South Texas Accelerated Research Therapeutics

BackgroundT-cell immunoglobulin and mucin-domain containing 3 (TIM-3) is an inhibitory receptor linked to decreased antitumor activity of immune cells. S095018 is a human anti-TIM-3 IgG2 antibody that blocks the binding of phosphatidyl serine to TIM-3. Sym021 is a humanized IgG1 antibody that inhibits the binding of programmed cell death protein-1 (PD-1) to its ligands programmed death-ligand 1 (PD-L1) and PD-L2.MethodsS095018 in combination with Sym021 was tested in patients with advanced/metastatic biliary tract cancers (BTC) whose disease progressed under treatment with at least 1 line of systemic therapy and who had not received prior treatment with PD-(L)1 inhibitors (NCT04641871). Patients received 3 mg/kg of Sym021 and 10 mg/kg of S095018 once every 2 weeks. Primary endpoints included overall response rate and incidence/severity of adverse events. Key secondary endpoints included pharmacokinetics, immunogenicity assessment, progression-free survival (PFS) and overall survival (OS).Results35 patients with stage IV BTC received S095018 in combination with Sym021. A partial response was achieved in 2 patients (5.7%) and stable disease in 11 patients (31.4%) for a disease control rate of 37%; 4 patients were not evaluable for response. Median PFS and OS were 1.9 months (90% CI 1.8 to 3.7) and 13.4 months (90% CI 8.2 to 27.1), respectively. The most common treatment-emergent adverse events of any grade included fatigue, pruritus, infusion-related reaction, and increases in amylase (8.6% each). Exploratory biomarker analyses in paired tumor biopsies showed an increase in intratumoral CD8 T-cell density and an upregulation of gene signatures related to interferon-γ signaling, antigen presentation, and T-cell activation with treatment without, however, clear association with efficacy endpoints.ConclusionsDual PD-1/TIM-3 inhibition was tolerable but exhibited modest antitumor activity in patients with advanced/metastatic recurrent BTC who had not received prior anti-PD-(L)1 treatment.

Abstract Background: BTX-9341 is a first-in-class bifunctional degrader of cyclin dependent kinase (CDK)4 and CDK6 that also inhibits the transcription of CDK2 and Cyclin E. Preclinical data highlight its superiority compared with approved CDK4/6 inhibitors (CDK4/6i) in inhibition of phosphorylation of retinoblastoma (p-RB), cell cycle arrest, and in vivo efficacy in breast cancer (BC) xenografts. BTX-9341 is active in CDK4/6i-resistant models with p-RB half-maximal inhibitory concentrations (IC50s) of 1-15 nM and can overcome key mechanisms that drive CDK4/6i resistance. Here we report early monotherapy data from the first-in-human study of BTX-9341 in patients (pts) with advanced and/or metastatic HR+/HER2- BC. Methods: BTX-9341-101 is a multicenter, nonrandomized, open-label trial to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of orally administered BTX-9341 in pts with RB1 wild type advanced and/or metastatic HR+/HER2- BC who received prior CDK4/6i therapy. An accelerated titration and Bayesian Optimal Interval design (BOIN) were used. The primary objective of dose escalation is to determine the maximum tolerated dose (MTD) or maximum evaluable dose (MED) of BTX-9341 monotherapy and in combination with fulvestrant. Secondary objectives include the characterization of BTX-9341 on PK and efficacy; exploratory objectives include the assessment of BTX-9341 on PD and PK/PD relationships. Results: As of June 9, 2025, 12 pts were evaluated at the following BTX-9341 once daily (QD) dose levels: 50 mg (dose level [DL]1), 100 mg (DL2), and 75 mg (DL3) monotherapy, and 50 mg in combination with fulvestrant (DLA). Pts received up to 4 lines of therapy in the metastatic setting prior to enrollment. No dose-limiting toxicities (DLTs) were observed at any dose levels during the 28-day DLT period. The most common adverse events (AEs) during the DLT period were decreased neutrophil and white blood cell counts (Grades 1-4). There were no dose reductions in DL1. The starting dose was reduced in all pts in DL2; DL3 is currently enrolling. At least 2-fold accumulation was observed after QD dosing, and steady-state trough concentrations were in the range of in vitro IC50 values at DL1 and higher dose levels. Serum thymidine kinase activity (sTKa), a clinical biomarker for tumor response to CDK4/6 inhibition, showed >50% reduction at Cycle 2 Day 1 (C2D1) compared with baseline for 7 of 8 evaluable monotherapy pts, with 6 pts below the sTKa detectable level. “On target” PD reductions in CDK4, CDK6, CDK2, and Cyclin E levels were observed in peripheral blood mononuclear cells. Of the 8 evaluable monotherapy pts, the best overall responses in pts with measurable disease included 1 pt with a confirmed partial response (PR) and 3 pts with stable disease ([SD] first assessed at 8 weeks; i.e., the first time point for assessment in the protocol), and in pts with non-measurable disease, 2 pts had non-complete response (CR)/non-progressive disease. For all pts, the longest duration on treatment was 10 cycles. A clinical benefit rate (defined as a best overall response of CR, PR, or SD for pts with measurable disease or non-CR/non-progressive disease for pts with non-measurable disease, per RECIST v1.1 at Week 24) of 66.7% was observed in the completed cohorts (DL1 and DL2). Conclusion: BTX-9341 monotherapy shows a favorable safety profile, with the most common AEs being decreased neutrophil and white blood cell counts, at doses that show encouraging preliminary PK/PD and efficacy, enabling further evaluation of monotherapy and in combination with fulvestrant. The trial is actively enrolling with anticipated completion of dose escalation enrollment by the end of 2025 (Clinical trial: NCT06515470). Citation Format: A. Patnaik, M. Block, M. Cristofanilli, Q. Liu, H. Majeski, A. Shakya, P. Rajagopalan, C. Deshpande, T. Marmon, S. Padam, D. Powell, A. H. Chourasia, R. Urbanski, M. Goetz, R. M. Layman. First-in-human Phase 1 study of BTX-9341, a CDK4/6 bifunctional degrader, as monotherapy and in combination with fulvestrant in patients with advanced and/or metastatic HR+/HER2- breast cancer - first emerging data [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-06-04.

186 Background: INCA33890 is an anti–PD-1/TGFβR2 bispecific antibody designed to antagonize TGFβR2/PD-1 signaling in immune cells co-expressing both targets. In the INCA33890-101 study (NCT05836324), patients (pts) with refractory non-MSI-H mCRC were treated with INCA33890 monotherapy at 3 expansion doses. Responses were observed in pts with and without active liver metastases. Here, we analyze associations between baseline biomarkers and clinical outcomes. Methods: Fresh or archival (≤3 years from study registration) baseline biopsies were required in the dose expansion part and assessed using immunohistochemistry (IHC) for CD8 and PD-L1 (SP263) and whole transcriptome and next-generation sequencing for DNA aberrations (both Tempus xT). Baseline ctDNA was analyzed using Predicine Atlas during dose escalation and expansion. Efficacy was assessed by investigators per RECIST v1.1. Results: As of July 25, 2025, efficacy data with INCA33890 monotherapy were available from 105 pts; 16 pts (15.2%) had a partial response (PR), including pts with liver and peritoneal metastases (Table). Of the 78 pts with evaluable baseline biopsies for IHC analysis, pts with PR or stable disease (SD) showed greater PD-L1 tumor area positivity scores than those with progressive disease (PD) (nominal p<0.05). mRNA expression of inflammatory genes (IFN-γ, CXCL9, CXCL10 and T-cell inflamed signature) were higher in pts with PR/SD vs PD. Pts with blood tumor mutation burden (bTMB) >20 mut/MB had a trend towards higher ORR (33.3%) vs pts with bTMB <20 mut/MB (12.5%). Consensus molecular subtypes (CMS) were assessed in 44 pts. Although CMS 4 is commonly associated with the presence of TGF-β, it was not associated with a higher ORR (7.7% [1/13]). Responses were also observed in CMS 2 (21.7% [5/23]) and CMS 1 (50% [1/2]), but not in CMS 3 (n=6). There was no relationship with tumor mRNA expression of TGFβ or TGFβ-associated signatures with clinical outcomes. In addition, SMAD4 mutations, determined by ctDNA, were present in both responders and non-responders. Mutations in KRAS (64%), TP53 (72%), and APC (47%) were the most common aberrations and had no impact on clinical outcomes. Conclusions: INCA33890 demonstrated preliminary efficacy in pts with non-MSI-H mCRC across a variety of subgroups. Higher baseline PD-L1 expression and mRNA expression of inflammatory genes enriched for clinical benefit while overexpression of TGF-β did not seem to enhance efficacy. Updated data will be presented. Clinical trial information: NCT05836324 . Efficacy across subgroups. N ORR, % DCR, % Overall 105 15.2 28.6 With/without Liver Metastases 75/30 12.0/23.3 20.0/50.0 Peritoneal Metastases 40 10.0 20.0 No Liver or Peritoneal Metastases 20 30.0 60.0 PD-L1 TAP <1% 22 9.1 22.7 PD-L1 TAP >1% 56 17.9 25.0 PD-L1 TAP >5% 13 38.5 61.5 bTMB high >20 mut/MB 15 33.3 40.0 bTMB <20 mut/MB 64 12.5 28.1

Circulating tumor DNA (ctDNA) is a valuable biomarker for assessing treatment response and molecular residual disease. In advanced esophageal and gastric cancer (gastroesophageal cancer [EGC]), ctDNA dynamics remain poorly understood. The authors investigated ctDNA in patients with advanced EGC to evaluate its clinical utility. This was a multi-institutional, retrospective analysis of 200 patients with recurrent/metastatic EGCs who underwent commercial ctDNA testing using a personalized, tumor-informed assay (Signatera; Natera, Inc.). Patients were divided into cohort A (N=36; stage I-III with recurrence) or cohort B (N=164; metastatic at diagnosis). Longitudinal ctDNA dynamics were correlated with clinical and radiographic findings. In cohort A, 31 of 36 patients (86.1%) had ctDNA collected ≤90 days before recurrence; of these, 25 of 31 patients (80.65%) were ctDNA-positive before recurrence. In cohort B, baseline ctDNA was available for 29 of 164 patients (17.68%), and all 29 were ctDNA-positive. Among 52 patients who had on-treatment ctDNA assessments, 62 treatment lines were analyzed (N=6 in cohort A; N=46 in cohort B). All who remained ctDNA-negative throughout treatment (Neg-Neg) showed treatment benefit (n=6 of 6). Those who converted to ctDNA-positive (Neg-Pos) progressed (n=2 of 2). Among ctDNA-positive patients (Pos-Pos), 27 of 40 (67.5%) showed treatment benefit, whereas 13 of 40 (32.5%) progressed. Patients who cleared ctDNA (Pos-Neg) had favorable outcomes (12 of 14 patients; 85.7%). A decrease >90% in ctDNA levels among Pos-Pos patients was linked to superior progression-fee survival. Grouping treatment lines into favorable (Neg-Neg, Pos-Neg, and Pos-Pos with >90% decrease) versus unfavorable (Neg-Pos and Pos-Pos with a <90% decrease or an increase) had significantly improved progression-free survival in the favorable group (p<.0001). ctDNA dynamics predicted progression and may guide treatment or imaging. ctDNA offers a minimally invasive, cost-effective adjunct to radiographic surveillance.

Hormone receptor-positive (HR+), human epithelial growth factor receptor 2 (HER2) overexpressed breast cancer (BC) represents the more aggressive subtype of HR + BC, typically associated with poor clinical outcomes. Despite significant advancements in the treatment of estrogen receptor-positive (ER+)/HER2 + BC, resistance to endocrine therapy (ET) poses a continued challenge. Imlunestrant is a next-generation, oral, brain-penetrant, pure antagonistic ER degrader designed to deliver continuous ER target inhibition. It has shown favorable clinical benefit, safety, and pharmacokinetics (PK) when used as monotherapy or with targeted therapy in patients with ER+/HER2- advanced BC (ABC). Here, we present the safety and efficacy of imlunestrant with HER2 targeted therapy in patients with ER+/HER2 + ABC of the EMBER trial. Patients were randomized to imlunestrant (400 mg RP2D) + trastuzumab (group A) versus imlunestrant + trastuzumab ± abemaciclib [(150 mg twice daily) group B] or received maintenance treatment with imlunestrant + trastuzumab + pertuzumab until progression or discontinuation at standard doses (group C). In the randomized allocation, eligible patients with locally advanced or metastastic disease had received ≥ 2 prior HER2-directed regimens in the metastatic setting, and no prior treatment with CDK4/6 inhibitors or fulvestrant. The maintenance cohort (group C) was added later to include patients without disease progression after first-line induction taxane-based chemotherapy (any duration), trastuzumab, and pertuzumab. Endpoints included safety, PK, antitumor activity, and tumor biomarker assessments. In total, 45 patients with ER+/HER2 + ABC were treated (group A, n = 18; group B, n = 21; group C, n = 6). Adverse events were consistent with the known safety profiles of the partner drugs. Imlunestrant PK was consistent with previously reported data. For groups A, B, and C, the objective response rates (ORRs) were 7%, 25%, and 33%, respectively, while the clinical benefit rates (CBRs) were 44%, 48%, and 100%. In group C, the duration of response ranged between 5.13 and 9.46 months. In groups A and B, baseline plasma ctDNA sample sequencing identified prevalent alterations in ERBB2 amplification (57%), CCND1 amplification (22%), and mutations in TP53 (49%), PIK3CA (30%), ESR1 (24%), and GATA3 (14%). Imlunestrant in combination with trastuzumab ± abemaciclib or pertuzumab presented a safety profile that was consistent with those of the partnered drugs. No new safety findings were observed. Furthermore, imlunestrant in combination with the partnered drugs demonstrated preliminary antitumor activity in patients with ER+/HER2 + ABC. ClinicalTrials.gov identifier NCT04188548 (Registered 18 November 2019).

Abstract BACKGROUND ACPs are brain tumors that typically originate in the suprasellar region and are associated with significant morbidity, with patients experiencing visual impairment, pituitary dysfunction and headaches. No systemic therapies are available for ACP, while surgery or radiation can be challenging and result in complications. Almost all ACPs have Wnt pathway-activating mutations (WPAMs), predominantly CTNNB1 activating mutations. FOG-001 is a Helicon™ peptide that competitively inhibits the interaction between β-catenin and TCF transcription factors in the Wnt-signaling pathway. Here we report safety and preliminary efficacy of FOG-001 in ACP patients. METHODS This is a first-in-human, phase 1/2, multicenter study of FOG-001 in patients with WPAM+ solid tumors, treated at doses ranging from 36-480 mg/m2 (NCT05919264). Patients with histologically confirmed, locally-advanced ACP are eligible. Disease assessments, per RECIST v1.1, are performed every 8 weeks for 48 weeks and every 12 weeks thereafter. Primary objective is safety and tolerability of FOG-001. Secondary objective is anti-tumor activity. RESULTS As of May 11, 2025, 3 ACP patients have received FOG-001 monotherapy at doses of 144 mg/m2 (n=1) and 360 mg/m2 (n=2). All patients are male and median age is 42 years (range 19-62). All patients had prior surgery and 1 received radiation. All treatment-related adverse events (TRAEs) were low-grade (no Grade ≥3 TRAEs). The most common TRAEs were hyponatremia (n=2) and thrombocytopenia (n=2), both reversable. No treatment-related serious adverse events or dose reductions have been reported. Tumor size has decreased in all patients, with one patient achieving a partial response (PR), with a 48.0% reduction, and the other two stable disease (24.0% and 19.2% decrease). CONCLUSIONS FOG-001 has been well tolerated in patients with locally-advanced ACP. All patients have had tumor size reductions, including one PR, suggesting that the Wnt-signaling pathway is an actionable target in ACP.

A series of carboxyamido-propanyl analogs is described as antiviral agents for inhibition of the replication of hRSV and hMPV. Human Respiratory Syncytial Virus (hRSV, RSV) belongs to the family Paramyxoviridae and the subfamily Pneumovirinae that are significant human and animal pathogens. After hRSV, hMPV (metapneumovirus) is the second most common cause of lower respiratory infection in young children. Therefore, inhibition of hRSV and hMPV is an important approach for the potential treatment of respiratory viral infections.