11505 Background: Afamitresgene autoleucel (afami-cel) is a melanoma-associated antigen A4 (MAGEA4)-directed genetically modified autologous T cell immunotherapy consisting of CD4 and CD8 positive T cells transduced with a self-inactivating lentiviral vector (LV) expressing an affinity-enhanced T cell receptor (TCR) specific for the human MAGE-A4. Here we report the pooled results of afami-cel in phase 1 and phase 2 trials in patients (pts) with advanced (unresectable/metastatic) synovial sarcoma (SyS). Methods: Pts who were HLA-A*02 positive with previously treated, advanced SyS positive for MAGE-A4 received afami-cel after lymphodepleting chemotherapy containing fludarabine and cyclophosphamide. The pooled analyses evaluated overall response rate (ORR) per RECIST v1.1 by investigator review, duration of response (DoR), ORR in sub-populations, overall survival (OS), safety and pharmacokinetics. Results: As of May 2025, 153 pts with advanced SyS received afami-cel (1.00 –9.99×10 9 MAGE-A4 TCR positive T cells). The median age was 40 years (range: 13–76 years), 54% of pts were male, and 86% of pts were white. The median MAGE-A4 expression by H-score was 256.0 (range: 60–300). All pts received prior anthracycline and/or ifosfamide therapy and received a median of 2 prior lines of therapy (range: 1–12). ORR by investigator review was 43.8% (95% CI 35.8, 52.0). Responses were observed across all subgroups, including pediatric SyS pts. The median DoR was 7.1 months (95% CI 4.7, 10.6) and ranged from 1 to 58+ months. Median OS was 18.7 months (95% CI: 14.1, 22.5) with 44% of pts censored at the data cut-off. The 12-month or longer and 24-month or longer OS probabilities were 64.4% and 40.5%, respectively. Among the 67 pts who had a RECIST response, the median OS was 37.5 months (95% CI 26.3, 50.5). The most common any-grade non-laboratory TEAEs (≥20% of pts) were cytokine release syndrome (CRS) (73.2%), nausea (64.1%), fatigue (45.8%), pyrexia (33.3%), vomiting (29.4%), constipation (28.1%), diarrhea (27.1%), headache (26.8%), and cough (20.9%). The most common Grade ≥3 laboratory TEAEs (≥20% of pts) were lymphopenia, neutropenia, leukopenia, and anemia. Afami-cel persisted long-term, including >3 years. Conclusions: To the best of our knowledge, this is the largest dataset of T-cell therapy treated pts with advanced SyS. The magnitude of ORR supported by DOR demonstrated with afami-cel treatment is considered clinically meaningful in this rare pt population with a poor prognosis and limited effective therapies. CRS and cytopenias were common and manageable. Pts with advanced SyS treated with afami-cel had encouraging survival, especially those pts with a RECIST response. Clinical trial information: NCT04044768 , NCT03132922

Heatmaps of expression of 29 key gene signatures in (A) SARC028 and (B) Stanford RNA sequencing data

e23566 Background: Advanced undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated liposarcoma (DDLS) are difficult to treat soft tissue sarcomas with response rates to first line systemic therapy between 10-30%. However, both UPS and DDLPS have been shown to have measurable tumor infiltrating lymphocyte (TIL) populations. LN-144 (lifileucel), an autologous TIL product derived from unresectable or metastatic melanoma, was shown to have an overall response rate (ORR) of 36% in heavily pretreated melanoma patients with a median DOR of 19.7 months. We hypothesized that generation and infusion of LN-145, an autologous TIL product from non-melanoma solid tumors, in this case UPS and DDLPS, would be both safe and feasible. Methods: NCT05607095 is a single center multi-cohort pilot trial with Cohort 2 enrolling patients with metastatic or unresectable UPS or DDLS to undergo autologous TIL therapy with LN-145. Eligible patients had to receive at least 1 prior line of systemic therapy, a lesion at least 1.5 cm in size available for TIL harvest, and adequate organ function and performance status (ECOG 0-1). After surgical excision of suitable tumor for TIL expansion, successful LN-145 product generation was determined by characteristics that meet pre-specified criteria in the LN-145 IND. Patients then underwent nonmyeloablative lymphodepletion with cyclophosphamide (60 mg/kg x 2 doses) and fludarabine (25 mg/m 2 x 5 doses). LN-145 was then infused and expanded with intravenous interleukin 2 (600,000 IU/kg up to 6 doses). Primary endpoints of the trial were feasibility, defined as ³6 of 10 harvested pts undergoing LN-145 therapy, and safety, defined by the incidence of Grade ³3 adverse events (AE) as measured by CTCAE v5.0. Key secondary endpoints included estimated LN-145 manufacture rates and efficacy (ORR) utilizing RECIST 1.1. Exploratory endpoints include persistence of LN-145 cells and immune correlates in tissue and peripheral blood and their potential association with objective response and toxicity. Safety and efficacy measures will be summarized using point estimates and a Clopper Pearson exact confidence interval will be used. The final results of the primary feasibility and safety endpoints and secondary feasibility endpoint for the first 10 enrolled patients as well as and preliminary secondary efficacy and exploratory correlative studies through week 12 for 7 treated patients will be reported as late-breaking abstract after data lock on March 1, 2026. Clinical trial information: NCT05607095 .

11553 Background: Immune checkpoint inhibitors (ICIs) are an established treatment for many malignancies, with an emerging role in sarcoma. While the impact of concomitant medications (CM) on ICIs has been described in other cancers, it has not been evaluated in sarcoma. We assessed the association between CM use and ICIs outcomes in sarcoma patients. Methods: This pooled post hoc analysis included 7 investigator-initiated phase II ICI-based trials enrolling patients with metastatic sarcoma between April 1, 2017, and May 30, 2024. Patients receiving ≥1 dose of ICIs were included. CM taken within 30 days prior to treatment initiation were defined as baseline; PRN medications were excluded. CM were recorded at each cycle through end of treatment and categorized by medication class; supplements/herbal agents included vitamins, minerals, probiotics, botanicals, amino acids, and other dietary substances. For progression-free survival (PFS), baseline and on-treatment CM were analyzed as time-dependent covariates using Cox proportional hazards models. Overall survival (OS) analyses were limited to baseline CM. Logistic regression evaluated associations between baseline CM and objective response (ORR) and immune-related adverse events (irAEs). Toxicity was graded per CTCAE v5.0. Results: A total of 321 patients (median age, 58 years) were included. The most common histologies were liposarcoma (all subtypes, 22%), undifferentiated pleomorphic sarcoma (22%), and leiomyosarcoma (19%); 46% had received ≥3 prior lines of therapy. ICI was combined with cytokine/oncolytic therapies (43%), targeted agents (38%), or chemotherapy (19%). After a median follow-up of 47.4 months, ORR was 18%, median PFS was 3.9 months (95% CI, 3.09–5.32), and median OS was 19.9 months (95% CI, 17.5–22.9). Grade ≥3 irAEs occurred in 25% of patients, most commonly hematologic (6%) and hepatic (5%). On-treatment use of supplements/herbal agents was associated with longer PFS (HR 0.64, 95% CI 0.50–0.82; p<0.01), while on-treatment anti-infective use was associated with shorter PFS (HR 1.55, 95% CI 1.06–2.25; p=0.02); baseline anti-infective use was not associated with PFS. Baseline supplement/herbal use was associated with longer OS (HR 0.69, 95% CI 0.53–0.90; p<0.01), whereas baseline non-opioid (HR 1.54, 95% CI 1.10–2.16; p=0.01) and opioid analgesic use (HR 2.14, 95% CI 1.45–3.14; p<0.01) were associated with shorter OS. Baseline antihistamine use showed a trend toward increased gastrointestinal irAEs (OR 2.37, 95% CI 0.97–5.98; p=0.06). No CM class was associated with ORR. Conclusions: Concomitant medication use is associated with differential ICI outcomes in metastatic sarcoma and warrants prospective evaluation. CM Timing Outcome HR SH OT PFS 0.64 AI OT PFS 1.55 AI BL PFS 1.37* SH BL OS 0.69 Non-OA BL OS 1.54 OA BL OS 2.14 *Not statistically significant; SH = Supplements/herbal agents, AI = Anti-infectives, OA = Opioid analgesia, OT = on-treatment, BL = Baseline.

TPS11598 Background: Fibroblast Activation Protein (FAP) is expressed on the surface of cancer-associated fibroblasts and is involved in the formation, maintenance, and spread of tumors. Sarcoma frequently demonstrates high expression of FAP on the tumor cells themselves in contrast to other solid tumors, where it is mainly expressed on CAFs within the tumor stroma. Radioligand therapies utilizing alpha emitting isotopes such as Ac-225 have emerged as promising treatment strategies across multiple targets and indications in oncology. Ac-225 and its daughter radionuclides emit high-energy alpha particles capable of inducing double-stranded DNA breaks, leading to significant cytotoxic effects within cells. Early clinical data for other Ac-225-labeled compounds have shown promising outcomes, particularly in settings where traditional therapies have failed. [Ac-225] RTX-2358 (Ratio Therapeutics Inc, Boston, MA) is a novel FAP-targeted radioligand designed for specific high-affinity binding, resulting in prolonged tumor residence and limited normal tissue uptake. This sustained tumor retention leads to extended delivery of cytotoxic radiation to FAP-expressing tumors. A beta-emitting analog, [Lu-177]RTX-2358, has been administered to more than 25 patients under the German §13.2b compassionate use framework across multiple tumor types. Longitudinal SPECT imaging performed as late as 14 days after administration demonstrated persistent tumor retention with minimal washout. Based on time–activity curve analysis from these data, tumor biological half-time is estimated to be well in excess of 1,000 hours. Renal clearance was observed to be consistent with that reported for established lutetium-177–labeled radioligand therapies. Methods: This study is a seamless Phase 1 / 2 dose escalation study. The Phase 1 portion consists of a 3 x 3 dose escalation design, with patients treated in 3 planned dose escalation cohorts (7.5, 11.25 and 15 MBq) with up to 6, 8-week cycles of [Ac-225]RTX-2358. Backfill of phase 1 cohorts is permitted to facilitate selection of the recommended administered activity level for the subsequent Phase 2 expansion cohort. Dose escalation / de-escalation decisions will be made by a Safety Review Committee. Patients over 18yrs with a history of histologically confirmed relapsed or refractory soft tissue sarcoma (measurable disease per RECIST v1.1) are eligible if they have a positive [Cu-64]LNTH-1363S FAP PET, an ECOG PS 0 to 1, and adequate organ reserve and renal function. Recruitment of the first cohort was completed in December 2025. The ATLAS Study: NCT07156565 Clinical trial information: NCT07156565 .

ABSTRACT Background Concomitant medications (CMs) influence outcomes in patients receiving immune checkpoint inhibitors (ICIs), but their impact in sarcoma remains undefined. We assessed the association between CM use and ICI outcomes in patients with advanced or metastatic sarcoma. Methods This pooled analysis included patients from seven investigator‐initiated phase II trials of ICI‐based therapy for sarcoma. CMs within 30 days of treatment were defined as baseline; on‐treatment exposure was captured longitudinally. The primary endpoint was progression‐free survival (PFS); secondary endpoints included overall survival (OS), objective response rate (ORR), and immune‐related adverse events (irAEs). Multivariable Cox models adjusted for age, ECOG performance status, histological subtype, treatment regimen, and race. Results Among 321 patients (median follow‐up: 47.4 months), in time‐dependent analyses, exposure to anti‐infective medications was associated with shorter PFS (adjusted hazard ratio [aHR] 1.54, 95% CI 1.05–2.27). Baseline use of vitamins/minerals/supplements/herbal products was associated with longer PFS (aHR 0.73, 95% CI 0.56–0.95) and OS (aHR 0.67, 95% CI 0.51–0.89). Baseline statin use was associated with longer PFS (aHR 0.64, 95% CI 0.47–0.87) but not OS. Baseline use of opioids was associated with shorter OS (aHR 1.71, 95% CI 1.12–2.61). No CM class was significantly associated with ORR or irAE occurrence. Conclusions CM use is associated with differential efficacy outcomes in sarcoma patients receiving ICIs. These findings highlight the need for prospective studies to define the impact of commonly prescribed medications on ICI outcomes and to optimize clinical trial stratification.

TPS11594 Background: Dedifferentiated liposarcoma (DDLPS) is a rare adipocytic malignancy characterized by frequent amplification of MDM2 and CDK4 and associated with poor outcomes, with a median overall survival of approximately 15 months. A phase II trial at Memorial Sloan Kettering Cancer Center demonstrated activity of the CDK4/6 inhibitor palbociclib in advanced WD/DDLPS, with a 12-week progression-free survival (PFS) rate of 57%, exceeding historical chemotherapy benchmarks (<35%) and leading to its inclusion in the NCCN Guidelines. Despite this, durability of benefit remains limited, and outcomes following progression are poor. Preclinical work from our group demonstrated that CDK4/6 inhibition in DDLPS induces cellular geroconversion from quiescence to irreversible senescence, accompanied by MDM2 downregulation. This process requires suppression of HRAS signaling and inhibition of the MAPK pathway and is associated with activation of the senescence-associated secretory phenotype (SASP). Preclinical models further suggest that dual CDK4/6 and MEK inhibition enhances SASP activation, providing a mechanistic rationale for combination therapy. Based on these findings, we initiated a phase Ib/II clinical trial of mirdametinib, a MEK1/2 inhibitor, in combination with palbociclib in patients with DDLPS (NCT06843967). Methods: This is an ongoing phase Ib/II, single-arm, open-label, single-center study evaluating the safety, tolerability, and efficacy of mirdametinib plus palbociclib in patients with unresectable, recurrent, or metastatic DDLPS (NCT06843967). Patients may enroll at any line of therapy, including first line, consistent with contemporary palbociclib use; patients with prior CDK4/6 inhibitor exposure are eligible for the phase Ib portion. Key eligibility criteria include ECOG performance status 0–2 and RECIST v1.1–measurable disease. Phase Ib uses a Bayesian optimal interval (BOIN) design with three dose levels to determine dose-limiting toxicities, maximum tolerated dose, and recommended phase II dose (RP2D), enrolling up to 24 patients. Phase II will assess efficacy at the RP2D, with the primary endpoint of PFS at 18 weeks by RECIST v1.1 in 30 patients. Enrollment began February 19, 2025. As of January 2026, accrual is ongoing at dose level 2. Enrollment to dose level 3 is anticipated in February 2026. Clinical trial information: NCT06843967 .

Histologic distribution by immunotype and response

T cell subpopulations associated with shorter survival after accounting for histologic subtype and treatment

2661 Background: CRD3874-SI is a first in class, systemically administered, allosteric STING agonist that blocks STING’s proton channel activity differentiating it from previously developed STING agonists. The drug has demonstrated pre-clinical anti-cancer activity in several murine tumor models and has pharmacological properties distinct from earlier generation STING agonists. Methods: This is a single institution, open-label, phase I study of CRD3874-SI in patients with advanced solid tumors. The dose escalation study follows a standard 3+3 design. CRD3874-SI is administered intravenously once per week for 2 cycles. Cycle duration is 28 days. From cycle 3 onwards, continuous weekly treatment +/- one week break (week 4) may be considered. The primary objective is to assess the safety of CRD3874-SI by determining the maximum tolerated dose, recommended phase 2 dose and schedule of administration. Secondary objectives include examining the pharmacokinetics and pharmacodynamics (IP10 analysis) of CRD3874-SI and evaluating the efficacy of CRD3874-SI as determined by best objective response rate per RECIST v 1.1. Clinical trial information: NCT06021626. Research sponsor: Curadev Pharma, Inc. Results: As of January 5th 2026, 21 patients (sarcoma n=20, adenoid cystic carcinoma n=1) received treatment at four escalating dose levels (0.1-1.8mg/kg). The median number of prior lines of treatment was 4 (1-11). The median duration of treatment was 7 weeks (range: 1-32 weeks). 2 patients continue treatment. Reasons for treatment discontinuation include: progression of disease (n=16), toxicity (n=2), patient withdrawal (n=1). Treatment emergent adverse events (TEAEs) were manageable and reversible. Only low-grade cytokine related symptoms were reported. TEAEs possibly related to study treatment reported in >20% of participants and were mostly low grade include: fatigue (43%), chills (38%), nausea (38%), diarrhea (33% (G3 (10%)), headache (29%) and flu-like symptoms (24%). Low grade colitis not typical of auto-immune mechanism, responding well to temporary treatment pause +/- oral budesonide, were reported in 4 patients. One DLT at dose level 4 (G3 dyspnea) was observed. 19 patients are evaluable for efficacy. The best objective response per RECIST v1.1: confirmed partial response, n=1 (malignant phyllodes tumor); stable disease, n=9; progressive disease, n=9. Dose level 3 (0.9mg/kg) represents a biologically active dose (one confirmed PR and a second case with -27% tumor regression was observed). Dose proportional increase in AUC with concomitant increase in plasma CXCL10 levels were observed. Conclusions: CRD-3874-SI has demonstrated clinical activity with manageable safety. Dose level 0.9mg/kg is biologically and clinically active. A dose expansion phase at this dose level in is planned in >5 histology specific cohorts. Clinical trial information: NCT06021626 .

Detailed histologic diagnoses according to TME subtype

Abstract Introduction: Identifying novel approaches that harness and augment anti-tumor immune response is an important area of ongoing research and drug development. Based on their performance in pre-clinical models, orthosteric activators of the Stimulator of Interferon Genes (STING) have been investigated in human trials. The activation of STING by its ligand cGAMP leads to both IFN dependent innate immune signaling as well as IFN independent pharmacology associated with STING's proton transport activity that leads to autophagy and pyroptosis. CRD3874 is a first in class small molecule allosteric STING agonist that binds to an allosteric site within STING's proton channel and decouples the IFN and non-IFN consequences of STING activation by blocking STING's non-IFN actions. CRD3874-SI, is a proprietary intravenous formulation of CRD3874, potent activator of all five human STING variants that has demonstrated promising pre-clinical anti-cancer activity in serval mouse tumor models when systemically administered as mono therapy or in combination with checkpoint therapy. Drug administration led to elevated plasma levels of CXCL10 and IFNβ in mice and monkeys. High IV doses up to 75mg/kg were systemically tolerated in cynomolgus monkeys. Methods: This is a single institution, phase Ia/b study of CRD3874-SI in patients with advanced solid tumors who received at least one line of prior therapy. The dose escalation phase will explore the safety and tolerability of CRD3874-SI following standard 3+3 design. CRD3874-SI is administered by intravenous infusion once per week for two cycles. From cycle 3 onwards, participants will received 3 or 4 consecutive weekly infusions, over a 28-day treatment cycle. The primary objective is to assess the safety and tolerability of CRD3874-SI by determining the maximum tolerated dose, recommended phase 2 dose and schedule of administration. Secondary objectives include further defining the safety profile, examining the pharmacokinetics and pharmacodynamics (CXCL10 analysis) of CRD3874-SI and evaluating the efficacy of CRD3874-SI as determined by the best objective response rate and clinical benefit rate per RECIST v1.1. Treatment will continue until disease progression or unacceptable toxicity. This study is currently open to enrollment. 21 patients have received treatment across 4 dose levels to date. Expansion cohorts are planned after determining the appropriate dose (RP2D). Clinical trial information: NCT 06021626. Research sponsor: Curadev Pharma, Inc. Citation Format: Ciara M. Kelly, Reinhard von Roemeling, Monali Banerjee, Viswatej Avutu, Olayade Babatunde, Lauren Banks, Ping Chi, Mark A. Dickson, Mrinal M. Gounder, Grace Gray, Camron Clark, Mary Louise Keohan, Robert G. Maki, Sujana Movva, Damon Reed, Kelly Schroeder, Li-Xuan Qin, Phillip Wong, Sandip Middya, Ritesh Shrivastava, Debjani Chakraborty, Rajib Ghosh, Sourav Basu, Arjun Surya, William D. Tap, Sandra P. D'Angelo. Phase I trial of CRD3874-SI, a systemically administered third generation allosteric STING agonist, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr CT295.

Supplementary Table S3. Representativeness of Study Participants

Proportion of PBMC immunotypes in sarcoma, melanoma, and urothelial carcinoma

Supplementary Table S1. Flow cytometry antibodies.

TRAEs occurring in ≥10% of patients.

Purpose: Immune checkpoint blockade (ICB) benefits only a subset of patients with sarcoma. Biomarkers of response and resistance are needed to help guide patient selection.Experimental Design: We analyzed peripheral blood and tumor samples from patients with sarcoma treated in five ICB-based clinical trials. Baseline peripheral blood mononuclear cells (PBMC) underwent 11-color flow cytometry to define T-cell immunotypes. Baseline tumor tissue underwent RNA sequencing (RNA-seq) to classify tumors into four tumor microenvironment (TME) subtypes using consensus clustering of 29 functional gene expression signatures. Associations between immune features and clinical outcomes were assessed. A deep learning model was applied to baseline hematoxylin and eosin (H&E) slides to detect and quantify lymphoid aggregates in patients with available RNA-seq.Results: Among 178 patients with PBMC available for analysis, a proliferative (PRO) circulating T-cell immunotype was associated with poorer overall survival (OS) than lymphocyte-activation gene 3 (LAG)- or LAG+ immunotypes. RNA-seq from 67 tumors identified an immune-enriched/nonfibrotic TME subtype associated with a higher response rate, longer progression-free survival, and longer OS compared with immune-enriched/fibrotic, immune-depleted, and fibrotic subtypes. Automated analysis of 48 baseline H&E slides identified lymphoid aggregates in five tumors; four were classified as immune-enriched and two of these responded to ICB.Conclusions: Patients with sarcoma and a PRO circulating T-cell immunotype had inferior outcomes to ICB, whereas those with an immune-enriched/nonfibrotic TME had superior outcomes. Automated analysis of H&E slides showed promise in identifying patients with an immune-enriched TME. These findings support the use of a multimodal approach to identify predictors of response to immunotherapy in sarcoma.

Supplementary Table S5. Transcriptome-wide differential gene expression between cluster 8 of P12 vs. all other P12 clusters.