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Chidamide combined with serplulimab and regorafenib or fruquintinib as third-line therapy for advanced colorectal cancer (C-ooperate/SCOG-C001): A single-arm, exploratory, multicenter, phase 2 trial.

e15583 Background: Despite established first- and second-line standards with chemotherapy plus anti-VEGF or anti-EGFR agents, third-line options remain limited in colorectal cancer (CRC). Subtype-selective histone deacetylase (HDAC) inhibition may enhance tumor immunogenicity, supporting synergy with PD-1 inhibition plus VEGF-pathway blockade. We therefore conducted a proof-of-concept, single-arm, phase II trial evaluating chidamide plus serplulimab with regorafenib or fruquintinib as third-line therapy for advanced CRC; preliminary findings are presented. Methods: This single-arm, phase Ⅱ study (ChiCTR2300077213) enrolled adults (≥18 years) with pathologically confirmed CRC, ECOG performance status 0-1, measurable disease per iRECIST, and progression after ≥2 lines of systemic therapy. Patients(pts) received chidamide 20 mg orally twice weekly and serplulimab 3 mg/kg intravenously every two weeks, combined with either regorafenib 120 mg or fruquintinib 5 mg orally once daily for three weeks followed by one week off. Treatment continued until disease progression, intolerable toxicity, withdrawal of consent, or up to 2 years. The primary endpoints were safety and objective response rate (ORR) determined by investigators. Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), PFS and OS rates at 6- and 12-month, quality of life (QoL), and nutritional score PG-SGA. Results: As of Jan 6, 2026, thirty pts had been enrolled, with a median age of 62.0 years. Most pts had a left-sided primary tumor (86.7%), and all were pMMR/MSS. Liver metastases were present in 22 pts (73.3%) and lung metastases in 13 pts (43.3%). Previous treatment lines ranged from 2 to 4, with 33.3% pts having received more than third-line treatment before. The incidence of ≥3 grade adverse events was 53.3% (n = 16). A total of 26 patients were evaluable for efficacy analysis at a median follow-up of 11.9 months. The ORR was 11.5% (95% CI: 2.4-30.2%) and DCR was 42.3% (95% CI: 23.4-63.1%), including 3 pts achieved partial response and 8 achieved stable disease. The median PFS was 3.0 months (95% CI: 2.3-5.9), and the 6-month PFS rate was 20.5% (95% CI: 9.1-46.3%). The median OS was 7.7 months (95% CI: 5.5-NA), with a 6-month OS rate of 65.9% (95% CI: 49.2-88.4%). Conclusions: Preliminary results indicated that chidamide plus serplulimab with regorafenib or fruquintinib is a feasible and promising third-line treatment option for advanced CRC, alongside manageable toxicity. Clinical trial information: ChiCTR2300077213.

Efficacy and safety of transarterial chemoembolization combined with donafenib for hepatocellular carcinoma with rupture and bleeding: A retrospective, cohort study.

4107 Background: The incidence of hepatocellular carcinoma (HCC) ranks 6th in the world, and rupture and bleeding of HCC is its fatal complication. Transarterial chemoembolization (TACE) is an effective measure for acute hemostasis, but the prognosis of TACE alone is limited. The ZGDH3 study showed that donafenib was the only targeted agent with better overall survival (OS) than sorafenib in monotherapy for HCC. This study aims to investigate the efficacy and safety of TACE combined with donafenib compared with TACE monotherapy in the treatment of HCC with rupture and bleeding. Methods: This study retrospectively analyzed patients with rupture and bleeding of HCC who received TACE combined with donafenib or TACE monotherapy in Qinghai University Affiliated Hospital from January 2022 to August 2024. Patient criteria for inclusion: (1) Definitive diagnosis of HCC with rupture and bleeding by imaging and laboratory examination; (2) Child-Pugh class A and B; (3) No previous systemic therapy. The efficacy and safety were evaluated by mRECIST and CTCAE 5.0. Results: A total of 62 patients were included in the study, of whom 35 in the TACE monotherapy group and 27 in the TACE plus donafinib group, and there was no significant difference in baseline characteristics between the two groups. Patients in TACE plus donafenib group demonstrated a significantly higher objective response rate (ORR) compared with TACE monotherapy group (55.6%vs 25.7%, P=0.008). The median progression-free survival (PFS) significantly better than TACE monotherapy group (13.6 months [95%CI: 4.354 - 22.846] vs 4.6 months [95% CI: 1.637 - 7.563]; HR=0.404, P=0.003). The median OS was longer in the TACE plus donafenib group compared to TACE monotherapy group (17.4 months [95%CI: 8.478 - 26.322] vs 7.6 months [95%CI: 1.301 - 13.899]; HR=0.479, P=0.012). Additionally, multivariate COX regression analysis showed that PVTT, Child-Pugh grade, tumor diameter and total bilirubin were independent prognostic factors for OS. The incidence of treatment-related adverse events (TRAEs) significantly higher in TACE plus donafenib group, the most common were skin-related adverse events (37% vs 0%), diarrhea (29.6% vs 0%) and alopecia (18.5% vs 0%), which can be controlled by symptomatic treatment. There were no grade ≥3 TRAEs. But there was no significant difference in the incidence of rebleeding, stomachache and fever. Conclusions: TACE combined with donafenib showed significant efficacy and controllable safety in HCC with rupture and bleeding.

Association between selective serotonin reuptake inhibitor use and outcomes in metastatic melanoma treated with immune checkpoint inhibitors: A real-world cohort study.

11188 Background: Immune checkpoint inhibitors (ICIs) have transformed outcomes for metastatic melanoma, yet substantial variability in response remains. Evidence suggests that concomitant medications may modulate antitumor immunity and influence ICI effectiveness. For example, recent mechanistic and translational studies indicate that selective serotonin reuptake inhibitors (SSRIs) enhance T-cell–mediated antitumor immunity and may synergize with PD-1 blockade, with preliminary clinical signals of improved survival. However, real-world evidence in melanoma is limited. We conducted a real-world cohort study to assess the association between baseline SSRI use and outcomes among metastatic melanoma patients treated with ICIs. Methods: We performed a retrospective cohort study using a nationally representative real-world dataset from the Atropos Evidence Network integrating open claims and EHR data mapped to OMOP CDM v5.3. Adults with metastatic melanoma treated with first-line pembrolizumab, nivolumab, or ipilimumab were identified using ICD and RxNorm codes. The index date was ICI initiation. The SSRI cohort required ≥30 days of use prior to index; comparators had no prior SSRI exposure. Patients were matched 1:1 using high-dimensional propensity scores (hdPS) derived from ICD, CPT, and RxNorm features and fitted with LASSO-regularized logistic regression. Outcomes included 1-year overall survival (OS), time to ICI discontinuation, ICI duration, and post-index steroid use. Results: Among 3,597 metastatic melanoma patients initiating ICIs, 307 had baseline SSRI exposure and 3,290 had no prior SSRI use. After 1:1 hdPS matching, 304 well-balanced pairs were identified. Baseline SSRI use was associated with a numerically lower but not statistically significant risk of death at 1 year (HR 0.70; 95% CI 0.46–1.06; p = 0.092). No significant difference in ICI discontinuation was observed between cohorts (HR 1.07; 95% CI 0.87–1.31; p = 0.53). Mean duration of ICI was similar in the propensity-matched analysis (158.7 days in no-SSRI vs 142.4 days in SSRI; mean difference −16 days; 95% CI −40 to 7.3; p = 0.175). Post-index steroid use also did not differ between groups (IRR 1.02; 95% CI 0.60–1.73; p = 0.94). Across all endpoints, effect estimates were consistent with no clinically meaningful association between baseline SSRI exposure and immunotherapy outcomes. Conclusions: In this large real-world analysis, baseline SSRI use was not associated with improved OS, reduced discontinuation, or increased steroid use among metastatic melanoma patients treated with ICIs. Despite strong mechanistic rationale suggesting potential synergy, these findings highlight a disconnect between preclinical observations and real-world outcomes. Prospective studies are needed to identify subpopulations that may benefit.

ctDNA for monitoring disease status in HPV-negative head and neck cancer in an underserved population.

e18035 Background: Head and neck squamous cell carcinoma (HNSCC) is clinically heterogeneous with significant morbidity and mortality, particularly in medically underserved populations. Circulating tumor DNA (ctDNA) is a non-invasive biomarker for disease monitoring and minimal residual disease detection. We evaluated a personalized, tumor-informed ctDNA assay in HNSCC patients at an urban, academic medical center. Methods: This single-institution retrospective study included patients with HPV negative HNSCC who underwent ctDNA testing during routine clinical care. The objective was to correlate ctDNA detectability and post-treatment changes with clinical outcomes. A personalized tumor-informed multiplex PCR next-generation sequencing assay was utilized for ctDNA detection. Demographic, clinical, and treatment variables were abstracted from medical records. Disease response was determined through radiographic and clinical assessments. Results: The study included 33 patients (median age 60 years; 70% male). The cohort was racially diverse: 33% Black, 24% Hispanic, 18% White, and 15% Asian. Primary sites included oral cavity (n=19), larynx (n=6), hypopharynx (n=3), and oropharynx (n=3). Most patients presented with advanced disease (Stage IVC, n=24; Stage IVB, n=6). Seven patients were excluded due to insufficient sample quality or incomplete documentation. Among the remaining patients, 80% (21/26) had detectable ctDNA. Serial testing was performed in seven patients. Two patients with initially negative tests developed positive results correlating with disease recurrence. Five patients had positive baseline testing; repeat testing after therapy showed decreased or undetectable levels. Of these, one had a significant response, two had stable disease, one had a mixed response, and one had disease progression despite ctDNA decrease. Conclusions: ctDNA may complement radiographic and clinical assessment in HNSCC by providing sensitive molecular response data. In this cohort, serial assays paralleled recurrence in some cases, though a post-treatment decrease did not always correlate with clear overall imaging response in minor percentage of cases. Further research is warranted to validate ctDNA utility in diverse HNSCC populations.

PD-L1 score: Tool effectiveness in non-small cell lung cancer.

e20594 Background: Programmed death (and ligand)-1 (PD-(L)1) inhibitors are standard of care for treatment of non-small cell lung cancer (NSCLC). There are four FDA approved PD1 immunohistochemistry (IHC) assays used to measure expression on tumor (TC) and immune cells. Prior studies note discordance in expression across assays with unclear clinical significance. It remains poorly understood whether PD-L1 scoring assays adequately predict response to immunotherapy (IO). Methods: We conducted a retrospective study to investigate discordance in PD-L1 IHC scores among patients with NSCLC. Pathology samples were obtained from patients diagnosed at TJUH between 2019-2022. All samples were stained for PD-L1 IHC using two FDA approved assays, Ventana SP142 and Ventana SP263. PD-L1 expression was categorized as < 1%, 1-49% and > 50%. Patients with assay results in different expression categories were discordant, while patients with assay expression in the same categories were concordant. Patients with concordant PD-L1 scores served as a comparator group. The influence of PD-L1 discordance on treatment was determined by treating physician documentation indicating assay results impacted therapy choice. Descriptive statistics were used to describe demographic and clinical characteristics. Kaplan-Meier curves were used to analyze overall survival (OS) and progression free survival (PFS). Results: Of 133 patients, 107 had discordant assays and 26 were concordant. There were no significant differences between groups with respect to race, stage, or histologic subtype. Median age at diagnosis was 66 vs 70 years (control vs discordant, p = 0.04). Discordant patients were largely female (56%) and concordant patients were largely male (65%, p = 0.011). Most patients presented with stage IV disease (64% discordant vs 56% concordant). Targetable mutations were more frequent in the discordant group (30% vs 3.8%, p = 0.005), predominately EGFR (17.8%). Among discordant patients Ventana SP142 assay scores were all < 50%, while Ventana SP263 assay scores were > 50%. There was no significant difference in IO use or toxicity between cohorts. Discordance in PD-L1 score influenced treatment choice in 26% of patients (p = 0.002). This remained significant after excluding patients eligible for frontline targeted therapy (30.7%, p = 0.001). In both groups, treatment choice remained largely guideline directed (72% concordant vs 67% discordant p = 0.8). Discordance did not significantly impact PFS or OS. Conclusions: Findings confirm higher rates of PD-L1 discordance in patients with targetable mutations, particularly EGFR. Among discordant patients Ventana SP142 scores were all less than 50%, consistent with prior studies showing reduced and discordant TC staining with this assay due to lower sensitivity. While discordance influenced frontline therapy choice, there was no significant impact on clinical outcomes, suggesting PD-L1 is not an optimal predictive marker.

TME-informed bioprinted 3D tissue model as used to characterize architecture-associated drug uptake and response in PDAC.

4220 Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumors despite extensive drug development efforts. Beyond tumor cell-intrinsic factors, therapeutic failure in PDAC is strongly influenced by the tumor microenvironment (TME), which is dominated by a collagen-rich desmoplastic extracellular matrix (ECM). This architecture alters tissue mechanics, restricts diffusion, and limits effective drug delivery to tumor cells. However, most preclinical platforms rely on 2D models that fail to capture human-relevant TME architecture, potentially leading to overestimation of drug uptake and potency. Amid growing regulatory and scientific momentum toward New Approach Methods (NAMs), there is an urgent need for human-relevant, architecture-aware models that improve translational predictivity in PDAC. Methods: Primary human PDAC specimens were analyzed using quantitative, spatially resolved TME mapping to characterize extracellular matrix (ECM) composition, collagen density, and intratumoral versus peripheral distribution. From our prior PDAC analysis, human tumors exhibited collagen-dominant ECM with diffuse intratumoral organization rather than peripheral confinement. These architectural features were used to configure a 3D bioprinted ex vivo slice tissue (BEST) PDAC model using PANC02 cells. Drug uptake kinetics and therapeutic response were evaluated in TME-informed 3D BEST models and directly compared with conventional 2D monolayer cultures using matched compounds and exposure paradigms. Results: Spatial TME mapping confirmed that human PDAC tumors harbor dense, heterogeneously distributed collagen spanning the tumor parenchyma, a feature not captured by simplified culture systems. Incorporation of these intratumoral collagen features into the 3D BEST model resulted in delayed drug uptake and attenuated response dynamics consistent with diffusion-limited transport. In contrast, 2D models demonstrated accelerated growth kinetics, more rapid drug uptake, and higher apparent drug potency over shorter exposure durations. These findings indicate that architecture-associated transport barriers intrinsic to PDAC substantially modulate therapeutic response and that conventional 2D systems may overestimate drug efficacy by failing to account for collagen-mediated resistance mechanisms. Conclusions: By directly linking quantitative TME mapping to 3D model configuration, this NAMs-aligned bioprinted PDAC platform captures architecture-associated constraints on drug uptake that are absent from conventional models. This approach provides a human-relevant framework for evaluating therapeutic response in desmoplastic tumors and supports improved translational fidelity and therapeutic prioritization in PDAC.

Precision DC: Personalized neoantigen dendritic cell vaccine pilot trial for high-risk triple-negative breast cancer after neoadjuvant therapy.

TPS643 Background: Treatment for stage II-III triple negative breast cancer (TNBC) uses neoadjuvant chemoimmunotherapy (NCT) with the goal of achieving pathologic complete responses. TNBC patients with significant residual cancer burdens (RCB II/III) after NCT have a high risk of early relapse/death despite use of adjuvant therapies like capecitabine. Moffitt Cancer Center's breast program uses a highly immunogenic dendritic cell vaccine platform (DC1) against HER2 overexpressing tumors in previous studies demonstrating anti-tumor efficacy (Han, JAMA Onc 2025). TNBC often has multiple somatic mutations leading to expression of altered immunogenic proteins known as neoantigens. We hypothesize that the residual primary TNBC after NCT can be sequenced to identify the most immunogenic neoantigens and include them as targets in an adjuvant DC1 vaccine to stimulate cytotoxic T cell responses that eliminate residual micrometastatic disease. The PRECISION DC trial was initiated to study the feasibility of adjuvant neoantigen DC1 vaccines for high risk TNBC. Correlatives include immune response to neoantigens using ELISPOT and immunopeptidomics to study processing of peptides by the dendritic cells (NCT06435351). Methods: PRECISION DC is a single-arm pilot study open at the Moffitt Cancer Center enrolling stage II-III TNBC patients with RCB II/III disease and who are within 18 months of their last dose of KEYNOTE-522 chemotherapy without known metastatic disease. Eligible patients will have their residual tumor tissue whole exome sequenced, and mutated 25 mer long peptides are analyzed using a modified NetMHCII pipeline to rank these mutations based on a combined score representing multiple factors including expression, predicted MHC binding, and agretopicity. The top ten scoring peptides that also pass a peptide synthesis screen for excessive hydrophobicity are selected for inclusion in each patient’s personalized DC1 vaccine. The relevant peptides for each patient are used to stimulate pheresed autologous dendritic cells ex-vivo. Moffitt’s GMP cell therapy facility creates cryopreserved aliquots of 50 million cells to create DC1 vaccine doses. Patients get three intranodal DC1 inguinal injections q2weeks under ultrasound guidance in the priming phase and then two booster shots at 6 and 12 months either before or after adjuvant capecitabine (if given) per treating physician guidance. PRECISION DC opened 10/2024 and accrual to date is 22/26 planned patients with 4 remaining patients already identified. Primary endpoint is feasibility (% pts with successful vaccine administration w/ goal > 60%); secondary endpoints include safety, immune responses, and 5-year disease-free outcomes. If successful, PRECISION DC will set the stage for a prospective randomized trial of personalized autologous DC1 neoantigen vaccines to prevent recurrence of residual TNBC following NCT. Clinical trial information: NCT06435351 .

GLP-1 receptor agonists vs 5-alpha reductase inhibitors for prostate cancer primary prevention in high-risk men: A real-world head-to-head comparison.

e17134 Background: Despite being the most prevalent malignancy among men, prostate cancer (PC) lacks FDA-approved primary prevention therapies. Current options, such as 5-alpha reductase inhibitors (5-ARIs), offer only modest risk reduction—approximately 23–25%—as shown in the PCPT and REDUCE trials. Emerging preclinical data indicate that GLP-1 receptor agonists (GLP-1RAs) may offer a novel alternative by inhibiting oncogenic pathways and inducing apoptosis in PC cell lines. To investigate this potential, we conducted the first real-world comparative analysis of PC incidence among high-risk men receiving GLP-1RAs versus 5-ARIs. Methods: Using the TriNetX global collaborative network (150M patients), we identified men with elevated PC risk (genetic risk, family history, or high-risk demographics/comorbidities). GLP-1RA users (cohort A) were propensity-score-matched 1:1 with 5-ARI users (cohort B) on demographics, metabolic comorbidities, baseline PSA, BMI and HbA1c. A minimum of 2 month’s prescription was required. The primary endpoint was incident PC. The secondary endpoint was adverse events related to GLP-1RA and 5-ARI. Patients with outcomes before the study inclusion were excluded. Sensitivity and subgroup analyses were performed, adjusting for screening frequency and baseline BMI. Kaplan–Meier curves assessed cumulative incidence, Cox models estimated hazard ratios (HRs, 95% CI), and logistic regression analyzed binary outcomes. Results: After matching, 118,904 high-risk men were identified (59,452 patients per cohort). Cohorts had comparable demographics with a mean age of 48 years, 77% White, 9% Black, and 2% Asian. GLP-1RA users had higher mean A1C (6.3% vs 5.7%) and BMI (38 vs 31), while 5-ARI users had higher mean PSA (3.1 vs 1.3). Median follow-up was 7 years for both cohorts. PC incidence was 2.10% (1,245/59,189) in GLP-1RAs users versus 2.85% (1,689/59,164) in 5-ARI users (NNT 133). GLP-1RAs were associated with a 20% reduction in PC risk (HR: 0.803; CI: 0.746–0.864). Safety outcomes showed that GLP-1RAs were associated with an increased risk of erectile dysfunction and nausea/vomiting. In contrast, GLP-1RAs were associated with lower risks of abdominal pain and constipation. No significant associations were observed for gynecomastia or diarrhea. Conclusions: In this large-scale, head-to-head comparison, GLP-1RAs demonstrated superior efficacy over 5-ARIs, providing a 20% relative risk reduction in PC incidence among high-risk men. Given the global surge in GLP-1RA utilization, these findings suggest a profound public health opportunity: the ability to achieve systemic oncologic protection through existing metabolic therapies. If validated by prospective trials, GLP-1RAs could transition from metabolic blockbusters to a cornerstone of precision oncology and primary cancer prevention.

Association of baseline vitamin D levels with survival and disease control in diffuse large B-cell lymphoma: A meta-analysis.

e19082 Background: Vitamin D enhances antibody-dependent cellular cytotoxicity, a key mechanism underlying anti-CD20 monoclonal antibody activity in diffuse large B-cell lymphoma (DLBCL). Prior studies suggest that baseline vitamin D deficiency may be associated with inferior outcomes, but the magnitude and consistency of this association remain incompletely defined. We performed a systematic review and meta-analysis to quantify the prognostic impact of baseline vitamin D deficiency on survival and disease control outcomes in DLBCL and related large B-cell lymphomas. Methods: PubMed, Embase, and Web of Science were searched through 2025 for studies reporting associations between baseline serum 25-hydroxyvitamin D levels and outcomes in DLBCL or large B-cell lymphoma. Eligible studies reported hazard ratios (HRs) for overall survival (OS), event-free survival (EFS), progression-free survival (PFS), or lymphoma-specific survival (LSS), comparing low versus higher vitamin D levels. Random-effects meta-analyses were performed using the generic inverse-variance method. Heterogeneity was assessed using the I² statistic. Results: Eleven studies comprising 2,218 patients were included. Baseline vitamin D deficiency was significantly associated with inferior disease control (EFS, PFS, and LSS), with a pooled HR of 1.97 (95% CI: 1.57–2.47; p < 0.0001) and moderate heterogeneity (I² = 41.6%). In the analysis of overall survival across nine studies, vitamin D deficiency was strongly associated with worse OS, with a pooled HR of 2.33 (95% CI: 1.89–2.87; p < 0.0001). Heterogeneity for OS was negligible (I² = 0%), indicating highly consistent effects across cohorts. The adverse prognostic association was most pronounced in patients treated with rituximab-containing immunochemotherapy. Conclusions: Baseline vitamin D deficiency is associated with significantly inferior overall survival and disease control in DLBCL and related large B-cell lymphomas, with approximately a two-fold increased risk of death and progression or relapse. These findings support baseline vitamin D status as a readily measurable prognostic biomarker and provide strong rationale for prospective interventional trials to determine whether correction of vitamin D deficiency can improve outcomes.

Impact of FES-PET imaging in the management of estrogen receptor–positive breast cancer: Real-world experience.

1080 Background: F18 labeled estradiol PET imaging (FES-PET) is endorsed by NCCN guidelines to identify advanced/recurrent estrogen receptor positive (ER+) breast cancer, especially invasive lobular disease. As an adjunct to conventional imaging, FES-PET may provide information about estrogen dependence in lesions that are not readily biopsied. We reviewed the use of FES-PET imaging at City of Hope, Southern California and how it impacted treatment. Methods: This is a retrospective chart review study of pts undergoing FES-PET imaging in the management of ER+ breast cancer. Demographic data, indications for FES-PET imaging, and impact on subsequent care were extracted from the electronic medical record. Results: Between 1/21/22 and 12/31/25, 191 patients with a median age of 52 (Range 32-89) underwent an initial FES-PET scan at City of Hope and its Southern California Network. All had a diagnosis of estrogen receptor + (ER+) breast cancer; 124 were Invasive Ductal Carcinoma (IDC), 59 Invasive Lobular Carcinoma (ILC), 7 mixed IDC with ILC features, and 1 adenocarcinoma. FES-PET was used to stage “high-risk” local disease in 85, 76 continued their initial treatment plan, 8 were found to have metastatic disease, and 1 underwent additional surgical resection for residual disease in the breast. Of 102 pts. with metastatic disease, 58 were FES positive; 44/50 responded to endocrine therapy, 7 received chemotherapy and 1 refused treatment; 44 were FES negative and 23 received chemotherapy, 10 had no response to endocrine therapy, and 11 received no further treatment. Four patients had synchronous primary tumors and FES was used to distinguish lesions that were attributable to breast cancer. Of the patients with metastatic FES+ disease, 33 underwent serial FES-PET imaging; 3 were part of a clinical trial assessing radiation therapy in oligometastatic disease, 3 had been on prolonged treatment with chemotherapy and FES-PET was obtained to assess potential for reintroduction of endocrine therapy, 27 had response evaluation to aromatase inhibitor therapy where conventional staging did not adequately assess the measurable/evaluable disease as well as FES-PET. Conclusions: Our data support the use of FES-PET which altered treatment in 11% of patients with high-risk localized and identified patients for whom chemotherapy was the appropriate choice of systemic therapy. In select pts, serial FES-PET imaging was more helpful in monitoring disease response to AI-based therapy than conventional imaging and should be considered in future guideline recommendations.

Feasibility and safety results from RAD-IO: A multi-stage trial of durvalumab with chemoradiotherapy with 5-fluorouracil and mitomycin C in patients with muscle-invasive bladder cancer.

4504 Background: Immune checkpoint inhibitors have a defined role peri-operatively and in the adjuvant setting when cystectomy is used as radical definitive treatment (Powles, T., et al. 2024, Galsky, M. D., et al. 2024). Their role when chemoradiation therapy (CRT) is used as definitive treatment remains to be established. RADIO is a multi-stage partially randomised trial comparing CRT (RT/5FU/mitomycin C) with durvalumab (CRT-D) given prior to, concurrently and 12 months following CRT in localized muscle-invasive bladder cancer. The trial is funded by AstraZeneca. Methods: Eligible patients had T2–T4aN0–N2M0 urothelial carcinoma of the bladder. Neoadjuvant chemotherapy was delivered as standard of care, where fit, prior to trial therapy. After randomised feasibility and safety criteria were met, the trial transitioned to a single-arm CRT-D design. Here we report the primary endpoint of 1-year disease-free survival rate (1yDFS) for all evaluable CRT-D participants, plus progression free survival (PFS), disease free survival (DFS), and overall survival (OS). DFS patients with disease present at 3-month imaging are categorised as having never been disease free. The design aimed to detect 1yDFS improvement, based on our previous trials, from 60% (CRT) to 75% (CRT-D) with 80% power and one-sided α=0.10. Results: All data are preliminary. Between Oct 2020–Mar 2024, 55 participants (45 male; 10 female) with median age 70 (IQR 62-76) years of whom 40 (73%) had T2N0, 8 (14%) had T3N0 and 7 (13%) had TxN1-2 were enrolled to receive CRT-D. 41 (74.5%) received neoadjuvant CT. Of the 54 participants who started treatment, all completed planned RT (55Gy/20Fr); 47 (87%) within the expected timeframe, 7 (13%) required an extension (2-6 days) (toxicity 3, patient choice 3, other 1). Toxicities extending RT: urinary tract infection, chest pain, and low platelets. At abstract submission, 48/55 were evaluable: 1yDFS 79% (38/18; 95% CI 66%, 88%). 12-month Kaplan-Meier estimates were: PFS 83% (95% CI 73%, 94%), DFS 72% (95% CI 61%, 85%), OS 96% (95% CI 91%, 100%). Safety: 35 SAEs; 17 unrelated SAEs, 12 SARs, 6 SUSARs. 10 SAEs were related to durvalumab, 3 were related to CT, and 5 were related to both durvalumab and CT. 3 SAEs led to discontinuation (5FU 2, durvalumab 1). 168 AESIs have been reported (most common: diarrhoea (19%), rash (12%), creatinine increased (8%)), and an additional 41 grade ≥3 AEs. Conclusions: Durvalumab combined with CRT demonstrated promising 1-year DFS and survival outcomes compared to our previously reported CRT outcomes (Hall, E., et al , 2022) with manageable safety profile. CRT-D is a safe treatment with a side effect profile in keeping with known side effects of CRT and durvalumab. Further investigation is warranted. Clinical trial information: 43698103.

Treatment modality and anatomic site as determinants of mortality in second primary cancers after head and neck cancer: A SEER analysis.

e18100 Background: Second primary malignancies (SPMs) are a major contributor to late mortality among survivors of head and neck cancer (HNC). However, the extent to which initial HNC treatment modality and the anatomic site of subsequent non-synchronous SPMs influence overall, and cancer-specific mortality remains incompletely characterized. We evaluated the independent association of prior HNC treatment and SPM site with survival outcomes in a large population-based cohort. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified adults diagnosed with primary squamous cell HNC who subsequently developed a non-synchronous SPM occurring ≥2 years after HNC diagnosis, a threshold chosen to minimize misclassification of synchronous disease and early recurrence. Modified Poisson regression with robust variance was used to estimate unadjusted and adjusted relative risks (aRRs) for overall mortality and cancer-specific mortality. Multivariable models adjusted for age at HNC diagnosis, race/ethnicity, tumor grade, latency interval, anatomic site of the SPM, and receipt of surgery, chemotherapy, and radiation for the index HNC. Results: Among 19,686 HNC survivors with non-synchronous SPMs, overall mortality occurred in 68.6% of patients, and 42.2% died from cancer-related causes. Survival outcomes varied by initial HNC treatment modality. Patients who had undergone surgical management of the index HNC had lower overall mortality (aRR 0.85, 95% CI 0.81–0.88) and cancer-specific mortality (aRR 0.91, 95% CI 0.85–0.98), whereas those treated with radiation had higher overall (aRR 1.08, 95% CI 1.06–1.11) and cancer-specific mortality (aRR 1.11, 95% CI 1.07–1.15), consistent with differences in baseline disease characteristics and treatment selection. Chemotherapy was not independently associated with cancer-specific mortality after adjustment. Marked heterogeneity in mortality risk was observed across SPM sites. Compared with second primary head and neck cancers, pancreatic (aRR 1.66), esophageal (aRR 1.53), lung (aRR 1.39), and stomach (aRR 1.27) SPMs were associated with substantially higher overall and cancer-specific mortality, whereas prostate, breast, melanoma, bladder, and kidney SPMs were associated with more favorable outcomes. Conclusions: Among survivors of head and neck cancer who develop non-synchronous second primary malignancies, long-term mortality risk varies substantially according to both initial treatment modality and the anatomic site of the subsequent cancer. These associations likely reflect underlying disease severity and biologic heterogeneity rather than treatment efficacy alone. Together, these findings highlight the importance of treatment-aware and site-specific survivorship risk assessment.

Paired Nectin4 expression analysis pre and post enfortumab vedotin and pembrolizumab in urothelial carcinoma.

4586 Background: Enfortumab vedotin and pembrolizumab (EVP) transformed the treatment of urothelial carcinoma (UC), yet resistance remains a challenge. Mechanisms of resistance including changes in target expression are poorly defined. Methods: We analyzed an institutional retrospective cohort of patients (pts) who had paired tissue samples obtained pre- and post-EVP. Membranous (mNectin4) and cytoplasmic (cNectin4) expression were measured by immunohistochemistry (H-score). mNectin4 was categorized as negative (<15), weak (15-99), moderate (100-199) or strong (200-300). Changes in Nectin4 were assessed as absolute differences (post–pre) and as scaled log change (%) [100xlog((post + c)/(pre + c))] to capture relative expression changes. Nectin4 dynamics were compared between primary (resistant disease ≤6 months from EVP initiation) and acquired resistance (>6 months) using Wilcoxon rank-sum and fisher’s exact tests. Results: Of 46 pts with paired samples, 40 had evaluable Nectin4 IHC. Median age was 72, 70% were men, and 30% had upper tract primary. Median H-scores were similar pre- and post-EVP for both mNectin4 (195 [IQR 115, 260] vs 200 [IQR 85, 230]; p=0.5) and cNectin4 (0 [IQR 0, 40] vs 0 [IQR 0, 60]; p >0.9). Post-EVP mNectin4 was moderate/strong in 29 pts (73%). Complete loss of mNectin4 was uncommon: of five pts (13%) with negative mNectin4 post-EVP, two were negative at baseline and three had weak expression pre-EVP. Post-EVP samples obtained on EV (≤21d from last dose; n=21) vs off EV (>21d; n=19) showed similar changes from pre-EVP for mNectin4 (p=0.3) and cNectin4 (p=0.4). Nectin4 changes differed by resistance pattern, with primary resistance (n = 14) showing a greater relative decrease in mNectin4 expression (median log change −57 vs 3; p = 0.035) and a relative increase in cNectin4 expression (median log change 52 vs 0; p = 0.029) compared with acquired resistance (n = 21). Paired analyses of NECTIN4 copy number by FISH will be reported. Conclusions: In a paired analysis, most tumors retained substantial mNectin4 expression post-EVP and complete loss was rare, supporting the rationale for Nectin4-targeted strategies in the post-EVP setting. Distinct Nectin4 dynamics suggest greater relevance of target expression changes in primary vs acquired resistance; further studies are needed. All*N=40 Primary resistanceN=14 Acquired resistanceN=21 p mNectin4 TrendDecreaseIncreaseStable 21 (53%)17 (43%)2 (5.0%) 10 (71%)3 (21%)1 (7.1%) 10 (48%)11 (52%)0 (0%) 0.11 Absolute change, median [IQR] -13 [-60, 45] -48 [-100, 0] 10 [-50, 55] 0.2 Log change, median [IQR] -8 [-57, 23] -57 [-195, 0] 3 [-21, 21] 0.035 cNectin4 TrendDecreaseIncreaseStable 12 (30%)14 (35%)14 (35%) 3 (21%)8 (57%)3 (21%) 8 (38%)5 (24%)8 (38%) 0.2 Absolute change, median [IQR] 0 [-28, 25] 13 [0, 100] 0 [-30, 0] 0.055 Log change, median [IQR] 0 [-137, 67] 52 [0, 304] 0 [-256, 0] 0.029 *Including 5 pts not meeting resistance definitions.

Randomized phase 2 trial of ruxolitinib in combination with radiation and temozolomide compared to radiation and temozolomide for newly diagnosed glioblastoma.

TPS2094 Background: Glioblastoma is the associated with poor outcomes despite treatment with radiation and temozolomide. Therapeutic resistance and disease recurrence are driven in part by glioma stem cell populations and activation of oncogenic signaling pathways, including the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Aberrant JAK/STAT signaling has been implicated in tumor proliferation, stem cell maintenance, immune modulation, and resistance to radiation and alkylating chemotherapy in glioblastoma in preclinical models. Ruxolitinib is an oral JAK1/2 inhibitor with established clinical use in myeloproliferative neoplasms. Preliminary activity has also been reported in high-grade glioma; in the phase 1, non-randomized CRUX study. Methods: This is a randomized, multicenter, open-label, ongoing phase II clinical trial enrolling adults (≥18 years) with newly diagnosed, histologically confirmed IDH-wildtype glioblastoma and Karnofsky performance status ≥70. Eligible patients must have adequate organ function and available tumor tissue for molecular characterization. Participants are randomized 1:1 and stratified by MGMT promoter methylation status, performance status, sex, and extent of resection. Patients assigned to the experimental arm receive oral ruxolitinib 20 mg administered twice daily in combination with standard radiation therapy (60 Gy delivered in 30 fractions) and concurrent temozolomide at 75 mg/m 2 , followed by adjuvant temozolomide at 150-200 mg/m 2 with continuous ruxolitinib at 20 mg bid. Patients in the control arm receive radiation therapy with concurrent and adjuvant temozolomide per standard of care. Treatment continues until disease progression, unacceptable toxicity, withdrawal of consent, or completion of protocol-defined therapy. The primary endpoint is overall survival (OS). Secondary endpoints include progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), and safety. Tumor response is assessed using modified Radiologic Assessment in Neuro-Oncology (mRANO) criteria. Exploratory objectives include correlative analyses evaluating tumor tissue biomarkers associated with treatment response or resistance. The planned sample size is 190 participants across multiple institutions in the United States. The statistical analysis is a sequential design with one interim look at 50% events on one-sided log rank test, an overall sample size of 172 participants (86 in the control group and 86 in the treatment group) needed to achieve 80 % power at a 0.1 significance level to detect a hazard ratio of 0.68182 when the control group median survival time is 15 months. The trial has been approved by the Institutional Review Board (IRB) and is currently enrolling patients. Clinical trial information: NCT06991101 .

Lung cancer screening in septuagenarians: Do survival benefits persist with advancing age?

e20095 Background: Low-dose CT (LDCT) for lung cancer screening (LCS) reduces lung-cancer-specific mortality in high-risk individuals and is recommended by the United States Preventive Services Task Force for adults 50-80 with significant smoking history. That said, clinical trials informing these recommendations did not enroll patients ≥75. We evaluated whether screening outcomes and survival benefits persist in older adults with high-risk screening findings. Methods: We conducted a retrospective cohort study of patients undergoing LDCT screening at a single institution between January 2019 and July 2023. Patients with Lung-RADS (Lung Imaging Reporting and Data System) category 4 findings were included. Demographics, comorbidities, staging data, procedural details, and outcome data were extracted from the health record. Biopsy and surgical complications were analyzed separately; the former including pneumothorax (PTX) and hemoptysis, and the latter including PTX, prolonged air leak, pneumonia, acute respiratory distress syndrome (ARDS), dysrhythmia, and surgical site infection. Patients were stratified by age: 65–69 (Cohort A), 70–74 (Cohort B), and ≥75 years (Cohort C). Outcomes were analyzed in RStudio (coding utilizing AI-assistance with human oversight) using regression modeling, Kaplan–Meier survival analysis, and Cox proportional hazards. Results: Among 25,571 screening examinations, 252 patients aged ≥65 with Lung-RADS 4 findings were identified: Cohort A (n = 118), Cohort B (n = 90), and Cohort C (n = 44). Demographics, comorbidities, smoking history, Lung-RADS subcategories, biopsy rates, and resection rates were similar across cohorts. Biopsy-related complications did not significantly differ by age, though patients ≥75 had higher post-resection complication rates (RR 3.19, 95% CI 1.47-6.94; p = 0.018). Overall survival (OS) at the time of administrative censoring (6.85 years from screening) differed significantly by age, with worse OS in patients ≥75 years (HR 2.43, 95% CI 1.39–4.23; p = 0.002). Lung cancer–specific survival (LCSS) and recurrence-free survival (RFS) did not differ significantly between groups (Table 1). Conclusions: Adults ≥75 undergoing LDCT for LCS with high-risk findings demonstrate LCSS and RFS similar to those of younger cohorts, despite higher postoperative complication rates and worse OS. These findings suggest that LDCT screening benefits persist in older adults and supports continued inclusion of select patients ≥75 in lung cancer screening programs, with careful consideration of surgical risk. Survival comparison using cox proportional hazards regression. Outcome Hazard Ratio (Cohort C vs A) p-value (C vs A) Hazard Ratio (Cohort C vs B) p-value (C vs B) Global p-value OS 2.43 (1.39 – 4.23) 0.002 1.84 (1.04 – 3.25) 0.037 0.012 LCSS 1.66 (0.57 – 4.82) 0.348 0.98 (0.35 – 2.76) 0.966 0.380 RFS 0.73 (0.15 – 3.47) 0.691 0.82 (0.16 – 4.08) 0.809 0.916

Impact of prior treatment setting on the efficacy of rucaparib vs physician’s choice in <i>BRCA</i> -mutated castration-resistant prostate cancer (mCRPC) in TRITON3.

5054 Background: Rucaparib significantly improved radiographic progression-free survival (rPFS) versus physician’s choice of docetaxel or an androgen-receptor pathway inhibitor (ARPI) (abiraterone or enzalutamide) in men with BRCA mutations who were chemotherapy-naïve in the mCRPC setting and had received one prior ARPI in the phase 3 TRITON3 trial (NCT02975934). This post-hoc analysis evaluated whether the timing of prior ARPI therapy impacted the efficacy of rucaparib. Methods: Patients were randomized 2:1 to rucaparib (600 mg BID) or physician’s choice of docetaxel or ARPI, after progression on 1 prior second-generation ARPI in any setting. The primary endpoint was rPFS. Outcomes were analyzed according to whether patients received the prior ARPI in the metastatic castration sensitive (mCSPC) or castration resistant (mCRPC) setting. Data cutoff was August 25, 2022. Results: Of the 302 BRCA1/2 patients, 68 received prior ARPI in the mCSPC setting (42 rucaparib; 26 physician’s choice) and 234 in the mCRPC setting (159 rucaparib; 75 physician’s choice). Baseline characteristics were generally similar. Prior treatments in the mCSPC and mCRPC groups, respectively, included abiraterone (73.5% vs 53.0%), enzalutamide (29.4% vs 48.3%), and docetaxel (17.6% vs 24.8%). Median rPFS favored rucaparib over physician’s choice in both groups (mCSPC: 13.6 vs 8.2 months; HR 0.60 [95% CI, 0.32–1.15]; mCRPC: 11.2 vs 5.8 months; HR 0.43 [95% CI, 0.30–0.61]). Median OS was similar between treatments in both settings (mCSPC: 23.2 vs 21.7 months; HR 0.81 [95% CI, 0.47–1.41]; mCRPC: 23.2 vs 21.0 months; HR 0.91 [95% CI, 0.66–1.25]). Treatment-related adverse events occurred at comparable rates (89.6% vs 86.1%). Conclusions: Rucaparib demonstrated efficacy in patients with BRCA-mutated mCRPC, regardless of whether prior ARPI was administered in the mCSPC or mCRPC setting. Clinical trial information: NCT02975934 .

Real-world eligibility for perioperative pembrolizumab in resectable locally advanced head and neck squamous cell carcinoma: A SEER-based analysis following KEYNOTE-689.

e18059 Background: KEYNOTE-689 demonstrated improved outcomes with perioperative pembrolizumab added to standard multimodality therapy in resectable, locally advanced head and neck squamous cell carcinoma(HNSCC). However, the real world proportion of patients who meet KEYNOTE-689 eligibility criteria remains unclear. We evaluated real-world patient characteristics and treatment patterns to estimate eligibility for perioperative pembrolizumab. Methods: We performed a retrospective cohort analysis using the SEER 17 registries database (2017-2021). Adults diagnosed with stage III-IVB (locally advanced, non metastatic) HNSCC were identified using ICD-O-3 histology and primary site codes. Patients were stratified by derived EOD 2018 stage groups (III, IVA, IVB) and age (&lt;60, 60-69, ≥70 years). Treatment patterns were assessed using SEER radiation and chemotherapy recode variables to characterize real world multimodality therapy consistent with KEYNOTE-689 clinical context. Descriptive analyses were performed. Results: A total of 9,135 patients with stage III-IVB HNSCC were identified. Stage distribution included 3,281 (35.9%) stage III, 3,439 (37.7%) stage IVB disease. Across all stages, patients were distributed across age groups, including many aged ≥70 years. Definitive radiation therapy was commonly delivered, with 7270 patients (79.6%) receiving beam radiation across all stage groups. Systemic therapy use was also frequent, with 6197 patients (67.9%) receiving chemotherapy, reflecting routine multimodality treatment patterns seen in everyday clinical practice. A smaller subset of patients declined or did not receive radiation or chemotherapy, reflecting real world limitations that may affect the ability to meet clinical trial treatment requirements. Conclusions: In a large U.S. population, many patients with locally advanced HNSCC have stage, age, and treatment characteristics similar to those included in KEYNOTE-689. These findings suggest that a meaningful number of real world patients could be considered for perioperative pembrolizumab. Further work is needed to better understand and address gaps between clinical trial criteria and treatment delivered in routine practice. Key characteristics and treatment patterns in locally advanced HNSCC (SEER 2017-2021). Variable Number (%) Stage III- IVB Stage III- 3,281(35.9), Stage IVA- 3,439 (37.7), Stage IVB- 1,562 (17.1) Age ≥ 70 years 2,487 (27.2%) Beam radiation received 7,270 (79.6%) Chemotherapy received 6,197 (67.9%) Total Patients 9,135 (100%)

Mapping access to retinoblastoma care: Geographic disparities and service availability across Africa, and West and Central Asia.

1525 Background: Retinoblastoma, the most common childhood eye cancer, is highly manageable with prompt diagnosis and appropriate care. Access to specialist services is, however, unequal in low- and middle-income countries (LMICs), leading to unnecessary morbidity and death. This study assesses the geographic reach of retinoblastoma treatment centers, estimates the burden of cases relative to available services, and analyzes referral barriers—in terms of distance and cost of travel—across Africa, West and Central Asia. Methods: We used the One Retinoblastoma World Map to categorize African, West and Central Asian (excluding India, China, and Mongolia eastern countries) specialized treatment centers. The centers were classified as Tier 1 (comprehensive care with focal therapy and radiotherapy) or Tier 2 (lacking at least one essential treatment modality). The availability of genetic testing was also recorded. Country-specific incidence of retinoblastoma was estimated at 1 case per 18,000 live births, using UN population and birth rate data. For countries without Tier 1 or Tier 2 centers, we calculated minimum travel distances and estimated one-way costs for a child and guardian to reach the nearest facility. Results: Among 71 countries analyzed, there were just 28 (39%) countries with Tier 1 or Tier 2 retinoblastoma centers and 43 (61%) countries without such centers. Tier 1 centers were available in just 16 countries (22.5%), predominantly middle- and high-income countries: only 2 of 25 low-income countries (Uganda, Mali) had access to Tier 1 versus 11 of 39 middle-income and 3 of 7 high-income countries (Saudi Arabia, Israel, Russia). Notably, 64% of low-income and 59% of middle-income countries did not have any retinoblastoma center. Twenty-two high-burden nations (≥10 cases/year) had no Tier 1 or Tier 2 center, including the Democratic Republic of Congo (242 cases/year), Mozambique (65), and Yemen (63). Average one-way travel distance in these environments exceeded 1,000 km at a cost of nearly $1,000 per referral trip. While some nations (e.g., Nigeria, Egypt, Pakistan) had acceptable case-to-center ratios (50–80 cases/center), others (e.g., Uganda, Tanzania) had possible overcapacity with single-center systems. Genetic testing was accessible in just 24% of nations. Conclusions: Despite potential underreporting of more recently established centers, this study reveals profound inequalities in the availability of retinoblastoma care, with most LMICs lacking sufficient essential services. Excessive case volumes within underserved regions overwhelm existing infrastructure and necessitate prompt interventions: (1) focused expansion of Tier 1 hubs within regions of greatest need, (2) streamlining of regional referral chains, and (3) integration of genetic and focal treatments to reduce disparities in survival.

Novel and facile aluminum foil-based reduction of oxidized MWCNTs to hybrid MWCNTs and graphene nanosheet oxides

Dynamic Zn ²⁺ ‐Conductive Protective Layer for Durable Zinc Anode in Aqueous Zinc‐Ion Batteries

ABSTRACT The Zn anode in aqueous zinc‐ion batteries (AZIBs) suffers from hydrogen evolution reaction (HER), by‐product accumulation, and dendrite growth, severely restricting practical viability. To address these challenges concurrently, we propose a dynamic Zn 2+ ‐conductive protective layer strategy, which involves constructing an in situ ZnOHF layer on the Zn anode and incorporating F − into the electrolyte. Zn 2+ ‐conductivity and reducibility of ZnOHF layer guide uniform Zn nucleation and deposition, thereby inhibiting dendrite formation. Crucially, the addition of F − to the electrolyte enables the dynamic regeneration of the ZnOHF layer during cycling and the conversion of detrimental by‐products into favorable ZnOHF. Additionally, HER is effectively suppressed by isolating the Zn anode from the aqueous electrolyte via ZnOHF interfacial layer, and decreasing water activity through F − ‐induced elevation of electrolyte pH from 4.1 to 5. As a result, the protected Zn anode enables the symmetrical cell to operate stably for 3100 h at 0.5 mA cm −2 , and a full cell to retain 85% capacity after 4000 cycles at 10 A g −1 . Moreover, a 90 cm 2 pouch cell delivers an initial capacity of 240 mAh and maintains 70% capacity after 200 cycles, highlighting its practical viability. This work presents an effective and scalable interface engineering approach to realize durable Zn anodes for practical AZIBs.