Survival data of U-LMS based on RNase H2 status and RNASEH2B/RB1 HomDel status A) Overall survival of U-LMS patients based on loss of RNase H2 (n=23) or intact RNase H2 (n=85) by IHC B) Overall survival of ULMS patients with or without RNASEH2B HomDels, based on the presence or absence of RB1 HomDels.

Anatomic location of ST-LMS and RNase H2 status. Absolute number and frequency of cases of RNase H2 loss in the ST-LMS cohort based on primary anatomic location.

BACKGROUND:Retroperitoneal sarcoma (RPS) encompasses a heterogenous group of rare malignancies that develop in the back of the abdomen. For localized primary disease, the mainstay of treatment is surgery. Beyond the primary site, patterns of disease manifestation vary by histologic type and include visceral organ metastasis, as well as intraabdominal multifocal disease. Although cure is extremely rare, some patients may still derive significant benefit from treatment. METHODS:A comprehensive literature search was performed and international, key opinion leaders for RPS met together to discuss principles of practice for multifocal and metastatic disease, summarized in 45 statements, each given a level of evidence and grade of recommendation. RESULTS:Patients should be evaluated in a multidisciplinary sarcoma center with experience in RPS and recognition of histologic type is critical to guide management. After pretreatment assessment that includes imaging and pathology review, the goals of treatment should be clarified upfront and aligned with the anticipated ability for the patient to tolerate treatment. Disease biology (e.g., disease-free interval) should be thoroughly understood. Treatment modalities can include a combination of surgery, non-surgical local therapy (radiation therapy, percutaneous tumor ablation and embolization) and systemic therapy. CONCLUSIONS:This updated consensus document gives comprehensive and practical clinical guidance to providers for the management of multifocal and metastatic RPS. The current document also serves as the foundation for future clinical and translational investigation, as we continue to optimize patient care in these complex and challenging cases.

e23545 Background: LMS is an aggressive soft-tissue sarcoma with an immunologically “cold” tumor microenvironment and historically poor responsiveness to ICB. With limited benefit from cytotoxic therapy beyond first-line and low ICB monotherapy activity, defining real-world ICB outcomes and identifying patients (pts) who may benefit remain an unmet clinical need. Methods: Adults with advanced/metastatic LMS treated with ICB at MD Anderson (2010–2025) were retrospectively identified via the pharmacy database. Response was assessed per trial RECIST v1.1 when available; otherwise, partial response/stable disease/progressive disease (PR/SD/PD) were extracted from documentation with radiology impressions. Disease control rate (DCR) was defined as PR+SD, and clinical benefit rate (CBR) as PR or SD ≥6 months (mo). Toxicity was graded per CTCAE v5. Subgroups were compared using chi-square/Fisher’s exact tests. Progression-free survival (PFS) was estimated by Kaplan–Meier, compared by log-rank, and evaluated with Cox regression. Results: Among 41 pts (median age 59; 76% female), 90% (n = 37) had metastatic disease at ICB start, 59% (n = 24) had ≥2 prior systemic therapy lines; 90% (n = 37) had doxorubicin; 76% (n = 31) had gemcitabine. Metastases involved lung in 83% (n = 34), liver in 66% (n = 27), and bone in 32% (n = 13). Primary sites were uterus in 29% (n = 12), retroperitoneum in 39% (n = 16), and other soft-tissue sites in 32% (n = 13). Overall, 85% (35/41) received ICB on a trial and 90% (37/41) received combination therapy: 57% (21) dual ICB, 24% (9) investigational targeted combinations, 11% (4) with concomitant radiotherapy, and 8% (3) with TKI. Best response was PR in 2 pts (5%), SD in 24 (59%), and PD in 15 (37%), yielding DCR 63% and CBR 22%. CBR differed by LMS type: 0/12 uterine LMS (uLMS) vs 9/29 (31%) for soft-tissue LMS (ST-LMS; p = 0.04) and by primary site (retroperitoneum 19% [3/16] vs other sites 46% [6/13]; Fisher’s exact p = 0.008). Median PFS was 3 mo overall and was longer with DCR vs PD (4.5 vs 1.5 mo; p < 0.001). PFS was longer with lung metastases (4.1 vs 1.3 mo; p < 0.001) and shorter with bone metastases (2.7 vs 4.1 mo; p = 0.02) and with prior gemcitabine exposure (2.8 vs 4.5 mo; p = 0.03), reflecting heavier pretreatment. In multivariable Cox regression, lung metastases (aHR 0.06; p < 0.001), bone metastases (aHR 4.8; p < 0.001), prior gemcitabine exposure (aHR 2.4; p = 0.04), and trial participation (aHR 0.2; p = 0.002; reflecting selection/regimen differences) remained independently associated with PFS. Toxicity occurred in 51%, with grade ≥3 events in 24%. Conclusions: In this real-world cohort of ICB-treated advanced LMS, trial participation and lung metastases predicted better PFS while bone metastases and prior gemcitabine exposure predicted worse PFS. ST-LMS had greater CBR than uLMS. Translational efforts are ongoing to identify LMS-specific biomarkers of ICB response.

Abstract Introduction As oncologic care continues to evolve with the advent of targeted therapies, survival of patients with metastatic spine disease (MSD) has also continued to improve. Thus, it is of an utmost priority for spine surgeons treating patients with MSD to understand the landscape of molecular subtypes and associated therapies. We sought to review the literature on this topic and develop a high-yield review for the treating spine surgeon. Methods A review of the literature was performed using PubMed, Google Scholar, and Medline databases. Histology-specific guidelines from the National Comprehensive Cancer Network (NCCN) were also reviewed. Articles that discussed the treatment of MSD patients with described molecular mutations with targeted therapies, as well as clinical outcomes, were included. Results The authors provide a framework for actionable mutations of malignancies commonly leading to MSD. Hormone receptor (HR) mutations as well as human epidermal growth factor receptor (HER2) mutations in primary breast cancer tumors confer a survival advantage as opposed to patients with triple negative breast cancer. Notably, a small number of patients with HR responsive breast cancer develop resistance to endocrine therapies in the setting of metastatic disease, and thus cannot receive targeted treatment following surgery. While prostate cancer is often initially hormone responsive, eventually tumors develop resistance, and few targeted therapies are limited. BRAF-targeted mutations for treatment of metastatic melanoma confer survival benefit when compared to chemotherapy alone. As with all systemic therapies, these medications all confer risk for patients undergoing surgical intervention, especially with regard to wound healing and bleeding. Conclusion While a vast range of targeted therapies exist, we present a review relevant to those treating patients with MSD. Many patients with MSD have a tumor histology with an actionable mutation, thus preserving neurologic function in these patients is of high priority but not without risk.

11509 Background: LMS remains a therapeutically challenging sarcoma with limited targeted options. Although ADCs are a promising strategy, none are FDA approved for sarcoma. Prior studies relying on bulk RNA or single-marker immunohistochemistry fail to capture spatial localization, co-expression, and intratumoral heterogeneity. Methods: LMS tissue microarrays were profiled using GeoMx DSP to generate spatial RNA and protein expression of ADC targets across multiple regions of interest (ROIs) per tumor. Cases were classified as soft-tissue (ST-LMS; n=23 patients; 94 ROIs) or uterine LMS (U-LMS; n=32 patients; 92 ROIs). A prespecified panel of 35 clinically relevant ADC targets was interrogated. Expression values were normalized to housekeeping genes with group-level scaling. Unsupervised clustering grouped ROIs by spatial expression. Intratumoral and inter-tumoral heterogeneity was quantified using coefficients of variance (CV) across ROIs. RNA–protein concordance and dual target co-expression were quantified using Spearman correlation (ρ). Survival differences between high- and low-expression groups, dichotomized by the median, were evaluated using Kaplan–Meier analysis. Results: Of the 35 ADC targets interrogated, 33 were evaluable at the RNA level and 10 at the protein level. Spatial profiling identified four distinct expression clusters. At the RNA level, F3, AXL, and PTK7 showed the highest expression, whereas CDH11, CD99, and ITGA11 exhibited lower expression. At the protein level, Tissue Factor, AXL, and CD70 showed the highest expression, while HER2, and CD99 were lower. Most ADC targets exhibited positive log₁₀ (CV) values, indicating substantial spatial variability. Across most targets, U-LMS showed greater intratumoral and intertumoral heterogeneity than ST-LMS. RNA–protein concordance was greatest for CD99, CD47, and Fibronectin/EDB (ρ≈0.44–0.69) and minimal for PDGFRA, AXL, ERBB2, EGFR, and MET (ρ≈-0.15-0.19). RNA co-expression identified seven significant pairs in ST-LMS (e.g., ROR2–FAP, ρ=0.54) and eighteen in U-LMS, including MRC2–CD248 (ρ=0.73). Dual protein co-expression revealed a strong ERBB2–EGFR correlation in both ST and U-LMS (ρ≈0.79–0.81), with moderate correlations of these two ADC targets to PDGFRA, AXL, and Tissue Factor (ρ≈0.53–0.70). High expression levels CD47 and AXL were associated with improved survival in ST-LMS (CD47 HR = 0.76, 95% CI 0.08–0.88, p = 0.021; AXL HR = 0.67, 95% CI 0.07–0.72, p = 0.0067). Conclusions: This study provides the first spatially resolved RNA–protein map of ADC targets in LMS, revealing differential expression, spatial heterogeneity, variable RNA–protein concordance, dual co-expression patterns, and survival associations. These findings establish a foundation for rational ADC development, biomarker-driven patient stratification, and dual ADC combination strategies in LMS.

Biallelic alterations in other DDR genes across all sarcomas in TCGA dataset. Assessment of the number of sarcomas with biallelic alterations in other DDR pathway members.

SNiPDx results of U-LMS and ST-LMS samples in the MDACC cohort, with RNase H2 IHC status also reported.

TPS11589 Background: GIST is the most common mesenchymal neoplasm of the digestive tract and is mainly driven by gain-of-function oncogenic mutations in the receptor tyrosine kinase KIT. Patients with GIST are typically treated with anti-KIT tyrosine kinase inhibitors (TKIs) such as imatinib. However, few patients achieve a complete response, and most eventually progress due to secondary KIT alterations that cause resistance to therapy. Other TKIs are approved in later lines but have shown only moderate clinical outcomes, highlighting the need for additional therapeutic approaches. Preclinical studies have shown that the menin-KMT2A complex epigenetically upregulates KIT expression in GIST cells. Ziftomenib is a potent and highly selective menin inhibitor that disrupts formation of the menin-KMT2A complex. Ziftomenib plus imatinib has demonstrated synergistic antitumor activity in imatinib-sensitive and -resistant GIST models, with reduced KIT protein levels and downstream oncogenic signaling observed in imatinib-resistant GIST patient-derived xenografts treated with the combination. Together, ziftomenib plus imatinib may enhance KIT recycling while reducing KIT transcription. This combination is currently being investigated clinically in patients with imatinib-sensitive and -resistant advanced GIST. Methods: KOMET-015 (NCT06655246) is an ongoing phase 1a/1b, open-label study to determine the safety, tolerability, recommended phase 2 dose (RP2D), and preliminary antitumor activity of ziftomenib plus imatinib (400 mg or <400 mg if previously reduced due to intolerance) for advanced/metastatic GIST. KOMET-015 includes dose-escalation, RP2D determination, and dose-expansion parts. Eligible patients (≥18 yrs) must have a biopsy-proven diagnosis of advanced/metastatic KIT -mutant GIST (T670X excluded) that progressed on imatinib (for dose-escalation and RP2D determination parts), with an ECOG PS of ≤2 and measurable disease per RECIST v1.1 modified for GIST (mRECIST). Dose escalation will be based on an i3+3 design to evaluate the safety and tolerability of up to 4 dose levels (with potential for additional doses) of ziftomenib combined with imatinib. Based on escalation, up to 2 dose levels will be selected for comparison to determine the RP2D. The dose-expansion part will examine the preliminary clinical activity of the RP2D in patients assigned to 1 of 3 cohorts: Cohort A: patients who progressed on imatinib as immediate prior therapy, Cohort B: patients who failed imatinib and had received ≥2 lines of therapy, and Cohort C: imatinib-naive patients. Tumor response will be assessed per mRECIST. All adverse events will be recorded, monitored, and graded based on CTCAE v5.0. The trial is open and actively recruiting in the United States. Clinical trial information: NCT06655246 .

e23556 Background: MMNST is a rare and aggressive peripheral nerve sheath tumor characterized by melanocytic differentiation and frequently misdiagnosed as melanoma due to overlapping histologic and immunophenotypic features. MMNST is commonly associated with PRKAR1A loss-of-function mutations and Carney complex, though it can also occur sporadically. Due to its rarity, optimal management and prognostic factors remain poorly defined. We performed a retrospective cohort study to characterize clinicopathologic features, genomic alterations, treatment patterns, and outcomes in patients with MMNST. Methods: We retrospectively identified patients with pathologically confirmed MMNST treated at MD Anderson Cancer Center between 2016-2025. Clinical data including demographics, tumor location, stage, treatments received, recurrence patterns, and survival outcomes were abstracted from medical records. Survival outcomes were estimated using the Kaplan-Meier method. Results: A total of 13 patients with MMNST were identified. Median age at diagnosis was 39 years (range 29-72), and 61.5% were male. Primary tumors most commonly arose in the paraspinal (46.2%, n = 6), head/neck (30.8%, n = 4), thoracic (15.4%, n = 2), and abdominopelvic (7.7%, n = 1) locations. Next generation sequencing testing was completed in 84.6% (11/13) of cases, and 72.7% (8/11) had PRKAR1A loss-of-function mutation. 7.7% (n = 1) of patients had metastatic disease at presentation. Surgical resection was performed in 83.3% (10/12) with localized disease, with radiation and/or systemic chemotherapy administered in 66.7% (8/12). At a median follow-up of 29.3 months, 66.7% (8/12) of patients with localized disease at presentation developed local recurrence (2/12) or distant metastases (6/12), with median recurrence-free survival of 25.9 months (95% CI 15.1-29.7 months). 88.9% (8/9) of patients with metastatic disease received systemic therapy, and the most common regimen was ipilimumab plus nivolumab (7/9); responses to different regimens will be detailed at the meeting. Median overall survival from the time of distant metastasis development was 50.6 months. Median overall survival in the whole cohort was 81.4 months. Conclusions: MMNST is a rare malignancy most commonly arising in paraspinal and head/neck locations. Despite aggressive local management, most patients with initially localized disease experienced recurrence or metastasis by about two years. These findings highlight the need for improved local and systemic treatment strategies and prospective, collaborative studies for this rare malignancy.

11527 Background: Unresectable/metastatic chordoma is a rare notochordal malignancy with no approved systemic treatments. EGFR is widely expressed on chordomas. Cetuximab is a recombinant, human/mouse chimeric monoclonal antibody that inhibits EGFR signaling. In vivo testing of cetuximab has demonstrated growth inhibition and regression of chordoma. An investigator-initiated, single center, phase II study (NCT05041127) was developed to evaluate the efficacy of cetuximab for patients (pts) with advanced/metastatic chordoma. Methods: Eligible pts were ≥18 years of age, had adequate organ function, and had an ECOG performance status (PS) of ≤2. Any prior line of therapy was allowed except EGFR inhibitors. A minimum of 10 pts and maximum of 29 pts were to be enrolled onto the trial based on Simon's two-stage optimal design (H 0 RR 5% vs H 1 RR 20%; one-sided α=0.05; power=80%). Pts received cetuximab 500 mg/m 2 IV Q2 weeks until disease progression or unacceptable toxicity. The primary end point was response rate (RR) according to RECIST 1.1. Secondary objectives included safety/tolerability and survival metrics. Efficacy was assessed in the modified intention-to-treat (mITT) population (≥1 dose; ≥1 post-baseline scan). Exploratory objectives included analysis of the EGFR pathway at 2 time points from research-related biopsies. Pt reported outcomes (PROs) were assessed with MDASI (general and spine) questionnaires at several time points on study. Results: From May 2022 to Dec 2025, 29 pts enrolled. 4 were excluded from the efficacy analysis (2 withdrawal, 1 cetuximab allergy, 1 has not completed the 1 st imaging assessment). Median age was 58 years (range 21-76), 15 (58%) were men, and 24 (92%) had ECOG PS of 0 or 1. The most common primary site was skull base (46%). Tumor was classified as locally recurrent in 8 pts (31%) and metastatic in 18 pts (69%). One median line of prior systemic therapy was noted (range, 0-6). At a median follow up of 28.7 months, 12 pts (48%) had radiographic cytoreduction (any tumor reduction [ATR]), but only 2 pts (8%) had a partial response (PR). Neither PR was associated with an EGFR gene alteration. Stable disease (SD) was noted in 23 pts (92%). Preliminary median PFS and median OS was 9.9 months (95% CI, 6.3 to 13.4) and 38.8 months (95% CI, 18.6 to NR), respectively. Significantly longer PFS was observed in SD-ATR (log-rank p=0.038), with median of 14.2 months in SD-ATR versus 9.6 months in SD without tumor reduction. 7/26 pts (27%) experienced a grade 3 cetuximab-related adverse event (AE), the most common being rash in 4 pts (15%). No grade 5 AE related to cetuximab was reported. Dose reduction occurred in 2 pts (8%). 4 pts (15%) discontinued the study due to toxicity. 4 pts remain on study. Conclusions: Although the primary end point has not been reached, 2 PRs are noted, and pts with SD-ATR have a longer PFS. Translational and PRO analysis are ongoing to better define biological predictors of cetuximab activity in chordoma. Clinical trial information: NCT05041127 .

11578 Background: Advanced LMS has limited effective therapies, with gem-based regimens being the most prescribed. Preclinical data suggest gemcitabine induces activation of the PI3K–mTOR pathway, supporting combination strategies with mTOR inhibition. Nab-S is a nanoparticle albumin-bound, IV formulation of sirolimus and has demonstrated greater intratumoral accumulation and antitumor activity in preclinical models compared to conventional mTOR inhibitors. Methods: This investigator-initiated, single-center phase I study evaluates gem (900mg/m2) plus nab-s (dose levels [DL]: DL1=75mg/m2 or DL2=100mg/m2) in patients (pts) using a Bayesian optimal interval (BOIN) design. Primary objective was to estimate the maximum tolerated dose (MTD) of the combination based on cycle 1 dose-limiting toxicities (DLT). Secondary objectives were to estimate objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Responses were assessed by RECIST1.1 and adverse events (AE) graded per CTCAEv5. Results: As of 01/22/26, all 12 pts initially planned for accrual have completed the DLT period. The original dosing schedule consisted of drug administration on Days 1 and 8 of a 21-day cycle. After the first 6 pts were enrolled, the protocol was amended to administer drugs on Days 1 and 15 of a 28-day cycle. This modification was implemented for all pts due to hematologic toxicities. While expected based on the known safety profile of nab-s and of gem, this frequently prevented Day 8 administration under the original schedule. All pts had advanced LMS, 10 pts were female and 7 had uterine LMS, the median age at time of consent was 55 yo. Three pts were included at DL1, and there was no DLT. DL2 included 9 pts: only one pt experienced a DLT of mucositis and diarrhea grade (Gr) 3 lasting for 3 days. The most frequent treatment-related Gr3-4 AE was thrombocytopenia. One pt had Gr3 pneumonitis attributed to gem and discontinued trial after 2 cycles. There was no other concern for safety. Ten pts were evaluable for response (1 pt died of disease and 1 pt chose to discontinue the trial before their first evaluation). ORR is 30% (n=3/10) at time of data cutoff and 90% pt had clinical benefit: 6 pts had stable disease with 5 pts experiencing shrinkage of disease (range: -8% to -21%) and 1 pt with 0% change. Only 1 pt had progressive disease as best response. With a median follow-up of 4 months (mo) for PFS, the median PFS (95% confidence interval [CI]) is 8.38 (1.68, not reached) mo, the 3-mo PFS (95% CI) is 78% (36%,94%), and the 6-mo PFS (95% CI) is 58% (16%,85%). With a median follow-up of 5.8 mo for OS, the 6-mo OS (95% CI) is 80% (39%,95%). Conclusions: The MTD was determined to be gem 900mg/m2 with nab-s 100mg/m2 on Days 1 and 15 of a 28-day cycle. Based on this preliminary safety and efficacy, an expansion with an additional 6 pts at this DL is ongoing. Clinical trial information: NCT06308419 .

e23531 Background: LMS is a rare, aggressive malignant tumor of smooth muscle origin, and its clinical heterogeneity complicates diagnosis, treatment, and research. Clinical trial enrollment among adult sarcoma patients (pts) remains low, with many eligible pts not routinely identified or referred. Understanding enrollment barriers and improving screening are critical to increase trial access. This study evaluated a standardized manual pre-identification and referral process for LMS pts at MDACC and assessed its impact on screening, enrollment, and participation barriers. Methods: This prospective study implemented a systematic pre-identification and referral workflow for LMS pts (Sept-Dec 2025). Medical charts were reviewed 2-3 days before each outpatient sarcoma oncology visit in EPIC to document tumor site, histopathology, prior therapy, stage, and inclusion/exclusion criteria for 6 active LMS trials in pre- and post-intervention periods. Eligible pts were identified and referred to physicians and the trial team by email. Primary outcomes: % improvement in monthly screening and enrollment. Secondary outcomes: the average monthly pts screened and enrolled during pre-intervention (03/2025-08/2025: 6 months) vs post-intervention (09/2025-12/2025: 4 months) periods, and recording of reasons for non-inclusion. Results: A total of 13 pts were screened and 12 enrolled during the pre-intervention period, versus 15 screened and 12 enrolled during the post-intervention period. Implementation of the pre-identification and referral workflow led to 73% and 50% improvement in monthly screening and enrollment, respectively. The average monthly screening of pts increased from 2.2 (±1.2) to 3.8 (±1.9), and the enrollment from 2.0 (±1.4) to 3.0 (±1.4). Example from one LMS trial (protocol 2023-0710): no pts screened/enrolled pre-intervention; post-intervention: 25 pre-identified, 2 screened and enrolled. Reasons for non-enrollment across all trials: summarized in Table 1, with clinical/protocol ineligibility most common. Post-intervention data collection is ongoing; a full 6-month comparison to be included in the final presentation. Conclusions: The implementation of pre-identification and referral workflow showed a trend toward increased screening and enrollment in LMS trials, with trial-level examples suggesting improved pt identification. The study also identified LMS-specific barriers, defining targets for future interventions. Incorporating AI-assisted screening may further increase pt identification, reduce manual workload, and improve trial enrollment. Reasons for non-enrollment among screened pts (%). Reason for non-enrollment (%) Clinical/protocol ineligibility 58 Difficulty in traveling to MDACC 17 Patient preference 14 Alternative treatment selection 7 Communication/administrative barriers 4

e18143 Background: Myoepithelial carcinoma (MEC) is a neoplasm derived from myoepithelial cells and characterized by an infiltrative growth pattern. These are very rare malignancies with limited published data describing outcomes. We sought to define the natural history of MEC and to identify best available treatments. Methods: In this retrospective series, we identified 70 patients with MEC seen at our institution from 1997-2025. Electronic medical records were reviewed to determine the patient and tumor characteristics, treatment regimens and response, and outcomes. The Kaplan Meier method was used to estimate survival, and log-rank tests were used to compare groups. Results: In our institutional cohort of 70 patients, MEC was most common in middle-aged individuals (median age = 52 years), with a predilection for head and neck sites (54/70, 77%). There was a slight predilection for male sex (40/70, 57%). The median overall survival (mOS) in our cohort was 87.2 months. Of 24 patients who developed metastatic disease, the predominant location was lung (n = 15, 62.5%) followed by bone (n = 11, 45%). For patients with localized disease (n = 66), the median recurrence-free survival (mRFS) was 55.4 months. The mRFS was not significantly different in patients who had resection alone (n = 39, mRFS = 60.0 months) compared with those treated with adjuvant radiation and/or chemotherapy (n = 27, mRFS = 51.1 months, p = 0.70). The primary systemic therapy utilized was platinum-based with few patients receiving doxorubicin or gemcitabine-based regimens. There were no significant clinical responses noted with systemic therapy. The median progression-free survival (mPFS) in patients with metastatic disease who received any systemic therapy was 3.1 months (n = 16). No significant difference in mOS was observed based on age, though there was a trend toward worse outcomes in younger patients (mOS for <30 years = 62.5 months, mOS for >30 years = 93.5 months, p = 0.88). The sample size of patients in the younger age group (n = 11) was small and only three patients in that subset were free of disease for >15 years. Conclusions: In our institutional experience with MEC, most patients were middle-aged with head and neck as the most common primary site. Outcomes were generally worse for younger patients. The lack of significant difference between the mOS between these age groups is attributed to a small sample size of patients in the younger age group with a wide confidence interval. Outcomes with currently available systemic therapy for metastatic disease were uniformly poor, emphasizing the need to develop novel treatment regimens moving forward. Future work is needed to discern the impact of specific genomic alterations (e.g. EWSR1-KLF15 fusion) on tumor biology and response to therapy.

e23536 Background: LMS-04 trial shows improved progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) with D+T followed by trabectedin (T) alone compared with doxorubicin alone in advanced LMS. Real-world outcomes with this regimen remain limited. This single-center retrospective study reports on the standard-of-care use of D+T in localized and advanced uterine LMS (ULMS) and soft-tissue LMS (STLMS). Methods: We included patients with confirmed histologic diagnosis of LMS treated with D+T at any point in routine clinical practice at MD Anderson Cancer Center (MDACC). The objective was to assess recurrence-free survival (RFS)/PFS, OS, ORR, and toxicity for both advanced and localized LMS patients treated with D+T in a real-world setting. Kaplan Meier method and log rank tests were used to assess survival outcomes and compare outcomes in subgroups. Data collection is ongoing with over 100 patients to date. Results: Fifty patients were included in this primary analysis (26 with ULMS, 24 with STLMS, cf. Table). In STLMS, primary tumor location was retroperitoneum in 20% (n=10), visceral in 10% (n=5), limb in 10% (n=5), abdominal wall in 4% (n=2), and scalp in 4% (n=2). In those with advanced LMS (n=40), median PFS was 10.5mo, PFS at 1 year was 37%. Overall, the ORR was 42% (21/50), and 40% (16/40) in patients with advanced disease. Median PFS for patients with advanced ULMS and STLMS was 9.6mo and 11mo months, respectively (p=0.73). Among 10 patients with localized disease, 5 underwent surgery before D+T (1 STLMS, 4 ULMS), and 6 received post-induction local therapy, including surgery alone (2 STLMS, 1 ULMS) or surgery and radiotherapy (3 STLMS). Nine patients with advanced disease received post-induction local therapy with surgery alone (1 ULMS, 4 STLMS), surgery plus radiotherapy (1 ULMS, 1 STLMS), surgery plus ablation (1 STLMS), or ablation alone (1 ULMS), with median PFS not reached (NR) versus 8.6 months in those without local therapy (p=0.011). Median OS for patients with advanced disease was 32.6mo. Grade ≥3 toxicity occurred in 92% (46/50), with 46% (23/50) requiring dose reductions; common toxicities were anemia, fatigue, and thrombocytopenia. Conclusions: In a real-world setting, outcomes with D+T are consistent with LMS-04 for ORR though slightly inferior in PFS for ULMS. We observe improved PFS in patients receiving local treatments after induction. ORR, toxicity, and dose-reduction rates were also comparable. Updated results with larger cohorts will be presented. Localized ULMS (N=5) Advanced ULMS (N=21) Localized STLMS (N=5) Advanced STLMS (N=19) Median age, yrs 45 48 49 54 Gender - - 60% F40% M 53% F47% M Size≥10 cm 4 (80%) 13 (62%) 3 (60%) 4 (21%) ORR 40% 42.9% 60.0% 36.8% RFS/PFS, mo (95% CI) 9.7 (5.1 – NR) 9.6 (4.5 – 14.7) NR 11 (8.6 – 16.6) RFS/PFS at 12 mo 40% 40.4% 100% 34.2% OS, mo NR 22.5 NR 32.6 Dose reduction, N (%) 2 (40%) 10 (48%) 2 (40%) 9 (48%) % of grade ≥3 toxicity 100% 90.5% 80.0% 89.5%

Treemap of most common drug mechanisms for patients treated in biomarker-matched studies.

STUDY DESIGN:Narrative Literature review. OBJECTIVE:To provide a general overview of important molecular markers and targeted therapies for the most common neoplasms (lung, breast, prostate and melanoma) that metastasize to the spine and offer guidance on how to best incorporate them in the clinical setting. METHODS:A narrative review of the literature was performed using PubMed, Google Scholar, Medline databases, as well as the histology-specific National Comprehensive Cancer Network guidelines to identify relevant articles limited to the English language. Relevant articles were reviewed for commonly described molecular mutations or targeted therapeutics, as well as associated clinical outcomes, and surgery-related risks. RESULTS:Molecular markers and targeted therapies have dramatically improved the survival of cancer patients. The increasing importance of prognostic molecular markers and targeted therapies provides rationale for their incorporation into clinical decision-making for patients diagnosed with metastatic spine disease. In this review, we discuss the molecular markers/mutations and targeted therapies associated with the most common malignancies that metastasize to the spine and provide a framework that the surgeon can utilize when evaluating patients for potential intervention. Finally, we provide case examples that highlight the importance of molecular prognostication and therapies in surgical decision-making. CONCLUSION:An integrated understanding of the implications of surgery, radiation, molecular markers and targeted therapies that guide prognostication and treatment is warranted in order to achieve the most favorable outcomes for patients with metastatic spine disease.

STUDY DESIGN:Systematic review. OBJECTIVES:The objective of this review paper was to summarize targeted molecular therapy options for spinal chordoma and chondrosarcoma, and to provide an update on the relevant clinical trials open for recruitment. METHODS:A systematic review of the current literature was performed, according to PRISMA guidelines, to summarize the latest developments in non-surgical molecular treatment options for low grade malignant primary spinal tumours. We also summarize those actively recruiting clinical trials based on clinicaltrials.gov. RESULTS:A total of 73 studies and completed clinical trials were reviewed. Twenty actively recruiting clinical trials (eight for chordoma and twelve for chondrosarcoma) were identified. CONCLUSIONS:There is a strong need to find new therapeutic options to complement surgical resection and radiation therapy, which remain the cornerstone of management. Targeted therapies against molecular pathways show promise as compared to conventional chemotherapy.

TPS11578 Background: GIST is the most common mesenchymal neoplasm of the digestive tract and is mainly driven by gain-of-function oncogenic mutations in the receptor tyrosine kinase KIT. Patients with GIST are typically treated with anti-KIT tyrosine kinase inhibitors (TKIs) such as imatinib. However, few patients achieve a complete response, and most eventually progress due to secondary alterations in KIT that cause resistance to therapy. Additional TKIs are approved in later lines but have shown only moderate clinical outcomes, highlighting the need for additional therapeutic approaches. Preclinical studies have shown that the menin-KMT2A complex epigenetically upregulates KIT expression in GIST cells. Ziftomenib is a potent and highly selective menin inhibitor that disrupts formation of the menin-KMT2A complex. Ziftomenib plus imatinib has demonstrated synergistic antitumor activity in imatinib-sensitive and -resistant GIST models, with reduced KIT protein levels and downstream oncogenic signaling observed in imatinib-resistant GIST patient-derived xenografts treated with the combination. Together, ziftomenib plus imatinib may enhance KIT recycling while reducing KIT transcription. This combination is currently being investigated clinically in patients with imatinib-sensitive and -resistant advanced GIST. Methods: KOMET-015 (NCT06655246) is a phase 1a/1b, open-label study to determine the safety, tolerability, recommended phase 2 dose (RP2D), and preliminary antitumor activity of ziftomenib plus imatinib (400 mg) for advanced/metastatic GIST. KOMET-015 includes dose-escalation, RP2D determination, and dose-expansion parts. Eligible patients (≥18 yrs) must have a biopsy-proven diagnosis of advanced/metastatic KIT -mutant GIST (T670X excluded) that progressed on imatinib (dose-escalation and RP2D determination parts), with an ECOG PS of ≤2 and measurable disease per modified RECIST (mRECIST). Dose escalation will be based on an i3+3 design to evaluate the safety and tolerability of up to 4 dose levels of ziftomenib combined with imatinib. Based on escalation, up to 2 dose levels will be selected for comparison to determine the RP2D. The dose-expansion part will examine the toxicity and preliminary clinical activity of the RP2D in patients assigned to 1 of 3 cohorts: Cohort A: patients who progressed on imatinib as immediate prior therapy, Cohort B: patients who failed imatinib and had received ≥2 lines of therapy, and Cohort C: imatinib-naive patients. Tumor response will be assessed per mRECIST. All adverse events will be recorded, monitored, and graded based on CTCAE v5.0. The trial is open and actively recruiting with sites in the United States. Clinical trial information: NCT06655246. Enrollment opens Feb 2025 .