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A tryptophan-phenylalanine binding motif for the histone methyltransferases MLL4 and MLL3

ResQ133A-NMIBC: A phase 1/2 clinical trial of intravesical recombinant mycobacterium bacillus Calmette-Guerin (rBCG) in participants living with non-muscle invasive bladder cancer eligible to receive conventional BCG.

TPS884 Background: Intravesical Bacillus Calmette-Guerin (BCG) is a standard and widely used therapy for non-muscle invasive bladder cancer (NMIBC). However, the global shortage of BCG has presented a need for alternative sources of BCG and/or treatments. Recombinant mycobacterium BCG (rBCG) may offer an alternative to BCG for both induction and maintenance therapy in NMIBC. Two gene modifications have been implemented in rBCG to improve its immunogenicity and safety in comparison to earlier strains and formulations of BCG. The urease G gene is deleted and the listeriolysin gene is added in this strain specifically designed for bladder cancer therapy. rBCG has completed Phase 1/2 human clinical studies in Europe as an immunotherapy in patients with NMIBC. As reported in the SAKK06/14 trial, rBCG VPM1002BC was found to be efficacious and safe in NMIBC recurrence after conventional BCG therapy [Rentsch 2022 ]. In ResQ133A-NMIBC, the safety and preliminary efficacy of rBCG will be assessed in NMIBC participants who have not received BCG (BCG-naïve). Methods: ResQ133A-NMIBC study is a phase 1/2, open-label, multicenter trial evaluating intravesical rBCG in BCG-naïve participants with NMIBC. To be eligible, participants must be 18 years or older, have histologically confirmed NMIBC, and be absent from resectable disease after TURBT procedures. They must also have an ECOG performance status of < 3. Exclusion criteria include participants with a life expectancy of less than 2 years, certain laboratory abnormalities, previous BCG treatment, or muscle-invasive bladder cancer are excluded from the study. Additionally, individuals with other progressing cancers within the past 5 years or being treated with investigational therapy are also not eligible. The study treatment involves weekly intravesical instillation of 1–19.2e8 CFU (1 vial) of rBCG for 6 weeks during the induction phase. For participants benefiting from treatment, maintenance installations will be administered weekly for 3 weeks, every 3 months. Response assessments occur every 12 weeks (3 months) through week 52 (month 12). Responses will be assessed by cystoscopy, confirmatory bladder biopsy, and urine cytology. The primary objective of the study is to assess the safety of intravesical rBCG, including vital signs, clinically significant changes in safety laboratory tests, and the incidence and severity of adverse events (AEs). The secondary objectives are to determine the complete response (CR) rate and median duration of CR in bladder CIS +/- Ta/T1 papillary, as well as disease-free survival in primary or recurrent papillary Ta and/or T1 disease. Response assessments will occur every 12 weeks through week 52. As of October 21, 2025, the study is open and awaiting the enrollment of its first participant. Clinical trial information: NCT06800963 .

Enfortumab vedotin and pembrolizumab (EVP) outcomes in patients (pts) with advanced urothelial carcinoma (aUC) and FGFR3 alterations: UNITE study analysis.

668 Background: EVP is the preferred 1 st line (1L) therapy for aUC pts and is increasingly used in the perioperative setting. Data on EVP outcomes in pts with FGFR3-altered aUC are limited. Methods: We analyzed aUC pts treated with EVP who had tumor genomic profiling in the multi-site retrospective UNITE study. Pts with and without FGFR3 alterations were compared using χ 2 test and logistic regression for observed response rate (ORR) and disease control rate (DCR). Log-rank test and Cox proportional hazard models were used to assess duration of response (DOR), progression-free survival (PFS), and overall survival (OS) from EVP start. Results: 521 pts from 16 sites were treated with EVP, including 313 pts with genomic profiling data. Median age was 71, 74% were male, 84% were Caucasian, 82% had ECOG PS 0-1, 20% had liver metastases, and 73% received 1L EVP. 67 pts (21%) had FGFR3 alterations, of which 73% had point mutations, 19% had fusions, and 9% had amplifications (1 pt had both fusion and amp). FGFR3-altered pts had more upper tract primary tumor (39% vs. 24%, p = 0.02), pure urothelial histology (82% vs. 61%, p = 0.002), and non-liver visceral metastases (60% vs. 45%, p = 0.04) relative to wild type (WT). At median follow-up of 8.3 mos from EVP start, the overall cohort had ORR 53%, DCR 82%, median DOR (mDOR) 9.9 mos (95% CI 7.7-11.5 mos), median PFS (mPFS) 6.9 mos (95% CI 6.1-10.2 mos), and median OS (mOS) 18.9 mos (95% CI 14.8-33.5 mos). WT pts had ORR 53%, DCR 80%, mDOR 9.0 mos, mPFS 7.4 mos, and mOS 19.8 mos. FGFR3-altered pts had ORR 53%, DCR 90%, mDOR 10.6 mos, mPFS 6.5 mos, and mOS 13.1 mos. The presence of FGFR3 alterations was not associated with significant outcome differences with EVP as 1L or subsequent-line (2L+) therapy (Table). Pts with FGFR3 amps trended towards worse PFS. Conclusions: In this retrospective study, aUC pts with FGFR3 alterations receiving EVP had concordant treatment outcomes with WT patients. These hypothesis-generating findings require validation in larger cohorts. ORR: OR (95% CI) DCR: OR (95% CI) DOR: HR (95% CI) PFS: HR (95% CI) OS: HR (95% CI) FGFR3 altered vs. WT  All EVP (n=313) 0.99 (0.6-1.8, p=0.98) 2.13 (0.9-5.9, p=0.10) 0.99 (0.7-1.5, p=0.96) 1.04 (0.7-1.5, p=0.84) 1.06 (0.7-1.6, p=0.78)  1L EVP (n=224) 0.93 (0.5-1.9, p=0.84) 1.72 (0.6-6.3, p=0.34) 0.91 (0.6-1.4, p=0.70) 1.06 (0.7-1.7. p=0.81) 1.02 (0.6-1.9, p=0.94)  2L+ EVP (n=85) 1.23 (0.4-3.7, p=0.70) 3.23 (0.8-20, p=0.14) 1.30 (0.5-3.2, p=0.57) 0.88 (0.5-1.6, p=0.70) 1.03 (0.5-2.0, p=0.92) FGFR3 alteration type vs. WT  Point mut (n=49) 0.93 (0.5-1.9, p=0.85) 1.82 (0.7-5.6, p=0.24) 1.06 (0.7-1.7, p=0.80) 1.09 (0.7-1.6, p=0.70) 1.04 (0.6-1.7, p=0.87)  Fusion (n=13) 0.89 (0.3-2.9, p=0.85) NA (100% DCR) 0.62 (0.3-1.4, p=0.25) 0.81 (0.4-1.7, p=0.57) 1.28 (0.6-2.8, p=0.53)  Amp (n=6) 0.89 (0.1-7.7, p=0.91) 0.75 (0.1-16.7, p=0.81) 2.63 (0.6-11.1, p=0.18) 2.32 (0.9-6.3, p=0.09) 1.7 (0.5-5.3, p=0.39)

ctDNA monitoring of FGFR3-altered metastatic urothelial cancer treated with dabogratinib (formerly TYRA-300) in the SURF301 trial.

809 Background: Activating FGFR3 mutations and fusions occur in 10-20% of patients with metastatic urothelial carcinoma (mUC). Erdafitinib, a pan-FGFR inhibitor, is an approved targeted therapy for FGFR3 -altered mUC. However, low isoform specificity can lead to side effects, and dose reductions or interruptions occur due to inhibition of FGFR1/2/4. Dabogratinib is a highly selective inhibitor of FGFR3 with potentially less off-target toxicity relative to pan-FGFR inhibitors and has shown preclinical activity against FGFR3 gatekeeper mutations. SURF301 (NCT05544552) is a phase 1/2 study in solid tumors testing oral dabogratinib, with a previously reported 55% (6/11) of patients achieving confirmed partial responses at doses of 90mg QD or above. Here, we report phase 1 results on early circulating tumor DNA (ctDNA) dynamics in FGFR3 -altered patients with mUC enrolled in SURF301. Methods: Blood was collected at baseline, cycle 1 day 15 (C1D15), C2D1 and at each disease assessment visit (every 3 months). Plasma cell-free DNA (cfDNA) was sequenced using a custom targeted panel of 78 mUC genes. Somatic variants were called via an established bioinformatic pipeline, leveraging same-patient serial samples to boost detection sensitivity. The proportion of tumor-derived cfDNA was estimated using orthogonal approaches, and evaluated as an absolute (MTM/mL) and relative measure (ctDNA fraction). On-treatment ctDNA changes from baseline were calculated and statistical significance assessed using Fisher’s exact test and Bayesian posterior estimates derived from Beta–binomial models with Jeffreys priors. Results: Twenty-one mUC patients provided blood at baseline and on-treatment (n=72 samples). Median age was 68 (range 53-84) and 57% had 3 or more prior lines of therapy. Eleven patients received dabogratinib at ≥90mg QD, while 10 received 40-60mg QD. All FGFR3 variants (9 mutations, 7 TACC3 fusions, 1 both) detected in tumor tissue were also identified in baseline ctDNA (when ctDNA was detected; 17/21). On-treatment ctDNA fraction showed significant decreases as early as C1D15 across all dose groups, with 6 patients having reductions to below the level of quantification (ctDNA clearance) including 1 patient treated at 40mg QD. All patients in the higher dose groups had reductions or no baseline ctDNA. Conclusions: We observed frequent on-treatment reductions in plasma ctDNA in FGFR3 -altered mUC patients receiving dabogratinib in the SURF301 trial. Molecular responses, suggestive of anti–tumor effect and adequate target coverage, were seen at all doses, with the deepest molecular responses occurring at doses of ≥90mg QD, in alignment with reported pharmacokinetic and pharmacodynamic evidence of drug activity. Clinical trial information: NCT05544552 .

A randomized trial of neoadjuvant leuprorelin, darolutamide, or both prior to radical prostatectomy for intermediate- or high-risk prostate cancer.

TPS414 Background: While radical prostatectomy results in excellent survival in patients with low- and favorable intermediate-risk localized prostate cancer, the role of surgery in the setting of higher-risk disease remains controversial. Many unfavorable intermediate-, high- and very high-risk patients are treated with androgen deprivation therapy (ADT) in combination with radiation. Although surgery can be curative for these patients a subset will experience recurrence and has an increased risk of prostate cancer mortality. These recurrences result from either residual local disease and/or micrometastatic disease nondiagnosed. Neoadjuvant therapy may improve local disease control by downstaging the primary tumor, treat occult distant metastasis, facilitate surgical resection, reduce or delay need for post-surgery treatment and provide an in vivo assessment of response to treatment. Methods: COACTION is a prospective, randomized, open-label with blinded endpoint adjudication multicenter clinical trial to assess whether a neoadjuvant combined treatment with leuprorelin and darolutamide is superior to monotherapy in terms of complete or almost complete pathological response. Key inclusion criteria: age ≥ 18 years; unfavorable intermediate- or high-/very high-risk non metastatic prostate adenocarcinoma intended for surgery; ECOG PS ≤ 1; testosterone > 230 ng/dL; no prior prostate cancer treatment. 144 patients will be randomized 1:1:1 to three arms: darolutamide 600 mg PO BID for 24 weeks + leuprorelin 22.5 mg SC in 0 and 12 weeks; darolutamide 600 mg PO BID alone for 24 weeks; or leuprorelin 22.5 mg SC 0 and 12 weeks alone. Primary endpoint is the proportion of patients with minimal residual disease, defined as residual cancer burden (RCB) ≤ 0.25 cm 3 or complete pathological response. The study main analysis will compare the combination therapy group versus the pooled monotherapy groups. If null hypothesis is rejected, then the combination therapy group will be compared with either monotherapy group individually. Groups will be compared for the primary endpoint by a model from the binomial family and log link function will be used to generate risk ratios (RR) and 95% confidence intervals (CI). Models will be adjusted for the stratification variable (intermediate- versus high-risk groups), for age and race (white versus non-white). We anticipate that the proportion of patients with minimal residual disease will be 10% in the pooled monotherapy groups and 30% in the combination therapy groups. For an alpha error of 5% and 80% power, the study will need a total of 132 patients included in the analytical population (44 in each group). In order to compensate for losses and patients who do not undergo surgery, we decided to enroll a total of 144 patients. If all enrolled patients are included in the main analysis, the study will have 84% power to detect such difference. Clinical trial information: NCT06627530 .

Organelles stick together through PDZD8-mediated condensate formation

Engineering Dielectric Genes in Debye Relaxation Model toward Frequency‐Band‐Reliant Electromagnetic Responses

ABSTRACT Electromagnetic wave absorption (EMWA) materials are widely used in wireless communications and play an important role in contemporary smart economy. EMWA materials that show dielectric losses have attracted research attention owing to their unique advantages. However, previous studies have focused on material synthesis whereas few studies have systematically explained the mechanism of dielectric loss. Taking the concept of dielectric genes as the starting point and Debye relaxation model as the “compass,” the dependence of the electromagnetic wave absorption at different frequencies on each dielectric parameter is introduced in detail, and a dynamic trend model is constructed for the prediction of electromagnetic wave absorption characteristics, followed by discussion of the development and future prospects of EMWA materials, providing inspiration for the design of dielectric‐loss absorption materials in the future.

Multiphysics‐Driven Assembly of Biomimetic Vesicles

ABSTRACT Artificial extracellular vesicles (AEVs) are programmable, biomimetic materials that combine the structural and biological complexity of naturally secreted extracellular vesicles (NEVs) with the design flexibility of synthetic nanomaterials. A multiphysics‐driven microfluidics is developed to efficiently integrate the nanoknife‐assisted membrane rupture with flow dynamics and acoustothermal modulation for the reproducible, high‐yield, scalable, and standardized production of AEVs. Compared to empirical mechanical processes, this integrated microfluidic workflow, which exploits physical and biological insights for EV production, enables multiphysics‐based predictions for a precise control of material inputs, flow dynamics, and cell‐knife interactions within the channel. The biomimetic AEVs developed through this integrated, optimized single‐flow platform, with a sustained and efficient therapeutic encapsulation process, preserve native protein architectures to conduct biomimetic mechanisms of immune modulation and homologous targeting. The standardizable microfluidic platform paves the way for a structure–process–function design strategy, enabling the formation of scalable, adaptive biomaterials for the development of bioinspired interfacial engineering and biomedicine.

P-bodies act as dynamic control hubs for RNA processing and storage

Retrospective analysis of treatment responses to enfortumab vedotin combined with pembrolizumab (EVP) based on FGFR2/3 alterations in patients (pts) with advanced urothelial carcinoma (aUC).

688 Background: Reports vary as to the relationship between FGFR2/3 mutations (FGFR2/3m) and responses to EV in pts with aUC. As EVP has been rapidly adopted as first-line treatment based on results from the EV-302 trial, responses to treatment with EVP in patients with and without FGFR2/3m have not been well-described to date. We sought to examine a retrospective cohort of pts with aUC treated with EVP to determine whether there are differences in responses based on FGFR2/3m. Methods: Data from 5 academic institutions were collected from patients with aUC treated with first-line EVP from 8/13/2018 to 8/20/2025. Pts needed to have at least 1 whole body scan to assess for treatment response, which was interpreted using RECIST by the treating physician. Extracted data from the electronic health record (EHR) included demographic, clinical, and genomic variables. We also collected data on FGFR2/3m present, absent, or unknown. Those with unknown FGFR2/3 status were excluded from analysis. Primary endpoint was median PFS (mPFS), defined as time from EVP initiation to progressive disease by RECIST v1.1 criteria. Data were analyzed using descriptive statistics and Kaplan-Meier estimation. Results: Data were collected from 143 pts, with 122 pts having known FGFR2/3 status. Select clinical characteristics in the study population are outlined in Table 1. FGFR2/3m were noted in 34 pts, while 88 were wildtype (wt). Pts with FGFR2/3m experienced a shorter mPFS (5.2 months, 95% CI 4.0-24) than those with FGFR2/3 wt (16 months, 95% CI 9.2-35; p=0.029). Overall survival was not significantly different. Conclusions: While a limited retrospective dataset, shorter mPFS was observed in pts with FGFR2/3m aUC. This may inform future research development of first-line treatment of aUC in pts with FGFR2/3m. Clinical characteristics and efficacy. FGFR2/3m(n=34) FGFR2/3 wt(n=88) Age (median, range) 66 (37, 86) 73 (27, 95) Male (n,%) 24 (71%) 63 (72%) Upper Tract Primary (n,%) 11 (33%) 21 (24%) Lymph node only metastases (n,%) 24 (71%) 59 (67%) Median PFS (months, 95% CI) 5.2 (4.0, 24) 15 (9.2, 35) Median OS (months, 95% CI) 33 (24, --) 29 (20, --)

Switch androgen receptor pathway inhibitor strategies in metastatic castration-resistant prostate cancer: A meta-analysis of randomized trials.

198 Background: The optimal sequencing of therapy in metastatic castration-resistant prostate cancer (mCRPC) remains unclear. Real-world practice patterns show that over 50% of patients undergo sequential therapy with androgen receptor pathway inhibitors (ARPIs), and the ARPI switch serves as the control arm for multiple ongoing randomized controlled trials (RCTs). However, most existing reviews focus on the efficacy of individual agents, with limited attention to outcomes following ARPI-to-ARPI switch. This meta-analysis synthesizes randomized evidence comparing sequential ARPI therapy with alternative strategies to define efficacy, resistance, and the impact on survival. Methods: A systematic search, based on PRISMA 2020, for RCTs using switch ARPI strategies in mCRPC was completed in PubMed, Scopus, CINAHL, Ovid, and ASCO. A random effects model with a restricted maximum likelihood method was used for pooling medians and variance, utilizing R (4.3.3). Results: Eighteen studies comprising 7,514 patients were analyzed. Eight studies evaluated ARPI switch pre-taxane (Pre-T) chemotherapy, eight post-taxane (Post-T) exposure, and two included both. Nine studies evaluated abiraterone (ABI) to amide ARPI sequencing (enzalutamide, darolutamide, or apalutamide), two evaluated amide-to-ABI, and eight included pooled ARPI cohorts without sequence-level detail. The overall (OA) pooled PSA50 response rate was 20.0% (95% CI: 11-34%), with a median radiological progression-free survival (rPFS) of 5.08 months (4.24-5.92) and overall survival (OS) of 19.7 months (15.0-24.4). Stratified results are summarized in Table 1. In ARPI sequencing analyses among the Pre-T subgroup, OS was comparable between the ABI to amide and amide to ABI subgroups (22.6 vs 24.7 months, p=0.77). Conclusions: In the largest analysis to date, sequential ARPI therapy in mCRPC demonstrated limited benefit, consistent with existing evidence of cross-resistance among AR-targeted agents. Post-T outcomes were poor, reinforcing the limited clinical value of ARPI switching after initial progression. ARPI switch should be approached with caution; it should not be used as a control arm in large RCTs when alternative therapies are available with proven life-prolonging benefits. These findings underscore the need for alternative mechanisms and optimized sequencing strategies. Pooled outcomes by prior taxane exposure. Outcomes ARPI Cohorts No. of Studies No. of Patients (N or n/N) Pooled Value 95% CI I² (%) P-value PSA50 response (%) OA 9 258/1122 20 11-34 93.7 0.45 Pre-T 5 113/612 17 8-32 83.2 <0.05 Post-T 4 145/510 26 10-51 96.9 <0.05 Median rPFS (mo) OA 10 4401 5.08 4.24-5.92 70.5 <0.05 Pre-T 6 3191 5.54 4.35-6.73 81.4 <0.05 Post-T 4 1210 4.11 3.36-4.86 0 0.50 Median OS (mo) OA 7 2945 19.7 15.0-24.4 93.9 <0.05 Pre-T 5 1902 22.6 18.3-26.9 88.7 <0.05 Post-T 2 1043 12.7 9.2-16.3 82 <0.05

Early peripheral blood neutrophil/lymphocyte ratio (NLR) dynamics to predict primary refractory disease in metastatic urothelial carcinoma (mUC) patients receiving PD1/L1 inhibitors.

793 Background: Early identification of refractory vs. sensitive disease may inform precision medicine in patients (pts) with advanced malignancies receiving systemic therapy. While circulating tumor (ct)-DNA may be employed to detect early tumor burden dynamics, the access to the assay presents challenges in globalization. We have previously reported that an increase in peripheral blood NLR in the first 3-4 weeks after initiating PD1/L1 inhibitors for 144 patients with mUC was inversely associated with any regression of tumor (ART) (Thomas J, Genitourinary Cancer Symposium Feb 2022). We aimed to further investigate the impact of early dynamics in NLR as well as other readily available clinical and laboratory factors for the early discrimination of benefit from PD1/L1 inhibitors in pts with mUC. Methods: Deidentified data from mUC pts who were treated with PD1/L1 inhibitors at AdventHealth institutions in the US were reviewed retrospectively. Demographic data (age, sex), setting (untreated vs. post-therapy), sites of metastasis and performance status (PS) were collected. Additionally, clinical and laboratory variables were collected at baseline and 3-4 weeks after initiating the PD1/L1 inhibitor including body weight, NLR, platelets, eosinophils, albumin and hemoglobin. We assessed the association of dynamics in these factors with the best response category of progressive disease (PD) per RECIST1.1 and any regression of tumor (ART). Multivariable logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (CIs). Results: A total of 76 pts were evaluable. The median age was 69.5 years, 54 (71.05%) were male, and 24 (31.58%) were therapy naive. ART and PD as best response were seen in 38 (50%) and 34 (44.74%) pts, respectively. Multivariable logistic regression identified an increase in NLR to be associated with refractory disease and poor regression rate, i.e. PD as best response and absence of ART. The OR was 12.21 (95% CI 1.21–123.71, p = 0.034) for PD vs. the others (AUC 0.72), and 5.6 (95% CI 1.48– 21.13, p = 0.02) for absence of ART vs ART (AUC 0.7). Dynamics of other factors did not reach statistical significance. Conclusions: Our retrospective analysis demonstrates that early NLR dynamics, specifically an increase in 3-4 weeks, was validated to be associated with absence of tumor regression and was robustly associated with primary refractory disease in patients with mUC receiving PD1/L1 inhibitor therapy. Given the affordability and global availability of peripheral blood NLR, validation in large datasets is warranted in conjunction with its performance vs. ctDNA. Early identification of primary refractory disease may allow modification or intensification of therapy before clinical decline to improve long-term clinical outcomes.

Updated efficacy results from the phase 1 study of gotistobart (BNT316/ONC-392) in combination with lutetium Lu 177 vipivotide tetraxetan (Lu 177) in patients with metastatic castration-resistant prostate cancer (mCRPC).

175 Background: Lutetium-177 vipivotide tetraxetan (Lu 177) significantly improves progression-free survival (PFS) and overall survival (OS) in patients (pts) with pre-treated mCRPC. Combination strategies are being explored to enhance therapeutic outcomes. Preclinical models have demonstrated that radiotherapy selectively expands and activates regulatory T cells (Tregs) in the tumor microenvironment (TME). Gotistobart, an investigational pH-sensitive anti-CTLA-4 antibody, enhances Treg depletion in the TME and, combined with Lu 177, has demonstrated manageable safety and promising preliminary PSA50 rates in pts with mCRPC (#5067, ASCO 2025). Here, we report updated efficacy analyses from this Phase 1 trial. Methods: PRESERVE-006 (NCT05682443) is an open-label, randomized, phase 1/2 trial evaluating gotistobart with Lu 177 in pts with mCRPC post-androgen receptor pathway inhibition. Pts received gotistobart (3 mg/kg Q4W, 6 mg/kg Q6W, or 10 mg/kg Q6W, up to 13 doses) plus Lu 177 or Lu 177 alone (up to 6 doses). Efficacy endpoints were assessed per PCWG3 guideline. Results: As of August 8, 2025, this Phase 1 enrolled 25 pts who had a median age of 69 years (range: 52–86), 64.0% of the pts were White, 24.0% were Black and 4.0% were Asian. All pts had prior taxane and androgen receptor pathway inhibitors. Safety data for all 25 pts were reported at ASCO 2025, and no new safety signals were observed. With a median follow-up time of 11.9 m, median radiographic PFS (rPFS) was 4.8 m, 12.2 m, 8.3 m and not reached in the Lu 177 only, 3 mg/kg combo, 6 mg/kg combo, and 10 mg/kg combo group, respectively (Table). Among the 7 pts with measurable disease at baseline who received combination therapy, 5 (71.4%) achieved a partial response, and 2 pts achieved stable disease. Median PSA PFS was not reached for the cohorts dosed at 3 mg/kg and 6 mg/kg. Conclusions: Preliminary efficacy with a manageable safety profile was observed for gotistobart in combination with Lu 177 in pts with mCRPC during the Phase 1 study. The three arm randomized Phase 2 dose optimization stage (n=122) has completed enrollment at the 3 mg/kg combo, 6 mg/kg combo and Lu 177 only groups. Clinical trial information: NCT05682443 . Gotistobart 3 mg/kg + Lu 177(N = 6) Gotistobart 6 mg/kg + Lu 177(N = 6) Gotistobart 10 mg/kg + Lu 177(N = 6) Lu 177(N=7) Median follow-up time, m 17.8 9.2 11.9 12.3 Confirmed PSA50, n (%) (95% CI) 4 (66.7) (22.3, 95.7) 3 (50.0)(11.8, 88.2) 3 (50.0) (11.8, 88.2) 2 (28.6) (3.7, 71.0) PSA90, n (%) (95% CI) 3 (50)(11.8, 88.2) 0 (0.0, 45.9) 2 (33.3)(4.3, 77.7) 1 (14.3)(0.4, 57.9) Median rPFS, m(95% CI) 12.2(2.0, NE) 8.3(5.8, NE) Not reached (11.0, NE) 4.8(3.8, NE) 6m rPFS rate, (%) (95% CI) 66.7(28.9, 100) 75.0(32.6, 100) 83.3(53.5, 100) 28.6(0, 62.0) Median PSA-PFS, m (95% CI) Not reached(9.72, NE) Not reached (5.39, NE) 10.4(4.8, NE) 4.9(4.4, 6.0)

Correction to “Lossless Fast Drop Self‐Transport on Anisotropic Omniphobic Surfaces: Origin and Elimination of Microscopic Liquid Residue”

The protease cathepsin K can debulk the cancer glycocalyx

Circulating tumor DNA (ctDNA) to guide response-adapted bladder preservation in muscle invasive bladder cancer (MIBC): Integrated analysis of the RETAIN trials.

LBA632 Background: The phase II RETAIN 1 and 2 trials evaluated a response-adapted approach to identify pts with MIBC who may safely undergo cystectomy-sparing active surveillance (AS) after neoadjuvant therapy (tx). RETAIN-1 evaluated AMVAC and RETAIN-2 combined nivolumab with AMVAC. Although ctDNA is prognostic in pts treated with cystectomy, its role in selecting or monitoring pts on AS is unknown. We report updated RETAIN-2 outcomes and an integrated ctDNA analysis from RETAIN-1/2 to evaluate the role of ctDNA in risk stratification for bladder preservation. Methods: RETAIN-2 enrolled pts with cT2-T3N0M0 MIBC treated with AMVAC plus nivolumab. TURBT samples were sequenced for ATM , ERCC2 or RB1 mutations. Pts with >1 mutation and clinical complete response (restaging TUR, urine cytology and CT), entered AS; others received bladder-directed tx. The primary endpoint was 2-yr metastasis-free survival (MFS) in the ITT population. Plasma from both trials was analyzed with Signatera at baseline and post-tx; RETAIN-2 included 3- and 6- mo draws. Results: Among 71 evaluable RETAIN-2 pts (median age 68; 77% male; 42% cT3), 57 (80.3%) remained metastasis-free at 29.2-mo follow-up. The estimated 2-yr MFS was 79.8% (95% CI 70–90%) in the ITT population and 80% (95% CI 64–100%) in AS pts. Among 22 AS pts, 8 (36%) had bladder recurrence, 4 (18%) developed metastases, 4 needed salvage cystectomy, 3 salvage chemoradiation; 16 (73%) remained metastasis-free with an intact bladder. Across both trials (RETAIN-1/2), 274 ctDNA timepoints from 111 pts were analyzed. Baseline and post-tx ctDNA positivity were 42.2% and 13.6%, respectively. Among baseline positives, 72.7% (32/44) cleared ctDNA. Pts who were ctDNA-negative post-tx or cleared ctDNA (from baseline positive) had markedly lower recurrence risk than those who with post-tx ctDNA-positive or non-clearers (recurrence rates: 34.8% and 43.8% for negative/clearance vs 85.7% and 91.7% for positivity/non-clearance; p < 0.001 and p < 0.01, respectively). Among AS pts who were ctDNA-negative post-tx, the 12-/24-mo MFS was 97.1%/82.4%, indicating strong prediction of metastatic control. However, the 12-/24-mo recurrence-free survival (RFS) was 62.9%/50.7%, driven largely by local recurrences. Of 22 AS pts who recurred, 19 were ctDNA negative post-tx. Only 3 AS pts were ctDNA-positive. Conclusions: RETAIN-2 is expected to meet its primary endpoint of 2-yr MFS. While post-tx ctDNA negativity predicted metastatic control, it did not reliably predict local-only recurrences among AS pts. This limitation may reflect the field effect characteristic of bladder cancer or simply the poor sensitivity of plasma ctDNA for detecting minimal residual disease confined to the bladder. Future bladder-sparing strategies may benefit from integrating response-adapted selection with serial ctDNA and urine tumor DNA monitoring. Clinical trial information: NCT04506554 .

Bleeding risk with concurrent anticoagulation and VEGF-TKI therapy in mRCC: A real-world TriNetX analysis.

485 Background: Metastatic renal cell carcinoma (mRCC) is associated with both thromboembolic and hemorrhagic complications. VEGF-targeted tyrosine kinase inhibitors (TKIs); cabozantinib, lenvatinib, axitinib, and sunitinib are standard therapies, but their anti-angiogenic effects may heighten bleeding risk, particularly when combined with anticoagulants. Evidence guiding anticoagulation in this setting is limited, and clinical decisions remain challenging. We conducted a real-world analysis to evaluate bleeding risk with concurrent anticoagulation and VEGF-TKI therapy in mRCC. Methods: Using the TriNetX platform, we identified adults (≥18 years) with mRCC treated with cabozantinib, lenvatinib, axitinib, or sunitinib. Patients were grouped by anticoagulant use (rivaroxaban, apixaban, or warfarin) within 7 days before to 30 days after TKI initiation. Individuals who died before index were excluded. Propensity score matching (1:1) was applied for age and comorbidities. Bleeding events were assessed up to 1 year post-initiation; survival was analyzed up to 3 years. Results: After propensity matching: Lenvatinib: 132 patients per group; bleeding 25.0% vs 14.4% (RD 10.6%, p=0.03; RR 1.74, 95% CI 1.04–2.89); Axitinib: 284 per group; bleeding 20.4% vs 11.6% (RD 8.8%, p=0.004; RR 1.76, 95% CI 1.19–2.61); Sunitinib: 119 per group; bleeding 26.9% vs 9.3% (RD 17.7%, p=0.0004; RR 2.91, 95% CI 1.54–5.50); Cabozantinib: 470 per group; bleeding 18.1% vs 13.8% (RD 4.3%, p=0.07; RR 1.31, 95% CI 0.97–1.76). Bleeding was predominantly gastrointestinal; intracranial hemorrhage was rare. Survival was worse with anticoagulant use for lenvatinib (50% vs 37.1%, p=0.0348) and cabozantinib (53.96% vs 46.04%, p=0.0155); axitinib and sunitinib showed no significant survival differences. Conclusions: Concurrent anticoagulation with VEGF-TKIs in mRCC increases bleeding risk, particularly with sunitinib and axitinib, and to a lesser extent lenvatinib. Cabozantinib showed a non-significant trend. Most bleeding events were gastrointestinal. Survival was poorer among anticoagulant users on lenvatinib and cabozantinib. Clinicians should carefully weigh thrombosis prevention against bleeding risk and monitor closely. Personalized decision-making is essential in this high-risk population.

Ultra-sensitive whole-genome sequencing-based molecular residual disease detection in resectable renal cell carcinoma: Preliminary results from the MONSTAR-SCREEN-3 study.

421 Background: Circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) detection has shown promise across various malignancies, yet limited data exist for renal cell carcinoma (RCC), a traditionally low-shedding tumor type. Whole-exome sequencing (WES)-based approaches often lack sufficient sensitivity for effective MRD surveillance in RCC. The prospective, multicenter MONSTAR-SCREEN-3 study evaluates an ultra-sensitive whole-genome sequencing (WGS)-based MRD assay in patients with resectable solid tumors undergoing curative-intent therapy. Here, we report preliminary results from patients with resectable RCC enrolled in the definitive cohort (target n=1,100). Methods: Personalized ctDNA panels were generated using a WGS-based tumor-informed platform (Myriad Genetics), incorporating up to 1,000 tumor-specific variants identified through WGS of matched tumor tissue. Serial plasma samples were collected at baseline, 1 month post-surgery, quarterly during the first year, and biannually thereafter for up to two years. Results: As of September 2025, 30 patients with resectable RCC were enrolled; MRD results were available for 54 samples from 16 patients. Median age was 68 years (range: 41-88), with male predominance (87.5%). Clinical staging distribution included Stage I (6.3%), Stage II (6.3%), and Stage III (87.5%). All patients underwent upfront radical nephrectomy. Personalized panel creation succeeded in 100% of patients (16/16), identifying a median of 4,054 highly confident tumor-specific alterations per patient (range: 902-7712), yielding bespoke panels containing 518-1,000 alterations. The assay demonstrated 100% baseline ctDNA detection (16/16), with 56.3% (9/16) detected at ultra-sensitive levels (tumor fraction <100 parts per million [ppm]; minimum detection: 12.0 ppm). Post-surgical MRD positivity rates were 13.3% (2/15) at 1 month, 15.4% (2/13) at 3 months, and 10.0% (1/10) at 6 months. Among 16 evaluable patients, one developed radiographic recurrence, with MRD detection preceding imaging by 4.4 months. Extended follow-up and comprehensive longitudinal ctDNA dynamics will be presented. Conclusions: The WGS-based personalized ctDNA assay achieved high technical feasibility in RCC, with over half of patients demonstrating baseline ctDNA detection below 100 ppm, highlighting the critical importance of ultra-sensitive platforms for low-shedding tumors like RCC. Early data suggest potential clinical utility for recurrence surveillance. Updated molecular correlates and clinical outcomes will be presented.

Maintenance zanzalintinib with oral etoposide following high-dose chemotherapy in patients with relapsed metastatic germ-cell tumor (GCT).

TPS626 Background: While most patients (pts) with metastatic GCTs are cured with first line cisplatin-based chemotherapy, 20-30% relapse after treatment. In pts that relapse, many are still cured with second or third-line chemotherapy. High-dose chemotherapy (HDCT) with peripheral blood stem-cell transplant (PBSCT) remains a standard in the salvage setting. Maintenance chemotherapy after salvage therapy has been evaluated to improve cure rates. In a retrospective series, oral etoposide after HDCT and PBSCT improved PFS compared to observation alone. A randomized prospective trial of daily oral etoposide for 3 months vs observation after HDCT is ongoing. Testicular cancer has also been shown to have a higher expression of VEGF than non-neoplastic testis and an overexpression of c-MET. Zanzalintinib is an oral TKI with multiple targets including MET, VEGFR2 and the TAM receptors (Tyro3, AXL and MER) with a shorter half-life, likely improving tolerability and allowing it to be combined with oral maintenance chemotherapy options. Based on this, we proposed a phase I/II trial investigating the use of the combination of zanzalintinib with oral etoposide as maintenance therapy for pts w/ relapsed GCTs post-HDCT with PBSCT, with a safety lead-in cohort. Methods: This is an open label, single arm phase I/II trial of maintenance zanzalintinib in combination with oral etoposide in pts with relapsed GCT treated with HDCT and PBSCT with a safety lead-in cohort in pts with relapsed, refractory metastatic GCT. In the safety lead-in cohort, eligible pts are adult men and women with GCT that have progressed after first-line cisplatin-based combination chemotherapy in addition to at least 1 salvage regimen and are considered incurable with standard therapies. Nine pts will initially be enrolled, and zanzalintinib will be administered at 40 mg daily in combination with daily oral etoposide at 50 mg daily. Bayesian Optimal Interval (BOIN) design will be used to determine the recommended phase II dose (RP2D) of zanzalinitib based on Dose Limiting Toxicities (DLT). The DLT window will be 28 days from cycle 1, day 1. After the safety lead-in, the primary endpoint will be 1-year PFS for pts treated with the combination after HDCT with PBSCT. In phase II, we plan to enroll 29 pts after HDCT with PBSCT within 16 weeks and treat with zanzalinitib at RP2D daily in combination with oral etoposide at 50 mg daily for 3 months. Secondary outcomes include 12-month OS and safety and tolerability of maintenance zanzalintinib in combination with oral etoposide. Exploratory evaluation of next generation sequencing (NGS) at time of enrollment will be performed and its correlation with PFS and OS will be evaluated as part of our exploratory objective. This study is currently enrolling patients. Clinical trial information: NCT06937866 .

Observation of Dislocation Bound States and Skin Effects in Non‐Hermitian Chern Insulators

ABSTRACT The confluence of non‐Hermitian (NH) topology and crystal defects has culminated in significant interest, yet its experimental exploration has been limited due to the challenges involved in design and measurements. Here, we showcase experimental observation of NH dislocation bound states (NHDS) and the dislocation‐induced NH skin effect in 2D acoustic NH Chern lattices. By embedding an edge dislocations‐antidislocation pair in such acoustic lattices and implementing precision‐controlled hopping and onsite gain/loss via active meta‐atoms, we reveal robust defect‐bound states localized at dislocation cores within the line gap of the complex energy spectrum. We experimentally identify the emergence of bulk exceptional points (EPs) via spectral coalescence and phase rigidity analysis. We demonstrate that the NHDS survive against moderate NH perturbations but gradually delocalize and merge with the bulk (skin) states driven by these EPs under periodic (open) boundary conditions. Furthermore, our experiments demonstrate that the dislocation core can feature weak NH skin effects when its direction is perpendicular to the Burgers vector in periodic systems. Our findings, therefore, pave an experimental pathway for probing NH topology via lattice defects and open new avenues for defect‐engineered topological devices.