Nebraska Cancer Specialists

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.

AC699 is a novel, orally bioavailable chimeric estrogen receptor-α (ERα) degrader that induces proteasome-dependent ERα degradation via cereblon E3 ligase recruitment. Here we report findings from a first-in-human, phase 1, dose-escalation study of once-daily AC699 (100-600 mg) in patients with heavily-pretreated, locally-advanced/metastatic ER-positive/HER2-negative breast cancer (ClinicalTrials.gov Identifier: NCT05654532). Primary objectives are to assess dose-limiting toxicities and treatment-emergent adverse events (TEAEs). Secondary objectives are to evaluate pharmacokinetics, objective response rate (ORR), clinical benefit rate (CBR, including stable disease ≥24 weeks), duration of response (DOR), and progression-free survival (PFS). Among 37 treated patients, TEAEs occurred in 78% of patients, most commonly nausea (19%), fatigue (16%), and neutropenia (16%). All treatment-related adverse events were Grade 1/2, with no dose reductions/discontinuations; the maximum tolerated dose was not reached. Of 26 efficacy-evaluable patients, 4 (15%) achieved partial responses and CBR was 23%. In exploratory analysis of patients with ESR1 mutations, ORR and CBR were 40% and 45%, respectively. Median DOR and PFS were 6.5 and 3.6 months overall, and 6.5 and 7.4 months in ESR1-mutant patients. AC699 steady-state exposure increased approximately dose-proportionally between 100-400 mg, plateauing at 600 mg. AC699 demonstrated favorable safety, predictable PK, and encouraging antitumor activity, particularly in ESR1-mutant disease.

LBA4175 Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) is an aggressive malignancy with a median overall survival (mOS) of between 8 and 11 months. With the use of modern chemotherapy regimens, some patients with mPDAC have been shown to achieve long‐term survival of 18 months or longer (Rochefort et al. Oncol. 2019;24:1543–8). The aim of this analysis was to describe long‐term survivors among the North American population treated with liposomal irinotecan plus 5-fluorouracil/leucovorin and oxaliplatin (NALIRIFOX) in the NAPOLI 3 trial and to explore clinical and pathological factors that might be associated with prolonged survival. Methods: Patients with confirmed untreated mPDAC randomized to receive NALIRIFOX in NAPOLI 3 were treatment on days 1 and 15 of a 28-day cycle. In this post hoc analysis of patients enrolled from centers in North America (n = 120), baseline characteristics and NALIRIFOX dosing patterns were evaluated for individuals who survived for 18 months of longer (long-term survivors; n = 15). The analysis was descriptive; no statistical tests were performed. Kaplan–Meier methods were used to estimate mOS (interquartile range [IQR]). Results: Among the long-term survivors, the mOS was 19.5 (IQR: 18.8–22.6) months and 53.3% were male. At baseline, long-term survivors had a median age of 61.0 (IQR: 49.0–70.5) years, had a median CA 19-9 level of 166.8 U/ml (IQR: 32.7–1728.4), 53.3% had Eastern Cooperative Oncology Group Performance Score (ECOG PS) 0, 53.3% had the main pancreatic tumor located in the body of the pancreas, 66.7% had liver metastasis, and 53.3% had ≥ 3 metastatic sites. Liposomal irinotecan and oxaliplatin dose reductions were experienced by 66.7% and 80.0% of long-term survivors, respectively, and dose delays by 86.7% and 80.0%, respectively. Median cumulative dose of liposomal irinotecan was 1229.4 (IQR: 821.9–1513.9) mg/m 2 for long-term survivors and median cumulative dose of oxaliplatin was 962.3 (655.0–1470.3) mg/ml. Median duration of exposure was 65.1 (IQR: 40.1–89.0) weeks for liposomal irinotecan and 39.9 (26.6–76.4) weeks for oxaliplatin. Conclusions: This post hoc analysis investigated characteristics and dosing patterns of long-term survivors from NAPOLI 3 treated with NALIRIFOX in North America. Patients with prolonged OS were generally younger (vs typical mPDAC diagnosis), few had tumors in the head or tail of the pancreas and, overall, CA19-9 levels and ECOG PS were low. A large proportion of long-term survivors experienced liposomal irinotecan and/or oxaliplatin dose reductions or treatment delays, but had prolonged exposure and high cumulative doses of both drugs. Despite liver metastasis and ≥ 3 metastatic sites in a substantial proportion of long-term survivors, dose modifications and an otherwise good clinical profile enabled attainment of a long mOS. Small sample size limits the generalizability of these results. Clinical trial information: NCT04083235 .

TPS5125 Background: Prostate cancer (PC) is common and despite recent advances in treatment options, patients with metastatic disease still have poor outcomes. The double PSMA binding moiety of SAR-bisPSMA in 64 Cu-SAR-bisPSMA (imaging) and 67 Cu-SAR-bisPSMA (therapy) may offer advantages compared to currently used single-target PSMA agents. Clinical evidence demonstrated 2-3 times higher uptake of 64 Cu-SAR-bisPSMA compared to the single-target PSMA agent, 68 Ga-PSMA-11. Pre-clinical efficacy data of 67 Cu-SAR-bisPSMA in mice showed statistically significant tumor growth inhibition and increased survival in a PC xenograft study. These results led to the development of the SECuRE trial, which aims to assess the safety and anti-tumor efficacy of 67 Cu-SAR-bisPSMA in patients with metastatic castrate resistant PC (mCRPC). Methods: SECuRE is a Phase I/IIa multi-center, open-label, non-randomized, dose-escalation and cohort expansion study of 64 Cu-SAR-bisPSMA and 67 Cu-SAR-bisPSMA in patients with mCRPC. The target population is patients who have progressed despite having at least one androgen receptor pathway inhibitor and demonstrate positivity on 64 Cu-SAR-bisPSMA PET. The study comprises 3 phases: Dosimetry (N=6), Dose Escalation (N~24) and Cohort Expansion (N=24). The 67 Cu-SAR-bisPSMA dose levels investigated in the Dose Escalation Phase are: 4 GBq (cohort 1, single dose), 8 GBq (cohort 2, single dose), 12 GBq (cohort 3, single dose) and 24 GBq across two doses (cohort 4, two doses at the maximum tolerated dose or maximum feasible dose [MTD/MFD] established in cohorts 1-3; two additional doses may be offered in case of radiological non-progression). In the Cohort Expansion phase, participants will receive 2 doses of 67 Cu-SAR-bisPSMA at the recommended dose determined in the Dose Escalation Phase (those with radiological non-progression may be offered up to 2 additional doses). A recent protocol amendment increased the number of participants from 14 to 24 in the Cohort Expansion phase, in which 8 will receive combination therapy of 67 Cu-SAR-bisPSMA with enzalutamide. The primary and key secondary objectives include assessment of 64 Cu- and 67 Cu-SAR-bisPSMA’s safety and dosimetry and determining the anti-tumor efficacy of 67 Cu-SAR-bisPSMA. Response to 67 Cu-SAR-bisPSMA will be assessed biochemically (≥50% decline in prostate-specific antigen) and radiographically (by RECIST V1.1 and PCWG3). Clinical trial information: NCT04868604 .

5102 Background: Accurate staging of recurrent prostate cancer (PC) is essential to inform the best treatment strategy. 64 Cu-SAR-bisPSMA may offer several advantages over the currently approved PSMA positron emission tomography (PET) agents due to its bivalent structure (SAR-bisPSMA) and longer half-life of 64 Cu (12.7h vs. <2h for 18 F and 68 Ga), as previously reported (2-3x higher tumor uptake and detection of additional PC lesions vs. approved PSMA PET agents). Methods: This was a Phase 1/2 study assessing the safety/efficacy of 64 Cu-SAR-bisPSMA (200 MBq) in PC patients with biochemical recurrence (BCR) and negative/equivocal standard of care (SOC) imaging (NCT05249127). PET/computed tomography (CT) imaging was performed on Day 0 and Day 1 (1-4h and 24±6h post-dose, respectively) and interpreted by 3 blinded central readers. PET/CT results were assessed against a composite Reference Standard (histopathology, SOC imaging [interpreted by 2 readers], prostate specific antigen response post-focal therapy). Efficacy endpoints included detection rate (DR; % participants with a positive scan out of all scanned participants) and correct detection rate (CDR; % participants with a true positive scan out of all scanned participants with at least one evaluable Reference Standard). Results: Fifty-two participants were enrolled (50 had 64 Cu-SAR-bisPSMA PET results); 39 and 30 had follow-up SOC imaging by Day 90 and by Day 180, respectively, and 9 had histopathology. 64 Cu-SAR-bisPSMA DR range across readers on Day 0 was 44–58% (95% confidence interval [CI]: 30–71.8), increasing on Day 1 to 58–80% (95% CI: 43.2–90). DR on follow-up SOC imaging by Day 90 ranged from 15-31% and 7-10% by Day 180. CDR as assessed against the composite Reference Standard on Day 0 was 19.0–26.2% (95% CI: 8.6; 42.0), increasing to 26.2–33.3% (95% CI: 13.9; 49.5) on Day 1. CDR was considerably higher when using histopathology as the Reference Standard (44.4–55.6% and 55.6–77.8% for Day 0 and Day 1, respectively), than SOC imaging (10.3–20.5% and 23.1%–25.6% for Day 0 and Day 1, respectively). Conclusions: 64 Cu-SAR-bisPSMA is effective in detecting PC in BCR of PC, with lesions identified in up to 80% of participants with negative/equivocal baseline SOC imaging. CDR was considerably higher when using the gold standard of histopathology to verify 64 Cu-SAR-bisPSMA PET lesions vs SOC imaging, which highlights the limitations of using less sensitive methods to verify the 64 Cu-SAR-bisPSMA PET findings. These results have important clinical implications, as the identification of lesions in BCR patients can inform different treatment pathways. Clinical trial information: NCT05249127 .