP cycle to allow for primary tumor resection and metastatic surgeries. Dose-limiting toxicities (DLT) were assessed during weeks 1-6 of treatment; additional monitoring for post-surgical complications was conducted through completion of 4 th MAP cycle. The primary endpoint for this cohort was feasibility of combination therapy. Results: Ten patients (median age 11.5 years, 70% male) were enrolled and treated with CABO + MAP (DL1, n=4; DL2, n=6). Median cumulative doses of all MAP agents were maintained throughout treatment with no dose reductions. Concomitant dosing of CABO with MAP was tolerated with no protocol-specified DLTs occurring during the evaluation period. DL2 (35 mg/m 2 ) was established as the recommended dose for further study of combination therapy. Commonly reported adverse events included hematologic toxicities, febrile neutropenia, and alanine/aspartate aminotransferase (AST/ALT) elevation. Interruption of CABO was required in 6 patients for Grade 3+ AST/ALT elevation following methotrexate (n=3), wound complications (n=3), and Grade 3 pneumothorax (n=1). Wounds included two Grade 3 port site events and one Grade 1 primary tumor resection site; two patients later resumed CABO after healing without wound recurrence. Dose reduction of CABO was required in one patient for Grade 4 amylase elevation. Conclusions: The combination of CABO + MAP is feasible with no protocol-specified DLTs during the evaluation period. Generalizability is limited based on cohort size. Further evaluation of CABO + MAP is ongoing in a phase II/III randomized efficacy study in newly diagnosed standard and high-risk patients using CABO dose of 35 mg/m 2 /day (max 60 mg), with delayed initiation of CABO in patients with port placement and early safety monitoring for wound-related events, as well as full study monitoring of dose delivery, wound complications and systemic toxicity. Clinical trial information: NCT05691478 .

We previously reported initial results of the pivotal phase II trial of atezolizumab for patients with alveolar soft part sarcoma (ASPS; ClinicalTrials.gov identifier: NCT03141684 ). Here, we report on three additional years of observation. Fifty-three patients with ASPS received atezolizumab. Median duration of response increased to 37.0 months. Objective response rate (ORR) and median progression-free survival (mPFS) remained essentially as previously reported (35.8% [95% CI, 23.1 to 50.2] and 20.8 months [IQR, 7.6-not reached], respectively). ASPSCR1::TFE3 fusion type was determined for 47/53 patients; ORR and mPFS were higher among the 41 patients expressing type 1 (43.9% [95% CI, 28.5 to 60.2] and 28.3 months [IQR, 9.2-not reached], respectively) than the six patients expressing type 2 (0% [95% CI, 0 to 45.9] and 7.5 months [IQR, 3.9-not reached], respectively, PFS HR, 3.2 [95% CI, 1.01 to 10.2]). Eleven patients chose a per-protocol drug holiday (range, 3.5-26.4 months) after ≥2 years of treatment; two experienced disease progression during the holiday. Nine eligible patients elected to receive bevacizumab plus atezolizumab after progressing on monotherapy; ORR was 0% and mPFS was 18.5 months (IQR, 7.9-21.1) in this small cohort. Long-term results support using atezolizumab to treat ASPS, even for several years; a drug holiday with careful monitoring may be an option for some patients.

The treatment landscape for soft tissue sarcomas (STS) is evolving constantly. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for STS specific to surgical management and systemic therapy recommendations for various subtypes.

Abstract The addition of pembrolizumab to preoperative radiotherapy (RT) improved disease-free survival (DFS) for patients with stage III undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated/pleomorphic liposarcoma (LPS) in the randomized SU2C-SARC032 trial. To precisely identify patients who benefit from pembrolizumab and RT, we performed comprehensive multi-omics profiling of pre- and post-treatment tumor and blood samples, including bulk RNA-seq, flow cytometry, and cytometry by time of flight. Additionally, we built a single-cell RNA-seq atlas spanning 65,786 cells from UPS and LPS to recover single-cell states in bulk tumor samples using digital cytometry. Two opposing tumor microenvironments (TMEs), immune-cold sarcoma ecotype 1 (SE1) and immune-hot sarcoma immune class E (SIC E), benefited from pembrolizumab. Pembrolizumab combined with RT caused an overall increase in activated CD8 + T cells, CD56 low NK cells, and T cell receptor diversity, while diminishing matrix-remodeling stromal cells and sarcoma cells. Our findings identify different mechanisms of response to pembrolizumab in localized, high-risk UPS/LPS and suggest that sarcoma TME signatures may identify patients most likely to benefit from adding pembrolizumab to preoperative RT.

In the phase III placebo-controlled DeFi trial (ClinicalTrials.gov identifier: NCT03785964 ) primary analysis, nirogacestat showed significant improvement versus placebo in progression-free survival (PFS), objective response rate (ORR), and patient-reported outcomes (PRO) in adult patients with progressing desmoid tumors (DT; median [range] exposure: 20.6 [0.3-33.6] months). Here, long-term nirogacestat efficacy and safety were evaluated in patients randomly assigned to nirogacestat and followed through the final data cutoff date of December 19, 2024. End points included PFS and ORR per RECIST v1.1, PRO, and safety. The median (range) duration of exposure was 33.6 (0.3-61.8) months. Median PFS was not reached. The ORR with up to 4 years of nirogacestat treatment was 45.7% (32 of 70), with three additional partial and three additional complete responses since the primary analysis. Further target tumor size reduction occurred in most patients. Benefits in PROs were sustained while on treatment. Frequently reported treatment-emergent adverse events (TEAEs) decreased in incidence and severity over time. Since the primary analysis, four patients discontinued nirogacestat because of TEAEs between years 2 and 4. In conclusion, long-term continuous nirogacestat treatment was associated with further tumor size reductions, durable objective responses, sustained PRO benefits, and a manageable safety profile consistent with the primary analysis.

11558 Background: Nirogacestat (niro) is a targeted and selective gamma secretase inhibitor approved in the US for adults with progressing desmoid tumors (DT). In the phase 3 DeFi study, niro demonstrated significant improvement vs placebo (pbo) in progression-free survival (PFS: HR, 0.29 [95% CI: 0.15-0.55]; P<.001), objective response rate (ORR: 41% vs 8%; P<.001); and patient-reported outcomes (PROs) of pain, DT-specific symptom burden, physical and role functioning, and overall quality of life ( P≤.01, all). DT are driven by Wnt/β-catenin signaling pathway alterations and about 10-20% of DT are associated with mutations in the APC tumor suppressor gene, which may confer more aggressive DT behavior. Because patients with APC mutations may do worse, regardless of specific therapy, a post hoc analysis was conducted to assess effects of niro in patients with progressing DT and APC mutations. Methods: DeFi was a global, double-blind study that evaluated the efficacy, safety, and tolerability of niro in adults with progressing DT. Patients were randomized to oral niro (150 mg) or pbo twice-daily in continuous 28-day cycles. Descriptive post hoc analyses were conducted to assess effects of niro in patients with somatic and/or germline APC mutations. Results: Among 29 patients in DeFi with APC mutations (niro=13; pbo=16), 19 (66%) were female, 16 (55%) were aged ≤30 years, and 22 (76%) were refractory to prior treatment (with a median of 3 prior lines of treatment). In patients with APC mutation, PFS was improved with niro vs pbo (HR, 0.21 [95% CI: 0.05-1.00], P=.016). Confirmed ORR was 38% (5/13) for niro vs 13% (2/16) for pbo. Niro-treated patients also had greater reduction in median best percent change from baseline compared with pbo-treated patients in target tumor size (-29.5 vs +2.2), volumetric MRI (-71.0 vs +5.4), and T2 hyperintensity (-74.1 vs -21.0). Across all PROs assessed — Brief Pain Inventory, GODDESS DT Symptom Scale and DT Impact Scale, and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 — patients treated with niro had numerically greater improvement from baseline at cycle 10 than pbo. Analyses were limited due to the small sample size. Adverse events in >50% of niro-treated patients with APC mutation were diarrhea, nausea, rash maculopapular, and fatigue; ovarian toxicity occurred in 9 of 10 of females of reproductive potential (6 resolved, 2 lost to follow-up, 1 ongoing and receiving niro). Conclusions: Improvement in PFS, ORR, tumor imaging characteristics and PROs was observed with niro compared to pbo in patients with DT harboring APC mutations. Efficacy and safety of niro in patients with APC mutations were generally consistent with findings for the overall DeFi population, suggesting that niro can provide clinically meaningful benefit to patients with progressing DT and APCmutations. Clinical trial information: NCT03785964 .

11514 Background: The role of immunotherapy remains uncertain in most sarcomas. We recently showed significant antitumor benefit for cabozantinib (C) with N in AS previously treated with a taxane. Since chemotherapy-immunotherapy combinations may synergize, and paclitaxel remains a standard of care option for advanced AS, we hypothesized that P+N would be more effective than P alone. Methods: We report Arm 1 (P+N) and Arm 2 (P) of this open label, multi-arm, phase II study. Pts all had locally advanced/metastatic AS, and no prior taxane (including adjuvant) or checkpoint inhibitor prior to entry. Pts were randomized 1:1 (stratified scalp/face vs other) to receive P 80 mg/m2 on days 1, 8, 15 every 4 weeks (wks), with (Arm 1) or without (Arm 2) N (480 mg intravenously every 4 wks). A pt could remain on study beyond disease progression (PD), after the initial 12 wk evaluation (4 wk confirmatory scan required), but responses were censored at 12 wks. Primary endpoint was progression-free survival (PFS) comparing P+N to P, with an assumed improvement from a median of 4 to 7 months with N added to P (power = 85.3%, alpha = 0.148, and one interim analysis (Wieand rule) for futility planned after 30 events). Secondary endpoints were overall response rate (ORR), adverse events (AEs), overall survival (OS), and pt reported outcomes (PRO). At PD, Arm 2 (P) pts were permitted to receive C+N. Results: 62 evaluable pts (P+N = 30, P = 32 pts) were balanced for age, race, ECOG PS 0 vs. 1, site of disease (including radiation related vs. not), while P+N had more females (60%) and P had more males (63%). Median PFS for P+N was 7.2 mo (5.3-17 mo), and 8.3 mo (4.0-18 mo) for P (hazard ratio (HR) 1.01 (95%CI: 0.55-1.9), p = 0.96). Median PFS for scalp/face was 16 mo (95%CI: 10-NR) for P+N and 8.3 mo (95%CI: 3.7-NR) for P. Median PFS for all others was 5.5 mo (95%CI 4.3-16) for P+N, and 6.0 mo (95%CI 4.1-NR) for P. Median OS was 18 mo (13-NR) in P+N, and 23 mo (15-NR) in P (HR 1.3 (95%CI: 0.63-2.7), p = 0.48). Overall confirmed ORR: P+N = 33% (10/30 pts, with 4 partial responses (PR) and 6 complete responses (CR) with scalp/face ORR = 73%, all others ORR = 11%). Overall ORR for P = 34% (11/32 pts, with 7 PR and 4 CR, with scalp/face ORR = 38%, all others ORR = 26%). Grade 3-4 AEs regardless of attribution occurred in 57% of P+N, and 44% of P, most commonly ( > 10%) fatigue, AST increase, and dyspnea for P+N (n = 3 each), and anemia (n = 4) for P. Conclusions: P alone can be an effective therapy in a subset of pts with AS. The combination of P+N failed to demonstrate improvement in median PFS over P alone, but may show benefit in scalp/face AS. OS trended better with P alone. No new safety signals were observed. The impact of weekly steroid premedication prior to P+N on these outcomes remains to be determined. PRO and exploratory analyses are ongoing. Support: U10CA180821, U10CA180882, U24 CA196171; NCT04339738. https://acknowledgments.alliancefound.org . Clinical trial information: NCT04339738 .

11504 Background: Surgery & radiation therapy (RT) yield high local control rates for soft tissue sarcoma (STS) of the extremity and limb girdle. However, patients (pts) with high-grade stage III STS are at significant risk for developing metastasis. Median survival for pts with metastatic STS is < 2 years. SARC028 (NCT02301039) evaluated the efficacy of pembrolizumab (pembro) for metastatic STS, showing 20% and 8.7% response rates in undifferentiated pleomorphic sarcoma (UPS) and pleomorphic/dedifferentiated liposarcoma (LPS), respectively. We hypothesized that neoadjuvant pembro with concurrent RT followed by surgery and adjuvant pembro for stage III UPS, including myxofibrosarcoma, or LPS would stimulate an anti-tumor immune response to eliminate micrometastatic disease & improve disease-free survival (DFS). SU2C-SARC032 (NCT03092323) is a multi-institutional, international, randomized phase 2 trial evaluating the safety and efficacy of adding pembro to standard of care (SOC) RT & surgery for pts with stage III UPS or LPS. Methods: Pts aged > 12 yo with stage III (FNCLCC grade 2 or 3) UPS or LPS of the extremity and limb girdle were enrolled. Pts were randomized (1:1, stratified by grade) to neoadjuvant RT (50 Gy/25 fx) then surgery (SOC arm) or neoadjuvant pembro and RT then surgery & adjuvant pembro (EXP arm). Pembro was given 200 mg IV Q3 wk for 3 doses (before, during & after RT) & up to 14 adjuvant cycles. The primary endpoint was 2-yr DFS. Secondary endpoints included local recurrence-free survival (LRFS), distant disease-free survival (DDFS), & overall survival (OS). Target enrollment of 126 evaluable patients (max 144 total) provided 80% power (1-sided α = 0.05) to distinguish between a null hypothesis of 50% 2-yr DFS rate & alternative hypothesis of 75% 2-yr DFS rate by log-rank test, with initial analysis at 45 DFS events. Cox models were stratified by grade; primary analysis was a one-sided stratified log-rank test. Results: Between July 2017-November 2023, 143 patients were enrolled, predominantly with UPS (85%) & grade 3 (64%) histology. Median follow-up for alive patients is 24.1 mo. DFS in the EXP arm is significantly higher than the SOC arm (p = 0.023; HR 0.57, 90% CI: 0.35, 0.91). Estimated 2-yr DFS is 53% (90% CI: 43, 66%) for SOC vs 70% (90% CI: 61, 81%) for EXP arm. Currently, there is no statistically significant difference in LRFS (HR 0.55, 95% CI: 0.21, 1.42), DDFS (HR 0.57, 95% CI: 0.32, 1.01), or OS (HR 0.39, 95% CI: 0.14, 1.12). Pts with grade 3 sarcomas had improved DFS with pembro (HR 0.47, 95% CI: 0.25, 0.89), but no difference in DFS was observed in grade 2 tumors (HR 1.21, 95% CI: 0.35, 4.18). The proportion of patients with grade 3+ adverse events was significantly higher in EXP (52%) vs SOC arm (26%) (p = 0.002). Conclusions: Theaddition of neoadjuvant & adjuvant pembro to RT and surgery significantly improves DFS for pts with stage III UPS and LPS of the extremity and limb girdle. Clinical trial information: NCT03092323 .

Abstract Purpose: Epithelioid hemangioendothelioma (EHE) is a rare vascular cancer with pathogenic TAZ–CAMTA1 (calmodulinbinding transcription activator 1) operating as an oncogenic driver through activation of the MAPK pathway. Trametinib is an inhibitor of MEK, a critical kinase in the MAPK pathway. We sought to evaluate the effect of trametinib in patients with EHE. Patients and Methods: A phase 2 trial of trametinib was conducted in patients with locally advanced or metastatic EHE. Eligibility requirements included evidence of tumor progression or presence of EHE-related pain requiring opiates for management before enrollment. The primary endpoint was objective response rate (ORR) as per RECIST1.1 in cases with TAZ– CAMTA1 confirmed by fusion-FISH. Secondary objectives were to estimate ORR for all patients, median progression-free survival (PFS), 2-year overall survival (OS) rate, patient safety, and change in patient-reported global health and pain scores per PROMIS questionnaires. Results: 44 patients enrolled and 42 started trametinib. TAZ– CAMTA1 was detected in 27 tumor samples. TheORRwas 3.7%[95% confidence interval (CI), 0.094–19.0], median PFS was 10.4 months (95%CI, 7.1–NA), and 2-year OS rate was 33.3%(95%CI, 19.1–58.2) in the target population. Median pain intensity and interference scores improved significantly after 4 weeks of trametinib in patients using opiates. Common adverse events related to trametinib were rash, fatigue, nausea/vomiting, diarrhea/constipation, alopecia, and edema; one grade 5 ARDS/pneumonitis was related to trametinib. Conclusions: Trametinib was associated with reduction in EHE-related pain and median PFS of more than 6 months, providing palliative benefit in patients with advanced EHE, but the trial did not meet the ORR goal. See related commentary by Van Tine and Haarberg, p. 4552